Prospective analysis of the association between skeletal-related events and quality of life in patients with advanced lung cancer (CSP-HOR13).

A prospective study has previously reported on the incidence of bone metastasis (BM) and skeletal-related events (SREs) in patients with advanced lung cancer. The aim of the present study was to prospectively investigate how the quality of life (QOL) of patients with advanced lung cancer was affected by SREs. Patients with stage IIIB or IV non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) at any stage were followed up every four weeks to determine if they had developed SREs. QOL questionnaires were conducted at enrollment, at 3- and 12-months later and at 1 month after the onset of SREs, using QOL scores including the EuroQOL-5 Dimension (EQ-5D), Functional Assessment of Cancer Therapy-General (FACT-G) and activities of daily living (ADL) scores obtained by the Barthel Index. A total of 274 patients were enrolled in the study. At enrollment the EQ-5D and Barthel Index scores were lower in patients with SREs compared with patients without SREs. A chronological analysis revealed no statistically significant changes in either QOL or ADL in any of the patients. For 14 patients in whom QOL data was collected following the onset of SREs, the evaluation undertaken on the four subscales of the FACT-G revealed a significant decline in emotional functioning following the onset of SREs.

Prospective study on the incidence of bone metastasis (BM) and skeletal-related events (SREs) in patients (pts) with stage IIIB and IV lung cancer-CSP-HOR 13.

BACKGROUND: Bone metastasis (BM) is a frequent complication in patients with advanced lung cancer and it causes skeletal-related events (SREs). Our study aim is to prospectively investigate the incidence of BM, incidence and types of SRE, and predictive factors of BM and SREs. METHODS: Newly diagnosed, advanced non-small-cell lung cancer (NSCLC) or small-cell lung cancer (SCLC) patients were enrolled into the study. Patients were followed up every 4 weeks to monitor the development of SREs. Treatment for lung cancer was performed at the discretion of the investigator. RESULTS: Two hundred seventy-four patients were enrolled in this study between April 2007 and December 2009 from 12 institutions. Patients included 77 cases of SCLC and 197 of NSCLC (stage IIIB/IV = 73/124). Median follow-up time was 13.8 months. The incidence of BM at initial diagnosis was 48% in stage IV NSCLC and 40% in extensive stage (ED)-SCLC. Forty-five percent of patients who developed BM had SREs consisting of pathologic fracture (4.7%), radiation to bone (15.3%), spinal cord compression (1.1%), and hypercalcemia (2.2%). Multivariate analysis revealed that factors predicting BM are stage IV, performance status 1 or greater and higher bone alkaline phosphatase in NSCLC patients, higher lactate dehydrogenase, and lower parathyroid hormone-related peptide in SCLC patients. Factors predicting SREs were stage IV, age 64 or younger, and lower albumin in NSCLC patients. Multivariate analysis of SRE was not performed for SCLC because of the small number of events. CONCLUSION: Predictive factors should be taken into consideration in future randomized studies evaluating BM and SREs.

A randomized, double-blind, placebo-controlled study of fentanyl buccal tablets for breakthrough pain: efficacy and safety in Japanese cancer patients.

CONTEXT: Rapid-onset opioids for treating breakthrough pain (BTP) in patients with cancer are needed in the Japanese care setting. OBJECTIVES: To examine the efficacy and safety of fentanyl buccal tablets (FBTs) for treating BTP in Japanese cancer patients. METHODS: This was a randomized, double-blinded, placebo-controlled study. In subjects receiving around-the-clock (ATC) opioids at doses of 30 mg or more to less than 60 mg or 60-1000 mg of oral morphine equivalents (low and high ATC groups), dose titration was started from 50 to 100 µg FBT, respectively. Subjects whose effective dose was identified were randomly allocated to a prearranged administration order of nine tablets (six FBTs and three placebos), one tablet each for nine episodes of BTP (double blinded). Efficacy and safety of FBT were assessed for patients overall, and also for the low and high ATC groups. RESULTS: A significant difference was observed between FBT and placebo for the primary endpoint of pain intensity difference at 30 minutes. The analgesic onset of FBT was observed from 15 minutes in several secondary variables (e.g., pain relief). Adverse events were somnolence and other events associated with opioids were mostly mild or moderate. Of the low and high ATC group subjects, an effective FBT dose was identified in 72.2% and 73.1%, respectively. CONCLUSION: The safety of FBT and its analgesic effect on BTP were confirmed in Japanese cancer patients receiving opioids. Our findings suggest that analgesic onset may occur from 15 minutes after FBT, and that FBT can be administered to patients with low doses of ATC opioids.

A phase II study of cisplatin and irinotecan as induction chemotherapy followed by accelerated hyperfractionated thoracic radiotherapy with daily low-dose carboplatin in unresectable stage III non-small cell lung cancer: JCOG 9510.

OBJECTIVE: It is important to find optimal regimens of cisplatin (CDDP)-based third-generation chemotherapy and radiotherapy for patients with unresectable Stage III non-small cell lung cancer (NSCLC). METHODS: This Phase II study was designed to determine the toxicity and efficacy of two courses of chemotherapy (CDDP 80 mg/m(2) on day 1 and irinotecan 60 mg/m(2) on days 1 and 8) followed by accelerated hyperfractionated thoracic radiotherapy (60 Gy/40 fractions in 4 weeks) combined with daily carboplatin (CBDCA) administration. CBDCA was administered at a target area under the plasma level-time curve of 0.4 x (24 h creatinine clearance + 25), according to Calvert's formula. RESULTS: Twenty-six patients were enrolled in the study. The patients' median age was 63 years (range 40-74 years) and included 22 males and 4 females. Seven patients were Stage IIIA and 19 were Stage IIIB. Twenty had a performance status (PS) of 1 versus six with a PS of 0. There was one treatment-related death due to sepsis and pneumonia associated with Grade 4 neutropenia and diarrhea during chemotherapy. Grade 3 or 4 neutropenia and diarrhea were observed in 14 and 5 patients, respectively. Toxicity of the radiotherapy was mild. There were 0 complete response and 13 partial responses, giving a response rate of 50.0%. Median survival time and 2-year survival were 16.4 months and 21.5%, respectively. This study was designed with Simon's two-stage design, and the response rate did not meet the criteria to proceed to the second stage and the study was terminated early. CONCLUSIONS: This regimen might be inactive for patients with unresectable Stage III NSCLC.

Dose-escalating and pharmacokinetic study of a weekly combination of paclitaxel and carboplatin for inoperable non-small cell lung cancer: JCOG 9910-DI.

OBJECTIVE: Combined paclitaxel and carboplatin is a standard regimen for inoperable non-small cell lung cancer (NSCLC). Although an every-3-week schedule is common, weekly paclitaxel is clinically effective for various cancers. A Phase I clinical trial was conducted to determine maximum-tolerated doses (MTDs) for weekly combined paclitaxel and carboplatin, and to evaluate anti-tumor response, toxicity and pharmacokinetics of paclitaxel in patients with inoperable NSCLC. METHODS: Twenty patients with inoperable NSCLC received weekly carboplatin at area under the curve (AUC) = 2 mg/ml min and paclitaxel. Paclitaxel was escalated if MTD was not reached. Three patients each were entered at levels 1 and 2 (level 1, paclitaxel 50 mg/m(2) and carboplatin AUC = 2 mg/ml min; level 2, 60/2), six at level 3 (70/2), five at level 4 (80/2) and three at level 5 (90/2). RESULTS: One patient had grade 4 (G4) neutropenia at level 2, one had G3 hepatic toxicity at level 3 and one had G3 cardiac toxicity at level 4. MTD was not reached for all dose levels. Response rate (RR) was 35% (7/20) and median survival was 11.1 months. Severe neutropenia (G3 and G4) was seen in seven patients associated with greater AUC, peak concentration (C(max)) and the duration of plasma concentration >50 ng/ml of paclitaxel. CONCLUSIONS: Weekly combined paclitaxel (up to 90 mg/m(2)) and carboplatin (AUC = 2 mg/ml min) was well tolerated. A higher dose intensity of paclitaxel can be given, and RR and survival are not less than the every-3-week protocol. The weekly regimen is an alternative for untreated inoperable NSCLC patients.

[Case of bilateral chylothorax with systemic lupus erythematosus complicated by steroid-/immunosuppressant-resistant pleural effusion].

A 20-year-old woman, with systemic lupus erythmatosus complicated by steroid-and immunosuppressant-resistant bilateral pleural effusion, was admitted to the emergency room because of dyspnea and fever. Chest Xray film revealed bilateral massive pleural effusion. Bilateral thoracocentesis yielded fluid with chyle. Conservative treatment including intravenous hyper-alimentation and continuous drainage were performed but with no remarkable improvement. She underwent thoracoscopy-aided ligation of the thoracic duct. After the operation, bilateral pleurodesis was performed by intrathoracic injection of OK-432, because of uncontrolled pleural effusion. There have been no signs of recurrence at 10 months in this case of SLE with steroid-and immunosuppressant-resistant pleural effusion.

[A case of legionella pneumonia associated with acute respiratory distress syndrome (ARDS) and acute renal failure treated with methylprednisolone and sivelestat].

A 48-year-old man with diabetes mellitus and alcholic chronic pancreatitis was admitted to our hospital with fever and dyspnea. Chest x-ray film showed infiltration of the right upper lung field and blood exam demonstrated marked increase in CPK and renal dysfunction. Intravenous ceftriaxone sodium was started, but the next day, we started intravenous ciprofloxacin because the urine sample was positive for the Legionella antigen. Hemodialysis was started for acute renal failure due to rhabdomyolysis, and mechanical ventilation was introduced due to worsening of acute respiratory failure. Despite these treatments, bilateral infiltration on chest x-ray worsened, resulting in acute respiratory distress syndrome (ARDS). After administration of intravenous pulse methylpredonisolone and sivelestat (neutrophil elastase inhibitor), the patient was successfully weaned from mechanical ventilation. He was also removed from hemodialysis, and discharged from hospital with a good performance status 28 days later. The outcome in this case suggested that treatment with pulse steroid and sivelestat sodium in addition to antibiotics may be effective for Legionella pneumonia complicated by ARDS and acute renal failure.

[Perforation of the small intestine caused by metastasis from primary lung cancer: report of two cases and the discussion of 48 cases published in the Japanese literature].

Case 1 was a 62-year-old man who had performance status (PS) of 1 and stage IIIB adenocarcinoma of the lung. Because he showed progressive disease after induction chemoradiotherapy, he started to receive best supportive care alone. Three months after initial diagnosis, he complained of abdominal pain. As a result of computed tomography of the abdomen. He was diagnosed with abdominal pain probably caused by ileal perforation. An operation was undertaken and the surgical findings showed perforation by small intestine metastasis from lung adenocarcinoma. After the operation, he survived more than ten months. Case 2 was a 54-year-old man who had a PS of 3 and stage IV large cell carcinoma. After chemotherapy and sequential cranial radiotherapy, he developed anemia of unknown cause. He also complained of an abdominal pain during hospitalization and digestive tract perforation was diagnosed by a CT scan of the abdomen. He underwent surgery and the surgical findings showed a metastasis of large cell carcinoma in the small intestine. He died in a hospice two months after the operation. In the Japanese literature from 1983 to 2006. 48 operated cases with perforation caused by small intestine metastasis of lung cancer have been reported in full-length papers. Although the postoperative median survival time was 48 days, only one surgery-related death occurred. Patients who had a history of prior cancer treatment before surgery tended to achieve more prolonged survival compared to those who had not cancer treatment, probably due to poor PS. The preoperative PS may be one important prognostic factor in these patients.

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.

[Autopsy case of sarcomatoid malignant pleural mesothelioma].

A 61-year-old man with a sensation of chest compression was admitted to our hospital. He had hemothorax. After drainage with a chest tube, chest CT scan revealed multiple bilateral pulmonary nodules with slight pleural thickening. Open pleural biopsy was performed and the biopsy specimens showed tumor cells with sarcomatoid proliferation, but no definite epithelial pattern. Initial immunohistochemical staining was negative for keratin and carletinin, but positive for desmin, suggesting rhabdomyosarcoma. After supportive care, he died due to progression of the disease. Autopsy revealed extensive invasion suggesting mesothelioma, so the immunohistochemical staining was repeated. Because it revealed patchy staining for keratin and carletinin, this case was diagnosed as sarcomatoid mesothelioma. Differential diagnosis of sarcomatoid mesothelioma or rhabdomyosarcoma is made by immunohistochemical staining, but it is sometimes difficult. For the selection of the best treatment strategy for mesothelioma especially in the early stage, we should be aware of this difficulty.

Transbronchial needle aspiration cytology of subcarinal lymph nodes for the staging procedure in the diagnosis of lung cancer.

OBJECTIVE AND BACKGROUND: The aim of this study was to improve the staging of lung cancer with or without lymphadenopathy on chest CT by using transbronchial aspiration cytology (TBAC). METHODS: TBAC of the subcarinal lymph nodes was performed on 153 consecutive patients with lung cancer, with or without subcarinal lymphadenopathy on chest CT. RESULTS: Thirty-four patients had enlargement of the subcarinal lymph nodes (>1 cm). Eighteen of these had TBAC confirmation of metastases. Another seven patients with no mediastinal involvement on CT were positive for metastases on TBAC. TBAC was the only way to confirm lung cancer in two patients. Therefore, routinely performed subcarinal TBAC contributed to an improved non-operative staging of the patients and diagnosis in 16% (25/153) of the patients with lung cancer. Forty-nine patients with NSCLC had surgical resection of the tumour. Surgical procedure revealed metastases to the subcarinal lymph nodes in three patients in whom the preoperative TBAC diagnosis was normal. No significant complications due to TBAC occurred in any of the patients. CONCLUSION: TBAC of the subcarinal lymph nodes is a minimally invasive technique for staging of lung cancer and can provide useful information for the diagnosis of metastases to the subcarinal lymph nodes.

A combination chemotherapy of carboplatin and irinotecan with granulocyte colony-stimulating factor (G-CSF) support in elderly patients with small cell lung cancer.

BACKGROUND: We have previously reported that carboplatin plus etoposide is an effective and relatively non-toxic regimen in elderly patients with small cell lung cancer (SCLC). Recently, the Japan Clinical Oncology Group reported that irinotecan plus cisplatin was more effective than etoposide plus cisplatin in the treatment of non-elderly patients with extensive disease (ED)-SCLC. Therefore, we conducted a prospective feasibility study designed specifically to evaluate the efficacy of carboplatin (day 1) and irinotecan (days 1, 8, 15) with granulocyte colony-stimulating factor (G-CSF) support in elderly SCLC patients. METHODS: Three carboplatin AUC and irinotecan dose levels were used: 4 mg/ml x min and 50 mg/m2, respectively (level 1); 5 mg/ml x min and 50 mg/m2, respectively (level 2), and 5 mg/ml x min and 60 mg/m2, respectively (level 3). Although a phase I trial using this drug combination against non-SCLC performed at our institution found that the recommended dose was level 3, as the current trial included only elderly patients, the starting dose used was level 2. However, if a patient had history of prior chemotherapy, performance status (PS) of 2, or was aged 75 years or more, the dose administered was reduced by 1 level. If a patient had a PS of 0, the dose was increased by 1 level. Cycles were repeated every 4 weeks, and patients aged 70 years or more with a PS of 0-2 were eligible. RESULTS: Eighteen patients were enrolled, of which nine were given the level 1 dose, seven the level 2 dose, and two the level 3 dose. The patient group had a median age of 75 years, 8 patients had limited disease (LD) versus 10 with ED, 9 had received previous treatment for SCLC versus 9 previously untreated, and 13 had a PS of 0-1 versus 5 with a PS of 2. Seventeen (94%) patients received two or more cycles of chemotherapy, and the median actual delivery of irinotecan was 84% of the projected dose. Grade 3/4 neutropenia, anemia, and diarrhea occurred in 50%, 33% and 6% of patients, respectively. Other toxicities were mild and no treatment-related deaths occurred. The response rate was 89%, with two complete responses and 14 partial responses. The median survival time was 13.3 months and the 1-year survival rate was 62%. CONCLUSIONS: The combination of carboplatin and irinotecan with G-CSF support was an effective and non-toxic regimen in elderly SCLC patients and should be further evaluated in phase III trials.

Endobronchial ultrasonography for mediastinal and hilar lymph node metastases of lung cancer.

STUDY OBJECTIVES: Conventional radiologic procedures are frequently unreliable in the diagnosis of mediastinal and hilar lymph node metastases of lung cancer. In order to improve diagnostic accuracy, we performed endobronchial ultrasonography (EBUS) during bronchofiberscopic examinations of patients with lung cancer. METHODS AND PATIENTS: To evaluate mediastinal and hilar lymph node metastases, EBUS was performed prospectively using a radial scanning probe of 20 MHz through a bronchofiberscope. RESULTS: We observed hilar lymph nodes (10R, 11R superior, 11R inferior, 12R, 10L, 11L, 12L) in 20 of 37 patients who underwent EBUS, and we could clearly identify whether direct invasion of the pulmonary artery by a lymph node had occurred. Of the 27 patients who showed no hilar lymph nodes on chest CT scan, lymph node swellings < 10 mm or > or = 10 mm in diameter were identified by EBUS in 9 patients and 2 patients, respectively. Interestingly, EBUS also revealed that the pulmonary artery was directly invaded by an interlobar lymph node < 10 mm in diameter in one patient. In most patients, lymph node 7 was easily identified and was clearly differentiated from the surrounding esophagus, vessels, and mediastinal fat tissue by EBUS. However, fused lymph nodes or lymph nodes with low central density when visualized by chest CT scan were occasionally observed as independent lymph nodes by EBUS. When compared with the pathologic diagnosis of lymph node metastasis in 16 patients who underwent surgery, the most specific and sensitive method for identifying lymph node metastases were EBUS alone (92%) and EBUS in combination with CT scan (100%), respectively. The overall accuracy of EBUS was 94% for the diagnosis of direct invasion of the pulmonary arteries by a hilar lymph node. CONCLUSIONS: EBUS in combination with conventional radiologic tools may contribute to improved staging, especially in surgical cases with hilar lymph node metastases.