Tetsuhiko Taira

Prognostic impact of serum CYFRA 21–1 in patients with advanced lung adenocarcinoma: a retrospective study

BackgroundSerum CYFRA 21–1 is one of the most important serum markers in the diagnosis of non-small cell lung cancer (NSCLC), especially squamous-cell carcinoma. However, it remains unknown whether pretreatment serum CYFRA 21–1 values (PCV) may also have prognostic implications in patients with advanced lung adenocarcinoma.MethodsWe retrospectively reviewed the data of 284 patients (pts) who were diagnosed as having advanced lung adenocarcinoma and had received initial therapy.ResultsOf the study subjects, 121 pts (43%) had activating epidermal growth factor receptor (EGFR) mutations (Mt+), while the remaining 163 pts (57%) had wild-type EGFR (Mt-). Univariate analysis identified gender (male/ female), ECOG performance status (PS) (0-1/ ≥2), PCV (<2.2 ng/ml/ ≥2.2 ng/ml), EGFR mutation status (Mt+/ Mt-), pretreatment serum CEA values (<5.0 ng/ml/ ≥5.0 ng/ml), smoking history (yes/ no) and EGFR-TKI treatment (yes/ no) as prognostic factors (p = .008, p < .0001, p < .0001, p < .0001, p = .036, p = .0012, p < .0001 respectively). Coxs multivariate regression analysis identified PCV < 2.2ng/ml as the only factor significantly associated with prolonged survival (p < .0001, hazard ratio: 0.43, 95% CI 0.31-0.59), after adjustments for PS (p < .0001), EGFR mutation status (p = .0069), date of start of initial therapy (p = .07), gender (p = .75), serum CEA level (p = .63), smoking history (p = .39) and EGFR-TKI treatment (p = .20). Furthermore, pts with Mt+ and PCV of <2.2 ng/ml had a more favorable prognosis than those with Mt+ and PCV of ≥2.2 ng/ml (MST: 67.0 vs. 21.0 months, p < .0001), and patients with Mt- and PCV of <2.2 ng/ml had a more favorable prognosis than those with Mt- and PCV of ≥2.2 ng/ml (MST: 24.1 vs. 10.2 months, p < .0001).ConclusionPCV may be a potential independent prognostic factor in both Mt+ and Mt- patients with advanced lung adenocarcinoma.

Rebiopsy for patients with non‐small‐cell lung cancer after epidermal growth factor receptor‐tyrosine kinase inhibitor failure

Although third‐generation epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKI) can overcome T790M‐mediated resistance in non‐small‐cell lung cancer (NSCLC), rebiopsy to confirm T790M status is occasionally difficult. We aimed to investigate the current tendency and the limitations of rebiopsy in clinical practice. This study included 139 consecutive NSCLC patients with EGFR mutations, who had experienced progressive disease (PD) after EGFR‐TKI treatment. We retrospectively reviewed patient characteristics, tumor progression sites and rebiopsy procedures. Of 120 patients (out of the original 139) who were eligible for clinical trials, 75 (63%) underwent rebiopsy for 30 pleural effusions, 32 thoracic lesions, four bone, two liver, and seven at other sites. Rebiopsy procedures included 30 thoracocentesis, 24 transbronchial biopsies, 13 computed tomography (CT)‐guided needle biopsies and 8 other procedures. Of the 75 rebiopsied patients, 71 (95%) were pathologically diagnosed with malignancy; and 34 (45%) had available tissue samples for EGFR analyses. Of the 75 biopsied patients, 61 (81%) were analyzed for EGFR mutation, using tissue or cytology samples; T790M mutations were identified in 20 (33%) of the 61 patients. Of the 120 patients, 45 (38%) did not undergo rebiopsy, because of inaccessible tumor sites (n = 19), patient refusal (n = 6) or decision of physician (n = 10). In conclusion, among patients with EGFR mutations who had PD after EGFR‐TKI treatment, 63% underwent rebiopsy. Most rebiopsy samples were diagnosed with malignancy. However, tissue samples were less available and T790M mutations were identified less frequently than in previous studies. Skill and experience with rebiopsy and noninvasive alternative methods will be increasingly important.

Progression-free survival at 2 years is a reliable surrogate marker for the 5-year survival rate in patients with locally advanced non-small cell lung cancer treated with chemoradiotherapy

BackgroundIn locally advanced Non-Small-Cell Lung Cancer (LA-NSCLC) patients treated with chemoradiotherapy (CRT), optimal surrogate endpoint for cure has not been fully investigated.MethodsThe clinical records of LA-NSCLC patients treated with concurrent CRT at Shizuoka Cancer Center between Sep. 2002 and Dec. 2009 were reviewed. The primary outcome of this study was to evaluate the surrogacy of overall response rate (ORR) and progression-free survival (PFS) rate at 3-month intervals (from 9 to 30 months after the initiation of treatment) for the 5-year survival rate. Landmark analyses were performed to assess the association of these outcomes with the 5-year survival rate.ResultsOne hundred and fifty-nine patients were eligible for this study. The median follow-up time for censored patients was 57 months. The ORR was 72%, median PFS was 12 months, and median survival time was 39 months.Kaplan-Meier curve of progression-free survival and hazard ratio of landmark analysis at each time point suggest that most progression occurred within 2 years. With regard to 5-year survival rate, patients with complete response, or partial response had a rate of 45%. Five-year survival rates of patients who were progression free at each time point (3-months intervals from 9 to 30 months) were 53%, 69%, 75%, 82%, 84%, 89%, 90%, and 90%, respectively. The rate gradually increased in accordance with progression-free interval extended, and finally reached a plateau at 24 months.ConclusionsProgression-free survival at 2 years could be a reliable surrogate marker for the 5-year survival rate in LA-NSCLC patients treated with concurrent CRT.

Clinical impact of post-progression survival on overall survival in patients with limited-stage disease small cell lung cancer after first-line chemoradiotherapy

Abstract Background. The effects of first-line chemoradiotherapy on overall survival (OS) may be confounded by subsequent lines of therapy in patients with limited-stage disease small cell lung cancer (LD-SCLC). Therefore, we aimed to determine the relationships between progression-free survival (PFS), post-progression survival (PPS) and OS after first-line chemoradiotherapy in LD-SCLC patients. Patients and methods. We retrospectively analyzed 71 LD-SCLC patients with performance status (PS) 0-2 who received first-line chemoradiotherapy and had disease recurrence between September 2002 and March 2013 at Shizuoka Cancer Center (Shizuoka, Japan). We determined the correlation between PFS and OS and between PPS and OS at the individual level. In addition, we performed univariate and multivariate analyses to identify significant prognostic factors of PPS. Results. OS is more strongly correlated with PPS (Spearman’s r = 0.86, R2 = 0.72, p < 0.05) than PFS (Spearman’s r = 0.46, R2 = 0.38, p < 0.05). In addition, the response to second-line treatments, the presence of distant metastases at recurrence and the number of additional regimens after first-line chemoradiotherapy were significant independent prognostic factors for PPS. Conclusions. PPS has more impact on OS than PFS in recurrent LD-SCLC patients with good PS at beginning of the treatment. Moreover, treatments administered after first-line chemoradiotherapy may affect their OS. However, larger multicenter studies are needed to validate these findings.

Plasma epidermal growth factor receptor mutation testing with a chip-based digital PCR system in patients with advanced non-small cell lung cancer

OBJECTIVES Epidermal growth factor receptor (EGFR) mutation testing is a companion diagnostic to determine eligibility for treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). Recently, plasma-based EGFR testing by digital polymerase chain reaction (dPCR), which enables accurate quantification of target DNA, has shown promise as a minimally invasive diagnostic. Here, we aimed to evaluate the accuracy of a plasma-based EGFR mutation test developed using chip-based dPCR-based detection of 3 EGFR mutations (exon 19 deletions, L858R in exon 21, and T790M in exon 20). MATERIALS AND METHODS Forty-nine patients with NSCLC harboring EGFR-activating mutations were enrolled, and circulating free DNAs (cfDNAs) were extracted from the plasma of 21 and 28 patients before treatment and after progression following EGFR-TKI treatment, respectively. RESULTS Using reference genomic DNA containing each mutation, the detection limit of each assay was determined to be 0.1%. The sensitivity and specificity of detecting exon 19 deletions and L858R mutations, calculated by comparing the mutation status in the corresponding tumors, were 70.6% and 93.3%, and 66.7% and 100%, respectively, showing similar results compared with previous studies. T790M was detected in 43% of 28 cfDNAs after progression with EGFR-TKI treatment, but in no cfDNAs before the start of the treatment. CONCLUSION This chip-based dPCR assay can facilitate detection of EGFR mutations in cfDNA as a minimally invasive method in clinical settings.

A favorable clinical effect of an expectorant in allergic bronchopulmonary mycosis caused by Schizophyllum commune

An 80-year-old Japanese woman with wet cough and dyspnea was diagnosed with pneumonia at a clinic. Antibiotics did not improve her symptoms; therefore, she was referred to our hospital one month after symptom onset. Chest radiograph findings revealed complete collapse of the left lung. Bronchoscopy showed white mucus plug in the left main bronchus, which could not be removed. She was initially treated with bromhexine. Subsequently, culture results of the mucus plug specimen obtained during bronchoscopy yielded Schizophyllum commune. After three weeks, improvement of the collapsed lung was observed on chest radiograph.

Amrubicin monotherapy may be an effective second-line treatment for patients with large-cell neuroendocrine carcinoma or high-grade non-small-cell neuroendocrine carcinoma

There is no standard chemotherapy for pulmonary large-cell neuroendocrine carcinoma (LCNEC) and this type of cancer is difficult to diagnose using biopsy specimens. At the Shizuoka Cancer Center, when small biopsy specimens are used, they are diagnosed as high-grade non-small-cell neuroendocrine carcinoma (HNSCNEC) and the patients are treated according to the small-cell lung cancer (SCLC) guidelines. Amrubicin is an effective second-line treatment for patients with SCLC, although it remains unclear whether amrubicin monotherapy is effective for patients with LCNEC or HNSCNEC. Between September, 2004 and December, 2013, 18 patients with advanced LCNEC or HNSCNEC received amrubicin monotherapy in the second-line setting. The efficacy and toxicity of this treatment were retrospectively assessed. A total of 6 patients had LCNEC and 12 patients had HNSCNEC. The patients included 13 men, and the median age was 66 years (range, 57-82 years). A total of 16 patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. All the patients had received platinum-based chemotherapy as first-line treatment, and the median number of amrubicin cycles per patient was 4 (range, 1-9). The overall response rate was 11.1%. The median progression-free and overall survival were 4.0 and 9.1 months, respectively. Grade 3 or 4 neutropenia was observed in 44% of the patients, and grade 3 febrile neutropenia occurred in 17% of the patients. One patient developed pneumonia and succumbed to the disease. Non-hematological toxicities were generally mild and manageable. Therefore, the efficacy of amrubicin in the second-line setting for patients with LCNEC or HNSCNEC is limited. Development of new drugs and/or treatment strategies is warranted.

The effects of advanced age and serum α1‐acid glycoprotein on docetaxel unbound exposure and dose‐limiting toxicity in cancer patients

Aim α1‐Acid glycoprotein (AAG), which is a major binding protein of docetaxel, is considered to be a determinant for docetaxel pharmacokinetics. However, there are no reports about the impact of serum AAG on pharmacokinetics and pharmacodynamics in elderly patients treated with docetaxel. The aim of this prospective study was to elucidate the effects of advanced age and serum AAG on docetaxel unbound exposure and neutropenia, dose‐limiting toxicity, in cancer patients. Methods Docetaxel was administered at 60 mg m−2 to 51 patients with non‐small cell lung cancer, 17 of whom were ≥75 years of age. Pharmacokinetics, unbound fraction (fu), neutropenia, serum protein levels of AAG and albumin, as well as baseline absolute neutrophil count (ANC) were assessed during the first course. Population pharmacokinetic and pharmacodynamic analyses were performed to evaluate the influence of clinically relevant factors on docetaxel pharmacokinetics and neutropenia. Results Clearance of docetaxel and degree of fu were significantly associated with serum AAG level, but not with age. Area under the concentration–time curve of unbound docetaxel (fu·AUC) was significantly higher in patients aged ≥75 years (0.389 μg·h ml−1, 95% CI; 0.329–0.448 μg·h ml−1) compared with patients aged <75 years (0.310 μg·h ml−1, 95% CI; 0.268–0.352 μg·h ml−1). Percent decrease in ANC at nadir related to fu·AUC, and was dependent on baseline ANC. Conclusion Regardless of ageing, serum level of AAG determines docetaxel unbound exposure and related dose‐limiting toxicity. Serum AAG level and ANC at baseline appear to be predictive of neutropenia for patients of all ages following the administration of docetaxel.

Primary malignant melanoma of the trachea: A case report.

Primary cancer of the trachea is rare and accounts for only 0.1–0.4% of all newly diagnosed respiratory tract cancers, worldwide. In the present study, a case of primary tracheal malignant melanoma, a particularly rare type of cancer, is reported. A 68-year-old male presented with a cough and bloody sputum. A chest computed tomography scan revealed a 25×20×15-mm tracheal tumor, located immediately above the carina, which reduced the cross-sectional area of the trachea by ~90%. Histopathological analysis of biopsy specimens determined a diagnosis of malignant melanoma. The patient was treated with argon plasma coagulation and chemoradiotherapy, which restored airway patency, however, metastasis was detected in the lungs. The patient refused further treatment and received palliative care. Subsequently, the patient succumbed to the disease within four months. Thus, although primary malignant melanoma of the trachea is extremeley rare, the possibility should be considered during diagnosis.

Differences in the efficacy of S‐1 monotherapy according to histological type in pretreated patients with advanced non‐small cell lung cancer

S‐1 is a novel antimetabolic agent that inhibits thymidylate synthase. The expression of thymidylate synthase is higher in squamous (Sq) non‐small cell lung cancer (NSCLC) than in non‐Sq NSCLC. The aim of this retrospective study was to assess the efficacy of S‐1 monotherapy for advanced NSCLC according to the histological subtype.