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M. Boyer



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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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      P2.06-011 - Phosphorylated-Akt expression is a prognostic marker in early stage non-small cell lung cancer (NSCLC) (ID 1151)

      09:30 - 09:30  |  Author(s): M. Boyer

      • Abstract

      Background
      The 5-year survival for stage IB non-small cell lung cancer (NSCLC) is only 55%, but the benefit of adjuvant chemotherapy in this setting remains equivocal. Numerous prognostic markers have been examined, but none to date have moved into clinical practice. There is an urgent need to identify novel molecular markers that can select high risk patients, who may potentially benefit from adjuvant chemotherapy.

      Methods
      We identified 471 consecutive patients with stage IB primary NSCLC according to the American Joint Commission on Cancer, (AJCC) 6[th] edition tumour-node-metastasis staging system, who underwent surgical resection between 1990 and 2008. Patients who received neoadjuvant or adjuvant treatments were excluded. Pathology reports were reviewed and pathologic characteristics were extracted. Expression of phosphorylated Akt (pAkt) in both cytoplasmic and nuclear locations was assessed by immunohistochemistry, and clinicopathologic factors were analyzed against 10-year overall survival using Kaplan-Meier and Cox proportional hazards model.

      Results
      455 (96.6%) cancers were adequate for pAkt immunohistochemical analysis. The prevalence of pAkt expression in the cytoplasm and nucleus of the cancers was 60.7% and 43.7% respectively. Patients, whose cancers expressed higher levels of pAkt in the cytoplasm, had a trend towards longer overall survival than those with lower levels of cytoplasmic pAkt (p=0.06). Conversely, patients whose cancers expressed higher levels of pAkt in the nucleus had a poorer prognosis than those with lower levels of nuclear pAkt expression (p=0.02). Combined low cytoplasmic/high nuclear expression of pAkt was an independent predictor of overall survival [HR=2.86 (95% CI:1.35-6.04); p=0.006] when modeled with age [HR= 1.05 (95% CI: 1.03-1.07); p<0.001], extent of operation [HR= 2.11 (95% CI: 1.48-3.01); p<0.001], visceral pleural invasion [HR=1.63 (95% CI: 1.24-2.15); p<0.001], gender, tumour size, histopathologic type and grade (p>0.05).

      Conclusion
      Levels of expression of pAkt in the cytoplasm and nucleus and visceral pleural invasion are independent prognostic factors that can help to select patients with high risk disease, who may potentially benefit from adjuvant chemotherapy.

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-040 - Prognostic significance, accuracy and usefulness of oncologists' estimates of survival time for patients starting first-line chemotherapy for advanced non-small-cell lung cancer (ANSCLC) (ID 2560)

      09:30 - 09:30  |  Author(s): M. Boyer

      • Abstract

      Background
      Oncologists are frequently required to provide estimates of survival time for their patients with advanced cancer. The aims of this study were to determine the accuracy and prognostic significance of oncologists’ estimates of survival time above and beyond conventional prognostic factors.

      Methods
      Medical oncologists from 26 sites in Australia and New Zealand recorded the “expected survival time in months” for individual patients with ANSCLC prior to randomisation in a trial of first-line chemotherapy with a platinum-based doublet. Blood samples, demographics, tumour and treatment characteristics were collected at baseline along with the oncologist’s rating of each patient using Spitzer’s Quality of Life Index (SQLI). Based on previous studies, we deemed estimates within 0.75-1.33 times observed survival as precise, and expected 50% of patients to live longer (or shorter) than their oncologist’s estimate, 50% to live from half to double their oncologist’s estimate (typical scenario); 5-10% to live ≤¼ of their estimate (worst-case scenario); and, 5-10% to live ≥3 times their estimate (best-case scenario). Associations between estimated and observed survival times in months were assessed with Cox proportional hazards regression before and after adjustment for baseline prognostic factors including age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), cancer extent, histology, co-morbidities, laboratory results and SQLI.

      Results
      Estimates of survival were available for 244 (98%) of the first 250 patients randomised. Patient characteristics were: median age 64 years; female 40%; adenocarcinoma 64%; ECOG PS 0-1 92%; and distant metastases 71%. After a median follow-up of 21 months there were 172 deaths (69%). The median (interquartile range, IQR) for observed survival was 10 months (5-20) and for estimated survival was 11 months (9-12). Oncologists’ estimates were imprecise (22% from 0.75-1.33 times observed) but well calibrated (47% of patients lived shorter than expected and 53% lived longer than expected). The proportions of patients with observed survival times falling within ranges bounded by simple multiples of their estimated survival times corresponded closely with our a-priori hypotheses: 10% lived ≤1/4 of their estimated survival time, 53% lived from half to double their estimated survival time, and 13% lived ≥3 times their estimated survival time. The oncologist’s estimate of survival time at baseline was the strongest predictor of observed survival in both univariable analysis (HR 0.90, 95% CI 0.86-0.95, p<0.001) and multivariable analysis (HR 0.90, 95% CI 0.86-0.95, p<0.001) accounting for all other independently significant predictors, namely: estimated neutrophil-lymphocyte ratio >5 (HR 3.15, 95% CI 1.76-5.64, p<0.001); haemoglobin <120g/L (HR 1.93, 95% CI 1.3-2.9, p=0.001) and total white cell count >11x10[9]/L (HR 1.55, 95% CI 1.05-2.27, p=0.03).

      Conclusion
      Oncologists' estimates of survival time were independently associated with observed survival time and provided a reasonable basis for estimating worst-case, typical and best-case scenarios for survival. Oncologists’ estimates provide useful additional prognostic information, above and beyond that provided by established prognostic factors.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-032 - Patient Report of Dacomitinib (PF-00299804)-Associated Symptom and HRQoL Benefit in Previously Treated Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 2293)

      09:30 - 09:30  |  Author(s): M. Boyer

      • Abstract

      Background
      Decreasing tumor burden may reduce/delay cancer-related symptoms experienced by patients with NSCLC and favorably impact global health-related quality of life (HRQoL). Dacomitinib is an irreversible small-molecule inhibitor of all catalytically active members of the human epidermal growth factor receptor (HER) family of tyrosine kinases (EGFR/HER1, HER2, and HER4), and has shown anticancer activity and manageable toxicity in NSCLC clinical trials [Janne et al 2009; Park et al 2010; Ramalingam et al 2012; Mok et al 2012]. Qualitative assessment of the adverse event (AE) burden from the patient’s perspective helps to provide a greater understanding of the overall impact of treatment-related AEs than grading of AEs alone. Here we report the impact of dacomitinib on core lung cancer symptoms in patients with previously treated, advanced NSCLC in three phase II clinical trials [Janne et al 2009; Park et al 2010; Ramalingam et al 2012].

      Methods
      Dacomitinib was evaluated in advanced NSCLC, in patients who had received prior chemotherapy and erlotinib (study 1002; n=66) [Janne et al 2009], in Korean patients who had received prior chemotherapy and erlotinib or gefitinib (study 1003; n=43 in phase II) [Park et al 2010], and in comparison with erlotinib in patients who had received prior chemotherapy (study 1028; n=188) [Ramalingam et al 2012]. In each of the trials, HRQoL was evaluated using validated patient-reported outcome (PRO) measures. Disease/treatment‑related symptoms were recorded using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core module (EORTC QLQ-C30) and its lung cancer module (LC13). Scores were summarized using the mean (and 95% CI) for each group and plotted over time. Mean changes from baseline were also reported.

      Results
      On-study questionnaire mean completion rates were high (>90% of patients answered at least 1 question across treatment cycles) in each of the studies. Across the three trials, patients reported a rapid onset (typically ≤3 weeks of starting therapy) of improvement in key lung cancer symptoms (e.g. cough, pain in chest, and pain in arm/shoulder) relative to baseline scores, with symptomatic improvements remaining durable over the course of therapy. Diarrhea and sore mouth were the most commonly reported class-related AEs (for dacomitinib in studies 1002 and 1003, and for both dacomitinib and erlotinib in study 1028). These AEs peaked at weeks 3–6, were manageable, and remained stable or improved over time with intervention. Compared with erlotinib in study 1028, clinically meaningful improvements from baseline (>10 points difference on a 0–100-point scale) in key NSCLC symptoms (cough, dyspnea, pain in chest, pain in arm/shoulder, fatigue, and physical function) were reported by patients receiving dacomitinib. The difference in mean change from baseline was more favorable with dacomitinib at most time-points.

      Conclusion
      Dacomitinib demonstrated consistent improvements in common NSCLC symptoms across three clinical trials in pretreated patients with advanced NSCLC. PROs such as cough and pain improved within 3 weeks of initiating treatment, with benefits sustained throughout the course of therapy. Dacomitinib also demonstrated greater improvements in key NSCLC symptoms than erlotinib.

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    P3.14 - Poster Session 3 - Mesothelioma (ID 197)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 2
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      P3.14-004 - Adjuvant Hemithoracic Radiotherapy After Extrapleural Pneumonectomy For Malignant Pleural Mesothelioma: Experience At The Sydney Cancer Centre (ID 1249)

      09:30 - 09:30  |  Author(s): M. Boyer

      • Abstract

      Background
      Radiotherapy reduces local recurrence following extrapleural pneumonectomy (EPP), and forms part of a potentially curative, multimodality treatment of malignant pleural mesothelioma. Hemithoracic radiotherapy poses a significant dosimetric challenge. Conventional techniques have suffered with marked dose uncertainty, while modern IMRT techniques have been associated with increased pulmonary toxicity. We conducted a retrospective review of all patients referred to our institution for hemithoracic radiotherapy following EPP, with the aim of assessing treatment toxicity and outcomes. The present study is, to our knowledge, the largest Australian series of adjuvant radiotherapy for this disease.

      Methods
      53 patients were referred following EPP for malignant pleural mesothelioma, with or without neoadjuvant chemotherapy, between 2004 and 2012. 4 patients were excluded or did not commence radiotherapy due to poor performance (n = 3) or disease progression (n = 1). Radiotherapy involved a 3D conformal, mixed photon and electron technique, delivering 45-55 Gy in 25-28 fractions (2004-2009, n=31), and a 9-field IMRT technique, delivering 50.4-60 Gy in 28-30 fractions (2009-2012, n=18). We assessed toxicity, disease progression and survival in all patients who commenced radiotherapy (n = 49). Toxicity was assessed using the Common Terminology Criteria for Adverse Events version 4.0 and survival was calculated from the date of EPP using the Kaplan-Meier method.

      Results
      31 patients (59%) received neoadjuvant chemotherapy, with a combination of platinum agent and pemetrexed. 41 patients (84%) completed treatment as prescribed. 6 patients stopped prematurely due to toxicity, and 2 due to disease progression. Most patients discontinuing due to toxicity (n = 5) received over 90% of the prescribed dose. Low grade nausea, anorexia and fatigue were near universal, however severe (grade 3) skin toxicity, nausea and oesophagitis were 8%, 6% and 2%, respectively. One patient developed a grade 4 Pneumocystis carinii infection, however there were no cases of radiation pneumonitis. Late toxicities were rare, with the exception of a persistent elevation in the liver enzymes alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT). Of the patients treated with right-sided disease (n = 26), 9 (35%) developed grade 2-3 elevations in ALP or GGT. Grade 2-3 liver toxicity was more common in patients treated with a conventional technique (53%) than with IMRT (11%). No patients developed clinical hepatitis. With a median follow up of 19 months (range 2-102 months), median progression-free survival and overall survival were 22 and 30 months, respectively. 2-year overall survival was 53.8%. 7 patients (14%) were alive beyond 5 years.

      Conclusion
      Hemithoracic radiotherapy can be safely delivered in selected patients following EPP. Although associated with significant early toxicity, most patients complete treatment and late toxicity is uncommon. Our outcomes compare favourably with recently-published international series.

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      P3.14-012 - Pathological complete response after platinum-based chemotherapy in malignant pleural mesothelioma (ID 3072)

      09:30 - 09:30  |  Author(s): M. Boyer

      • Abstract

      Background
      Prior to the demonstration of the efficacy of cisplatin/pemetrexed chemotherapy, Malignant pleural mesothelioma (MPM) was previously considered a chemotherapy-resistant tumour. In order to assess the efficacy of chemotherapy in the pre-operative setting, we aimed to: (1) determine the radiological and pathological complete response (CR) rate; (2) evaluate any potential association between pathological CR and patient characteristics; and (3) assess if pathological CR is associated with a longer disease free survival (DFS) and overall survival (OS) in MPM patients.

      Methods
      A retrospective review of a prospectively collected database of MPM patients treated with induction chemotherapy followed by extrapleural pneumonectomy (EPP) at our institutions since 2003 were performed. Radiological response was determined by CT/PET scans while pathological response was assessed by examination of the EPP specimen. OS and DFS from the day of EPP was determined by the Kaplan Meier method and comparison was made by log rank test. Chi square tests were used to determine potential association between pathological CR and patient characteristics.

      Results
      Forty-two patients are included: median age 63 years; 81% male. Pathology was 91% epithelial and 9% biphasic subtype. A median of 3 cycles of induction chemotherapy was administered with either 67% cisplatin-based and 31% carboplatin-based treatment. The regimen in the remaining 2% of patients was unknown. All patients proceeded to EPP and 86% of patients received adjuvant radiotherapy. The median OS was 30.6 months (95% CI: 2.9 – 58.2 months), while the median DFS was 19.6 months (95% CI: 11.0 – 28.2 months). No-one achieved a radiological CR. Four patients (9.5%) had pathological CR and all were male (p=0.31) and had epithelial subtype (p=0.50). No association was found between pathological CR and the type of chemotherapy (cisplatin vs. carboplatin; p=0.76) or the number of cycles administered (≤3 vs. >3; p=0.64). Median OS was 30.6 months vs. median not reached (p=0.31), while median DFS was 19.4 vs. 36 months (p=0.34), for those without pathological CR and those with pathological CR respectively.

      Conclusion
      A 9.5% pathological CR rate was demonstrated after induction chemotherapy, indicative of chemo-sensitivity in a subgroup of MPM patients. There was a trend for longer OS and DFS in MPM patients achieving a pathological CR.