Yusuke Okuma

Clinical outcomes with chemotherapy for advanced thymic carcinoma

BACKGROUND The clinical characteristics and prognostic factors of thymic carcinoma have not been investigated in detail because of its rarity. The aim of this study was to elucidate the disease profile, outcomes, and prognostic factors for survival among patients with advanced thymic carcinoma treated with palliative-intent chemotherapy. PATIENTS AND METHODS A retrospective review was conducted of the medical records of 40 patients treated with palliative-intent chemotherapy for advanced thymic carcinoma between 1991 and 2011 in our institution. Clinical demographics, histology, overall survival, and factors expected to predict survival were analyzed. Differences in survival were assessed using Kaplan-Meier analysis and univariate and multivariate Cox proportional hazards regression analyses. RESULTS The study included 22 males (55.0%) and 18 females (45.0%). The median age at diagnosis was 58.5 years. The most common metastatic sites at diagnosis were lung (45.0%), lymph nodes (20.0%), liver (15.0%), bone (15.0%), and brain (5.0%). The most common histological subtypes were squamous cell carcinoma (70.0%), followed by neuroendocrine carcinoma (17.5%), and mucoepidermoid carcinoma (7.5%). The response rate for first-line chemotherapy was 47.5%. The median survival time was 24.5 months (95% confidence interval 20.9-43.5 months). Overall survival rates at 1-, 2-, and 5-years were 72.5%, 52.5%, and 17.5%, respectively. In uni- and multivariate analyses, the only favorable prognostic factor for overall survival was response to first-line chemotherapy (p=0.01). CONCLUSION Response to first-line chemotherapy may be implicated as a potential surrogate for survival in advanced thymic carcinoma.

Cisplatin and irinotecan combination chemotherapy for advanced thymic carcinoma: Evaluation of efficacy and toxicity

BACKGROUND Thymic carcinoma is a rare, malignant mediastinal tumor that is definitively distinguished from thymoma by its wide extensiveness and poor prognosis. At present, cisplatin-based triplet or quartet chemotherapy with the second generation antitumor agents, referred to as Einhorns protocol for germ cell tumors, is used as first-line chemotherapy for advanced thymic carcinoma, though an optimal chemotherapeutic regimen has not yet been established. In this retrospective study, the effectiveness and toxicity of cisplatin and irinotecan combination chemotherapy were evaluated over a nine-year period. PATIENTS AND METHODS Patients with advanced thymic carcinoma who were treated with cisplatin and irinotecan combination chemotherapy between January 1, 2002 and December 31, 2010, were retrospectively identified from our database and medical records. The endpoints in this study were disease control, response rate, progression-free survival (PFS), and overall survival (OS). Significant hematological and non-hematological toxicities were also assessed. RESULTS Among identified nine patients, disease control was achieved in 8 patients (88.9%), and a clinical response was achieved in 5 (55.6%). The median PFS was 7.9 months, and the median OS was 33.8 months. One- and two-year OS were 77.7% and 55.6%, respectively. Grade 3/4 hematological toxicities were observed in 2 patients (22.2%), and Grade 3/4 non-hematological toxicities were seen in 2 patients (22.2%). No febrile neutropenia or toxic death was recorded. CONCLUSION Cisplatin and irinotecan combination chemotherapy appears to be acceptable for advanced thymic carcinoma as first-line chemotherapy with respect to efficacy, toxicity, and usage in the clinical setting.

S-1 is an active anticancer agent for advanced thymic carcinoma

BACKGROUND Thymic carcinoma is a rare intrathoracic malignant tumor, and the prognosis for patients with advanced stage of the disease is poor. However, no definitive chemotherapeutic regimen has been established for advanced thymic carcinoma in front-line settings. The efficacy and benefit of second-line or salvage chemotherapy are also unknown, as few cases or case series have been reported. PATIENTS AND METHODS We evaluated the efficacy and toxicity of S-1 monotherapy with S-1, a novel oral fluoropyrimidine agent, as salvage therapy in four consecutive patients with previously treated advanced thymic carcinoma from January, 2008 to May, 2010. RESULTS Two patients achieved stable disease, and two achieved partial response. Median progression-free survival was 8.1 months. Hematological toxicity was mild, but gastrointestinal toxicity led to discontinuation in two of four patients. CONCLUSIONS We concluded that oral S-1 monotherapy is useful as second-line or later chemotherapy in previously treated patients with advanced thymic carcinoma and is a potential alternative choice for patients who cannot tolerate platinum-containing treatments.

High plasma levels of soluble programmed cell death ligand 1 are prognostic for reduced survival in advanced lung cancer

OBJECTIVES Programmed cell death-ligand 1 (PD-L1) expressed in tumor tissues is a key molecule for immune suppression, given its role in immune checkpoints. The significance and implication of soluble PD-L1 (sPD-L1) in the blood of lung cancer patients remain unknown. PATIENTS AND METHODS Blood samples were prospectively collected from patients with advanced lung cancer, and the plasma sPD-L1 concentrations were measured by enzyme-linked immunosorbent assay. The correlations of the plasma sPD-L1 levels with clinico-pathological status, laboratory data, and survival of the patients were analyzed. RESULTS Ninety-six patients with advanced lung cancer were analyzed, including 73 with adenocarcinoma, 12 with squamous cell carcinoma, and seven with small-cell lung cancer. Sixty-five were naïve to chemotherapy, and 20 had received two or more lines of chemotherapy. The mean plasma sPD-L1 concentration of all the patients was 6.95±2.90ng/ml (range 2.30-20.0ng/ml), and this value is significantly increased compared with that previously reported for normal subjects. No correlation of the plasma sPD-L1 level with histological subtypes, adenocarcinoma genetic status, smoking history, clinical stage or laboratory data was found. However, overall survival was significantly reduced in patients with high (≥7.32ng/ml) compared with low (<7.32ng/ml) plasma sPD-L1 levels (13.0 vs. 20.4 months, p=0.037). Multivariate analysis revealed that high sPD-L1 levels were significantly related to poor prognosis (hazard ratio 1.99, p=0.041). CONCLUSION High plasma sPD-L1 levels were associated with poor prognosis in patients with advanced lung cancer, possibly associated with suppression of anti-tumor immunity. Clinical trial register and their clinical registration number: UMIN%000014760.

Immune-related pancreatitis secondary to nivolumab in a patient with recurrent lung adenocarcinoma: A case report

Immune checkpoint inhibitor is a verified standard of care as a second-line chemotherapy for non-small cell lung cancer. Management of immune-related adverse effects (irAEs) is crucial for ensuring patient safety. However, less frequent irAEs may result in complications. Here, we report a patient with recurrent lung adenocarcinoma who was treated with nivolumab and developed immune-related pancreatitis. A 66-year-old Japanese female with recurrent lung adenocarcinoma and metastatic lymph nodes presented with anorexia, vomiting, and back pain on day 18 of two cycles of nivolumab. Laboratory data demonstrated a grade 3 elevation of serum amylase and lipase levels. Initially, no abnormality could be detected on computed tomography (CT), magnetic resonance cholangiopancreatography (MRCP), or the Gallium scan. The patient was treated with high-dose prednisone, resulting in gradual improvement of symptoms and laboratory data. A follow-up MRCP revealed a swollen pancreas and pancreatic inflammation. Immune-related pancreatitis is a rare type of nivolumab-induced irAE that shows no significant changes on radiologic imaging, except for a swollen pancreas on CT, and can be suppressed using high-dose prednisone.

A Prospective Study of Shortened Vitamin Supplementation Prior to Cisplatin–Pemetrexed Therapy for Non-Small Cell Lung Cancer

BACKGROUND Prior supplementation with folic acid and vitamin B12 is required to reduce pemetrexed therapy toxicity; the recommended lead-in time is at least 7 days. On the basis of previous pharmacokinetic and clinical studies, we hypothesized that the lead-in time could be shortened to 24 hours, enabling earlier commencement of standard chemotherapy; thus, we planned the first prospective trial of this regimen. METHODS Patients with advanced nonsquamous non-small cell lung cancer who had not previously received cytotoxic chemotherapy were enrolled. After measurement of homocysteine concentrations, the patients received 1,000 μg of vitamin B12 by intramuscular injection and began taking 350-500 μg of oral folic acid daily. Starting 24-48 hours after the vitamin B12 injection, the patients received intravenous 500 mg/m(2) pemetrexed and 75 mg/m(2) cisplatin for 4 cycles at 3 weekly intervals. The primary endpoint was the proportion of patients who developed neutropenia grade ≥3. RESULTS Thirty patients received chemotherapy starting within 48 hours of the vitamin B12 injection. No treatment-related deaths or grade 4 toxicity occurred. Neutropenia grade ≥3, other laboratory toxicities grade ≥3, and nonlaboratory toxicities grade ≥3 occurred in 6.7%, 13%, and 13% of patients, respectively. The baseline homocysteine concentrations were not higher in patients with grade ≥3 toxicities than in the remainder of the cohort (mean values, 8.6 and 10.7 μmol/L, respectively). The response rate to chemotherapy was 43%. CONCLUSION The shortened vitamin supplementation was well tolerated and retained antitumor efficacy. Analysis of baseline homocysteine concentrations confirmed the efficacy of short-term vitamin supplementation.

Eligibility for Bevacizumab as an Independent Prognostic Factor for Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer: A Retrospective Cohort Study

Background Bevacizumab requires some unique eligibility criteria, such as absence of hemoptysis and major blood vessel invasion by the tumor. The prognostic impact of these bevacizumab-specific criteria has not been evaluated. Methods Patients with stage IIIB/IV, non-squamous non-small cell lung cancer who started chemotherapy before the approval of bevacizumab were reviewed. Patients with impaired organ function, poor performance status or untreated/symptomatic brain metastasis were excluded before the evaluation of bevacizumab eligibility. We compared overall survival and time to treatment failure among patients who were eligible (Group A) or ineligible (Group B) to receive bevacizumab. Results Among 283 patients with stage IIIB/IV non-squamous non-small cell lung cancer, eligibility for bevacizumab was evaluated in 154 patients. Fifty-seven patients were considered ineligible (Group B) based on one or more of a history of hemoptysis (n = 20), major blood vessel invasion (n = 43) and cardiovascular disease (n = 8). The remaining 97 patients were classified into Group A. Overall survival was significantly better in Group A (median, 14.6 months) than in Group B (median, 7.1 months; p<0.0001). Time to treatment failure was also significantly longer in Group A (median, 6.9 months) than in Group B (median, 3.0 months; p<0.0001). Adjusted hazard ratios of bevacizumab eligibility for overall survival and time to treatment failure were 0.48 and 0.38 (95% confidence intervals, 0.33–0.70 and 0.25–0.58), respectively. Conclusion Eligibility for bevacizumab itself represents a powerful prognostic factor for patients with non-squamous non-small cell lung cancer. The proportion of patients who underwent first-line chemotherapy without disease progression or unacceptable toxicity can also be biased by bevacizumab eligibility. Selection bias can be large in clinical trials of bevacizumab, so findings from such trials should be interpreted with extreme caution.

A prospective, multicentre phase II trial of low-dose erlotinib in non-small cell lung cancer patients with EGFR mutations pretreated with chemotherapy: Thoracic Oncology Research Group 0911

BACKGROUND Low-dose erlotinib may be as effective as gefitinib or erlotinib at full dose in non-small cell lung cancer (NSCLC) patients with activating mutations of the epidermal growth factor receptor (EGFR) gene. METHODS Patients with chemotherapy pretreated NSCLC harbouring EGFR mutations received erlotinib at 50 mg/d until disease progression or unacceptable toxicities. The dose was escalated to 150 mg/d in patients showing no response (i.e. without major tumour shrinkage according to Response Evaluation Criteria in Solid Tumours (RECIST)) to the initial dose during the first 4 weeks. The primary end-point was the objective response rate at the dose of 50 mg/d. RESULTS Thirty-four patients from seven institutes were enrolled. The study was closed early when no response was confirmed in 15 patients, excluding the possibility that the primary end-point would be met. The objective response and disease control rates at the dose of 50 mg/d as determined by an independent review committee were 54.5% and 84.8%, respectively. Four additional patients achieved partial response with increased 150 mg/d dose. Progression-free survival and median survival times during the entire period of the study were 9.5 and 28.5 months, respectively. Treatment-related toxicities were generally mild, the most common being skin disorders and diarrhoea. Only one case experienced grade 3 toxicity, which was transient increase of hepatic enzymes. CONCLUSION The primary end-point was not met; low-dose erlotinib is not recommended for fit patients with NSCLC harbouring EGFR mutations. However, it may merit further evaluation for elderly or frail patients.

Response to cytotoxic chemotherapy in patients previously treated with palliative-intent chemotherapy for advanced thymic carcinoma.

BACKGROUND Clinical efficacy of second- and later-line chemotherapy for patients with thymic carcinoma previously treated with chemotherapy remains uncertain; limited data are available about this carcinoma because of its rarity. The aim of this study was to investigate effective chemotherapy for patients with thymic carcinoma previously treated with chemotherapy using a retrospective analysis of responses and times to event. PATIENTS AND METHODS We conducted a retrospective review of the medical records of 23 advanced thymic carcinoma patients previously treated with palliative-intent chemotherapy between 1980 and 2014 in our institution. Clinical demographic characteristics, agents, response, and time to treatment failure for each treatment line and overall survival were reviewed. Factors expected to be associated with survival rates were analyzed. Differences in survival were assessed using Kaplan-Meier analysis and univariate and multivariate Cox proportional hazards regression analyses. RESULTS The study included 13 men (56.5%) and 10 women (43.5%). The median age at diagnosis was 58.5 years. The most common histological subtypes were squamous cell carcinoma (16 patients [69.6%]), followed by neuroendocrine carcinoma (4 patients [17.4%]). The objective response rates of first-, second-, third-, and fourth-line chemotherapy were 60.9%, 39.1%, 23.1%, and 25.0%, respectively. The median survival time was 18.8 months (95% confidence interval, 7.5-40.9 months). Uni- and multivariate analyses of all assessed variables failed to identify any statistically significant indicators of overall survival. CONCLUSION Patients with thymic carcinoma previously treated with palliative-intent chemotherapy might respond to second- or later-lines of cytotoxic chemotherapy.

Clinicopathological analysis of thymic malignancies with a consistent retrospective database in a single institution: from Tokyo Metropolitan Cancer Center

BackgroundThymic epithelial tumors (TETs), which comprise thymoma and thymic carcinoma, are rare cancers with specific morphological and clinical features. Their clinical characteristics and outcomes have gradually been clarified by assessing large-scale, retrospective data obtained with international cooperation.MethodsThe study is a retrospective review of 187 Japanese patients with TETs who attended our institution from 1976 to 2012. Relevant clinical features of patients with TETs and their tumors, including histology, staging, treatment strategies, and overall survival, were investigated. Differences in survival were assessed by the Kaplan–Meier method and uni- and multi-variate Cox proportional hazards regression analyses.ResultsThe 187 patients included 52 patients with stage I, 37 with stage II, 22 with stage III, and 76 with stage IVa/IVb tumors according to the Masaoka–Koga Staging System. As to histological type, five patients had type A, 33 type AB, 19 type B1, 39 type B2, and 15 type B3 thymomas, whereas 68 patients had thymic carcinoma, including 11 with neuroendocrine carcinomas according to the 2004 WHO classification. Either insufficient data were available to classify the tumors of the remaining eight patients or they had rare types. Immunological abnormalities were present in 26 patients, most of whom had thymomas (21.8% of the thymoma group). Most of the patients who presented with symptoms had myasthenia gravis or extensive thymic carcinoma. Secondary cancers were present in 25 patients (13.3%). The overall 5- and 10-year survival rates for thymoma were 85.4 and 71.5%, respectively, and those for thymic carcinoma were 33.8 and 2.3%, respectively. OS differed significantly between stage IVa thymomas and thymic carcinomas. The stage and whether the tumors were thymomas or thymic carcinomas were significant determinants of survival according to multivariate analysis.ConclusionThe efficacy of treatments for thymoma and thymic carcinoma should be investigated separately because these tumors differ in their clinical features and prognosis.