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Hideo Kunitoh

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    MS 11 - Combined Modality Treatment for Superior Sulcus Tumors (ID 533)

    • Event: WCLC 2017
    • Type: Mini Symposium
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      MS 11.01 - Preoperative Chemoradiotherapy Followed by Surgical Resection (ID 7694)

      11:00 - 12:30  |  Presenting Author(s): Hideo Kunitoh

      • Abstract
      • Presentation
      • Slides

      Superior sulcus tumors (SSTs), involving structures at the thoracic inlet, have posed a challenging problem for surgeons, radiation oncologists and medical oncologists alike, ever since they were first described[1)]. Pre-operative radiotherapy had long been the community standard in the management of SSTs. However, both the complete resection rate (approximately 50%) and long-term survival (approximately 30%) rate had remained poor and unchanged over 40 years, since the first treatment strategy was reported in the 1960’s. Local control had remained the main problem, adversely affecting the quality of life as well as the survival of the patients[2)]. Encouraged by the promising data of concurrent chemoradiotherapy for mediastinal node-positive N2 NSCLC, two prospective studies applied this modality as preoperative therapy for patients with SSTs; one from the US (led by the Southwest Oncology Group SWOG9416-Intergroup Trial 0160[3)]), and the other from Japan (by the Japan Clinical Oncology Group, JCOG 9806[4)]). In both trials, patients with SSTs received two cycles of cisplain-based chemotherapy (etoposide-cisplatin in US, mitomycin-vindesine-cisplatin in Japan), concurrently given with thoracic radiotherapy 45Gy/27fr. Then they underwent surgical resection. Boost radiotherapy was given to unresected/imcompletely resected tumors. In spite of minor differences, the results of the two trials were strikingly similar (Table). The intensive trimodality approach was found to be feasible in both reports, with a reasonably low toxic death rate of 4%. The resection rate, which had remained unchanged at about 50% for almost 40 years with conventional preoperative radiotherapy, was approximately 70% in both studies. Particularly noteworthy was the reproducibility of the favorable survival data, with a 5-year OS of 44% in the US trial and 56% in the Japanese trial, which were clearly superior to the historical value of 30%. Although T factor (T3 vs. T4) was not a significant prognostic factor in the US trial, T3 patients did far better than T4 in the Japanese study (Figure), reflecting lower resection rate (78% vs. 40%).Figure 1 A shift in the trend of clinical problems also became clear. The relapse patterns changed from predominantly locoregional to mainly distant recurrences in cases with complete resection, and a significant number of such patients suffered from metastasis in the brain as the initial site of relapse. In the JCOG study, 7-year follow-up data[5)] revealed that 21 (41%) of the 51 patients who underwent R0 resection relapsed; initial site of relapse included locoregional only in 1, distant metastasis only in 14 (5 were “brain only”), and both in 6. In contrast, out of the 24 patients who failed to get R0 resection, 18 got tumor recurrence, with 13 locoregional relapses. In order to improve the outcome, SWOG subsequently launched another trial, S0220, with docetaxel consolidation after the induction therapy[6)]. However, the overall survival was no better than the initial two reports, with the 3-year OS of 61%. The relapse pattern remained predominantly distant. Preoperative chemoradiotherapy was compared to conventional pre-operative radiotherapy in the Massachusetts General Hospital. In their retrospective analysis, Wright et al[7)] did show that pre-op chemoradiotherapy was better that pre-op radiotherapy, with 4-year OS of 84% vs. 49%. In their single-institute trial (#92-038) at the MD Anderson Cancer Center, Gomez et al reported[8)] the results of initial surgery followed by chemoradiotherapy in “resectable” SST. The result was comparable with those of the multi-institutional studies (Table), which included many “marginally resectable” tumors. Given the potential selection biases, the evidence would favor pre-operative chemoradiotherapy strategy.

      Trial JCOG9806 SWOG9416 MDA92-028
      Patient accrual 76/ 3.6 years 116/ 4.3 years 32/ 13 years
      No. institutions 19 NR (5 groups) 1
      Chemotherapy Pre-op Pre- & post-op Post-op
      Chemotherapy MVP EP EP
      Radiotherapy Pre-op Pre-op Post-op
      Radiotherapy 45Gy/25fr 45Gy/25fr 60Gy/50fr
      %T4 disease 26% 29% 22% (pathological)
      Radiological ORR 61% 42% N/A
      Resection rate 75% 80% 100%
      Complete resection rate 68% 76% 72%
      Pathological CR rate 16% 29% N/A
      Toxic death rate 4% 4.5% 0
      OS at 3-years 62% NR NR
      OS at 5-years 56% 44% 50%
      OS at 7-years 52% 41% 50%
      In summary, preoperative chemoradiotherapy is the current standard of care for patients with SSTs. Several critical questions remain unsolved, however, including effective suppression of micrometastases in cases with R0 resection, prevention of brain metastases, and management of N2 SSTs, which were excluded from the hitherto reported trials. References 1) N Engl J Med 337: 1370-1376, 1997 2) J Thorac Cardiovasc Surg 119: 1147-1153, 2000 3) J Clin Oncol 25: 313-318, 2007 4) J Clin Oncol 26: 644-649, 2007 5) Proc Am Soc Clin Oncol 28 suppl: 2010, (abstr 7025) 6) Ann Thorac Surg. 98: 402–410, 2014 7) Ann Thorac Surg 73:1541-4, 2002 8) Cancer 118: 444-51, 2012

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    P3.01 - Advanced NSCLC (ID 621)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.01-055 - The Usefulness of Liquid Biopsy for ctDNA in Patients with EGFR-Mutant NSCLC During and After Treatment with EGFR-TKIs (ID 9811)

      09:30 - 16:00  |  Author(s): Hideo Kunitoh

      • Abstract
      • Slides

      Non-small-cell lung cancer (NSCLC) patients with activating mutation of epidermal growth factor receptor (EGFR) gene inevitably develop disease progression to EGFR-tyrosine kinase inhibitors (TKIs). T790M gatekeeper mutation accounts for approximately 60% of the acquired resistance, and osimertinib, third generation EGFR-TKI, is effective against such tumors. Demonstration of T790M requires second biopsy, which is inconvenient and sometimes hazardous. Liquid biopsy of circulating tumor DNA (ctDNA) in the plasma is a non-invasive alternative, but clinical relevance of this method is yet to be fully elucidated.

      NSCLC patients with EGFR mutation undergoing 1st- or 2nd-generation EGFR-TKI treatment are monthly or bi-monthly monitored for plasma ctDNA EGFR mutations, including T790M, by Cobas EGFR mutation test® via 10 ml blood sampling. The treatment could be changed on the attending physicians’ discretion, including osimertinib in patients with documented T790M mutation, with continuation of the monitoring. The primary endpoints are T790M positivity rate of ctDNA among patients with tissue-confirmed T790M mutation, and T790M positivity rate of ctDNA at landmark points, such as radiological progression, clinical deterioration or second biopsy of the tumor. The secondary endpoints include EGFR mutation detection rate of plasma ctDNA at landmark points, the interval of tissue and plasma T790M detections, and response rate and progression-free survival in patients treated with osimertinib according to plasma/tissue T790M status.

      From Oct 2016 to Mar 2017, 121 eligible patients were enrolled. The median age 73 years (range, 42-92), 42 male (34.7%), PS 0, 1 and 2 were 64 (52.9%), 54 (44.6%) and 3 (2.5%) respectively. EGFR mutation types were 61 patients (50.4%) del 19, 55 (45.5%) L858R and 5 (4.0%) others. 80 (66.1%) were never smokers. At the time of EGFR-TKI initiation, 82 (67.8%) had advanced and 39 (32.2%) had recurrent diseases. 65 (53.7%) had any prior therapy, including 21 (14.8%) with prior cytotoxic chemotherapy. Used EGFR-TKIs were gefitinib 50 (41.3%), erlotinib 40 (33.1%), and afatinib 31 (25.6%). Newly-diagnosed/on TKI therapy at enrollment was 18 (14.9%)/103 (85.1%). The median follow-up is 12[鈴木1] months. So far, plasma T790M was detected in 8 patients.

      This observational study will elucidate the clinical usefulness and limitations of monitoring of ctDNA for T790M mutation in the real-world setting.

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