Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial.

IMPORTANCE: The prognosis for patients with pancreatic cancer is poor, even after resection with curative intent. Gemcitabine-based chemotherapy is standard treatment for advanced pancreatic cancer, but its effect on survival in the adjuvant setting has not been demonstrated. OBJECTIVE: To analyze whether previously reported improvement in disease-free survival with adjuvant gemcitabine therapy translates into improved overall survival. DESIGN, SETTING, AND PATIENTS: CONKO-001 (Charité Onkologie 001), a multicenter, open-label, phase 3 randomized trial to evaluate the efficacy and toxicity of gemcitabine in patients with pancreatic cancer after complete tumor resection. Patients with macroscopically completely removed pancreatic cancer entered the study between July 1998 and December 2004 in 88 hospitals in Germany and Austria. Follow-up ended in September 2012. INTERVENTIONS: After stratification for tumor stage, nodal status, and resection status, patients were randomly assigned to either adjuvant gemcitabine treatment (1g/m2 d 1, 8, 15, q 4 weeks) for 6 months or to observation alone. MAIN OUTCOMES AND MEASURES: The primary end point was disease-free survival. Secondary end points included treatment safety and overall survival, with overall survival defined as the time from date of randomization to death. Patients lost to follow-up were censored on the date of their last follow-up. RESULTS: A total of 368 patients were randomized, and 354 were eligible for intention-to-treat-analysis. By September 2012, 308 patients (87.0% [95% CI, 83.1%-90.1%]) had relapsed and 316 patients (89.3% [95% CI, 85.6%-92.1%]) had died. The median follow-up time was 136 months. The median disease-free survival was 13.4 (95% CI, 11.6-15.3) months in the treatment group compared with 6.7 (95% CI, 6.0-7.5) months in the observation group (hazard ratio, 0.55 [95% CI, 0.44-0.69]; P < .001). Patients randomized to adjuvant gemcitabine treatment had prolonged overall survival compared with those randomized to observation alone (hazard ratio, 0.76 [95% CI, 0.61-0.95]; P = .01), with 5-year overall survival of 20.7% (95% CI, 14.7%-26.6%) vs 10.4% (95% CI, 5.9%-15.0%), respectively, and 10-year overall survival of 12.2% (95% CI, 7.3%-17.2%) vs 7.7% (95% CI, 3.6%-11.8%). CONCLUSIONS AND RELEVANCE: Among patients with macroscopic complete removal of pancreatic cancer, the use of adjuvant gemcitabine for 6 months compared with observation alone resulted in increased overall survival as well as disease-free survival. These findings provide strong support for the use of gemcitabine in this setting. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN34802808.

Repeated short-term use of eltrombopag in patients with chronic immune thrombocytopenia (ITP).

Eltrombopag is a thrombopoietin-receptor agonist that stimulates platelet production and increases platelet counts in patients with chronic immune thrombocytopenia (ITP). This open-label, single-arm study evaluated consistency of response and safety following repeated intermittent dosing of eltrombopag 50 mg daily over 3 cycles (1 cycle = up to 6 weeks on therapy followed by up to 4 weeks off therapy). The primary endpoint was proportion of patients with a response (platelet count ≥50 × 10(9) /l and ≥2× baseline) in Cycle 1 who subsequently responded in Cycle 2 or 3. Fifty-two of 65 evaluable patients (80%) responded in Cycle 1; these responding patients comprised the primary analysis population. Of these, 45/52 (87%) responded in Cycle 2 or 3 [95% confidence interval (CI), 74-94%] and 34/48 (71%; 95% CI, 56-83%) responded in both Cycles 2 and 3. Time to response was consistent, with >50% of responders responding by Day 8 in each cycle. Bleeding rates relative to baseline decreased by approximately 50% during each treatment cycle. The frequency or severity of adverse events, most commonly headache, did not increase over successive cycles. If a chronic ITP patient not requiring consistent therapy responds to short-term eltrombopag, then subsequent courses of eltrombopag, as needed, are likely to be safe and effective.

Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study.

Patients with chronic immune thrombocytopenia may have bleeding resulting from low platelet counts. Eltrombopag increases and maintains hemostatic platelet counts; however, to date, outcome has been reported only for treatment lasting ≤ 6 months. This interim analysis of the ongoing open-label EXTEND (Eltrombopag eXTENded Dosing) study evaluates the safety and efficacy of eltrombopag in 299 patients treated up to 3 years. Splenectomized and nonsplenectomized patients achieved platelets ≥ 50 000/µL at least once (80% and 88%, respectively). Platelets ≥ 50 000/µL and 2 × baseline were maintained for a median of 73 of 104 and 109 of 156 cumulative study weeks, respectively. Bleeding symptoms (World Health Organization Grades 1-4) decreased from 56% of patients at baseline to 20% at 2 years and 11% at 3 years. One hundred (33%) patients were receiving concomitant treatments at study entry, 69 of whom attempted to reduce them; 65% (45 of 69) had a sustained reduction or permanently stopped ≥ 1 concomitant treatment. Thirty-eight patients (13%) experienced ≥ 1 adverse events leading to study withdrawal, including patients meeting protocol-defined withdrawal criteria (11 [4%] thromboembolic events, 5 [2%] exceeding liver enzyme thresholds). No new or increased incidence of safety issues was identified. Long-term treatment with eltrombopag was generally safe, well tolerated, and effective in maintaining platelet counts in the desired range.

Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study.

BACKGROUND: Eltrombopag is an oral thrombopoietin receptor agonist for the treatment of thrombocytopenia. We aimed to compare the response to once daily eltrombopag versus placebo in patients with chronic immune thrombocytopenia during a 6-month period. METHODS: We undertook a phase 3, double-blind, placebo-controlled study in adults with previously treated immune thrombocytopenia of more than 6 months' duration who had baseline platelet counts lower than 30,000 per µL. Patients were randomly allocated (in a 2:1 ratio) treatment with local standard of care plus 50 mg eltrombopag or matching placebo once daily for 6 months. Randomisation was done centrally with a computer-generated randomisation schedule and was stratified by baseline platelet count (≤ 15,000 per µL), use of treatment for immune thrombocytopenia, and splenectomy status. Patients, investigators, and those assessing data were masked to allocation. Dose modifications were made on the basis of platelet response. Patients were assessed for response to treatment (defined as a platelet count of 50,000-400,000 per µL) weekly during the first 6 weeks and at least once every 4 weeks thereafter; the primary endpoint was the odds of response to eltrombopag versus placebo. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, number NCT00370331. FINDINGS: Between Nov 22, 2006, and July 31, 2007, 197 patients were randomly allocated to treatment groups and were included in the intention-to-treat analysis (135 eltrombopag, 62 placebo). 106 (79%) patients in the eltrombopag group responded to treatment at least once during the study, compared with 17 (28%) patients in the placebo group. The odds of responding were greater in patients in the eltrombopag group compared with those in the placebo group throughout the 6-month treatment period (odds ratio 8·2, 99% CI 3·59-18·73; p<0·0001). 37 (59%) patients receiving eltrombopag reduced concomitant treatment versus ten (32%) patients receiving placebo (p=0·016). 24 (18%) patients receiving eltrombopag needed rescue treatment compared with 25 (40%) patients receiving placebo (p=0·001). Three (2%) patients receiving eltrombopag had thromboembolic events compared with none in patients on placebo. Nine (7%) eltrombopag-treated patients and two (3%) in the placebo group had mild increases in alanine aminotransferase concentration, and five (4%) eltrombopag-treated patients (vs none allocated to placebo) had increases in total bilirubin. Four (7%) patients taking placebo had serious bleeding events, compared with one (<1%) patient treated with eltrombopag. INTERPRETATION: Eltrombopag is effective for management of chronic immune thrombocytopenia, and could be particularly beneficial for patients who have not responded to splenectomy or previous treatment. These benefits should be balanced with the potential risks associated with eltrombopag treatment. FUNDING: GlaxoSmithKline.

Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Eltrombopag is an oral, non-peptide, thrombopoietin-receptor agonist that stimulates thrombopoiesis, leading to increased platelet production. This study assessed the efficacy, safety, and tolerability of once daily eltrombopag 50 mg, and explored the efficacy of a dose increase to 75 mg. METHODS: In this phase III, randomised, double-blind, placebo-controlled study, adults from 63 sites in 23 countries with chronic idiopathic thrombocytopenic purpura (ITP), platelet counts less than 30 000 per muL of blood, and one or more previous ITP treatment received standard care plus once-daily eltrombopag 50 mg (n=76) or placebo (n=38) for up to 6 weeks. Patients were randomly assigned in a 2:1 ratio of eltrombopag:placebo by a validated randomisation system. After 3 weeks, patients with platelet counts less than 50 000 per microL could increase study drug to 75 mg. The primary endpoint was the proportion of patients achieving platelet counts 50 000 per microL or more at day 43. All participants who received at least one dose of their allocated treatment were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00102739. FINDINGS: 73 patients in the eltrombopag group and 37 in the placebo group were included in the efficacy population and were evaluable for day-43 analyses. 43 (59%) eltrombopag patients and six (16%) placebo patients responded (ie, achieved platelet counts >/=50 000 per microL; odds ratio [OR] 9.61 [95% CI 3.31-27.86]; p<0.0001). Response to eltrombopag compared with placebo was not affected by predefined study stratification variables (baseline platelet counts, concomitant ITP drugs, and splenectomy status) or by the number of previous ITP treatments. Of the 34 patients in the efficacy analysis who increased their dose of eltrombopag, ten (29%) responded. Platelet counts generally returned to baseline values within 2 weeks after the end of treatment. Patients receiving eltrombopag had less bleeding at any time during the study than did those receiving placebo (OR 0.49 [95% CI 0.26-0.89]; p=0.021). The frequency of grade 3-4 adverse events during treatment (eltrombopag, two [3%]; placebo, one [3%]) and adverse events leading to study discontinuation (eltrombopag, three [4%]; placebo, two [5%]), were similar in both groups. INTERPRETATION: Eltrombopag is an effective treatment for managment of thrombocytopenia in chronic ITP.

Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura.

BACKGROUND: The pathogenesis of chronic idiopathic thrombocytopenic purpura (ITP) involves antibody-mediated platelet destruction and reduced platelet production. Stimulation of platelet production may be an effective treatment for this disorder. METHODS: We conducted a trial in which 118 adults with chronic ITP and platelet counts of less than 30,000 per cubic millimeter who had had relapses or whose platelet count was refractory to at least one standard treatment for ITP were randomly assigned to receive the oral thrombopoietin-receptor agonist eltrombopag (30, 50, or 75 mg daily) or placebo. The primary end point was a platelet count of 50,000 or more per cubic millimeter on day 43. RESULTS: In the eltrombopag groups receiving 30, 50, and 75 mg per day, the primary end point was achieved in 28%, 70%, and 81% of patients, respectively. In the placebo group, the end point was achieved in 11% of patients. The median platelet counts on day 43 for the groups receiving 30, 50, and 75 mg of eltrombopag were 26,000, 128,000, and 183,000 per cubic millimeter, respectively; for the placebo group the count was 16,000 per cubic millimeter. By day 15, more than 80% of patients receiving 50 or 75 mg of eltrombopag daily had an increased platelet count. Bleeding also decreased during treatment in these two groups. The incidence and severity of adverse events were similar in the placebo and eltrombopag groups. CONCLUSIONS: Eltrombopag increased platelet counts in a dose-dependent manner in patients with relapsed or refractory ITP. (ClinicalTrials.gov number, NCT00102739.)

Medical costs associated with non-Hodgkin's lymphoma in the United States during the first two years of treatment.

OBJECTIVES: To determine the direct costs of medical care associated with aggressive and indolent non-Hodgkin's lymphoma (NHL) in the United States; to show how costs for aggressive NHL change over time by examining costs related to initial, secondary and palliative treatment phases; and to evaluate the economic consequences of treatment failure in aggressive NHL. PATIENTS AND METHODS: A retrospective cohort analysis of 1999 - 2000 direct costs in newly diagnosed NHL patients and controls (subjects without any cancer) was conducted using the MarketScan medical and drug claims database of large employers across the United States. Treatment failure analysis was conducted for aggressive NHL patients, and was defined by the need for secondary treatment or palliative care after initial therapy. Cost of treatment failure was calculated as difference in regression-adjusted costs between patients with initial therapy only and patients experiencing initial treatment failure. RESULTS: Patients with aggressive (n = 356) and indolent (n = 698) NHL had significantly greater health service utilization and associated costs (all P < 05) than controls (n = 1068 for aggressive, n = 2094 for indolent). Mean monthly costs were 5871 dollars for aggressive NHL vs. 355 dollars for controls (P < 0001) and 3833 dollars for indolent NHL vs. 289 dollars for controls (P < 0001). The primary cost drivers were hospitalization (aggressive NHL = 44% of total costs, indolent NHL = 50%) and outpatient office visits (aggressive NHL = 39%, indolent NHL = 34%). For aggressive NHL, mean monthly initial treatment phase costs (10,970 dollars) and palliative care costs (9836 dollars) were higher than costs incurred during secondary phase (3302 dollars). The mean cost of treatment failure in aggressive NHL was 14,174 dollars per month, and 85,934 dollars over the study period. CONCLUSION: The treatment of NHL was associated with substantial health care costs. Patients with aggressive lymphomas tended to accrue higher costs, compared with those with indolent lymphomas. These costs varied over time, with the highest costs occurring during the initial treatment and palliative care phases. Treatment failure was the most expensive treatment pattern. New strategies to prevent or delay treatment failure in aggressive NHL could help reduce the economic burden of NHL.

Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium.

PURPOSE: To assess the antitumor activity and toxicity of pemetrexed as second-line chemotherapy in patients with locally advanced or metastatic transitional cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Eligible patients had a performance status of 0 or 1, adequate organ function, previous treatment with one prior chemotherapy regimen for locally advanced or metastatic TCC of the urothelium or relapsed within 1 year of adjuvant or neoadjuvant treatment. Patients received pemetrexed 500 mg/m2 intravenously on day 1 every 21 days, with vitamin B12, folic acid, and dexamethasone prophylaxis. RESULTS: Forty-seven patients were enrolled and included in the intent-to-treat efficacy analysis. Responses: 3 (6.4%) complete responses and 10 (21.3%) partial responses produced an overall response rate of 27.7%. Ten patients (21.3%) had stable disease and 22 patients (46.8%) progressed. The median time to progressive disease was 2.9 months (95% CI, 1.7 months to 4.6 months) and median overall survival was 9.6 months (95% CI, 5.1 months to 14.6 months). Median duration of response was 5.0 months (95% CI, 3.9 months to 13.8 months). Of the 47 patients assessable for safety, grade 3 or 4 hematologic events were thrombocytopenia (8.5%; 0.0%), neutropenia (4.3%; 4.3%) and anemia (2.1%; 2.1%), respectively. Nonlaboratory toxicities included grade 4 stomatitis/pharyngitis, sepsis syndrome (one patient each), and grade 3 fatigue (three patients) and diarrhea (two patients). CONCLUSION: Single-agent pemetrexed is safe and active as second-line treatment of patients with advanced TCC of the urothelium. Additional evaluation in the first- or second-line setting in TCC of the urothelium is warranted.

Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer.

PURPOSE: To compare long-term survival in patients with locally advanced or metastatic transitional cell carcinoma (TCC) of the urothelium treated with gemcitabine/cisplatin (GC) or methotrexate/vinblastine/doxorubicin/cisplatin (MVAC). PATIENTS AND METHODS: Efficacy data from a large randomized phase III study of GC versus MVAC were updated. Time-to-event analyses were performed on the observed distributions of overall and progression-free survival. RESULTS: A total of 405 patients were randomly assigned: 203 to the GC arm and 202 to the MVAC arm. At the time of analysis, 347 patients had died (GC arm, 176 patients; MVAC arm, 171 patients). Overall survival was similar in both arms (hazard ratio [HR], 1.09; 95% CI, 0.88 to 1.34; P = .66) with a median survival of 14.0 months for GC and 15.2 months for MVAC. The 5-year overall survival rates were 13.0% and 15.3%, respectively (P = .53). The median progression-free survival was 7.7 months for GC and 8.3 months for MVAC, with an HR of 1.09. The 5-year progression-free survival rates were 9.8% and 11.3%, respectively (P = .63). Significant prognostic factors favoring overall survival included performance score (> 70), TNM staging (M0 v M1), low/normal alkaline phosphatase level, number of disease sites (

A report on serious pulmonary toxicity associated with gemcitabine-based therapy.

BACKGROUND: Serious pulmonary toxicity (SPT) has recently been noted with gemcitabine-based therapy (G). However, the incidence of SPT has not been fully evaluated. This retrospective review estimates the incidence of, and the factors influencing, SPT with G. PATIENTS AND METHODS: Pulmonary toxicity was defined as dyspnea, interstitial pneumonitis, lung disorder, lung edema, lung fibrosis, pneumonia, respiratory disorder, and respiratory distress syndrome. Patients were identified from 2 worldwide Lilly databases--the clinical trial database (CTD) and the safety database (SD). Events designated as serious and possibly/probably related to therapy by the primary physician were independently evaluated and confirmed. Serious pulmonary toxicity events were categorized as dyspnea or other SPT events. RESULTS: Of the 91 patients identified by the investigator in the CTD as having G-related SPT, 32 had G-related SPT per the independent reviewers. Based on the 4448 patients treated with G in the CTD, the incidences of dyspnea and other SPT events were 0.45% and 0.27%, respectively. Of the 295 patients identified by the investigator in the SD as having G-related SPT, 167 had G-related SPT per the independent reviewers. Based on an estimated 217,400 patients treated with commercial G worldwide, the crude incidences of dyspnea and other SPT events were 0.02% and 0.06%, respectively. CONCLUSIONS: SPT associated with G is uncommon. Incidences from the CTD for dyspnea and other SPT are 0.45% and 0.27%, respectively. Incidences from the SD for dyspnea and other SPT are 0.02% and 0.06%, respectively. The influence of other factors, such as anticancer therapies, on these incidences needs to be better understood.