A Phase II Study of S-1 for Previously Untreated Elderly Patients with Advanced Non-Small Cell Lung Cancer.

BACKGROUND: S-1, a novel oral fluoropyrimidine, is active in the treatment of non-small cell lung cancer (NSCLC). However, data on S-1 for elderly patients with NSCLC are insufficient. METHODS: Eligibility criteria were no prior chemotherapy, stage IIIB or IV NSCLC, performance status 0-1, age >70 years, and adequate hematological, hepatic, and renal functions. Patients received S-1 (40 mg/m(2) twice a day) for 28 consecutive days. This schedule was repeated every 6 weeks. The primary end point was the tumor response rate. RESULTS: Thirty-two patients were enrolled and 31 patients were evaluable for response. The patients' median age was 80 years (range: 71-88). The response rate was 22.6% (95% CI: 11-38). Neutropenia, anemia, thrombocytopenia, febrile neutropenia, and diarrhea of grade ≥ 3 occurred in 6, 6, 10, 3, and 3%, respectively. CONCLUSIONS: In elderly patients with previously untreated advanced NSCLC, S-1 appears to be well tolerated and demonstrates encouraging activity.

The definition of healthcare-associated pneumonia (HCAP) is insufficient for the medical environment in Japan: a comparison of HCAP and nursing and healthcare-associated pneumonia (NHCAP).

Healthcare-associated pneumonia (HCAP) is a new concept of pneumonia, which was proposed in the ATS/IDSA guidelines. The guidelines explain that HCAP patients should be treated with broad-spectrum antimicrobial drugs directed at multidrug-resistant pathogens. However, in Japan, there are many elderly people who received in-home care service. These patients seemed to be consistent with the concept of HCAP, but they did not meet the definition of HCAP. Therefore, the Japanese Respiratory Society modified the definition of HCAP according to the medical environmental in Japan. We retrospectively observed HCAP patients and nursing home and healthcare-associated pneumonia (NHCAP) patients who were hospitalized during 24 months at the Japanese Red Cross Nagasaki Genbaku Hospital (Nagasaki, Japan). Patient background, disease severity, identified pathogens, initial antibiotic regimens, and outcomes were compared. A total of 108 patients (77 HCAP and 31 NHCAP except HCAP patients) were evaluated. Of NHCAP except HCAP patients, 27 (87.1 %) were above 3 in the ECOG PS score. There were almost no significant differences between the two groups in characteristics, pneumonia severity, identified bacteria, initial antibiotic regimens, and response rate of initial antibiotic therapy. Although the in-hospital mortality of HCAP patients and NHCAP except HCAP patients was 9.1 % and 19.4 %, respectively, this difference did not reach statistical significance (P > 0.05). Our study suggested that, in the criteria of HCAP, some Japanese patients, who were consistent with the concept of HCAP, were classified as community-acquired pneumonia (CAP). Therefore, there is a need to change the definition of HCAP according to the medical environment in Japan.

Phase I study of vinorelbine and irinotecan in previously untreated patients with advanced non-small cell lung cancer.

INTRODUCTION: Vinorelbine alone and irinotecan alone have been shown to have efficacy against non-small cell lung cancer (NSCLC); each drug has different mechanisms of action. A phase I study using a combination of vinorelbine and irinotecan as first-line treatment for advanced NSCLC was done to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT). METHODS: Previously untreated patients (or=4 days or febrile neutropenia, grade 4 thrombocytopenia, >or=grade 3 non-hematological toxicities, or the need to cancel drug administration on both days 8 and 15. RESULTS: A total of 23 patients were enrolled. DLT was observed in 1 of 6 patients at level 3 (20 mg/m(2) vinorelbine, 50 mg/m(2 )irinotecan), in 2 of 3 at level 4 (25 mg/m(2), 50 mg/m(2)), and in 2 of 5 at modified level 4 (20, 60 mg/m(2)). Level 4 and modified level 4 were considered to be the MTD; dose level 3 was therefore recommended. DLTs included liver dysfunction, pneumonitis, colitis, and arrhythmia. Injection site reactions were mild. Hematological and non-hematological toxicities were mild and easily controlled. CONCLUSION: Use of 20 mg/m(2) vinorelbine on days 1 and 8 followed by 50 mg/m(2 )irinotecan on days 1, 8, and 15 every 4 weeks warrants a phase II study.

Phase I study of irinotecan and gemcitabine in previously untreated patients with advanced non-small cell lung cancer.

BACKGROUND: Irinotecan and gemcitabine are effective against non-small cell lung cancer. We conducted a phase I study of the combined use of irinotecan and gemcitabine in previously untreated patients with advanced non-small cell lung cancer to determine dose-limiting toxicities and maximum tolerated dose. METHODS: Patients were treated with irinotecan followed by gemcitabine on days 1 and 8 every 3 weeks. Gemcitabine dose was fixed at 1000 mg/m2, and irinotecan dose was increased from 60 mg/m2. RESULTS: A total of 16 patients was enrolled. Maximum tolerated dose of irinotecan was determined up to level 3 (irinotecan 100 mg/m2). In Japan, the maximum approved weekly dose of irinotecan is 100 mg/m2, so this was the dose that was used. Only very mild hematological and non-hematological toxicities were noted. CONCLUSION: Use of 100 mg/m2 irinotecan followed by 1000 mg/m2 gemcitabine on days 1 and 8 every 3 weeks warrants a phase II study.

A phase I trial of carboplatin and etoposide for elderly (>or=75 year-old) patients with small-cell lung cancer.

PURPOSE: The combination of carboplatin and etoposide is currently considered the most appropriate regimen for treating elderly patients with small-cell lung cancer (SCLC). Previous reports on elderly patients, 70 years or older, found that the recommended dose was close to that of younger patients. Then, we conducted a phase I study of carboplatin and etoposide in elderly patients, 75 years or older, with SCLC. This study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). METHODS: Twenty-six patients fulfilling the eligibility criteria, chemotherapy-naive, performance status (PS) of 0-2, age>or=75, and adequate organ functions were enrolled. Patients' characteristics were: male/female=21/5; PS 0/1/2=9/11/6; median age (range)=78 (75-82); and limited/extensive stage=16/10. The patients intravenously received carboplatin with a target AUC of 4 or 5 mg min/ml (Chatelut formula) on day 1 and etoposide at 80-120 mg/m2 on days 1, 2 and 3. Therapy was repeated four times in every 4 weeks. RESULTS: The MTD of carboplatin/etoposide was AUC=5/80, 4/110, and 4/120. The DLTs were thrombocytopenia, neutropenia, leukopenia, and febrile neutropenia. Overall, grade 4 thrombocytopenia, neutropenia (>or=4 days), leukopenia (>or=4 days), and febrile neutropenia occurred in 27, 20, 7, and 13% of cases at MTD levels, respectively, and 0% at other levels. Twenty of 26 patients showed objective responses (2CR, 18PR; RR=77%). CONCLUSION: A dose of carboplatin of AUC=4 and etoposide of 100 mg/m2 was recommended in this regimen.

[A case of Heerfordt's syndrome with an elevated serum TNF alpha].

A 27-year old man who had developed uveitis, swelling of the right parotid gland, right facial nerve paralysis and fever, was admitted to our hospital. A chest X-ray film showed bilateral hilar lymphadenopathy. Serum levels of angiotensin-converting enzyme and lysozyme were elevated. Histological findings of transbronchial lung biopsy specimens showed non-caseous epithelioid cell granulomas. Therefore, sarcoidosis was diagnosed. This case also fulfilled the criteria for Heerfordt's syndrome. Adiministration of prednisolone (PSL) initially improved the patient's symptoms, but rapid tapering of PSL worsened his symptoms. Thus, administration of high-dose PSL for a long time was required. He also showed elevated levels of TNF alpha in serum.

[A case of multiple pulmonary arteriovenous fistulae associated with hereditary hemorrhagic telangiectasia that deteriorated during pregnancy].

A 29-year-old woman was admitted to our hospital because of persistent breathlessness on exertion after the delivery of her second child. Although at the age of 26 she had been given a diagnosis of multiple pulmonary arteriovenous fistula (PAVF), treatment was not done because of the absence of symptoms. An intrauterine growth retardation (IUGR) due to hypoxemia occurred during the second pregnancy, and then she delivered a 1,283g baby by cesarean section in the 36th gestation week. Her symptoms and hypoxemia improved after transcatheter embolization. Hereditary hemorrhagic telangiectasia was diagnosed on the basis of recurrent epistaxis since her childhood, pulmonary and hepatic vascular abnormality (PAVF and hepatic arterioportal shunt) and telangiectasis of the buccal mucosa and tongue. We should consider an early treatment of PAVF for young female because pregnancy may induce increase of arteriovenous shunt, fatal hemoptysis, infertility, miscarriage and IUGR.

[Clinical studies of sixteen cases with pulmonary cryptococcosis mainly with respect to serum level of cryptococcal antigen].

Clinical studies of sixteen cases with pulmonary cryptococcosis, during the past six years between 1998 and 2004, were peformed mainly with respect to serum cryptococcal antigen titer. Serum cryptococcal antigen was positive in twelve of 16 cases, the other three cases were diagnosed by VATS, the other one by positive culture of cryptococcus in BALF. In these twelve cases, the serum cryptococcal antigen titer was continuously tested after treatment. The serum cryptococcal antigen titer decreased from half to 6 months after treatment. And the cryptococcal Ag changed to negative in six of the 12 cases by antifungal agents from 5 to 19 months. But four cases whose pneumonia was severe tended to have a high titer level of cryptococcal antigen and were positive for a long period. In the Chest CT of four pulmonary cryptococcosis case with negative cryptococcal antigen, all of the maximum nodule size was less than or equal to 15mm in diameter.

Phase II study of irinotecan combined with carboplatin in previously untreated non-small-cell lung cancer.

PURPOSE: Irinotecan, a topoisomerase I inhibitor, is an effective agent for non-small-cell lung cancer (NSCLC). To determine the efficacy and toxicity of irinotecan and carboplatin, we conducted a phase II study in 61 patients with advanced NSCLC. METHODS: Every 4 weeks, the patients received irinotecan 50 mg/m2 (days 1, 8 and 15) and carboplatin (day 1) with a target AUC of 5 mg min/ml using the Chatelut formula. RESULTS: All patients were evaluable for toxicity, and of 59 patients evaluable for response, 20 achieved a partial response and 26 showed no change. The overall response rate was 34% (95% confidence interval 23-48%). Grade 3 or 4 anemia, leukopenia, neutropenia, thrombocytopenia and diarrhea occurred in 32%, 32%, 60%, 25%, and 7%, respectively. The median survival time and 1-year, and 2-year survival rates were 10.0 months, 37.6%, and 15.2%, respectively. CONCLUSIONS: Irinotecan with carboplatin is effective for advanced NSCLC and safe.

Phase II study of irinotecan and cisplatin with concurrent split-course radiotherapy in limited-disease small cell lung cancer.

BACKGROUND: Irinotecan and cisplatin are one of active regimens for patients with extensive-stage small cell lung cancer (SCLC). To determine the efficacy and toxicity of irinotecan and cisplatin with concurrent split-course thoracic radiotherapy in limited-disease (LD) SCLC, we conducted a phase II study. PATIENTS AND METHODS: Thirty-four patients fulfilling the following eligibility criteria were enrolled: chemotherapy-naïve, good performance status (PS 0-1), age ≤75, LD-SCLC, and adequate organ function. The patients received irinotecan 40 mg/m(2) i.v. on days 1, 8, and 15, and cisplatin 60 mg/m(2) i.v. on day 1. Four cycles of chemotherapy were repeated every 4 weeks. Split-course thoracic radiotherapy of once-daily 2 Gy/day commenced on day 2 of each chemotherapy cycle, with 26 and 24 Gy administered in the first and second cycles, respectively. RESULTS: Thirty-four patients were eligible and assessable for response, toxicity, and survival. Patients' characteristics were as follows: male/female = 29/5; PS 0/1 = 18/16; median age (range) = 67 (50-73); and stage IB/IIA/IIB/IIIA/IIIB = 2/2/3/16/11. The overall response was 100 % (CR 8, PR 26). Grade 4 leukopenia, neutropenia, grade 3-5 pneumonitis, diarrhea, and esophagitis occurred in 24, 38, 6, 3, and 0 %, respectively. There were 2 treatment-related deaths from pneumonitis. The median time to tumor progression was 14.3 months. The median overall survival time and the 2- and 5-year survival rates were 44.5 months, 66.7 and 46.1 %, respectively. No tumor progression was observed in patients with CR. CONCLUSION: Irinotecan plus cisplatin with concurrent split-course thoracic radiotherapy was effective and tolerable in untreated LD-SCLC.

Phase I and II trials of vinorelbine with carboplatin for patients 75 years of age or older with previously untreated non-small-cell lung cancer.

BACKGROUND: The safety and efficacy of platinum-based combination chemotherapy for elderly patients with advanced non-small-cell lung cancer (NSCLC) remains unclear. We conducted phase I and phase II trials of a combination of vinorelbine and carboplatin for patients ≥75 years of age and with advanced NSCLC. PATIENTS AND METHODS: Previously untreated patients (≥75 years of age) with stage IIIB or IV NSCLC were enrolled. Based on a 4-week cycle, vinorelbine was given on days 1 and 8, and carboplatin was given on day 1. Dose-limiting toxicity was defined as grade 4 hematologic toxicity that lasted 4 days or more, febrile neutropenia; grade 3 or worse nonhematologic toxicities; or the omission of vinorelbine administration on day 8 in the first cycle. RESULTS: Thirteen patients were enrolled in phase I. dose-limiting toxicity was grade 4 neutropenia that lasted 4 days or more, observed in 2 of 4 patients at level 4. Phase II study used the dose of level 3 (20 mg/m(2) vinorelbine, area under the curve of 4 mg/mL/min carboplatin). Forty-two patients were enrolled. The response rate was 14.6% of 41 assessable patients (95% CI, 3.8-25.4). The median time to progression was 98 days (95% CI, 61-135 days), and the median survival time was 366 days (95% CI, 321-411 days). All toxicities were mild and manageable. CONCLUSION: Use of 20 mg/m(2) vinorelbine on days 1 and 8, followed by carboplatin area under the curve of 4 mg/mL/min on day 1 every 4 weeks warrants a phase III study for elderly patients with advanced NSCLC.

Randomized phase II trial of irinotecan with paclitaxel or gemcitabine for non-small cell lung cancer: association of UGT1A1*6 and UGT1A1*27 with severe neutropenia.

HYPOTHESIS: Irinotecan-containing regimens are known to be active and tolerable in patients with non-small cell lung cancer (NSCLC). A randomized phase II trial was conducted to evaluate the efficacy of irinotecan plus paclitaxel or gemcitabine for previously untreated stage IIIB or stage IV NSCLC. PATIENTS AND METHODS: Previously untreated patients with adequate organ function who gave written informed consent were randomly assigned to receive irinotecan (50 mg/m on days 1, 8, and 15) plus paclitaxel (180 mg/m on day 1) every 4 weeks (IP group) or irinotecan (100 mg/m on days 1 and 8) plus gemcitabine (1000 mg/m on days 1 and 8) every 3 weeks (IG group). The primary endpoint was the response rate. We also evaluated the relationship of response and toxicity to polymorphisms of the uridine diphosphate glucuronosyltransferase (UGT) gene. RESULTS: Eighty patients were enrolled, and 78 patients were eligible (38 in the IP group and 40 in the IG group). The response rate was 31.6% (95% confidence interval: 17.5-48.7%) in the IP group and 20.0% (9.1-35.6%) in the IG group. The median progression-free survival time was 86 days and 145 days, respectively. Both regimens were well tolerated. The most common severe adverse event was grade 4 neutropenia (36.8% and 10.0%, respectively), which was associated with UGT1A1*6 and UGT1A1*27. UGT polymorphisms did not correlate with response. CONCLUSIONS: Irinotecan plus paclitaxel may be more active against NSCLC than irinotecan plus gemcitabine. The UGT1A1*6 and UGT1A1*27 genotypes might be useful predictors of grade 4 neutropenia in patients who receive irinotecan-based chemotherapy.

Serum levels of surfactant protein D predict the anti-tumor activity of gefitinib in patients with advanced non-small cell lung cancer.

PURPOSE: Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that has dramatic effects in selective patients with non-small cell lung cancer (NSCLC). A simple non-invasive method for predicting the efficacy of gefitinib is preferable in clinical settings. In this study, we evaluated prospectively whether surfactant protein-A (SP-A) and -D (SP-D) may be new conventional predictors of the efficacy of gefitinib treatment. METHODS: We measured serum SP-A and SP-D levels on days 0 and 29 in 40 patients with advanced NSCLC treated with 250 mg gefitinib daily. Eligibility criteria included performance status ≤3, age ≤80 years, and stage IIIB-IV disease. In addition, EGFR mutations were analyzed in 24 patients. RESULTS: Multivariate analysis showed that favorable progression-free survival (PFS) after gefitinib treatment was associated with adenocarcinoma and high serum SP-D levels before treatment. EGFR mutation analysis of 24 patients showed that 16 patients had exon 19 deletion and/or exon 21 point mutations. EGFR mutations were significantly correlated with response to gefitinib and serum SP-D levels before treatment was significantly high in patients with the EGFR mutations. Serum SP-A levels were not associated with PFS. CONCLUSIONS: The present study showed that measurement of serum SP-D levels before treatment in patients with NSCLC may be a new surrogate marker for predicting the response to gefitinib.

Pharmacokinetics of gefitinib predicts antitumor activity for advanced non-small cell lung cancer.

INTRODUCTION: We assessed the relationship between the plasma concentration of gefitinib and its efficacy in Japanese patients with advanced non-small cell lung cancer (NSCLC). METHODS: Plasma trough levels of gefitinib were measured on days 3 (D3) and 8 (D8) by high-performance liquid chromatography in 44 patients with advanced NSCLC treated with 250 mg gefitinib daily. Eligibility criteria included performance status < or =3, age < or = 80 years, and stages IIIB-IV cancer. Epidermal growth factor receptor mutations in 23 patients were analyzed retrospectively. RESULTS: The median plasma gefitinib values were 662 ng/ml on D3 and 1064 ng/ml on D8, and the D8/D3 ratio was 1.587. The median progression-free survival (PFS) was 71 days, and the median overall survival was 224 days. Adenocarcinoma, never smoking, and high D8/D3 ratio were associated with better PFS. Multivariate analysis showed that PFS was associated with never smoking and high D8/D3 ratio. Never-smokers with a high D8/D3 ratio showed the best PFS. Overall survival was not associated with the D8/D3 ratio. Epidermal growth factor receptor mutation analysis of 23 patients showed that 15 patients had exon 19 deletion and/or exon 21 point mutation. Median PFS was similar between mutation-positive and mutation-negative individuals in the high D8/D3 group, whereas mutation-negative individuals in the low D8/D3 group showed the worst median PFS. CONCLUSIONS: A high D8/D3 ratio was independently associated with better PFS in patients with NSCLC treated with gefitinib. Our findings suggest that the pharmacokinetics of gefitinib may be involved in its antitumor activity.

A phase I study of amrubicin and carboplatin for previously untreated patients with extensive-disease small cell lung cancer.

BACKGROUND: Amrubicin and cisplatin are active in the treatment of small cell lung cancer (SCLC), and carboplatin is an analogue of cisplatin with less nonhematological toxicity. The appropriate dose of amrubicin and carboplatin combination chemotherapy for previously untreated patients with extensive-disease (ED) SCLC has not been established. PURPOSE: To determine the maximum-tolerated dose and dose-limiting toxicity (DLT) of amrubicin and carboplatin in ED-SCLC. PATIENTS AND METHODS: Eligibility criteria were chemotherapy-naive ED-SCLC patients, performance status 0-1, age < or =75, and adequate hematological, hepatic, and renal function. Patients received escalating amrubicin doses under a fixed target area under the curve (AUC) 5 of carboplatin (Chatelut formula). Amrubicin and carboplatin were administered by intravenous (IV) infusion on days 1, 2, and 3, and day 1, respectively. The initial dose of amrubicin was 30 mg/m(2), and the dose was escalated to 35 and 40 mg/m(2). RESULTS: Sixteen patients were enrolled and 15 eligible patients were evaluated. One of six patients in level 1, one of six in level 2, and three of three in level 3 experienced DLTs. The presentation of DLTs included neutropenia, leukopenia, thrombocytopenia, febrile neutropenia, and liver dysfunction. Evaluation of responses were two complete response, nine partial response, three stable disease, and one progressive disease (response rate 73%), and the median survival time was 13.6 months. The maximum-tolerated doses of amrubicin and carboplatin were determined as 40 mg/m(2) and AUC 5. A dose of 35 mg/m(2) amrubicin and carboplatin AUC 5 was recommended in this regimen. CONCLUSIONS: This regimen is associated with an acceptable tolerability profile, and warrants evaluation in the phase II setting.

Irinotecan and cisplatin with concurrent split-course radiotherapy in locally advanced nonsmall-cell lung cancer: a multiinstitutional phase 2 study.

BACKGROUND: The purpose was to determine the efficacy and toxicity of irinotecan and cisplatin with concurrent split-course thoracic radiotherapy (TRT) in locally advanced nonsmall-cell lung cancer. METHODS: Fifty patients fulfilling the following eligibility criteria were enrolled: chemotherapy-naive, good performance status (PS, 0-2), age <75, stage III, and adequate organ function. The patients received irinotecan 60 mg/m(2) intravenously on Days 1, 8, and 15, and cisplatin 80 mg/m(2) intravenously on Day 1 in the first group. The doses were reduced to 50 and 60 mg/m(2), respectively, in the second group. Two cycles of chemotherapy were repeated every 4 weeks. Split-course thoracic radiotherapy of 2 Gy/day commenced on Day 2 of each chemotherapy cycle, with 28 and 32 Gy administered in the first and second cycles, respectively. RESULTS: Fifty patients were eligible and 48 (16 in the first, 32 in the second group) patients were assessable for response, toxicity, and survival. The overall response was 83% (95% confidence interval [CI], 70%-93%). Grade 4 leukopenia, neutropenia, grade 3 or 4 diarrhea, pneumonitis, esophagitis, and fatigue occurred in 21%, 48%, 19%, 10%, and 19%, respectively. The median time to progression was 8.2 months. The median overall survival time and the 2- and 5-year survival rates were 20.1 months, 47.1%, and 17.1%, respectively. In subgroup analysis, grade 4 neutropenia, grade 3 or 4 diarrhea, the overall response, and the median survival times of the first/second groups were 63%/41%, 19%/19%, 75%/88%, and 13.1/33.4 months, respectively. CONCLUSIONS: This combined modality of irinotecan and cisplatin with concurrent TRT is active and further investigations are warranted at the second group dose level.