Biomedical subjects

David H Johnson

Publications and source records attributed to David H Johnson.

At least 37 records · Page 2Linked to original sources

PubMed2005

Systemic therapy of advanced bronchioloalveolar cell carcinoma: challenges and opportunities.

Bronchioloalveolar cell carcinoma (BAC) has fascinated physicians with its unique epidemiology, pathology, clinical manifestations, and natural history when compared with other non-small-cell lung cancer (NSCLC) subtypes. However, the relative rarity of pure BAC as defined by the WHO, and the inconsistent definitions used in various series, has limited systematic study of this entity. Retrospective and prospective studies suggest that patients with BAC treated with cytotoxic chemotherapy have a longer median survival than those with other subtypes of NSCLC. However, the widely accepted view that BAC is less chemosensitive than other NSCLCs is not clearly supported by the small body of available literature. Antitumor activity of cytotoxic agents and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors has been documented in phase II trials but no phase III trials have been conducted in this disease. The observation that profound responses to gefitinib and erlotinib often occurred in NSCLC patients with BAC, and that EGFR tyrosine kinase domain mutations were identified in large part by careful study of such patients, serves as a paradigm for translational research in this disease. The recognition that pure BAC and adenocarcinoma with BAC features behave similarly and as such represent a relatively common entity will facilitate accrual to BAC specific studies. Alternatively, stratification of these histologic subtypes in broader clinical trials in NSCLC is warranted. However, for either strategy to succeed in advancing our understanding of the molecular biology of BAC, it must be accompanied by central pathologic review with detailed classification of such, and of adequate tissue for measurement of known or putative targets of action of the agent under study.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed2005

Phase III study of the Eastern Cooperative Oncology Group (ECOG 2597): induction chemotherapy followed by either standard thoracic radiotherapy or hyperfractionated accelerated radiotherapy for patients with unresectable stage IIIA and B non-small-cell lung cancer.

PURPOSE: To compare once-daily radiation therapy (qdRT) with hyperfractionated accelerated radiation therapy (HART) after two cycles of induction chemotherapy. PATIENTS AND METHODS: Eligible patients were treatment naive, and had stage IIIA and B unresectable non-small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0/1, and normal organ function. Induction chemotherapy consisted of two cycles of carboplatin area under time-concentration curve 6 mg/mL . min plus paclitaxel 225 mg/m2 on day 1. RT consisted of arm 1 (qdRT), 64 Gy (2 Gy/d), versus arm 2 (HART), 57.6 Gy (1.5 Gy tid for 2.5 weeks). A total of 388 patients were needed to detect a 50% increase in median survival from 14 months of qdRT to 21 months of HART; accrual was not achieved and the study closed prematurely. RESULTS: Of 141 patients enrolled, 83% were randomly assigned after chemotherapy to qdRT (n = 59) or HART (n = 60). Median survival was 20.3 and 14.9 months for HART and qdRT, respectively (P = .28). Overall response was 25% and 22% for HART and qdRT, respectively (P = .69). Two- and 3-year survival was 44% and 34% for HART, and 24% and 14% for qdRT, respectively. Grade > or = 3 toxicities included esophagitis in 14 v nine patients, and pneumonitis in 0 v 6 patients for HART and qdRT, respectively. Any subsequent trials of the HART regimen must address the issues that led to early closure, including slow accrual, logistics of HART, mucosal toxicity, and the fact that concurrent chemoradiotherapy now seems more effective than sequential treatment. CONCLUSION: After two cycles of induction chemotherapy with carboplatin-paclitaxel, HART is feasible with an acceptable toxicity profile. Although statistical significance was not achieved and the study closed early, there was a positive statistical trend suggesting a survival advantage with the HART regimen.

Adult↗

PubMed2005

Nuclear survivin predicts recurrence and poor survival in patients with resected nonsmall cell lung carcinoma.

BACKGROUND: Survivin, which is a member of the inhibitor of apoptosis protein gene family, regulates both programmed cell death and mitosis. It has been shown that survivin expression and its subcellular localization both have prognostic value for patients with malignant disease. In this study, the authors investigated whether nuclear or cytoplasmic staining of survivin was a prognostic marker for patients with lung carcinoma. METHODS: Paraffin-embedded tissue blocks from 144 patients with Stage I and II resected nonsmall cell lung carcinoma (NSCLC) were obtained for immunohistochemical staining. Three specimens from each patient were prepared and stained with a survivin-specific antibody. Nuclear and cytoplasmic staining was graded from 1 to 3 based on intensity. RESULTS: Patients who had nuclear staining for survivin had a significantly increased risk of disease recurrence (hazard ratio, 2.95; P = 0.0046) and death (hazard ratio, 2.74; P = 0.0086). CONCLUSIONS: The nuclear presence of survivin may be an independent biomarker for disease recurrence and overall survival in patients with resected Stage I and II NSCLC.

Adult↗

PubMed2005

Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer.

PURPOSE: Bevacizumab (Avastin; Genentech, South San Francisco, CA) is a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody. Erlotinib HCl (Tarceva, OSI-774; OSI Pharmaceuticals, New York, NY) is a potent, reversible, highly selective and orally available HER-1/epidermal growth factor receptor tyrosine kinase inhibitor. Preclinical data in various xenograft models produced greater growth inhibition than with either agent alone. Additionally, both agents have demonstrated benefit in patients with previously treated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A phase I/II study in two centers examined erlotinib and bevacizumab (A+T) in patients with nonsquamous stage IIIB/IV NSCLC with > or = one prior chemotherapy. In phase I, erlotinib 150 mg/day orally plus bevacizumab 15 mg/kg intravenously every 21 days was established as the phase II dose, although no dose-limiting toxicities were observed. Phase II assessed the efficacy and tolerability of A+T at this dose. Pharmacokinetic parameters were evaluated. ResultsForty patients were enrolled and treated in this study (34 patients at phase II dose); the median age was 59 years (range, 36 to 72 years), 21 were female, 30 had adenocarcinoma histology, nine were never-smokers, and 22 had > or = two prior regimens (three patients had > or = four prior regimens). The most common adverse events were mild to moderate rash, diarrhea, and proteinuria. Preliminary data showed no pharmacokinetic interaction between A + T. Eight patients (20.0%; 95% CI, 7.6% to 32.4%) had partial responses and 26 (65.0%; 95% CI, 50.2% to 79.8%) had stable disease as their best response. The median overall survival for the 34 patients treated at the phase II dose was 12.6 months, with progression-free survival of 6.2 months. CONCLUSION: Encouraging antitumor activity and safety of A + T support further development of this combination for patients with advanced NSCLC and other solid tumors.

Adult↗

PubMed2005

Post-operative radiotherapy (PORT) or chemoradiotherapy (CPORT) following resection of stages II and IIIA non-small cell lung cancer (NSCLC) does not increase the expected risk of death from intercurrent disease (DID) in Eastern Cooperative Oncology Group (ECOG) trial E3590.

To determine the influence of adjuvant therapy on the risk of DID following resection of NSCLC, we compared the actuarial rate of non-cancer related deaths of patients who had been entered in Eastern Cooperative Oncology Group E3590 (a phase III trial of adjuvant therapy in patients with completely resected stages II and IIIA NSCLC) to the actuarial death rate of age and gender matched controls. Following surgery, patients were randomized to receive either PORT (5040 cGy in 28 daily fractions) or CPORT (PORT plus four cycles of cisplatin (60 mg/m2, day 1) and etoposide (120 mg/m2, days 1-3) administered concurrently). The study accrued 488 patients, 242 to the PORT only arm and 246 to the CPORT arm. The overall 4 years actuarial rate of DID for the two arms combined, with a median follow-up of 82 months, was 12.9%, not significantly different from the 10.1% expected rate of DID, based on mortality rates for age and gender matched controls derived from US vital statistics and corrected for smoking status (p=0.16). Survival distributions with regard to DID did not differ between the two treatment arms (p=0.96). DID increased with age (treated as a continuous variable, p<0.01), but was not affected by histology, side of chest irradiated, type of surgery, FEV1 or weight loss in the previous 6 months. The risk of DID following resection of stages II and IIIA NSCLC is not increased in patients who received PORT or CPORT.

Age Factors↗

PubMed2005

Clinical model to predict survival in chemonaive patients with advanced non-small-cell lung cancer treated with third-generation chemotherapy regimens based on eastern cooperative oncology group data.

PURPOSE: (1) Identify clinical factors that can be used to predict survival in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) treated with third-generation chemotherapy regimens, and (2) build a clinical model to predict survival in this patient population. PATIENTS AND METHODS: Using data from two randomized, phase III Eastern Cooperative Oncology Group (ECOG) trials (E5592/E1594), we performed univariate and multivariate stepwise Cox regression analyses to identify survival prognostic factors. We used 75% of randomly sampled data to build a prediction model for survival, and the remaining 25% of data to validate the model. RESULTS: From 1993 to 1999, 1,436 patients with stage IV or IIIB NSCLC with effusion were treated with platinum-based doublets (involving either paclitaxel, docetaxel, or gemcitabine). The response rate and median survival time were 20% and 8.2 months, respectively. One- and 2-year survivals were 33% and 11%, respectively. In multivariate analysis, six independent poor prognostic factors were identified: skin metastasis (hazard ratio [HR], 1.88), lower performance status (ECOG 1 or 2; HR, 1.46), loss of appetite (HR, 1.62), liver metastasis (HR, 1.32), >/= four metastatic sites (HR, 1.20), and no prior surgery (HR, 1.16). A nomogram using six pretreatment prognostic factors was built to predict 1- and 2-year survival. CONCLUSION: Six pretreatment factors can be used to predict survival in chemotherapy-naive NSCLC patients treated with standard chemotherapy. Using our prognostic nomogram, 1- and 2-year survival probability of NSCLC patients can be estimated before treatment. This prognostic model may help clinicians and patients in clinical decision making, as well as investigators in research planning.

Aged↗

PubMed2005

Redefining bronchioloalveolar carcinoma.

Bronchioloalveolar carcinoma (BAC) is a subtype of non-small cell lung cancer (NSCLC) with distinct clinical and pathologic features. Although BAC appears to be on a pathologic continuum with adenocarcinoma, the most recent World Health Organization (WHO) classification system has set stringent criteria for the diagnosis. Though malignant, these cancers tend to be peripheral and grow in a lepedic fashion along the alveolar septae without parenchymal invasion. This clear distinction based on histopathology allows for a more definite separation of the natural history and behavior of BAC in clinical studies. Recent clinical trials of molecular targeted anticancer therapies have led to a deeper understanding of the unique features of this cancer and suggest that BAC may require a different therapeutic paradigm from other NSCLCs.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed2005

Increasing chemotherapy dose density and intensity: phase I trials in non-small cell lung cancer and non-Hodgkin's lymphoma.

Dose densification and dose escalation of cytotoxic chemotherapy may be important in improving the cure rates of chemotherapy-responsive cancers. We conducted two phase I studies, in non-small cell lung cancer (NSCLC) and in lymphoma, to explore the possibility of intensifying chemotherapy by compressing the delivery of and escalating the dose of standard combination chemotherapy. One study used etoposide and cisplatin chemotherapy in patients with unresectable stage III or IV NSCLC, intensifying chemotherapy by reducing the cycle length. The second study used cyclophosphamide, doxorubicin, vincristine, and prednisone, CHOP chemotherapy, in the treatment of stage II-IV intermediate or immunoblastic high-grade lymphoma, intensifying chemotherapy first by reducing the cycle length and then by escalating the dosages of cyclophosphamide and doxorubicin. Filgrastim support was used during dose intensification. Fifty-five patients with NSCLC and 49 with non-Hodgkin's lymphoma (NHL) were enrolled and treated in successive cohorts. At standard dosages and intervals of chemotherapy, filgrastim support resulted in incidences of grade 3 and 4 neutropenia that were between 62% and 77% lower than those in the no-filgrastim control; the mean duration of neutropenia was, likewise, more than 80% lower. Absolute neutrophil counts were >/=2 x 10(9)/l at day 14 in virtually 100% of patients receiving filgrastim. In the NSCLC trial, etoposide and cisplatin were intensified by >50%, and in the lymphoma trial, cyclophosphamide was intensified by 270% and doxorubicin was intensified by 87%. Chemotherapy reductions or delays for neutropenia were rare in the groups receiving filgrastim; but at higher chemotherapy intensities, dose-limiting thrombocytopenia was encountered. We conclude that the delivery of myelosuppressive chemotherapy in both a dose-intense and a dose-dense manner is feasible with filgrastim support.

Adult↗

PubMed2004

Quantification of the major urinary metabolite of PGE2 by a liquid chromatographic/mass spectrometric assay: determination of cyclooxygenase-specific PGE2 synthesis in healthy humans and those with lung cancer.

Prostaglandin (PG)E2 is a major cyclooxygenase (COX) product that is important in human physiology and pathophysiology. Quantification of systemic PG production in humans is best assessed by measuring excreted urinary metabolites. Accurate and easy-to-perform assays to quantify the major urinary metabolite of PGE2, 11alpha-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), do not exist. We now report the development of a robust and facile method to measure urinary PGE-M excretion in humans using stable isotope dilution techniques employing liquid chromatography/tandem mass spectrometry (LC/MS/MS). Concentrations of the metabolite in urine from healthy humans are nearly twofold greater in men than in women (10.4+/-1.5 vs. 6.0+/-0.7 ng/mg creatinine). Levels of PGE-M in healthy humans are suppressed significantly not only by the nonselective COX inhibitor ibuprofen but also by the COX-2 selective inhibitor rofecoxib, suggesting that the majority of PGE2 formed in vivo is derived from COX-2. Increased COX-2 expression and increased PGE2 production are associated with malignancy. Levels of PGE-M were found to be greatly increased in humans with unresectable non-small cell cancer of the lung, and this increase is dramatically reduced by administration of the COX-2 inhibitor celecoxib, implying that COX-2 contributes significantly to the overproduction of PGE2. In summary, quantification of PGE-M using LC/MS/MS provides a facile and accurate method to assess PGE2 formation in human physiological and pathophysiological processes.

Carcinoma, Non-Small-Cell Lung↗

PubMed2004

Anti-vascular endothelial growth factor monoclonals in non-small cell lung cancer.

There is an urgent need for new therapies to treat non-small cell lung cancer (NSCLC) because current chemotherapy regimens are of limited effectiveness. The role of vascular endothelial growth factor in promoting tumor angiogenesis, in maintaining existing vasculature, and in resistance to traditional therapies, together with its negative prognostic significance in NSCLC, make it an appropriate target for therapy. Bevacizumab (Avastin), a monoclonal antibody directed against vascular endothelial growth factor, has shown promise in treating a number of different cancers. In a recent Phase II trial in patients with advanced metastatic NSCLC, the addition of bevacizumab to standard carboplatin/paclitaxel chemotherapy significantly increased the time to progression and increased the response rate when compared with chemotherapy alone. This was particularly impressive in the subset of patients with non-squamous histology. Bevacizumab is generally well tolerated and did not appear to increase the incidence or severity of nausea/vomiting, neuropathy and renal toxicity, which are typically associated with carboplatin/paclitaxel chemotherapy. Adverse events in Phase I and II studies included hypertension, thrombosis, proteinuria (with occasional nephrotic syndrome), and epistaxis. Serious tumor-related bleeding episodes (hemoptysis/hematemesis) seem to be the main safety concern in patients with NSCLC, with squamous cell histology as a possible risk factor. Present ongoing studies are under way in NSCLC including (a) a Phase II neo-adjuvant study in combination with paclitaxel and carboplatin in patients with stage IB-IIA NSCLC; (b) a Phase I/II study of bevacizumab in combination with the epidermal growth factor receptor tyrosine kinase inhibitor agent, Tarceva, in patients with previously treated NSCLC; and (c) an Eastern Cooperative Group randomized Phase III study of paclitaxel and carboplatin with/without bevacizumab in patients with previously untreated IIIB (malignant pleural effusion) or metastatic NSCLC. These studies will help to establish the role of bevacizumab in NSCLC.

Antibodies, Monoclonal↗

PubMed2004

Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer.

PURPOSE: To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer. PATIENTS AND METHODS: In a phase II trial, 99 patients were randomly assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (area under the curve = 6) and paclitaxel (200 mg/m(2)) every 3 weeks or carboplatin and paclitaxel alone (n = 32). Primary efficacy end points were time to disease progression and best confirmed response rate. On disease progression, patients in the control arm had the option to receive single-agent bevacizumab 15 mg/kg every 3 weeks. RESULTS: Compared with the control arm, treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months). Of the 19 control patients that crossed over to single-agent bevacizumab, five experienced stable disease, and 1-year survival was 47%. Bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns; minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels. CONCLUSION: Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.

Antibodies, Monoclonal↗

PubMed2004

Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2.

PURPOSE: Preclinical studies indicate that gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE), an orally active epidermal growth factor receptor tyrosine kinase inhibitor, may enhance antitumor efficacy of cytotoxics, and combination with paclitaxel and carboplatin had acceptable tolerability in a phase I trial. Gefitinib monotherapy demonstrated unparalleled antitumor activity for a biologic agent, with less toxicity than docetaxel, in phase II trials in refractory, advanced non-small-cell lung cancer (NSCLC). This phase III, randomized, placebo-controlled, double-blind trial evaluated gefitinib plus paclitaxel and carboplatin in chemotherapy-naive patients with advanced NSCLC. PATIENTS AND METHODS: Patients received paclitaxel 225 mg/m(2) and carboplatin area under concentration/time curve of 6 mg/min/mL (day 1 every 3 weeks) plus gefitinib 500 mg/d, gefitinib 250 mg/d, or placebo. After a maximum of six cycles, daily gefitinib or placebo continued until disease progression. End points included overall survival, time to progression (TTP), response rate (RR), and safety evaluation. Results A total of 1,037 patients were recruited. Baseline demographic characteristics were well balanced. There was no difference in overall survival (median, 8.7, 9.8, and 9.9 months for gefitinib 500 mg/d, 250 mg/d, and placebo, respectively; P =.64), TTP, or RR between arms. Expected dose-related diarrhea and skin toxicity were observed in gefitinib-treated patients, with no new significant/unexpected safety findings from combination with chemotherapy. Subset analysis of patients with adenocarcinoma who received > or = 90 days' chemotherapy demonstrated statistically significant prolonged survival, suggesting a gefitinib maintenance effect. CONCLUSION: Gefitinib showed no added benefit in survival, TTP, or RR compared with standard chemotherapy alone. This large, placebo-controlled trial confirmed the favorable gefitinib safety profile observed in phase I and II monotherapy trials.

Adult↗

PubMed2004

Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1.

PURPOSE: The purpose of this study was to determine whether the addition of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE) to standard first-line gemcitabine and cisplatin provides clinical benefit over gemcitabine and cisplatin alone in patients with advanced or metastatic non-small-cell lung cancer (NSCLC). Gefitinib has demonstrated encouraging efficacy in advanced NSCLC in phase II trials in pretreated patients, and a phase I trial of gefitinib in combination with gemcitabine and cisplatin showed favorable tolerability. PATIENTS AND METHODS: This was a phase III randomized, double-blind, placebo-controlled, multicenter trial in chemotherapy-naive patients with unresectable stage III or IV NSCLC. All patients received up to six cycles of chemotherapy (cisplatin 80 mg/m(2) on day 1 and gemcitabine 1,250 mg/m(2) on days 1 and 8 of the 3-week cycle) plus either gefitinib 500 mg/d, gefitinib 250 mg/d, or placebo. Daily gefitinib or placebo was continued until disease progression. End points included overall survival (primary), time to progression, response rates, and safety evaluation. RESULTS: A total of 1,093 patients were enrolled. There was no difference in efficacy end points between the treatment groups: for the gefitinib 500 mg/d, gefitinib 250 mg/d, and placebo groups, respectively, median survival times were 9.9, 9.9, and 10.9 months (global ordered log-rank [GOLrank] P =.4560), median times to progression were 5.5, 5.8, and 6.0 months (GOLrank; P =.7633), and response rates were 49.7%, 50.3%, and 44.8%. No significant unexpected adverse events were seen. CONCLUSION: Gefitinib in combination with gemcitabine and cisplatin in chemotherapy-naive patients with advanced NSCLC did not have improved efficacy over gemcitabine and cisplatin alone. The reasons for this remain obscure and require further preclinical testing.

Adult↗

PubMed2004

Trastuzumab in the treatment of advanced non-small-cell lung cancer: is there a role? Focus on Eastern Cooperative Oncology Group study 2598.

PURPOSE: Multiple non-small-cell lung cancer (NSCLC) cell lines and 20% to 50% of pathologic specimens express HER-2/neu, the target of trastuzumab, and HER-2/neu expression has proven to be an independent, unfavorable prognostic factor in resected patients with NSCLC. Trastuzumab, in vitro, has demonstrated growth-inhibiting synergy with platinating agents, and additivity with paclitaxel. The Eastern Cooperative Oncology Group therefore launched a phase II study evaluating combination carboplatin, paclitaxel, and trastuzumab in patients with advanced NSCLC. MATERIALS AND METHODS: Eligibility stipulated the following: measurable tumor, HER-2/neu positivity (1+ to 3+ by Herceptest [Dako Corp, Carpinteria, CA], confirmed by central review), Eastern Cooperative Oncology Group PS 0 to 1, adequate marrow, hepatic and renal function, and left ventricular ejection fraction >or= 45%. Patients received paclitaxel 225 mg/m(2)/3 hours, and carboplatin (area under the curve, 6) every 3 weeks, and trastuzumab 4 mg/kg intravenously on day 1, then 2 mg/kg weekly for or= 3 neutropenia and thrombocytopenia was 57% (34%) and 16% (2%), respectively. Asymptomatic grade <or= 2 reduction in left ventricular ejection fraction occurred in 7%. Other nonhematologic toxicities, including nausea, fatigue, arthralgias, and peripheral sensory neuropathy, were mild to moderate and matched those expected with carboplatin and paclitaxel alone. Eighteen patients (35%) received maintenance trastuzumab. Median progression-free survival was 3.3 months; median survival was 10.1 months, and 1-year survival rate was 42%. CONCLUSION: Combination paclitaxel, carboplatin, and trastuzumab is feasible. Toxicity appears no worse than cytotoxic therapy alone. Overall survival is similar to historical data using carboplatin and paclitaxel alone. However, patients with 3+ HER-2/neu expression did well in contrast to historical data suggesting potential benefit for trastuzumab in this rare subset of NSCLC. Critical assessment of trastuzumab's role in advanced NSCLC will require phase III trials.

Adult↗

PubMed2004

Octreotide alone or with prednisone in patients with advanced thymoma and thymic carcinoma: an Eastern Cooperative Oncology Group Phase II Trial.

PURPOSE: To determine the objective response rate, duration of remission and toxicity of octreotide alone or with the later addition of prednisone in patients with unresectable, advanced thymic malignancies in whom the pretreatment octreotide scan was positive. PATIENTS AND METHODS: Forty-two patients with advanced thymoma or thymic carcinoma were entered onto the trial, of whom 38 were fully assessable (one patient had inconclusive histology; three patients had negative octreotide scan). Patients received octreotide 0.5 mg subcutaneously tid. At 2 months, patients were evaluated. Responding patients continued to receive octreotide alone; patients with progressive disease were removed from the study. All others received prednisone 0.6 mg/kg orally qid for a maximum of 1 year. RESULTS: Two complete (5.3%) and 10 partial responses (25%) were observed (four partial responses with octreotide alone; the remainder with octreotide plus prednisone). None of the six patients without pure thymoma responded. The 1- and 2-year survival rates were 86.6% and 75.7%, respectively. Patients with an Eastern Cooperative Oncology Group performance status of 0 lived significantly longer than did those with a performance status of 1 (P =.031). CONCLUSION: Octreotide alone has modest activity in patients with octreotide scan-positive thymoma. Prednisone improves the overall response rate but is associated with increased toxicity. Additional studies with the agent are warranted.

Adult↗

PubMed2004

Prolonged survival in patients with resected non-small cell lung cancer and single-level N2 disease.

OBJECTIVES: To test the hypothesis that patients with non-small cell lung cancer and single-level N2 metastases constitute a favorable subgroup of patients with mediastinal metastases, we analyzed the results of the Eastern Cooperative Oncology Group 3590 (a randomized prospective trial of adjuvant therapy in patients with resected stages II and IIIa non-small cell lung cancer) by site of primary tumor and pattern of lymph node metastases. METHODS: Accurate staging was ensured by mandating either systematic sampling or complete dissection of the ipsilateral mediastinal lymph nodes. The overall survival of patients with left lung non-small cell lung cancer and metastases in only 1 of lymph node levels 5, 6, or 7 and right lung non-small cell lung cancer with metastases in only 1 of levels 4 or 7 was compared with that of patients with N1 disease originating in the same lobe. RESULTS: The median survival of the 172 patients with single-level N2 disease was 35 months (95% confidence interval: 27-40 months) versus 65 months (95% confidence interval: 45-84 months) for the 150 patients with N1 disease (median follow-up 84 months, P =.01). However, among patients with left upper lobe tumors, survival was not significantly different between patients with N1 disease and patients with single-level N2 disease (49 vs 51 months, P =.63). The median survival of the 71 patients with single-level N2 metastases without concomitant N1 disease (skip metastases) was 59 months (95% confidence interval: 36-107 months) versus 26 months (95% confidence interval: 16-36 months) for the 145 patients with both N1 and N2 metastases (P =.001). CONCLUSIONS: Survival of patients with left upper lobe non-small cell lung cancer and metastases to single-level N2 lymph nodes is not significantly different from that of patients with N1 disease. The presence of isolate N2 skip metastases is associated with improved survival when compared with patients with both N1 and N2 disease. Survival should be reported by the lobe of primary tumor and metastatic pattern to guide future clinical trial development, treatment strategies, and revisions of the TNM staging system.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels.

OBJECTIVE: To evaluate whether administration of afelimomab, an anti-tumor necrosis factor F(ab')2 monoclonal antibody fragment, would reduce 28-day all-cause mortality in patients with severe sepsis and elevated serum levels of IL-6. DESIGN: Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial. SETTING: One hundred fifty-seven intensive care units in the United States and Canada. PATIENTS: Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels. INTERVENTIONS: Patients were stratified into two groups by means of a rapid qualitative interleukin-6 test kit designed to identify patients with serum interleukin-6 levels above (test positive) or below (test negative) approximately 1000 pg/mL. Of the 2,634 patients, 998 were stratified into the test-positive group, 1,636 into the test-negative group. They were then randomly assigned 1:1 to receive afelimomab 1 mg/kg or placebo for 3 days and were followed for 28 days. The a priori population for efficacy analysis was the group of patients with elevated baseline interleukin-6 levels as defined by a positive rapid interleukin-6 test result. MEASUREMENTS AND MAIN RESULTS: In the group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively. Afelimomab resulted in a significant reduction in tumor necrosis factor and interleukin-6 levels and a more rapid improvement in organ failure scores compared with placebo. The safety profile of afelimomab was similar to that of placebo. CONCLUSIONS: Afelimomab is safe, biologically active, and well tolerated in patients with severe sepsis, reduces 28-day all-cause mortality, and attenuates the severity of organ dysfunction in patients with elevated interleukin-6 levels.

APACHE↗

PubMed2004

Outcomes and costs among seniors requiring hospitalization for community-acquired pneumonia in Alberta.

OBJECTIVES: To determine the age-specific rates of hospital discharge, cost per day, and overall in-hospital 1- and 4-year mortality for seniors who required hospitalization for the treatment of community-acquired pneumonia (CAP). DESIGN: Retrospective analysis of two administrative health service databases. SETTING: Province of Alberta, Canada. PARTICIPANTS: Residents of Alberta aged 18 and older. MEASUREMENTS: Hospital abstracts and vital statistics from April 1, 1994, to March 31, 1999, were analyzed, and mortality and cost outcomes statistically modeled by regression. RESULTS: There were 8,500 annual hospital discharges for CAP costing more than $40 million per year. The overall in-hospital all-cause mortality rate was 12%, and the 1-year mortality rate was 26%. The mean age of pneumonia cases increased (P<.000) from 62.8 in 1994/1995 to 67.2 in 1998/1999. The proportion of hospital discharges in those aged 85 and older was 13% in 1994/1995, increasing to 18% in 1998/1999 (P<.000). The age-specific hospital discharge rate and length of hospitalization increased with age. After adjustment for other factors using modeling, it was found that the relative risk (RR) of in-hospital and 1-year mortality increased with age, the RR of using special medical care and higher-than-average daily hospital cost decreased with age, and the RR of greater-than-average daily hospital cost was not associated with an increase in comorbidity. Total costs per hospital stay were similar in patients aged 85 and older to those in patients aged 65 to 74, despite a one-third longer length of stay, which was consistent with reduced use of special medical care in those aged 85 and older. CONCLUSION: The increased use of hospital resources for CAP in the setting of an aging population may have been partially avoided because of limitations in care provided for seniors aged 85 and older.

Aged↗