Randomized phase III and extension studies: efficacy and impacts on quality of life of naldemedine in subjects with opioid-induced constipation and cancer.

BACKGROUND: The efficacy and safety of naldemedine (a peripherally acting µ-opioid receptor antagonist) for opioid-induced constipation (OIC) in subjects with cancer was demonstrated in the primary report of a phase III, double-blind study (COMPOSE-4) and its open-label extension (COMPOSE-5). The primary end point, the proportion of spontaneous bowel movement (SBM) responders, was met. Here, we report results from secondary end points, including quality of life (QOL) assessments from these studies. PATIENTS AND METHODS: In COMPOSE-4, eligible adults with OIC and cancer were randomly assigned 1:1 to receive once-daily oral naldemedine 0.2 mg (n = 97) or placebo (n = 96) for 2 weeks, and those who continued on to COMPOSE-5 received naldemedine for 12 weeks (n = 131). Secondary assessments in COMPOSE-4 included the proportion of complete SBM (CSBM) responders, SBM or CSBM responders by week, and subjects with ≥1 SBM or CSBM within 24 h postinitial dose. Changes from baseline in the frequency of SBMs or CSBMs per week were assessed at weeks 1 and 2. Time to the first SBM or CSBM postinitial dose was also evaluated. In both studies, QOL impact was evaluated by Patient Assessment of Constipation-Symptoms (PAC-SYM) and PAC-QOL questionnaires. RESULTS: Naldemedine improved bowel function for all secondary efficacy assessments versus placebo (all P ≤ 0.0002). The timely onset of naldemedine activity versus placebo was evidenced by median time to the first SBM (4.7 h versus 26.6 h) and CSBM (24.0 h versus 218.5 h) postinitial dose (all P < 0.0001). In COMPOSE-4, significant differences between groups were observed with the PAC-SYM stool domain (P = 0.045) and PAC-QOL dissatisfaction domain (P = 0.015). In COMPOSE-5, significant improvements from baseline were observed for overall and individual domain scores of PAC-SYM and PAC-QOL. CONCLUSIONS: Naldemedine provided effective and timely symptomatic relief from OIC and improved the QOL of subjects with OIC and cancer. TRIAL REGISTRATION ID: www.ClinicalTrials.jp: JAPIC-CTI-132340 (COMPOSE-4) and JAPIC-CTI-132342 (COMPOSE-5).

A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician's choice in patients with advanced non-small cell lung cancer.

BACKGROUND: Eribulin is a microtubule dynamics inhibitor with a novel mechanism of action. This phase 3 study aimed to compare overall survival (OS) in patients with heavily pretreated non-small cell lung cancer (NSCLC) receiving eribulin to treatment of physician's choice (TPC). PATIENTS AND METHODS: Patients with advanced NSCLC who had received ≥2 prior therapies, including platinum-based doublet and epidermal growth factor receptor tyrosine kinase inhibitor, were randomly assigned to receive eribulin or TPC (gemcitabine, pemetrexed, vinorelbine, docetaxel). The primary endpoint was OS. Secondary endpoints were progression-free survival and objective response rate. RESULTS: Five hundred and forty patients were randomized to either eribulin (n = 270) or TPC (n = 270). Median OS for eribulin and TPC was the same: 9.5 months [hazard ratio (HR): 1.16; 95% confidence interval: 0.95-1.41; P = 0.13]. Progression-free survival for eribulin and TPC was 3.0 and 2.8 months, respectively (HR: 1.09; 95% confidence interval: 0.90-1.32; P = 0.39). The objective response rate was 12% for eribulin and 15% for TPC. Clinical benefit rate (eribulin, 57%; TPC, 55%) and disease control rate (eribulin, 63%; TPC, 58%) were similar between treatment arms. The most common adverse event was neutropenia, which occurred in 57% of eribulin patients and 49% of TPC patients at all grades. Other non-hematologic side-effects were manageable and similar in both groups except for peripheral sensory neuropathy (all grades; eribulin, 16%; TPC, 9%). CONCLUSION: This phase 3 study did not demonstrate superiority of eribulin over TPC with regard to overall survival. However, eribulin does show activity in the third-line setting for NSCLC. TRIAL REGISTRATION ID: www.ClinicalTrials.gov; NCT01454934.

A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer.

Background: Amrubicin is approved for treating non-small-cell lung cancer (NSCLC) and small-cell lung cancer. However, no direct comparisons between amrubicin and docetaxel, a standard treatment for NSCLC, have been reported. Patients and methods: We conducted a randomized phase III trial of Japanese NSCLC patients after one or two chemotherapy regimens. Patients were randomized to amrubicin (35 mg/m2 on days 1-3 every 3 weeks) or docetaxel (60 mg/m2 on day 1 every 3 weeks). Outcomes included progression-free survival, overall survival, tumor responses, and safety. Results: Between October 2010 and June 2012, 202 patients were enrolled across 32 institutions. Median progression-free survival (3.6 versus 3.0 months; P = 0.54) and overall survival (14.6 versus 13.5 months; P = 0.86) were comparable in the amrubicin and docetaxel groups, respectively. The overall response rate was 14.4% (14/97) and 19.6% (19/97) in the amrubicin and docetaxel groups, respectively (P = 0.45). The disease control rate was 55.7% in both groups. Adverse events occurred in all patients, and included grade ≥3 neutropenia occurred in 82.7% and 78.8% of patients in the amrubicin and docetaxel groups, respectively, grade ≥3 leukopenia occurred in 63.3% and 70.7%, and grade ≥3 febrile neutropenia occurred in 13.3% and 18.2% of patients in the amrubicin and docetaxel groups, respectively. Of eight cardiac-related events in the amrubicin group, three were considered related to amrubicin and resolved without treatment discontinuation. Conclusions: This was the first phase III study to compare amrubicin and docetaxel in patients with pretreated NSCLC. Amrubicin did not significantly improve the primary endpoint of PFS compared with docetaxel. Clinical trial registration: NCT01207011 (ClinicalTrials.gov).

A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial.

BACKGROUND: Platinum-based two-drug combination chemotherapy has been standard of care for patients with advanced nonsmall-cell lung cancer (NSCLC). The primary aim was to compare overall survival (OS) of patients with advanced NSCLC between the two chemotherapy regimens. Secondary end points included progression-free survival (PFS), response, safety, and quality of life (QoL). PATIENTS AND METHODS: Patients with previously untreated stage IIIB or IV NSCLC, an Eastern Cooperative Oncology Group performance status of 0-1 and adequate organ function were randomized to receive either oral S-1 80 mg/m(2)/day on days 1-21 plus cisplatin 60 mg/m(2) on day 8 every 4-5 weeks, or docetaxel 60 mg/m(2) on day 1 plus cisplatin 80 mg/m(2) on day 1 every 3-4 weeks, both up to six cycles. RESULTS: A total of 608 patients from 66 sites in Japan were randomized to S-1 plus cisplatin (n = 303) or docetaxel plus cisplatin (n = 305). OS for oral S-1 plus cisplatin was noninferior to docetaxel plus cisplatin [median survival, 16.1 versus 17.1 months, respectively; hazard ratio = 1.013; 96.4% confidence interval (CI) 0.837-1.227]. Significantly higher febrile neutropenia (7.4% versus 1.0%), grade 3/4 neutropenia (73.4% versus 22.9%), grade 3/4 infection (14.5% versus 5.3%), and grade 1/2 alopecia (59.3% versus 12.3%) were observed in the docetaxel plus cisplatin than in the S-1 plus cisplatin. There were no differences found in PFS or response between the two arms. QoL data investigated by EORTC QLQ-C30 and LC-13 favored the S-1 plus cisplatin. CONCLUSION: Oral S-1 plus cisplatin is not inferior to docetaxel plus cisplatin and is better tolerated in Japanese patients with advanced NSCLC. CLINICAL TRIAL NUMBER: UMIN000000608.

A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV nonsquamous nonsmall-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study).

BACKGROUND: A previous randomized phase II study demonstrated that the addition of a c-Met inhibitor tivantinib to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib might prolong progression-free survival (PFS) in patients with previously treated, nonsquamous nonsmall-cell lung cancer (NSCLC). On a subset analysis, the survival benefit was greater in patients with wild-type EGFR (WT-EGFR) than in those with activating EGFR mutations. Herein, this phase III study compared overall survival (OS) between Asian nonsquamous NSCLC patients with WT-EGFR who received erlotinib plus tivantinib (tivantinib group) or erlotinib plus placebo (placebo group). METHODS: A total of 460 NSCLC patients were planned to be randomized to the tivantinib or placebo group. Primary end point was OS. Secondary end points were PFS, tumor response, and safety. Tissue was collected for biomarker analysis, including c-Met and HGF expression. RESULTS: Enrollment was stopped when 307 patients were randomized, following the Safety Review Committee's recommendation based on an imbalance in the interstitial lung disease (ILD) incidence between the groups. ILD developed in 14 patients (3 deaths) and 6 patients (0 deaths) in the tivantinib and the placebo groups, respectively. In the enrolled patients, median OS was 12.7 and 11.1 months in the tivantinib and the placebo groups, respectively [hazard ratio (HR) = 0.891, P = 0.427]. Median PFS was 2.9 and 2.0 months in the tivantinib and the placebo groups, respectively (HR = 0.719, P = 0.019). The commonly observed grade ≥ 3 adverse events in the tivantinib group were neutropenia (24.3%), leukopenia (18.4%), febrile neutropenia (13.8%), and anemia (13.2%). CONCLUSIONS: This study was prematurely terminated due to the increased ILD incidence in the tivantinib group. Although this study lacked statistical power because of the premature termination and did not demonstrate an improvement in OS, our results suggest that tivantinib plus erlotinib might improve PFS than erlotinib alone in nonsquamous NSCLC patients with WT-EGFR. TRIAL REGISTRATION NUMBER: NCT01377376.

A randomised, placebo-controlled, double-blind study of aprepitant in nondrinking women younger than 70 years receiving moderately emetogenic chemotherapy.

BACKGROUND: We evaluated the efficacy of aprepitant plus granisetron and an increased dose of dexamethasone in selected patients undergoing moderately emetogenic chemotherapy (MEC). METHODS: Nondrinking women <70 years undergoing MEC were randomly assigned to aprepitant (day 1, 125 mg; days 2 and 3, 80 mg) or placebo. Dexamethasone on days 1-3 was 12, 4, and 4 mg with aprepitant and 20, 8, and 8 mg with placebo. The primary end point was complete response (CR; no emesis or rescue therapy) during 120 h of the first cycle. Logistic regression analysis was performed to identify predictors of overall CR. RESULTS: Of the 94 patients enrolled, 91 were assessable. Most received carboplatin-based chemotherapy. In the aprepitant (n=45) and placebo (n=46) groups, the overall, acute (day 1), and delayed (days 2-5) CR rates were 62% and 52%, 98% and 96%, and 62% and 52%, respectively. Although not statistically significant, the overall CR rate was 10% higher in the aprepitant group. Both regimens were well tolerated. On multivariate analysis, advanced ovarian cancer (OR, 0.26 (0.10-0.72)) was independently associated with a lower CR. CONCLUSION: Even with an increased dose of dexamethasone, aprepitant seemed more effective than placebo in these selected patients undergoing MEC; however, delayed phase management remains a significant problem.

Efficacy and safety of single-dose fosaprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving high-dose cisplatin: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: We evaluated the efficacy and safety of single-dose fosaprepitant in combination with intravenous granisetron and dexamethasone. PATIENTS AND METHODS: Patients receiving chemotherapy including cisplatin (≥70 mg/m(2)) were eligible. A total of 347 patients (21% had received cisplatin with vomiting) were enrolled in this trial to receive the fosaprepitant regimen (fosaprepitant 150 mg, intravenous, on day 1 in combination with granisetron, 40 µg/kg, intravenous, on day 1 and dexamethasone, intravenous, on days 1-3) or the control regimen (placebo plus intravenous granisetron and dexamethasone). The primary end point was the percentage of patients who had a complete response (no emesis and no rescue therapy) over the entire treatment course (0-120 h). RESULTS: The percentage of patients with a complete response was significantly higher in the fosaprepitant group than in the control group (64% versus 47%, P = 0.0015). The fosaprepitant regimen was more effective than the control regimen in both the acute (0-24 h postchemotherapy) phase (94% versus 81%, P = 0.0006) and the delayed (24-120 h postchemotherapy) phase (65% versus 49%, P = 0.0025). CONCLUSIONS: Single-dose fosaprepitant used in combination with granisetron and dexamethasone was well-tolerated and effective in preventing chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic cancer chemotherapy, including high-dose cisplatin.

A phase II trial of dose-dense chemotherapy, followed by surgical resection and/or thoracic radiotherapy, in locally advanced thymoma: report of a Japan Clinical Oncology Group trial (JCOG 9606).

BACKGROUND: This study aimed to evaluate the safety and efficacy of dose-dense weekly chemotherapy, followed by resection and/or thoracic radiotherapy. METHODS: Patients with histologically documented thymoma with unresectable stage III disease received 9 weeks of chemotherapy: cisplatin 25 mg m(-2) on weeks 1-9; vincristine 1 mg m(-2) on weeks 1, 2, 4, 6 and 8; and doxorubicin 40 mg m(-2) and etoposide 80 mg m(-2) on days 1-3 of weeks 1, 3, 5, 7 and 9. Patients went on to surgery and post-operative radiotherapy of 48 Gy; those with unresectable disease received 60 Gy radiotherapy. RESULTS: total of 23 patients were entered. The main toxicities of the chemotherapy regimen were neutropenia and anaemia, and 57% of patients completed the planned 9 weeks of therapy. There were no toxic deaths. Of the 21 eligible patients, 13 (62%) achieved a partial response (95% confidence interval: 38-82%). Thirteen patients underwent a thoracotomy and nine (39%) underwent complete resection. Progression-free survival at 2 and 5 years was 80 and 43%, respectively. Overall survival at 5 and 8 years was 85 and 69%, respectively. Survival did not seem to be affected by resection. CONCLUSION: In thymoma patients, weekly dose-dense chemotherapy has activity similar to that of conventional regimens. Although some patients could achieve complete resection, the role of surgery remains unclear.

A phase II study of palonosetron combined with dexamethasone to prevent nausea and vomiting induced by highly emetogenic chemotherapy.

BACKGROUND: This is a randomized, double-blind, dose-ranging study in patients receiving highly emetogenic chemotherapy (HEC) to evaluate the safety, efficacy, and pharmacokinetics of palonosetron, in combination with dexamethasone. MATERIALS AND METHODS: We randomized 233 patients to receive palonosetron as a single i.v. bolus dose of 0.075, 0.25, or 0.75 mg before administration of HEC. Dexamethasone (12-16 mg i.v. on day 1, 8 mg i.v. on day 2, and 4-8 mg i.v. on day 3) was administered for prophylactic antiemesis. Pharmacokinetics of palonosetron was analyzed in 24 patients. RESULTS: In this study, all patients were given > or =50 mg/m(2) cisplatin, which was considered to be HEC. No significant differences in complete response (CR: no emesis and no rescue medication) rates were found in the first 24 h between the 0.075-, 0.25-, and 0.75-mg groups (77.6%, 81.8%, and 79.5%, respectively). In the 120-h period of overall observation, CR rates increased in a dose-dependent manner. In the 0.75-mg group, we observed a significantly longer time to treatment failure than in the 0.075-mg group (median time >120 versus 82.0 h, P = 0.038). Palonosetron was tolerated well and did not show any dose-related increase in adverse effects. CONCLUSIONS: Palonosetron at doses of 0.25 and 0.75 mg was shown to be effective in preventing chemotherapy-induced nausea and vomiting with high CR rates of patients treated with HEC in Japan. All tested doses of palonosetron were tolerated well.

Combined effect of oxidative stress-related gene polymorphisms on atherosclerosis.

It is well known that oxidative stress plays critical roles in the pathogenesis of atherosclerosis. In this study, we enrolled 1746 type 2 diabetic subjects, determined 4 common genetic variants related to oxidative stress (glutamate-cysteine ligase modifier subunit (GCLM) C-588T, myeloperoxidase G-463A, human paraoxonase 1 Gln192Arg and NAD(P)H oxidase p22phox C242T polymorphisms), and measured carotid intima-media thickness (IMT) as a surrogate marker for atherosclerosis. GCLM C-588T polymorphism was associated with average IMT (AveIMT) (r=0.090, p=0.0008), but the association between the other 3 polymorphisms and AveIMT did not reach the statistical significance. However, AveIMT was significantly greater as the total number of 4 concomitant "pro-oxidant alleles" in each subject was increased (r=0.108, p<0.0001). Furthermore, the number of "pro-oxidant alleles" was a risk factor for a high AveIMT independently of conventional risk factors (p=0.0003). In conclusion, accumulation of oxidative stress-associated alleles was associated with carotid atherosclerosis in type 2 diabetic patients.

[Lobectomy for local recurrence following stereotactic radiotherapy to non-small cell lung cancer].

A 78-year-old man had non-small cell lung cancer (NSCLC) in the left upper lobe (squamous cell carcinoma, cT1N0M0). He preferred less invasive treatment and undertook stereotactic radiotherapy (SRT)[48 Gy/4 Fr] because his forced expiratory volume in 1 second percent (FEV1.0%) was 53.50%. The therapeutic effect was partial response and the adverse reaction was dermatitis (grade 1). Seven months after SRT, local recurrence was detected. The tumor was growing from 3 x 5 mm to 25 x 25 mm in size. Nine months after SRT, left upper lobectomy was performed successfully unaffected by SRT. He is doing well 14 months after the operation without any signs of recurrence. This case might help develop a new strategy for the treatment of stage I NSCLC. It is that patients with stage I NSCLC have SRT as 1st line treatment, and if local recurrence is observed after SRT, lobectomy may be performed.

Quantitative Analysis of Conebeam CT for Delineating Stents in Stent-Assisted Coil Embolization.

BACKGROUND AND PURPOSE: Innovative techniques and device-related advances have improved the outcomes of neuroendovascular treatment. 3D imaging has previously used 2 × 2 binning, but 1 × 1 binning has recently been made available. The aim of this study was to evaluate the quantitative ability of conebeam CT for stent delineation and to investigate its effectiveness in the clinical environment. MATERIALS AND METHODS: Four acquisition groups of 3D MIP images acquired using conebeam CT with varying conditions (acquisition time, 10 or 20 seconds and binning, 1 × 1 or 2 × 2) were compared. Two methods of analysis were performed, a phantom study and an analysis of 28 randomly selected patients. The phantom study assessed the contrast-to-noise ratio and full width at half maximum values in conebeam CT images of intracranial stent struts. In the clinical subjects, we assessed contrast-to-noise ratio, full width at half maximum, and dose-area product. RESULTS: In the phantom study, the contrast-to-noise ratio was not considerably different between 10- and 20-second acquisition times at equivalent binning settings. Additionally, the contrast-to-noise ratio at equivalent acquisition times did not differ considerably by binning setting. For the full width at half maximum results, equivalent acquisition times differed significantly by binning setting. In the clinical analyses, the 10-second/1 × 1 group (versus 20 second/2 × 2) showed a higher contrast-to-noise ratio (P < .05) and a dose-area product reduced by approximately 70% (P < .05), but the difference in full width at half maximum was not significant (P = .20). CONCLUSIONS: For stent-assisted coil embolization, quantitative assessment of conebeam CT showed that 10 second/1 × 1 was equivalent to 20 second/2 × 2 for imaging deployed intracranial stents. Furthermore, the 10-second/1 × 1 settings resulted in a much smaller DAP.

Cholecystokinin-B/gastrin receptor: a novel molecular probe for human small cell lung cancer.

The brain-gut hormones, gastrin and cholecystokinin, have a trophic effect on the gastrointestinal mucosa in vivo and promote the growth of several neoplastic cell lines. In this study, cholecystokinin-B/gastrin receptor has been demonstrated to provide a novel molecular marker for the diagnosis of small cell lung cancer by using biopsy specimens. Physiological expression of the receptor mRNA is detectable in particular areas of the human brain, stomach, and pancreas but not in the lung. The receptor mRNA was detected selectively in all small cell lung cancer (10 cases) with a RT-PCR assay. By contrast, it was detectable in only 1 of 13 squamous cell carcinomas or 21 adenocarcinomas of the lung. Thus, the cholecystokinin-B/gastrin receptor could be an attractive therapeutic target for small cell lung cancer.

Isolation of the phosphatidylinositol 4-monophosphate dissociable high-affinity profilin-actin complex.

Profilin was originally discovered in a tight complex with monomeric actin from bovine spleen, leading to its description as an actin monomer sequestering protein that maintains a pool of unpolymerized actin in cells. Subsequent purifications of profilin using different methods from diverse cells have consistently yielded preparations that affect the kinetics of actin assembly but do not efficiently maintain actin monomeric at steady state in solutions containing mM magnesium. Recent evidence that profilin inhibits phospholipase C and enhances nucleotide exchange of actin has led some to question whether profilin is ever truly an actin monomer sequestering agent. Here we report that the extraction of bovine spleen with fluoride- and pyrophosphate-containing solutions facilitates isolation of monomeric actin that is bound to profilin and does not polymerize in mM magnesium ion. The integrity of this complex depends on the presence of ATP. Phosphatidylinositol 4-monophosphate (PIP), previously shown to dissociate the low-affinity profilin-actin complex (Kd = 0.4 microM in mM Mg2+), also dissociates the high-affinity profilin-actin complex (Kd less than 0.02 microM in mM Mg2+) yielding actin that is polymerization competent and profilin that functions like profilins purified by conventional methods. Although the chemical basis of these results is not known, they indicate that profilin can tightly sequester actin monomers and support the earlier suggestion that the affinity of profilin for actin may be under metabolic control.

Irinotecan and etoposide for previously untreated extensive-disease small cell lung cancer: a phase II trial of West Japan Thoracic Oncology Group.

Irinotecan is a topoisomerase I inhibitor that is highly active against small cell lung cancer (SCLC). Etoposide is another drug that is effective for SCLC. Since combination of these two topoisomerase inhibitors revealed a synergistic effect in vitro and showed a safety in phase I study, we conducted a phase II study in patients with previously un-treated extensive disease (ED) SCLC to evaluate the efficacy and toxicity of this combination. Fifty patients with previously untreated ED-SCLC were enrolled. Irinotecan was administered intravenously at 60mg/m(2) on days 1, 8, and 15, while etoposide was given at 80mg/m(2) on days 2-4. Treatment was repeated every 4 weeks for four cycles. The overall response rate was 66.0%, with a complete response rate of 10.0%. The median survival time was 11.5 months and the 1- and 2-year survival rates were 43.2 and 14.4%, respectively. The major toxicity of this regimen was myelosuppression, including grade 3 or 4 neutropenia (62.9%), leukopenia (28.0%), and anemia (14%). The other grade 3 toxicity was diarrhea (2%). This irinotecan and etoposide regimen is active against ED-SCLC with relatively mild toxicity.

Induction chemoradiotherapy for advanced stage III non-small cell lung cancer: long-term follow-up in 42 patients.

This multi-institutional phase II study was designed to assess the feasibility, efficacy, toxicity, and long-term survival of induction chemoradiotherapy followed by surgery in previously untreated patients with advanced stage III non-small cell lung cancer. Chemotherapy regimen included cisplatin 20 mg/m2 on days 1-5 and 29-33, and VP-16 40 mg/m2 on days 1-5 and 29-33. Radiotherapy (50 Gy in 25 fractions) began on day 1. Clinically downstaged patients underwent thoracotomy 3-5 weeks after the completion of radiotherapy. Forty-two eligible patients (ten stage IIIA and 32 IIIB) were followed for a median period of 64 months. The response rate was 81%, and 20 patients had a clinically good response. Twenty-one patients underwent thoracotomy. Nineteen patients had complete resections and there were seven pathologic complete responses. There were four treatment related deaths (all stage IIIBs). There were significant survival differences between stage IIIA versus IIIB patients (P = 0.028; median survivals, 24.9 vs. 11.1 months; 5-year survival rates, 20% vs. 8.3%), and patients that achieved pathologic complete response (CR) versus those that did not (P = 0.045; median survivals 30.1 vs. 11.1 months; 5-year survival rates, 28.6% vs. 8.3%). Although the induction chemoradiotherapy employed in this study was not appropriate for stage IIIB patients, it proved feasible in stage IIIA patients in whom it resulted in good 5-year survival rates. It also provided good survival rates in patients achieving pathologic CR.

Long-term follow-up of patients with a history of near fatal episodes; can inhaled corticosteroids reduce the risk of death from asthma?

We retrospectively studied the use of inhaled corticosteroids in patients who experienced near fatal episodes (NFE) to determine whether such therapy reduces the risk of death. Forty-eight patients who had near fatal episodes of asthma between January 1981 and December 1989 were divided into two groups. Group A comprised 19 patients who received beclomethasone dipropionate (BDP) daily (mean dose of BDP:687 micrograms/day: 200-2,000) following NFE, and Group B, 28 patients who did not take BDP or who took less than 6 mg BDP/month. During the follow-up period (Group A:82.9 months, Group B:66.2 months), no patients in Group A died, but eight deaths occurred in Group B (mean period between near fatal episode and death was 31.5 months: 12-66). These results suggest that the regular use of inhaled corticosteroids, even at low doses, may reduce the risk of death in patients who experience NFE.

Duration of systemic corticosteroids in the treatment of asthma exacerbation; a randomized study.

OBJECTIVE: To determine an appropriate duration for a short course of oral steroids in cases of asthma exacerbations. SETTING: A 1,000 bed city hospital in Kobe, Japan. PATIENTS: Patients with asthma exacerbations who needed hospital admission. METHODS: Following an initial treatment with a 3-day course of intravenous methylprednisolone, patients were allocated to either a 1-week (1 W) or a 2-week (2 W) course of oral prednisolone (PSL, 0.5 mg/kg). OUTCOME MEASURES: Peak expiratory flow rate (PEF) and rate of unscheduled hospital visits and readmission. RESULTS: Twenty patients were enrolled (10 in 1 W, 10 in 2 W). Mean PEF just before starting oral PSL in 1 W and 2 W were 51 and 58% of each patient's best value. PEF was significantly improved and to a similar degree over the course of time in both 1 W and 2 W. The frequency of unexpected hospital visits during a 3-month period after discharge was similar (2 in 1 W and 2 in 2 W). No readmission occurred during the same period. CONCLUSIONS: Because both the 1-week and the 2-week course of oral PSL were equally effective in the treatment of asthma exacerbations, 1 week may be appropriate as the maximum duration of a short rescue course of oral steroids.

Influence of high dose inhaled steroids on hypothalamo-pituitary-adrenal axis function in Japanese patients with asthma: a comparison over the course of time.

Although the influence of high dose inhaled steroids on hypothalamo-pituitary-adrenal (HPA) function in patients with asthma has been extensively studied worldwide, there has been limited information on Japanese asthmatics, especially in terms of a prospective analysis of HPA function in the course of time. We analyzed the changes in HPA function using 2 serial short tetracosactrin tests (STT) separated by an interval of one year in 11 Japanese asthmatics who were treated with high dose inhaled steroids alone [beclomethasone dipropionate (BDP); mean dose 982 micrograms/day] during the period between 2 STTs. Mean values of plasma cortisol before administration of ACTH, maximum cortisol and the rise in cortisol in response to ACTH in the 2 STTs were 7.8, 20.5 and 12.7 micrograms/dl for the 1st test, and 8.9, 23.6 and 14.7 micrograms/dl for the 2nd test, respectively. Overall, there was no significant change in the course of time in each of these 3 values. Although the results of the 1st STT proved to be abnormal in 3 patients who had been receiving systemic steroids before their 1st STT, they improved uniformly in their 2nd STT. In the remaining 8 patients, who had never received systemic steroids, 4 patients showed improvements while the other 4 showed deterioration in HPA function in their serial STTs over the course of time. The dose of BDP was 800 micrograms/day in the former 4 patients, while it was 1,200 micrograms/day in the latter 4. Furthermore, only one patient, in whom BDP had been increased from 800 micrograms/day to 1,200 micrograms/day between the 2 tests, developed an abnormal response in the 2nd STT. On the other hand, one patient whose BDP dose was increased from 800 micrograms/day to 1,600 micrograms/day showed an improvement in HPA function in the 2nd test. These results indicate that the threshold dose of BDP which may cause HPA suppression in Japanese asthmatics lies between 800-1,200 micrograms/day, although there is a large inter-individual variation in terms of such doses.