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S. Kudoh



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    MO25 - NSCLC - Combined Modality Therapy II (ID 112)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      MO25.02 - Thoracic Radiotherapy With or Without Concurrent Daily Low-Dose Carboplatin in Elderly Patients With Locally Advanced Non-small Cell Lung Cancer: Updated Results of the JCOG0301 and Pooled Analysis With the JCOG9812 Trial. (ID 734)

      10:35 - 10:40  |  Author(s): S. Kudoh

      • Abstract
      • Presentation
      • Slides

      Background
      The Japan Clinical Oncology Group (JCOG) undertook 2 randomized phase III trials (JCOG9812 and JCOG0301) to assess whether daily low-dose carboplatin plus radiotherapy could improve survival in elderly patients with stage III non-small cell lung cancer (NSCLC) when compared to radiotherapy alone. Although JCOG9812 was prematurely terminated because of a high incidence of treatment-related deaths (TRDs) and instances of protocol violation, especially with regard to radiotherapy planning, the trial regimen was assumed promising. Therefore, JCOG0301 was conducted for the same subjects using the same protocol regimen with modified inclusion criteria regarding pulmonary function and radiotherapy quality control (RTQC) measures. We then carried out a preplanned pooled analysis of these 2 studies.

      Methods
      The eligibility criteria for both trials were age of ≥71 years and unresectable stage III NSCLC. Patients were randomized to receive radiotherapy alone (60 Gy, RT arm) or chemoradiotherapy (radiotherapy, 60 Gy plus concurrent carboplatin, 30 mg/m[2] per fraction up to the first 20 fractions, CRT arm). The primary endpoint for both studies was overall survival (OS). The pooled analysis included OS, progression-free survival (PFS), response rate, and toxicities.

      Results
      In JCOG9812, 46 patients (RT arm, n=23; CRT arm, n=23) were enrolled from November 1999 to August 2001. In JCOG0301, 200 patients (RT arm, n=100; CRT arm, n=100) were enrolled from September 2003 to May 2010, and in total, 246 patients were included in the pooled analysis. Patient characteristics for the RT (n=123) and CRT (n=123) arms were as follows: median age, 77 years (range, 71–93) and 77 years (range, 71–89); stage IIIA/IIIB, 65/58 patients and 63/60 patients; performance status (PS) 0/1/2, 44/74/5 patients and 50/69/4 patients; men/women, 103/20 patients and 96/27 patients, respectively. The median OS for the RT (n=121) and CRT (n=122) arms were 16.3 months (95% CI, 13.4–18.6) and 20.7 months (95% CI, 16.3–26.9), respectively (HR, 0.672; 95%CI, 0.502–0.898, stratified log-rank test one-sided p=0.0034). The pooled HR for PFS was 0.671 (95%CI, 0.514–0.875, stratified log-rank test one-sided p=0.0015). Response rates for the RT and CRT arms were 46.3% and 53.3%, respectively. The number of patients with grade 3/4 hematological toxicities was higher in the CRT arm than in the RT arm: leucopenia (62.2% vs 1.7%), neutropenia (54.6% vs none), and thrombocytopenia (30.3% vs 3.3%). The incidence of grade 3/4 pneumonitis decreased from 4.4% (JCOG9812; RT, 4.5% and CRT, 4.3%) to 2.1% (JCOG0301; RT, 3.1% and CRT, 1.0%), and that of late lung toxicity, from 14.0% (JCOG9812; RT, 10.0% and CRT, 17.4%) to 5.9% (JCOG0301; RT, 5.3% and CRT, 6.5%). The incidence of TRD also decreased from 8.9% (JCOG9812; RT, 1 patient and CRT, 3 patients) to 3.6% (JCOG0301; RT, 4 patients and CRT, 3 patients). As per subgroup analyses, ≤75 years, stage IIIA, male, PS 0, and smoking history were associated with statistically significant improvement in OS in the CRT arm.

      Conclusion
      This combination chemoradiotherapy for elderly patients with locally advanced NSCLC provides clinically significant benefits and RTQC measures are imperative to improve treatment outcome.

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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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      P1.10-020 - Dose adjustment of single agent amrubicin in lung cancer patients with impaired hepatic function (ID 1348)

      09:30 - 09:30  |  Author(s): S. Kudoh

      • Abstract

      Background
      The pharmacokinetics (PK) of amrubicin (AMR) in lung cancer patients with impaired hepatic function have not been reported. The objectives of this study were to evaluate the PK of AMR and its major metabolite, amrubicinol (AMR-OH), in lung cancer patients with or without impaired hepatic function, and to assess the validity of dose adjustment of AMR based on hepatic function.

      Methods
      Eligibility criteria included the presence of histologically or cytologically proven lung cancer, an ECOG PS of 0 to 2, age 20 to 70 years old, and no evidence of hepatitis B virus infection. The dose was adjusted from 25 to 45 mg/m[2]/day (iv, days 1-3, q3w) based on the history of prior treatment and baseline values of total bilirubin (T-bil), AST and ALT (Table 1). Figure 1

      Results
      Five patients with impaired hepatic function (arm I) and 10 patients with normal hepatic function (arm N) were enrolled. Terminal half-life (t~1/2~) and clearance of AMR in plasma, and t~1/2~ of AMR-OH in blood did not differ between the two arms. Area under the curve (AUC~0-24~) of AMR in plasma and AUC~0-120~ of AMR-OH in blood in arm I were similar or lower compared to those in arm N (Table 2). The dose-adjusted AUCs of AMR and AMR-OH did not show a tendency to increase with increases in baseline T-bil, AST and ALT. Two deaths occurred in arm I (one due to disease progression, and the other due to an unspecified reason), but the toxicities in arm I were not severe compared with those in arm N. Figure 1

      Conclusion
      These data show the validity of dose adjustment of AMR in patients with impaired hepatic function.

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    P1.22 - Poster Session 1 - Epidemiology, Etiology (ID 166)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P1.22-010 - Goddard classification is associated with clinical characteristics in patients with COPD and advanced NSCLC. (ID 2726)

      09:30 - 09:30  |  Author(s): S. Kudoh

      • Abstract

      Background
      Chronic obstructive pulmonary disease (COPD) is a frequent complication seen in 24.9% in patients with lung cancer. In practice, a decreased respiratory function due to COPD influences to decision of treatment. The airway obstruction is assessed by the Global Initiative for obstructive lung disease (GOLD) classification. On the other hand, Goddard classification is a method for evaluating the emphysema using CT images. The respiratory function of an advanced lung cancer has various modifications such as tumor airway obstruction or atelectasis. The hypothesis is that in patient with COPD and advanced lung cancer patients, GOLD classification may not correspond to the Goddard classification. We evaluated the associations of clinical characteristics with Goddard classification as well as GOLD classification.

      Methods
      Between May 2007 and April 2012, the pre-treatment respiratory function was assessed for patients diagnosed at Osaka City University Hospital as non-small cell lung cancer stage IIIB or IV without EGFR gene active mutations. FEV/FVC% less than 70% were diagnosed for COPD. GOLD and Goddard classification were evaluated. Two doctors independently determined the Goddard classification, and the final score was adopted from the average of two scores. The association of clinical characteristics with Goddard classification as well as GOLD classification was performed by fisher exact test. An univariate analysis was performed to evaluate the prognosis by COX regression method. In multivariate analysis, histology, stage, number of cigarette smoking, and FEV/FVC% were performed to evaluate the prognosis by COX regression selected variable method (stepwise method).

      Results
      A total of 67 patients were enrolled with median age of 70 (49-81). GOLD classification showed normal (n=32), mild (stage I/II, n=30), and moderate (stage III, n=5) airflow obstructions. There was no severe COPD (stage IV) patient. In GOLD classification, no-significant associations of clinical characteristics were observed such as lobe site of primary lesion (p=0.84), tumor histology (p=0.21), gender (p=0.17), and cigarette smoking (p=0.42). Goddard classification showed non (score zero, n=12), mild (score <8, n=32), and moderate-severe (score 8-20, n=23) emphysema findings. In Goddard classification, there were significant associations of clinical characteristics in tumor histology of squamous cell carcinoma (p=0.010), male (p=0.031), and number of cigarette smoking (p=0.020). Univariate analyses showed neither GOLD nor Goddard classification was associated with overall survival. In multivariate analysis, FEV/FVC% was not associated with overall survival.

      Conclusion
      As compared with Goddard classification, the distribution of GOLD classification shift relatively mild direction. Therefore, there is no-significant association of clinical characteristics in GOLD classification, and Goddard classification was significant association of squamous cell carcinoma, male, and cigarette smoking. Surprisingly, the FEV/FVC% did not become a prognostic factor for NSCLC received chemotherapy. The severity of COPD might not influence outcome of chemotherapy in advanced NSCLC.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-037 - Transforming growth factor-β1 genetic polymorphisms relate to erlotinib induced diarrheaTransforming growth factor-β1 genetic polymorphisms relate to erlotinib induced diarrheaTransforming growth factor-β1 genetic polymorphisms relate to erlotinib induced diarrhea (ID 2681)

      09:30 - 09:30  |  Author(s): S. Kudoh

      • Abstract

      Background
      Rash, liver dysfunction, diarrhea and pneumonitis are known as adverse events of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Transforming growth factor-β1 (TGF-β1) is a cytokine and acts as an anti-proliferative factor in normal epithelial cells and epithelial-mesenchymal transition (EMT) with invasion and metastasis in cancer cells. TGF-β1 mediated Smad activation caused EMT, and activation of the EGFR. TGF-β1-mediated EGFR activation was abolished by EGFR suppression or extracellular EGF depletion pathway. TGF-β1 genotypes are associated with serum level of TGF-β1. It has been hypothesized that TGF-β1 genotypes may be implicated in clinical outcomes of EGFR-TKIs.

      Methods
      Patients were identified through a query of patient information for subjects enrolled in the Medical Information System in Osaka City University Hospital between January 1999 and February 2012. The associations between three genetic polymorphisms of TGF-β1 (C-509T, T869C, and G915C) and adverse events of erlotinib and gefitinib have been studied. Genomic DNA was extracted from peripheral blood or formalin-fixed and paraffin-embedded tissues. TGF-β1 genotypes were determined using RT-PCR method. The primers were designed to amplify the target fragments of TGF-β1 rs1800469, rs1800471, and rs1982073, respectively. In order to identify the risk factors for the adverse events, gender, age, stage and three genetic polymorphisms of TGF-β1 were selected and estimated for their potential confounding effects on rash, diarrhea, and liver dysfunction by multivariate analysis. Unconditional logistic regressions were used to compute the odds ratios (ORs) and their 95% confidence intervals (CIs). All analyses were two-sided, and p values of less than 0.05 were considered statistically significant. This study was approved by the ethics committee of Osaka City University (approval number, 1700).

      Results
      A total of 255 patients received gefitinib, and 75 patients received erlotinib. In the gefitinib group, the rates of rash, diarrhea, and liver dysfunction of grade 1 or more were 66.7%, 26.0% and 48.5%, respectively. In the erlotinib treatment group, the rates of rash diarrhea, and liver dysfunction of grade 1 or more were 84.1%, 43.5% and 33.3%, respectively. The C-509T consisted of TT in 26.6%, CT or CC in 73.3% of patients (n=289), respectively. The T869C consisted of CC in 26.1%, TC or TT in 73.9% of patients (n=272), respectively. The G915C consisted of GG in 100% of (n=313) patients. TT of the C-509T and CC of the T869C were significantly associated diarrhea of grade 1 or more in erlotinib group (OR 0.21, 95% confidence interval [CI] 0.054-0.72, p < 0.001, and OR 0.21, 95% CI 0.05-0.73, p = 0.014, respectively). No associations were observed between TGF-β1 genotypes and any adverse events in gefitinib group.

      Conclusion
      Minor alleles of TT of the C-509T and CC of the T869C were associated with erlotinib induced diarrhea. These alleles are generally associated with high level of TGF-β1 in serum. The increase level of TGF-β1 may be a risk factor for mucosal damage of the gastrointestinal tract in patients treated with erlotinib.

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    P3.03 - Poster Session 3 - Technology and Novel Development (ID 152)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.03-003 - The relationship between fresh macroscopic appearance of tissue specimen by CT guided biopsy and its clinicopathological feature in 58 patients with NSCLC. (ID 2688)

      09:30 - 09:30  |  Author(s): S. Kudoh

      • Abstract

      Background
      The CT-guided lung needle biopsy is a well-established and safety technique for diagnosis. A biopsy specimen often had loose connection and broke to tiny pieces before formalin fixation. Tumor invasion often involves the epithelial-mesenchymal transition (EMT) during which cells lose the lateral attachments to their neighbors and become more motile. The hypothesis is the fresh macroscopic appearance of specimens may relate pathological features and predict clinical features in patients with lung cancer.

      Methods
      The correlations between fresh macroscopic appearance of specimens and pathological findings or clinical outcomes were examined in patients who underwent CT-guided lung needle biopsy in our institution between May 2009 and May 2013. The intensity of fiber stained Azan staining (0, 1+, 2+, and 3+) and the percentage of positive cells (<1%, <25%, <50%, <75, and >75%) were assessed. The score of each case was multiplied to give a final score and the fibrosis was finally classified as low (<200) or high (>200). Comparisons of variables were performed by using Fisher exact tests.

      Results
      A total of 93 (86.1%) of 108 patients had adequate samples for diagnosis. The mean nodule diameter was 26 mm (range 4-75mm). CT findings revealed only three of 93 lesions showed ground-glass opacity, and all of them were in tight connection group. Macroscopically, 21.3% (n=23) specimens had loose connection, and 78.7% (n=85) specimens had tight connection. In loose connections, 73.9% (n=17) diagnosed as malignant and 26.1% (n=6) as benign, with sensitivity of 77.3%, specificity of 100%, and accuracy of 78.3%. In tight connections, 75.3% (n=64) as malignant and 24.7% (n=21) as benign, with sensitivity of 86.5%, specificity of 100%, and accuracy of 88.2%. There were 58 NSCLC samples, including 30 well or moderate (w/d or m/d), and 8 poorly differentiated (p/d) adenocarcinomas (Ad), 7 w/d or m/d, and 6 p/d squamous cell carcinomas (Sq), and 7 undifferentiated carcinoma. In 58 samples, 20.7% (n=12) specimens had loose connection and 79.3% (n=46) specimens had tight connection. In Azan staining, the tight connection group had 32 samples of high and 14 of low scores with the mean score of 213.6, and the loose connection group had 4 of high and 8 of low scores with the mean score of 118.6. The tight connection group had significantly higher scores than the loose connection group (p=0.042). The patients with loose connection had significantly higher rate of distant metastasis than those with tight connection (58.3% vs 21.7%, p=0.028). The median survival times are not reached in both groups.

      Conclusion
      Macroscopically loose connection specimens can afford to provide adequate amount of samples for diagnosis with sensitivity of 77.3%, and this appearance was negatively correlated with amount of fiber. Furthermore, the patients with loose connection tissue were associated with distal metastasis. The loose connection specimens may represent the status of EMT acquisition which is induced tumor initiation, growth, and metastasis. These findings suggest that the macroscopic appearance of tissue specimens obtained from CT guided biopsy can be an effective evaluation for prediction of metastasis in patients with NSCLC.

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    P3.09 - Poster Session 3 - Combined Modality (ID 214)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P3.09-007 - Update data of biomarker analysis of WJOG4107 (A randomized phase II trial of adjuvant chemotherapy with S-1 versus CDDP+S-1 for resected stage II-IIIA non-small cell lung cancer (NSCLC)) (ID 1504)

      09:30 - 09:30  |  Author(s): S. Kudoh

      • Abstract

      Background
      We conducted a randomized phase II trial for patients with resected stage II-IIIA NSCLC comparing postoperative oral S-1 (80 mg/m2/day for consecutive 2 weeks q3w for 1 year) (S) (N=100) or cisplatin (CDDP) (60 mg/m2 day1) plus oral S-1, (80 mg/m2/day for 2 weeks) q3w for 4 cycles (PS)(N=100). We reported that disease free survival rate at 2 years (DFS@2) (95% confidence interval: CI), a primary endpoint, was 66 (55-74) % for S and 58 (48-67)% for PS. Here, we report the preliminary results of preplanned biomarker analysis, a co-primary endpoint, to identify molecules whose expression is significantly associated with patient outcome.

      Methods
      　cDNA extracted from macro-dissected formalin-fixed paraffin-embedded specimens were available for 197/200 patients. Thirty-one genes including those whose expressions have been potentially associated with　CDDP (e.g. ERCC1, XRCC1, BRCA1, GSTpi, HMG1, TBP) or fluorouracil (FU) sensitivity (TS, DHFR, DPD, UMPS, UPP1) were measured by QGE analysis (MassArray, Sequenom, CA). Additional analysis are being performed to assess ERCC1 isoform expression with an isoform-specific TaqMan probe (Applied Biosystems, CA). The expression of each gene was dichotomized according to its median value.

      Results
      Molecules such as ERCC1 and GSTpi whose expression have been previously associated with CDDP sensitivity did not emerge as predictive markers (P=0.7908, 0.6406, respectively). We quantitated ERCC1 by isotype (202 and 204 cannot be distinguished). There was a trend in patients with high 201 or 202/204, CDDP/S-1 was worse than S-1.

      Conclusion
      Quantitation of ERCC1 by isotype may define a patient subset that would benefit from postoperative platinum therapy.