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Y. Okuma



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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-012 - Activity of S-1 for non-small cell lung cancer pretreated with or without pemetrexed. (ID 882)

      09:30 - 16:30  |  Author(s): Y. Okuma

      • Abstract

      Background
      S-1, a 5-fluorouracil derivative, and pemetrexed (PEM) are antimetabolites that both mainly target thymidylate synthase. S-1 received approval as a therapeutic drug for treating non-small cell lung cancer (NSCLC) in Japan in December 2004, and has been primarily used as a single agent for salvage chemotherapy. To our knowledge, there has been no clinical evidence whether the activity of S-1 is influenced by PEM resistance.

      Methods
      Patients with pretreated NSCLC who underwent S-1 monotherapy were identified from an institutional database. This study was approved by the institutional review board. Eligible patients were classified into three groups; patients with non-squamous NSCLC pretreated with PEM (PEM+) or not (PEM−), or those with squamous cell lung cancer (SQ). Progression-free survival (PFS) and overall survival (OS) from S-1 administration were estimated using the Kaplan-Meier method and the log-rank test was used for inter-group comparisons. Impacts of prior PEM therapy on PFS and OS were examined using Cox proportional hazards modeling with variables including number of prior chemotherapy regimens, histological subtype of NSCLC, sex and age (<70 vs. ≥70 years).

      Results
      We identified 125 patients who underwent S-1 monotherapy for pretreated NSCLC. Median age was 69 years (range, 39-86 years), with 31% female. Histological subtype was 82 (66%) adenocarcinoma, 33 (26%) squamous cell carcinoma and 10 (8%) NSCLC not otherwise specified. Number of prior chemotherapy regimens was one in 32 (26%), two in 54 (43%), three in 26 (21%) and four or more in 13 (10%) patients. Among 108 patients with measurable disease, response rate was 12% and disease control rate was 45%. Response rates for S-1 monotherapy as second-, third- and fourth-line chemotherapy were 19% (5/27), 13% (6/45) and 9% (2/23), respectively. Forty-eight patients had received PEM-based chemotherapy prior to S-1 administration. Median PFS were 2.0 months for the PEM− group (reference), 2.1 months for the PEM+ group (crude hazard ratio (HR) 1.11, 95%CI 0.73-1.69, p = 0.6), and 2.2 months for SQ group (crude HR 0.72, 95%CI 0.44-1.15, p = 0.2). Median OS were 4.5 months for the PEM− group (reference), 5.9 months for the PEM+ group (crude HR 0.65, 95%CI 0.41-1.03, p = 0.07), and 8.4 months for SQ group (crude HR 0.76, 95%CI 0.47-1.23, p = 0.3). Multivariate analyses revealed that only female sex was associated with longer PFS (HR 0.59, 95%CI 0.38-0.91, p = 0.02) and OS (HR 0.58, 95%CI 0.36-0.91, p = 0.01), with history of PEM therapy or histological subtype exerting no influence.

      Conclusion
      Activity of S-1 is unaffected by prior PEM therapy. These results are compatible with recent preclinical findings. Further study is warranted.

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    P1.15 - Poster Session 1 - Thymoma (ID 189)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Thymoma & Other Thoracic Malignancies
    • Presentations: 1
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      P1.15-008 - A multivariate analysis of factors predicting survival in 70 patients with thymic carcinoma: implications for treatment strategy (ID 2941)

      09:30 - 16:30  |  Author(s): Y. Okuma

      • Abstract

      Background
      BACKGROUND: Thymic carcinomas are considered to be more aggressive than thymomas and carry a worse prognosis. Although a multimodality treatment is made in many cases as for thymic carcinomas, optimal therapeutic strategy still remains controversial especially in thymic carcinomas having poor prognostic factors. In the present study, we attempted to clarify the prognostic factors based on the survival to establish suitable treatment strategy.

      Methods
      METHODS: We performed a single-institution retrospective cohort study. Between June 1987 and October 2012, 70 patients were eventually given a diagnosis of thymic carcinoma. Data included patient demographics, stage, first treatment (e.g. chemotherapy (CT), chemoradiotherapy (CRT), and surgery (S)), pathologic findings, and outcomes. For the univariate analysis, we constructed survival curves using the Kaplan-Meier method and compared survival between groups using log-rank tests. Multivariate analysis was performed by constructing a Cox proportional hazards model using the significant factors from the univariate analysis. The analyses were performed with the Stat view v5.0 statistical software program.

      Results
      RESULTS: The overall 2- and 5-year survival rate was 61.9% and 36.4%, respectively ; mean and median observation time was 30M and 24M, respectively. Two-year survival rates in patients treated with CT, CRT, and S group were 38.7, 52.4, and 80.5%, and 5-year survival rates in patients treated with CT, CRT, and S group were 17.4, 21.0, and 55% for all patients. S group showed significantly better prognosis than the others in overall stage (p=0.0006). Patients undergoing S, however, had similar survival compared with undergoing CT or CRT alone in stage IV a,b subset; CT vs. CRT (p=0.6598), CT vs. S (p=0.1159), CRTvs.S (p=0.3030). Univariate analysis among patients underwent surgery revealed two significant prognostic factors (P <.05): stage by the Masaoka system and resection status. Based on the result, 5-year survival rate in each factor were compared statistically by Kaplan–Meier’s method; Masaoka stage II,III vs. IVa,b =82.5% vs.35.3% (p=0.0182), complete resection vs. incomplete resection=76.4% vs.34.1% (p=0.0173). Multivariate analysis revealed no statistically significant independent prognostic factor, probably due to confounding. The hazard ratio for death for being Masaoka stage II,III was 0.463【95%CI 0.082-2.623】(p=0.3843), for being complete resection was 0.552【95%0.110-2.762】(p=0.4701). According to the subset analysis on CT group, response to first-line chemotherapy was an independent prognostic factor.

      Conclusion
      CONCLUSIONS: Our analyses indicated that stage by the Masaoka system and resection status would have the prognostic impact. If complete excision is possible at earlier than Masaoka stage III, it may be cured completely. The role of debulking surgery at stage IV a,b was negative. Patient selection, accurate staging, and choice of anticancer drug with a high response rate may be critical to optimizing outcomes.

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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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      P2.10-003 - A multicenter, proof-of-concept study of short-term supplementation of folic acid and vitamin B<sub>12</sub> prior to cisplatin-pemetrexed therapy for non-small cell lung cancer. (ID 186)

      09:30 - 16:30  |  Author(s): Y. Okuma

      • Abstract

      Background
      Pemetrexed, a multi-targeted antifolate, requires supplementation with folic acid and vitamin B~12~ prior to its first administration in order to reduce toxicity. The lead-in time for this vitamin supplementation is advised to be at least seven days on the drug package insert. Previous studies suggested that parenteral vitamin B~12~ pervades the major organs in 24 hours, while oral folic acid supplementation usually takes much longer than seven days to correct folic acid deficiency. We hypothesized that the lead-in time for vitamin supplementation can be shortened to 24 hours, enabling earlier administration of standard chemotherapy and potential avoidance of treatment alterations due to rapid disease progression before starting chemotherapy. Since only a few retrospective analyses related to early initiation of pemetrexed have been conducted, the first prospective study evaluating shortened vitamin supplementation for pemetrexed-based chemotherapy was planned.

      Methods
      A multicenter, single-arm phase 2 study was conducted. Patients with advanced non-squamous non-small cell lung cancer were enrolled. Major eligibility criteria were adequate organ function, performance status 0-1, no symptomatic brain metastasis, and no prior cytotoxic chemotherapy. Patients who had provided written informed consent were administered 1000 μg of vitamin B~12~ by intramuscular injection and started taking 350-500 μg of folic acid per day. Cisplatin (75 mg/m[2]) plus pemetrexed (500 mg/m[2]) therapy was commenced 24-48 hours after vitamin B~12~ injection and repeated for four cycles unless disease progression or unacceptable toxicity was observed. The primary endpoint was the proportion of patients experiencing neutropenia ≥grade 3. Thirty patients were to be accrued to detect the difference between the expected 30% of patients with neutropenia ≥grade 3 and the null hypothesis of 50%, using a two-stage design with 70% power and 5% alpha. Clinical trial registry number UMIN000006546.

      Results
      From November 2011 to March 2013, 31 patients were enrolled. Their median age was 66 years (range, 34-74 years), with 32% female. Most patients had adenocarcinoma (87%) and stage IV disease (90%). Performance status was 0 in 16 (52%) and 1 in 15 (48%) patients. Of the 30 patients who started chemotherapy within 48 hours from vitamin administration, 21 (70%) patients completed four cycles of cisplatin/pemetrexed therapy. Six (20%) patients discontinued chemotherapy due to disease progression, and the treatment of three (10%) patients was stopped due to adverse events. No treatment-related deaths or grade 4 toxicity occurred. Grade 3 neutropenia was observed in 7% (95%CI, 2-21%) of patients. Other grade 3 toxicities were anemia (two patients), decreased white blood cell count, diarrhea, thromboembolic event, hypertension, and myocardial infarction (one patient, respectively). The plasma homocysteine level before vitamin administration, a marker for vitamin B~12~ and/or folate deficiency, was elevated in four patients, but none of the patients experienced grade 3 toxicities. The response rate and the disease control rate of chemotherapy were 43% (95%CI, 27-61%) and 77% (95%CI, 59-88%), respectively.

      Conclusion
      This study met its primary endpoint. Absence of relationship between baseline homocysteine levels and toxicities of chemotherapy suggests the efficacy of short-term vitamin supplementation. A pragmatic study with a larger cohort that can detect uncommon toxicities is being conducted.