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S. Mandrekar



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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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      P1.06-014 - A nomogram for predicting 5-year RFS in patients with pulmonary carcinoid tumors incorporating Ki-67 and clinical variables (ID 1567)

      09:30 - 16:30  |  Author(s): S. Mandrekar

      • Abstract

      Background
      Evaluation of prognostic factors in carcinoid tumors of the lung is limited due to the rarity of disease. This study assessed Ki-67 expression and other clinical variables as prognostic factors in cohort of 262 patients seen at Mayo Clinic, and subsequently developed a nomogram for predicting recurrence-free survival (RFS).

      Methods
      A systematic search of Mayo Clinic lung cancer epidemiology and tumor registry databases from 1997 to 2009 identified 448 consecutive patients, with 262 having available tissue blocks [40 atypical carcinoids (AC) and 222 typical carcinoids (TC)]. Clinical data were collected by chart review. Tissue blocks were reviewed by 1 of 3 pathologists using WHO criteria. Tumors were tested for the Ki-67 index using digital image analysis (tumor tracing) by two operators. The associations of the factors with RFS were explored using multivariable Cox proportional Hazards models, including concordance (c) index. A nomogram was developed using the variables from the final multivariate model.

      Results
      Age, smoking history, lymph node (LN) involvement, tumor size, and Ki-67 index were significant prognostic factors for RFS from a multivariate model (Table 1). Median follow-up on alive-patients was 5.6 years (0.008-16.2). Median percentage of Ki-67 index of AC and TC were 1.61% and 0.56% (P<0.0001), respectively. The multivariable model with Ki-67 index showed a c-index of 0.79 which was identical to a multivariable model with pathological diagnosis (c-index 0.79). The nomogram showing the probability of 5-year RFS estimates is shown in Figure 1. Figure 1

      Variables Adjusted by Ki-67 and Clinical Variables HR; 95% CI (P) Adjusted by Pathological Diagnosis and Clinical Variables HR; 95% CI (P)
      Ki-67 1.25; 1.11-1.41 (0.0016) --
      AC vs. TC -- 2.01; 1.05-3.88 (0.0436)
      Age 1.05; 1.03-1.08 (<0.0001) 1.06; 1.03-1.09 (<0.0001)
      Smoking Never Former Current (<0.0001) -- 3.11; 1.68-5.74 4.34; 1.94-9.74 (0.0003) -- 2.86; 1.56-5.24 3.74; 1.67-8.40
      Size of Tumor 1.42; 1.20-1.67 (0.0002) 1.33; 1.13-1.56 (0.0012)
      Metastatic LN Negative Positive (0.0007) -- 3.05; 1.66-5.59 (0.0068) -- 2.51; 1.33-4.76

      Conclusion
      Ki-67 index is a valuable prognostic biomarker for pulmonary carcinoids based on this large cohort. The nomogram based on Ki-67 index, age, smoking history, LN involvement, and tumor size is a useful clinical tool for predicting the 5-year RFS rate. Updating this nomogram with additional clinical follow-up, as well as external validation of this nomogram is critical before routine clinical use.

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    P1.14 - Poster Session 1 - Mesothelioma (ID 194)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P1.14-005 - Preliminary Results - "A Phase I Trial of Oncolytic Measles Virotherapy in Mesothelioma" Investigating the Intrapleural Administration of the Modified Vaccine Strain Measles Virus (MV-NIS) to Patients with Malignant Pleural Mesothelioma (ID 1922)

      09:30 - 16:30  |  Author(s): S. Mandrekar

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM) remains an almost universally fatal disease. Preclinical models indicate that the oncolytic modified vaccine strain measles virus (MV) carrying the gene for the human sodium-iodine symporter (NIS) - MV-NIS preferentially targets MPM tumors cell. In patients with refractory ovarian cancer the intraperitonial administration of MV-NIS was recently found to be safe and induced an anti-tumor immune response.

      Methods
      Phase I dose escalation study (3+3 design). MV-NIS is administered intrapleurally. Starting dose level was 10[8] TICID 50 (Level 1) and the current dose level is 3 x 10[8] TICID 50 (Level 2). In the absence of dose limiting toxicity and disease progression patients continue MV-NIS therapy for up to six 28-day cycles. MV-NIS infection and replication is monitored by Iodine[123] SPECT/CT and RT-PCR and anti-tumor and anti-viral immunity are monitored in correlative studies. Patients are followed clinically using modified RECIST criteria.

      Results
      Up to now 4 patients have received MV-NIS therapy. Three patients were treated at Level 1 and the fourth patient at Level 2. No dose limiting adverse events occurred. The best therapeutic response was stable disease, observed in patient #1 for 6 months and patient #2 for 2 months. The remaining two patients progressed radiologically after one treatment cycle. I[123] SPECT-CT imaging did not demonstrate changes in iodine uptake compared to baseline in any of these patients. However, we detected MV RNA by QRT-PCR within the pleural cells 24-48 hours after the intrapleural administration of MV-NIS in 3/4 patients. In patient #4, treated with 3x10[8] TCID 50, MV replication was detectable within the pleural space by plaque assay 24 hours after MV-NIS administration. Following MV-NIS therapy a profound influx of neutrophils into the pleural space occurred in 3/4 patients and pleural fluid cytokine concentrations changed significantly. In addition, a humoral anti-tumor immune response emerged in patients #2.

      Patient # Age Disease Stage Histology Line therapy
      1 75 II (T2N0M0) Epitheloid First
      2 53 IV (T4N0M0) Epitheloid Second
      3 84 IV (T4N0M0) Epitheloid First
      4 73 IV (T2N3M0) Mixed First

      Conclusion
      Thus far the intrapleural administration of MV-NIS appears to be safe and well tolerated in MPM. Our study will continue to enroll patients.