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C.B. Simone



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    MO05 - Prognostic and Predictive Biomarkers II (ID 95)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO05.10 - Metformin as a Radiosensitizer for Lung Cancer (ID 3306)

      17:10 - 17:15  |  Author(s): C.B. Simone

      • Abstract
      • Presentation
      • Slides

      Background
      In vitro data and early clinical results suggest that metformin, an agent commonly used in diabetes therapy, has direct cancer growth inhibition potential via mammalian target of rapamycin (mTOR) pathway suppression. Furthermore, a number of observational studies have associated lower cancer incidence and a lower risk of nonspecific cancer-related mortality with metformin use. Our first objective is to determine whether the use of metformin is associated with improved local recurrence (LRR) and overall survival (OS) rates in diabetic patients with non-small cell lung cancer (NSCLC) treated with definitive chemoradiation. Based on encouraging retrospective clinical results, we moved on to establish an in-vivo murine model of lung cancer and to evaluate the tumor growth delay from using metformin as a radiosensitizing agent.

      Methods
      Data from 760 consecutive patient treatment courses from our institution for patients with NSCLC and small cell lung cancer treated with radiation therapy between 6/2008 and 6/2013 were analyzed. All patients with diabetes and stage IIIA and IIIB NSCLC who received metformin during definitive radiotherapy were analyzed to determine clinical outcomes. For the in-vivo murine study, H1299 adenocarcinoma cells were injected in the flanks of nude mice for the subcutaneous tumor model. On day 2, mice began receiving daily intraperitoneal injection of metformin or vehicle for 5 days, after which they underwent irradiation to the flanks of 3Gy X 3 fractions. Tumor measurements were taken every other day and tumor growth delay was plotted. In order to assess the effect of metformin in the lungs as well as in-situ tumor effects, an orthotopic mouse model using bioluminiscence imaging (BLI) will be developed to allow serial lung tumor measurements as well as assessment of metformin effects on the normal lung when combined with irradiation.

      Results
      Of 760 patient treatment courses analyzed, 16 distinct patients with stage III NSCLC were identified that received metformin for diabetes while undergoing definitive chemoradiation. Patients were predominantly female (63%) and had stage IIIA disease (69%). They were treated to a median of 66.6/1.8 Gy with concurrent (81%) or sequential (19%) chemotherapy.A dramatic improvement in LLR in patients receiving metformin was seen compared to historical controls. With a median follow-up time of 10.4 months, only 2 local recurrences (9.6 and 14.9 months post-radiotherapy) have occurred. The median disease-free survival and OS have not been reached. From our in vivo murine data, early data supports the use of metformin as a radiosensitizing agent in the treatment of locally advanced NSCLC.

      Conclusion
      Our clinical experience demonstrates patients receiving definitive chemoradiation for stage III NSCLC who took metformin for diabetes had improved local control and OS compared with our patients not taking metformin and compared with historical controls. Additional evidence is needed to supporting radiation potentiation effects of metformin in the setting of definitive chemoradiation for locally advanced NSCLC patients. Such findings, along with our clinical retrospective data, will lead to institutional prospective clinical trials, for the first-time, using metformin as a radiosensitizing agent in combination with radiation therapy and chemotherapy in the treatment of lung and potentially other cancers.

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    MO22 - Advanced Disease and Outcomes (ID 103)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Surgery
    • Presentations: 1
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      MO22.11 - Prospective Study of Surgery with Curative Intent and Intraoperative Photodynamic Therapy to Achieve Long-term Pleural Control and Improve Overall Survival for Patients with Non-small Cell Lung Cancer with Pleural Dissemination (ID 3141)

      11:30 - 11:35  |  Author(s): C.B. Simone

      • Abstract
      • Presentation
      • Slides

      Background
      Non-small cell lung cancer (NSCLC) with pleural spread carries a dismal prognosis of 6-9 months median survival. Standard treatment is palliative chemotherapy. Surgery typically has no role, with studies showing no overall survival (OS) benefit and high rates of local recurrence of up to 90% due to microscopic residual disease following resection. This study investigated the use of surgery with the intent of achieving a gross total resection and intraoperative photodynamic therapy (PDT) to target microscopic residual disease for patients with NSCLC with pleural metastasis to improve local control and OS.

      Methods
      All patients with NSCLC with pleural metastasis treated with definitive surgery and PDT (porfimer sodium, 24hr drug-light interval, 630nm, 30-60J/cm[2]) from 1997-2012 on either of two IRB-approved prospective clinical trials were assessed. Progression-free survival (PFS) and OS were defined as the time from surgery to recurrence and death, respectively, or to last contact. Pleural control was defined as absence of ipsilateral pleural disease after surgery, whereas locoregional control was defined as absence of lung parenchymal or intrathoracic nodal disease.

      Results
      34 consecutive patients were assessed, all with ECOG performance status 0-1. The cohort was 50% male, predominantly Caucasian (85%), and a median of 55yrs at the time of surgery (range, 35-73yrs). Most had adenocarcinoma (79%), clinical N2 nodal metastasis (64%), and received neoadjuvant chemotherapy (94%) and/or radiotherapy (12%). Over half (56%) underwent pneumonectomy, whereas 38% received a lesser anatomic resection. Two patients were found intraoperatively to have unresectable disease due to pericardial effusion (n=1) or trans-diaphragmatic extension (n=1). Pathologic staging was pT4N0 (24%) or pT4N2 (76%). Four patients (3/19 pneumonectomy, 1/13 lung-sparing) suffered peri-operative mortality (day 11-98), with one death attributable to PDT (ARDS, day 11). Following surgery/PDT, 59% of patients received mediastinal radiotherapy (median 50.4Gy/1.8Gy) and 50% received chemotherapy. Pleural recurrence rates and OS were similar for patients undergoing pneumonectomy or other procedures (p>0.05 for both). Cohort median OS was 21.4 months (0.4-161.1 months), and survival rates were 59% at 1yr and 41% at 2yrs. Median overall PFS was 7.5 months, with numerous patients achieving durable disease-free intervals (mean PFS 18.4 months). Median pleural PFS was 13.6 months, with pleural recurrences occurring in only 32%. Overall, 79% experienced recurrence or unresectable disease progression, and distant failure was most commonly observed (53%).

      Conclusion
      This study demonstrates that surgery and intraoperative PDT can achieve durable local control and prolonged survival for NSCLC patients with pleural dissemination. Compared with current standard treatment, which offers a median survival of 6-9 months from pleural metastasis diagnosis, our cohort lived a median of 24.7 months from pleural diagnosis and 21.4 months from surgery/PDT. This study also demonstrates that surgery/PDT can be performed with acceptable morbidity. Distant recurrence was the most common failure, indicating need for improved adjuvant systemic therapy. These results are sufficiently encouraging to warrant further study and suggest that stage IVA NSCLC patients with pleural dissemination, good performance statuses, disease limited to one hemithorax, and of the mind to be aggressive about their disease could be considered for this investigational treatment approach.

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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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      P1.14-014 - Patients' Willingness to Participate in a Randomized Controlled Trial for Malignant Pleural Mesothelioma: A New Paradigm to Improve Accrual to Thoracic Oncology Trials (ID 3147)

      09:30 - 09:30  |  Author(s): C.B. Simone

      • Abstract

      Background
      Predicting if a trial will accrue is critical, especially for thoracic oncology trials that have notoriously low accruals. Our group demonstrated unusually good results treating malignant pleural mesothelioma (MPM) with radical pleurectomy (RP), intraoperative photodynamic therapy (PDT), and chemotherapy. To establish if PDT is contributing to our results, a randomized trial of RP+/-PDT is needed. To determine if such a trial is feasible, we conducted a willingness to participate (WTP) study. We quantified differences in WTP before and after physician training designed to increase WTP.

      Methods
      All consecutive MPM patients who were candidates for RP+PDT were prospectively enrolled in this IRB-approved study. Patients participated in structured interviews, reviewed a written description of a hypothetical RCT comparing RP to RP+PDT, answered open-ended and focused questions regarding their motivations for and concerns about enrollment, and completed a written questionnaire. WTP was assessed using a 6-point Likert scale (1=definitely not, 6=definitely). Interview transcripts were analyzed using thematic data analysis and constant comparison techniques. Questionnaire and transcript data were used to educate physicians and modify their presentation of the RCT to subsequent patients.

      Results
      25 participants (median age 66yrs, 72% male, 88% epithelial histology) enrolled. Some had pre-existing knowledge of RP (44%) or PDT (40%). Following the first 8 patients enrolled, we identified 15 factors impacting WTP focusing on five themes: randomization, hope for cure, desire to compare treatments, altruism, and physician opinion (Table 1). Based on these findings, physicians were trained to more thoroughly explain the WTP and proposed RTC and addressed concerns raised by these initial 8 patients when meeting with subsequent patients. Physician time explaining the WTP increased following training (median 9min vs. 3min, p<0.0001). Overall, 56% “definitely” or “probably” would, 28% “may,” and 16% would “probably not” or “definitely not” participate. More patients would be “definitely” or “probably” willing to participate after physician training (71% vs. 25%, p=0.03). Furthermore, none of the initial 8 patients were “definitely” willing, compared with 8 of the subsequent 17 (p=0.02). Following consultation, 16 underwent surgical-based therapy, with no difference before or after training (50% vs. 71%, p=0.34).

      Table 1. Motivations (m) and concerns (c) reported by patients (N=25) when deciding if they would enroll in the proposed randomized clinical trial for malignant pleural mesothelioma
      Trial Design Factors N= Therapy-relate Factors N= Humanistic/Ethical Factors N=
      Randomization (c) 12 Hope for a cure (m) 10 Altruism towards other patients (m) 9
      Deference to physician opinion (m) 7 Desire to compare treatments (m) 8 Deference to family opinion (m) 4
      Concerns with experimentation (c) 2 PDT side effects (c) 6 Altruism towards science/physician/ hospital (m) 1
      Financial incentives (m) 1 Potential benefit of PDT (m) 3
      Reputation of the hospital (m) 1 Prior knowledge of PDT (m) 1
      Close follow-up (m) 1 Availability of alternative treatments (c) 1

      Conclusion
      This study demonstrated analyzing and addressing patient motivations and concerns about enrollment, physician training, and increasing time spent with patients can increase WTP. In this study, most patients expressed a WTP in a RCT of RP+/-PDT for MPM. Performing WTP studies prior to planned prospective thoracic oncology trials should be considered to optimize trial design and accrual strategies.

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    P3.08 - Poster Session 3 - Radiotherapy (ID 199)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P3.08-027 - Radiation Pneumonitis in IMRT vs. 3D Conformal Radiation Therapy (ID 3161)

      09:30 - 09:30  |  Author(s): C.B. Simone

      • Abstract

      Background
      Radiation pneumonitis is a common cause of morbidity and is a radiation dose-limiting toxicity in patients with locally advanced NSCLC treated with definitive radiotherapy. NSCLC patients are increasingly receiving intensity modulated radiation therapy (IMRT), in part in an attempt to reduce irradiation doses to organs at risk, like the lungs. It is unclear whether the incidence of pneumonitis in IMRT patients differs from that in patients receiving the more commonly available 3D conformal radiation therapy (3DCRT). This retrospective study reports on outcomes at the University of Pennsylvania.

      Methods
      All consecutive patients with non-metastatic locally advanced NSCLC treated with curative intent at the University of Pennsylvania between January 2003 and October 2011 with 3DCRT (n=208) and IMRT (n=58) were graded for post-treatment radiation pneumonitis using Common Toxicity Criteria (CTC) and SWOG criteria in this IRB-approved study. Any short- or long-course initiation of prednisone for dyspnea 1-10 months following treatment was scored as grade 3 pneumonitis. Associations between type of treatment and clinical and demographic factors and outcomes were assessed using Χ[2] and non-parametric equality-of-medians tests. Logistic regression was used to determine predictors of pneumonitis.

      Results
      Patient characteristics, including age, gender, race, marital status, smoking history and pulmonary function were well balanced across treatment groups (p = 0.18 – 0.97). Patients also had similar tumor TNM-stage, histology, differentiation, and involved lobe (p = 0.26 – 0.62). No differences in the proportion receiving concurrent chemotherapy, radiation prescription, lung V5, lung V20 and mean lung doses, or planning target volume (PTV) were identified (p >0.05 for all). Pneumonitis rates did not differ between the IMRT and 3DCRT patients. In 3DCRT patients, 54% had grade 2+ and 27% had grade 3+ CTC pneumonitis compared to 59% and 34% in IMRT patients, respectively (p >0.05). Additionally, 45% and 17% of 3DCRT patients had grade 2+ and 3+ SWOG pneumonitis compared to 45% and 16% in IMRT patients, respectively (p> 0.05). Lower lung lobe, single marital status, pack-years smoked, low pre-treatment pulmonary function DLCO status, increased lung V5, increased lung V20 and mean lung dose all associated with pneumonitis on univariate logistic regression for both 3DCRT and IMRT patients (p <0.05 for all). A multivariate analysis was performed but yielded no significant results.

      Conclusion
      Our findings suggest that treatment with IMRT is associated with similar rates of pneumonitis as treatment with 3DCRT for locally advanced NSCLC patients treated with definitive radiation therapy. As opposed to treatment modality, several factors were identified that were associated with pneumonitis risk, included lung lobe, marital and smoking status, pre-treatment lung function, and irradiation dose received by the lung. Thus, care should be taken to limit the lung V5, lung V20, and mean lung doses when administering curative-intent radiotherapy, regardless of treatment with IMRT or 3DCRT.