Nobuhiko Seki

Phase II Trial of Amrubicin for Treatment of Refractory or Relapsed Small-Cell Lung Cancer: Thoracic Oncology Research Group Study 0301

PURPOSE This multicenter, phase II study was conducted to evaluate the activity of amrubicin, a topoisomerase II inhibitor, against refractory or relapsed small-cell lung cancer (SCLC). PATIENTS AND METHODS SCLC patients with measurable disease who had been treated previously with at least one platinum-based chemotherapy regimen and had an Eastern Cooperative Oncology Group performance status of 0 to 2 were eligible. Two groups of patients were selected: patients who experienced first-line treatment failure less than 60 days from treatment discontinuation (refractory group), and patients who responded to first-line treatment and experienced disease progression > or = 60 days after treatment discontinuation (sensitive group). Amrubicin was administered as a 5-minute daily intravenous injection at a dose of 40 mg/m2 for 3 consecutive days, every 3 weeks. RESULTS Between June 2003 and December 2004, 60 patients (16 refractory and 44 sensitive) were enrolled. The median number of treatment cycles was four (range, one to eight). Grade 3 or 4 hematologic toxicities comprised neutropenia (83%), thrombocytopenia (20%), and anemia (33%). Febrile neutropenia was observed in three patients (5%). Nonhematologic toxicities were mild. No treatment-related death was observed. The overall response rates were 50% (95% CI, 25% to 75%) in the refractory group, and 52% (95% CI, 37% to 68%) in the sensitive group. The progression-free survival, overall survival, and 1-year survival in the refractory group and the sensitive group were 2.6 and 4.2 months, 10.3 and 11.6 months, and 40% and 46%, respectively. CONCLUSION Amrubicin exhibits significant activity against SCLC, with predictable and manageable toxicities; this agent deserves to be studied more extensively in additional trials.

Lung Cancer with Localized Ground-Glass Attenuation Represents Early-Stage Adenocarcinoma in Nonsmokers

Background: Studies of lung cancer showing localized ground-glass attenuation (GGA) on thin-section computed tomography (TSCT) have been limited to resected stage IA adenocarcinomas. This study aimed to clarify the features of localized GGA cancer as a distinct clinicoradiological entity through a survey of lung cancers of all types. Methods: From 2000 through 2002, 492 patients with newly diagnosed stage I–IV lung cancer underwent TSCT at a single institution. The tumors were semiquantitatively classified into four groups on the basis of GGA area as a percentage of the whole tumor shadow (GGA ratio) on TSCT images: 100%, 99–50%, 49–1%, and 0%. The relationship between clinicopathological data and the GGA ratio, predictors of the presence of GGA, survival data, and prognostic factors were evaluated retrospectively. Results: All localized GGA cancers were adenocarcinomas (p < 0.05). A GGA component was not found in patients with advanced cancer (p < 0.05). GGA cancer was related to nonsmoking status (Odds ratio 6.17, p < 0.05). A threshold tumor size of 30 mm in GGA cancer (hazard ratio, 2.86; p < 0.01) and the GGA ratio (hazard ratio, 4.17; p < 0.01) were independent prognostic factors. Survival rates were higher in patients with a GGA ratio ≥50% and stage IB lung cancer than in patients with a GGA ratio <50% and stage IA lung cancer. Conclusion: Localized GGA cancer, with presurgical prognostic factors of tumor size and GGA ratio, represents early-stage lung adenocarcinoma in nonsmokers.

Plasmablastic lymphoma of the retroperitoneum in an HIV-negative patient

Herein is reported a case of plasmablastic lymphoma (PBL) of the retroperitoneum in an HIV‐negative patient. This is the first reported case of PBL at this location and of PBL from Japan in the English‐language literature. A 76‐year‐old Japanese man was admitted to hospital with a chief complaint of right inguinal lymph node swelling. Lymph node biopsy indicated large tumor cells with both diffuse and cohesive growth patterns, and conspicuous tumor cell proliferation in lymph node sinuses. The initial pathological diagnosis was metastatic carcinoma. The patient died approximately 1 month after admission, and autopsy showed that the main lesion was a very large retroperitoneal mass. On histology diffusely proliferated plasmablast‐like or immunoblast‐like tumor cells were identified, which were positive on immunohistochemistry for CD138 and negative for B‐cell and epithelial markers. Approximately 90% of the tumor cells were positive for Ki‐67. Tumor cells were diffusely positive for EBV‐encoded small RNA on in situ hybridization. The autopsy findings suggested a diagnosis of PBL. Accordingly, PBL should be considered as a differential diagnosis when lymph node biopsy findings resemble those of the present patient.

Randomized, double-blind, phase III trial of palonosetron versus granisetron in the triplet regimen for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy: TRIPLE study

BACKGROUND There has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC). PATIENTS AND METHODS Patients with a malignant solid tumor who would receive HEC containing 50 mg/m(2) or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2-4) and aprepitant (125 mg on day 1 and 80 mg on days 2-3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0-120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea). RESULTS Between July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0-120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0-24 h) period, while at the delayed (24-120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0-120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369). CONCLUSION The present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point. CLINICAL TRIAL REGISTRY IDENTIFIER UMIN000004863.

Gefitinib‐induced lung injury successfully treated with high‐dose corticosteroids

Abstract:  A 55‐year‐old man was treated with gefitinib for disseminated pleural lesions, 1 year after resection of the left lower lobe for non‐small cell lung cancer. After 6 weeks of continuous daily treatment with oral gefitinib, he developed dyspnoea on exertion and a non‐productive cough. CXR and CT revealed focal areas of ground‐glass opacity (GGO) in the right upper lobe. Despite gefitinib being discontinued, high‐resolution CT revealed extension of GGO and restructuring of lung parenchyma, suggesting acute interstitial pneumonia. Transbronchial biopsy revealed acute‐phase diffuse alveolar damage. After administration of methylprednisolone pulse therapy (1 g/day intravenously) for three consecutive days, the areas of GGO shrank on high‐resolution CT and symptoms resolved. Diffuse alveolar damage caused by gefitinib can be successfully treated in the early phase with high‐dose corticosteroids. Patients receiving gefitinib should be carefully examined for symptoms and undergo CT if their condition deteriorates.

Prognostic significance of expression of eukaryotic initiation factor 4E and 4E binding protein 1 in patients with pathological stage I invasive lung adenocarcinoma

BACKGROUND Both eukaryotic initiation factor 4E (eIF4E) and eIF4E binding protein 1 (4E-BP1) are involved in the malignant progression of human cancers. However, the role of eIF4E and 4E-BP1 expression as prognostic markers has not been evaluated concurrently in any human cancers. METHODS The expression of eIF4E and 4E-BP1 was semiquantitatively examined with immunohistochemical staining in 80 patients with pathological stage I invasive lung adenocarcinoma. RESULTS The 10-year survival rate was significantly lower for patients with high eIF4E expression (64.0% [n=36]) than for patients with low eIF4E expression (89.9% [n=44], P=0.024), and in patients with high eIF4E expression the 10-year survival rate was lower for patients with low 4E-BP1 expression (39.0% [n=12]) than for patients with high 4E-BP1 expression (85.2% [n=24], P=0.036). In patients with low eIF4E expression, the 10-year survival rate was lower for patients with low 4E-BP1 expression (87.6% [n=36]) than for patients with high 4E-BP1 expression (100% [n=8]), but statistical analysis was impossible because all patients with high 4E-BP1 expression were censored. Unfavorable prognostic factors for survival were age greater than 65 years (P=0.015), pathological stage IB disease (P=0.045), high eIF4E expression (P=0.008), and low 4E-BP1 expression (P=0.007). CONCLUSIONS Both eIF4E and 4E-BP1 are potential new prognostic factors for survival and stratification in patients with pathological stage I lung adenocarcinoma. The eIF4E and 4E-BP1 status may provide a basis for individualized therapy.

Phase II Study of Sequential Triplet Chemotherapy, Irinotecan and Cisplatin Followed by Amrubicin, in Patients with Extensive-Stage Small Cell Lung Cancer: West Japan Thoracic Oncology Group Study 0301

Introduction: Combination chemotherapy of irinotecan, a topoisomerase I inhibitor, and cisplatin is a standard treatment in patients with extensive-stage small cell lung cancer (SCLC). Amrubicin, a novel 9-aminoanthracycline, inhibits topoisomerase II. We investigated a sequential triplet chemotherapy consisting of irinotecan and cisplatin followed by amrubicin in patients with extensive-stage SCLC. Methods: Eligible patients were aged 20 to 70 years and had Eastern Cooperative Oncology Group performance status of 0 or 1, measurable lesions, and adequate organ functions. Chemotherapy consisted of irinotecan 60 mg/m2 on days 1 and 8 plus cisplatin 60 mg/m2 on day 1 every 3 weeks for three cycles and then amrubicin 40 mg/m2 alone on days 1 to 3 every 3 weeks for three cycles. Results: From September 2004 to September 2006, 45 patients were enrolled, 43 were evaluable for response and survival, and 44 were evaluable for toxicity. Twenty-eight patients (64%) completed the full planned chemotherapy. One patient achieved complete response and 33 had partial response for an overall response rate of 79%. Median progression-free survival was 6.5 months. Median overall survival was 15.4 months. Major toxicity was myelosuppression. Grade 3 or 4 neutropenia, anemia, thrombocytopenia, and febrile neutropenia occurred in 57%, 7%, 0%, and 7% of patients during irinotecan/cisplatin cycles and in 91%, 27%, 9%, and 15% of patients during amrubicin cycles, respectively. Conclusions: The sequential triplet chemotherapy, irinotecan and cisplatin followed by amrubicin, is an effective and well-tolerated treatment in patients with extensive-stage SCLC. Further investigation of this treatment is warranted.

The need for measures to prevent "solitary deaths" after large earthquakes - based on current conditions following the Great Hanshin-Awaji Earthquake.

Department of Internal Medicine, Division of Respiratory and Infectious Diseases, St Marianna University School of Medicine, Kanagawa 216-8511, Japan Department of Public Health, Fujita Health University School of Medicine, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan Department of Internal Medicine, Division of Medical Oncology, Teikyo University School of Medicine, Tokyo 173-8605, Japan Department of Urology, St Marianna University School of Medicine, Kanagawa 216-8511, Japan Seigakuin Schools, Saitama 362-8585, Japan

Phase I/II trial of gemcitabine plus oral TS-1 in elderly patients with advanced non-small cell lung cancer: Thoracic oncology research group study 0502

A phase I/II trial of TS-1 combined with gemcitabine was designed to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate the efficacy and toxicity in elderly patients with advanced non-small cell lung cancer (NSCLC). Patients older than 70 years of age received TS-1 orally b.i.d. on days 1-14 and gemcitabine intravenously on days 8 and 15 every 4 weeks. In phase I (n=22), each cohort received escalating doses of TS-1 (30-40 mg/m(2) b.i.d.) and gemcitabine (800-1000 mg/m(2)); MTD was 40 mg/m(2) b.i.d. TS-1 and 1000 mg/m(2) gemcitabine; RD was 30 mg/m(2) b.i.d. TS-1 and 1000 mg/m(2) gemcitabine. Dose-limiting toxicities included a grade 3 infection, skin toxicity, and stomatitis. In phase II (n=37), the overall response rate was 27% (90% confidence interval (CI): 15-42%) and the median time to progression and overall survival were 4.2 months (90% CI: 3.2-5.7) and 12.9 months (90% CI: 10.4-14.7), respectively. The most common grade 3 or higher toxicity was neutropenia (45.9%), and thrombocytopenia was observed in 13.5% of patients. Two cases each of grade 3 pneumonitis and skin toxicity were observed, but nonhematological toxicities occurred at generally low frequencies. TS-1 with gemcitabine is a promising doublet regimen in elderly patients with advanced NSCLC with acceptable toxicities.

Long-Term Administration of Second-Line Chemotherapy with S-1 and Gemcitabine for Platinum-Resistant Non-small Cell Lung Cancer: A Phase II Study

Background: Standard second-line chemotherapies for non-small cell lung cancer (NSCLC) have been established but have limited clinical relevance. S-1 is a recently developed agent with potential activity against NSCLC. Methods: Patients with confirmed NSCLC recurrence after previous single- or two-regimen chemotherapy with platinum, performance status of 0 to 1, adequate organ functions, and measurable lesions were treated with S-1 (60 mg/m2/d, twice a day) on days 1 to 14 and gemcitabine (1000 mg/m2) on days 8 and 15, which were repeated every 3 weeks until tumor progression. Results: Treatment was administered for a median of 4 courses (range, 1–13) over a median of 125-day period in 34 patients. The overall response rate was 23.5% (no complete response and eight partial response; 95% confidence interval: 9.1–38.0%). The median progression-free and overall survival times were 6.6 and 19.9 months, respectively. The 1- and 2-year survival rates were 58.8 and 30.9%, respectively. Toxicity was mild during the entire treatment period, except for three grade 3 interstitial pneumonia. Conclusion: The primary end point was met with the relatively high overall response rate. Randomized phase III studies for elucidating survival outcome of the regimen are warranted.