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David E Dawe



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    P1.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 944)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.12-08 - The Effect of Cisplatin Versus Carboplatin on Cancer Outcomes for Small Cell Lung Cancer Patients in a Population-Based Cohort (ID 14373)

      16:45 - 18:00  |  Presenting Author(s): David E Dawe

      • Abstract
      • Slides

      Background

      Small cell lung cancer (SCLC) is associated with high rates of mortality and treatment involves chemotherapy. In non-small cell lung cancer, using cisplatin results in superior response and survival compared to carboplatin, but causes more toxicity. Little research regarding this drug choice in SCLC exists, but available studies suggest equivalent survival. Nevertheless, many oncologists continue to use cisplatin preferentially.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Using the population-based Manitoba Cancer Registry, we identified SCLC cases diagnosed from 2004 to 2013 in Manitoba and completed a retrospective chart review for those treated with chemotherapy. Demographics, tumour response, and treatment toxicity were compared between cisplatin and carboplatin treated groups. Overall survival (OS) and progression free survival (PFS) were evaluated using multivariate Cox proportional hazard methods. Likelihood of completing chemotherapy (at least 4 cycles) was assessed using multivariable logistic regression.

      4c3880bb027f159e801041b1021e88e8 Result

      Of the 531 patients identified, 139 (26.2%) received carboplatin and 392 (73.8%) received cisplatin as part of first line chemotherapy. More patients who received carboplatin had poor performance status (13.7% v 7.4%), elevated LDH (58.3% v 42.3%), and extensive stage disease (69.8% v 54.1%), all p<0.01. Unadjusted median OS was 224 v 322 days for carboplatin and cisplatin. Multivariable adjusted analysis for OS using cisplatin patients not completing treatment as the reference comparator showed hazard ratios for carboplatin completers – 0.65 (0.43-0.98), cisplatin completers – 0.69 (0.47-1.00), and carboplatin incompleters – 1.00 (0.64-1.55), p = 0.13. For PFS carboplatin completers – 1.07 (0.60-1.90), cisplatin completers – 0.83 (0.51-1.36), and carboplatin incompleters – 0.96 (0.64-1.46), p = 0.59. There was not significant difference between carboplatin and cisplatin in likelihood of completing chemotherapy, when adjusted for other patient characteristics - 0.75 (0.47-1.22), p=0.26 Those treated with carboplatin had significantly less neutropenia (57.6% v 74.7%), nephrotoxicity (2.9% v 13.5%), neurotoxicity (0.7% v 12.0%), and nausea/vomiting (28.1% v 42.6%) associated with treatment, all p<0.01.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In a real world, population-based setting, carboplatin appears to be an equally effective treatment option for SCLC, facilitating equivalent survival while avoiding toxicity. Clinicians may wish to re-examine their preference for cisplatin.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      P1.12-09 - The Effect of Site of First Chemotherapy on Small Cell Lung Cancer Patient Outcomes (ID 13082)

      16:45 - 18:00  |  Presenting Author(s): David E Dawe

      • Abstract
      • Slides

      Background

      Small cell lung cancer (SCLC) ischaracterized by a rapid doubling time and high responsiveness to chemotherapy (CT) with a rapid relapse. Due to the sensitivity of SCLC to CT, it is one of the few malignancies treated in acutely ill patients admitted to hospital with a poor performance status (PS). However, there is little available information on the outcomes and toxicity experienced by patients with SCLC who require initial CT as an inpatient.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A retrospective cohort study was conducted evaluating patients consecutively diagnosed with SCLC in Manitoba from 2004 to 2013 treated with platinum-doublet CT. Patient demographics, staging, treatment, CT toxicities, Eastern Cooperative Oncology Group(ECOG) PS, treatment response, and survival were collected using the Manitoba Cancer Registry and chart review. Outcomes of progression free survival (PFS) and overall survival (OS) were evaluated based on site of first CT (inpatient versus outpatient) and PS.

      4c3880bb027f159e801041b1021e88e8 Result

      530 patients received CT for SCLC with 82 patients (15%) receiving their first CT as an inpatient. Sixty-three percent of inpatients received the full CT course, compared to 81% of outpatients, (p=0.0006). Outpatients had a greater likelihood of responding to CT (p=0.0043). Neutropenia, febrile neutropenia, thrombocytopenia, nephrotoxicity and fatigue were all experienced less often by the inpatient cohort, (p<0.0001), (p=0.0040), (p<0.0001), (p<0.0001) and (0.0068). For inpatients, OS at 12, 24 and 60 months was 22%, 9% and 7%, versus outpatient OS of 43%, 20% and 9%, (each p<0.0001). Median PFS and OS were longer for outpatients, 212 versus 161 days, (p=0.0035) and 321 versus 192 days, (p=0.0003). Patients with poorer ECOG PS had shorter PFS and OS; with a median PFS for PS 0, 1-2, 3-4 of 316, 203 and 147 days, (p<0.0001) and median OS for PS 0, 1-2 and 3-4 of 498, 303 and 179 days, (p<0.0001). On multivariate analysis, ECOG PS was an independent predictor of outcome, (p=0.0005) while site of first CT was not significant when ECOG PS was included, (p=0.3494).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Although SCLC patients initially treated as inpatients had shorter PFS and OS, some experienced long term survival, including a 7% five-year survival. CT toxicities were not more common for inpatients. This validates that administration of CT in hospital can be considered as these patients may have a meaningful long-term response to therapy if properly selected. As previously identified in the literature, this data demonstrated that patients with poorer ECOG PS have shorter PFS and OS.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.12 - Small Cell Lung Cancer/NET (Not CME Accredited Session) (ID 978)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.12-01 - Targeting Mitochondrial Metabolism as a Selective Therapeutic Approach in Small Cell Lung Cancer (SCLC) (ID 13644)

      12:00 - 13:30  |  Author(s): David E Dawe

      • Abstract

      Background

      SCLC accounts for 13% of new lung cancer diagnoses and is the most aggressive form of the disease. Altered cellular metabolism is considered a hallmark of cancer and a target for therapeutic intervention. Mitochondria represent an important cellular compartment and selectively targeting mitochondrial bioenergetics may be an effective therapeutic approach for SCLC. Nicotinamidephospho-robosyltransferase (NAMPT) is a key enzyme in the mitochondrial nicotinamide adenine dinucleotide salvage pathway. Recent high-throughput drug screens identified SCLC as the most sensitive cancer subtype to NAMPT inhibitors like FK866. Genomic studies of SCLC have also suggested the constitutive activation of the PI3K/AKT/mTOR pathway in a significant portion of SCLC cases. Idelalisib a phosphatidylinositol-3-kinase-delta inhibitor is approved for the treatment of B-cell malignancies. We hypothesize that the inhibitors FK866 and idelalisib will alter SCLC mitochondrial bioenergetic profiles and function, and that combination therapy may enable lower drug doses in clinical use.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Mitochondrial bioenergetics profiles at baseline and in response to drug were assessed in SCLC cell lines H69, DMS79, and H209 using a high resolution Oroboros Oxygraph 2K. Corresponding cell survival was determined using ATP glow and flow cytometry. Western blot analysis was used to evaluate cell death pathways.

      4c3880bb027f159e801041b1021e88e8 Result

      Cell survival and mitochondrial bioenergetics parameters i.e. basal respiration, maximal respiration, spare respiratory capacity, and respiratory control ratio were measured in a dose-dependent manner for FK866 (0.5 – 2.5 nM) and idelalisib (1 – 50 μM) at 24 and 48 hours in SCLC. The IC50 for cell survival with FK866 in the 3 lines ranged between 1 and 8 nM. FK866 did not induce apoptosis as measured by Caspase 3 cleavage, but induced γH2X phosphorylation suggesting a role for DNA damage at lethal doses. Mitochondrial bioenergetics was inhibited as low as 0.5 nM dose of FK866 and 6.25 μM of idelalisib. Our preliminary data also demonstrate that the combination of 1 nM FK866 and 6.25 μM idelalisib significantly decreases the major mitochondrial bioenergetic parameters compared to FK866 alone after 24 or 48 hours treatment.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Both FK866 and idelalisib affected bioenergetics profile in SCLC cells and the combined effect of both drugs is on the mitochondrial bioenergetics profile is greater than the impact of single agents. The combined use of these drugs at lower doses targeting mitochondrial metabolism may allow for a greater therapeutic index in clinical trials.

      6f8b794f3246b0c1e1780bb4d4d5dc53