scholarly journals Enhanced neutrophil extracellular trap formation in COVID-19 is inhibited by the PKC inhibitor ruboxistaurin.

2021 ◽  
Author(s):  
Rebecca Dowey ◽  
Joby Cole ◽  
A A Roger Thompson ◽  
Chenghao Huang ◽  
Jacob Whatmore ◽  
...  
Keyword(s):  
Lung Damage ◽  
Neutrophil Extracellular Trap ◽  
Phase Iii ◽  
Pkc Inhibitor ◽  
Hospitalised Patients ◽  
Significant Damage ◽  
Phase Iii Trials ◽  
Healthy Control ◽  
Epithelial Cell Death

Neutrophil extracellular traps (NETs) are web-like DNA and protein lattices which are expelled by neutrophils to trap and kill pathogens, but which cause significant damage to the host tissue. NETs have emerged as critical mediators of lung damage, inflammation and thrombosis in COVID-19 and other diseases, but there are no therapeutics to prevent or reduce NETs that are available to patients. Here, we show that neutrophils isolated from hospitalised patients with COVID-19 produce significantly more NETs in response to LPS compared to cells from healthy control subjects. A subset of patients were captured at follow-up clinics (3-4 month post-infection) and while LPS-induced NET formation is significantly lower at this time point, it remains elevated compared to healthy controls. LPS- and PMA-induced NETs were significantly inhibited by the protein kinase C (PKC) inhibitor ruboxistaurin. Ruboxistaurin-mediated inhibition of NETs in healthy neutrophils reduces NET-induced epithelial cell death. Our findings suggest ruboxistaurin could reduce proinflammatory and tissue-damaging consequences of neutrophils during disease, and since it has completed phase III trials for other indications without safety concerns, it is a promising and novel therapeutic strategy for COVID-19.

scholarly journals Evaluating Intermittent Androgen-Deprivation Therapy Phase III Clinical Trials: The Devil Is in the Details

2016 ◽  
Vol 34 (3) ◽  
pp. 280-285 ◽  
Author(s):  
Maha Hussain ◽  
Catherine Tangen ◽  
Celestia Higano ◽  
Nicholas Vogelzang ◽  
Ian Thompson
Keyword(s):  
Prostate Cancer ◽  
Statistical Power ◽  
Progression Free Survival ◽  
Androgen Deprivation ◽  
Phase Iii ◽  
End Point ◽  
Phase Iii Clinical Trials ◽  
Noninferiority Trials ◽  
Phase Iii Trials

Purpose Intermittent androgen deprivation (IAD) has been widely tested in prostate cancer. However, phase III trials testing continuous androgen deprivation (CAD) versus IAD have reached inconclusive and seemingly contradictory results. Different design and conduct issues must be critically evaluated to better interpret the results. Patients and Methods Seven published phase III trials were examined for prespecified design and outcomes. Treatment specifications; primary end point; superiority versus noninferiority design assumptions, including magnitude of assumed versus observed noninferiority margin (NIM); duration of follow-up; and quality-of-life (QOL) outcomes were considered in terms of the results and conclusions reported. Results Five trials had a superiority and three had a noninferiority primary hypothesis. Only three trials had a uniform population and overall survival (OS) end point. All trials observed better outcomes in terms of OS and progression-free survival (PFS) than assumed at time of study design, translating into prespecified NIMs or hazard ratios that reflected larger absolute differences in OS or PFS between arms. Lower-than-expected event rates also reduced statistical power for the trials. Other factors, including length of follow-up, cause of death, QOL, and primary end point, and their impact on trial interpretation are discussed. Conclusion No trial to date has demonstrated survival superiority of IAD compared with CAD. Trials concluding IAD is noninferior to CAD were based on wide NIMs that included clinically important survival differences, not likely to be considered comparable by physicians or patients. Interim analyses relying on short follow-up and including a majority of non–prostate cancer deaths will favor a noninferiority conclusion and should be interpreted cautiously. Adequate follow-up is required to ensure capture of prostate cancer deaths in both superiority and noninferiority trials.

040 An analysis of malignancy risk in the clinical development programme of cladribine tablets in patients with relapsing multiple sclerosis

2018 ◽  
Vol 89 (6) ◽  
pp. A17.1-A17
Author(s):  
Andrew Galazka ◽  
Axel Nolting ◽  
Stuart Cook ◽  
Thomas Leist ◽  
Giancarlo Comi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Case Reports ◽  
Meta Analysis ◽  
Reference Population ◽  
Phase Iii ◽  
Disease Modifying Drugs ◽  
Malignancy Risk ◽  
Phase Iii Trials ◽  
Relapsing Multiple Sclerosis

IntroductionAn independent meta-analysis; Pakpoor et al. Neurol Neuroimmunol Neuroinflamm 2015;2:e158) in Phase III trials (with a 2 year duration) of disease modifying drugs (DMDs) in patients with relapsing multiple sclerosis found no increased rate of malignancy with cladribine tablets (CT) versus other DMD treatments. Data from additional trials involving CT 3.5 mg/kg (CT3.5) and a safety registry (up to 8 years’ follow-up) allow further insights into malignancy risk. Objective is to assess malignancy risk with CT3.5 monotherapy and placebo (PBO) in data from 3 Phase III trials and a registry, and compare the incidence rate with a global database.MethodsThe CT 3.5 population comprised 923 patients (3433 patient-years’ [PY] total exposure time) and the PBO group comprised 641 patients (2026 PY). Individual case reports of malignancies were reviewed by independent, blinded adjudication committee. Standardised incidence ratios (SIR) were calculated using the GLOBOCAN reference population (excluding non-melanoma skin cancers [NMSCs]) and a Danish reference population for NMSC rates.ResultsThe incidence per 100 PY of confirmed malignancy was CT3.5 0.293 (95%CI 0.158–0.544) and PBO 0.148 (95%CI 0.048–0.460); the risk difference 95% CI included 0 (−0.166–0.414). The CT 3.5 malignancy SIR was almost identical (0.97, 95% CI 0.44–1.85) to the GLOBOCAN matched reference population. The PBO group SIR was numerically lower (0.48, 95% CI 0.14–1.53). There were no cases of haematological, lymphoproliferative or virus-induced cancers. There was no clustering of specific tumour types, and the incidence of skin cancer was not increased after treatment with CT3.5 versus PBO. The incidence of malignancies with CT3.5 was constant and did not increase over time.ConclusionAnalysis of malignancy rates in a cohort that includes patients with up to 8 years’ follow-up confirms the Conclusion of the earlier meta-analysis; the incidence of malignancies with CT3.5 is similar to a matched reference population.

Prognostic value of immunohistochemical phenotypes (IP) of 141 operable breast cancer patients (pts) included in phase III trials of adjuvant therapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21040-21040
Author(s):  
R. Trujillo ◽  
E. Gallego ◽  
A. Márquez ◽  
N. Ribelles ◽  
J. Trigo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cox Regression ◽  
Phase Iii ◽  
Rank Test ◽  
Prognostic Effect ◽  
Log Rank Test ◽  
Kaplan Meier ◽  
Phase Iii Trials ◽  
Her 2

21040 Background: Gene expression arrays and IP studies classified breast cancer in three distinct subtypes: basal, HER2/neu and luminal that are associated with different clinical outcomes. Methods: In 141 pts with operable breast cancer, included in phase III trials of adjuvant therapy in our center, immunohistochemical staining was performed on 3μm sections of paraffin blocks, containing tissue-arrays of tumour tissue.A basal phenotype (BP) was defined by negative estrogen receptor (ER) and progesterone receptor (PR) and positive cytokeratin (CK) 5/6 or EGFR immunoreactivity. HER2/neu phenotype as positive c-erb B2 by HercepTest™ and luminal phenotype (LP) by positive ER, PR and CK 7/8 and negative HER-2. Survival curves were calculated by the Kaplan-Meier method. The differences between survivals were estimated using the log rank test. Multivariate Cox regression analysis was used to evaluate any independent prognostic effect of the variables on disease-free survival (DFS). Results: Complete clinical follow-up information was available for 141 pts. The median follow-up period was 52 months (range 1–103 months). During this period, 13.8% pts died from breast cancer and 27.7% pts relapsed. At the time of the primary diagnosis 10.4% of the pts had lymph node negative disease and 89.6% had positive lymph nodes. 50.8% pts received taxane chemotherapy, 7.7% Trastuzumab, 62.3% radiotherapy and 61% pts received hormonotherapy. Positivity for LP was 65.2%, BP 9.9% and Her-2 phenotype 8.5%. 16.3% didn't fit for any of the three subtypes. Median DFS for BP: 24 moths, for LP and Her-2 phenotypes median DFS was not reached. 5 years DFS were; BP: 19%, LP: 63% and Her-2: 56%. Kaplan-Meier survival analyses demonstrated that the presence of a detectable BP was highly significantly associated with a worse DFS compared with the presence of a LP, log rank test (p= 0.0001). Multivariate Cox regression analyses estimated that the prognostic effect of BP in relation to DFS was independent of lymph node, stage and tumor size, HR: 0.12 95% CI (0.05–0.2). Conclusions: We found that expression of BP was associated with poor prognostic in the context of randomized phase III trials. No significant financial relationships to disclose.

Long-term follow-up of autotransplant (AT)-supported high-dose melphalan (hdm) for multiple myeloma (MM): Update of Intergroup Francophone du Myelome (IFM), Southwest Oncology Group (SWOG), and Arkansas (ARK) Total Therapy (TT) trials

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8519-8519
Author(s):  
B. Barlogie ◽  
M. Attal ◽  
J. Crowley ◽  
J. Harousseau
Keyword(s):  
Phase Iii ◽  
Long Term Results ◽  
High Dose ◽  
Long Term Follow Up ◽  
Phase Iii Trials ◽  
Trial Outcomes ◽  
Total Therapy ◽  
High Dose Melphalan

8519 Background: Clinical trial outcomes are usually published when statistical protocol objectives have been met, with short median follow-up not exceeding 5 years. Due to treatment innovations, MM survival beyond 10 years has become more common but formal long-term results are seldom reported. Methods: IFM, SWOG and ARK provide an update of their major trials. IFM-90: 1 AT v standard therapy (STD), IFM-94: 2 v 1 AT, IFM-9902: 2AT ± THAL, IFM-9904: 2AT for high-risk MM; SWOG-9321: 1 AT v STD; TT1: 2 AT with interferon, TT2: 2AT ± THAL, TT3: 2AT + THAL + bortezomib. Results: OS clustered in 3 groups with superior outcomes for TT3/TT2/IFM-99 v TT1 v IFM-94/ IFM-90/SWOG-9321 with 5/10/15-yr estimates of 70%/50%/TE v 57%/35%/20% v 43%/25%/15% (p<0.0001). EFS also clustered in 3 groups with superior outcomes for TT3 v TT2 v remainder with estimates of 71%/TE/TE v 50%/35%/TE v 27%/ 15%/10% (p<0.0001). Among phase III trials, added THAL in TT2 increased 10-yr OS/EFS from 40%/25% to 60%/40% (p=0.04/p=0.0005); 10-yr OS was 30% v 8% with 1 v 0 AT in IFM-90 (p=0.005), 31% v 21% with 2 AT v 1 AT in IFM-94 (p=0.08), and 20% for both arms of S9321. On multivariate analysis involving 2962 patients, OS was adversely affected by B2M >=3.5mg/L (p<0.001), LDH >=ULN (p<0.001), hemoglobin <10g/dL (p=0.001) and albumin <3.5g/dL (p=0.02). 2AT (65%) and THAL (21%) both contributed independently to superior OS (p<0.001, p=0.002); among individual trials, IFM-9902 (19%) and TT2/TT3 (33%) both improved OS significantly (both p<0.001). For each of the 3 major OS clusters, 228 patients could be matched on B2M, LDH, hemoglobin and albumin, with 10-yr OS/EFS estimates of 65%/30% for the TT3/TT2/IFM-9902 group significantly exceeding 30%/15% each for the other 2 groups (p=0.001/p=0.001). Conclusions: A 15-yr EFS plateau of 10% with older trials and superior 10-yr EFS/OS estimates of 50%/35% with recent studies emphasize that cure should be a realistic trial objective in contemporary MM therapy, requiring however very long-term follow-up beyond 15 years. [Table: see text]

Intraoperatively assessed macroscopic serosal changes in patients with curatively resected advanced gastric cancer (GC): Clinical implications for prognosis and peritoneal recurrence.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 23-23
Author(s):  
Changhoon Yoo ◽  
Min-Hee Ryu ◽  
Heung-Moon Chang ◽  
Jeong Hwan Yook ◽  
Young Soo Park ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Peritoneal Recurrence ◽  
Phase Iii ◽  
Diffuse Gastric Cancer ◽  
Type Iv ◽  
Borrmann Type ◽  
Phase Iii Trials ◽  
N Stage ◽  
Borrmann Type Iv

23 Background: To validate the prognostic relevance of macroscopic serosal changes in patients with resected GC, we analyzed prospectively collected databases of two multicenter randomized phase III trials on adjuvant chemotherapy. Methods: In total, 655 patients in the control groups of AMC 0101 (NCT00296322) and 0201 (NCT00296335) trials were selected. Macroscopic serosal changes were determined according to disruptions in serosal continuity, such as changes in color or nodular texture by the operating surgeon. Correlations with recurrence-free survival (RFS), overall survival (OS), and time-to-peritoneal recurrence were analyzed. Results: About two-thirds of the patients were male (69%), and the median age was 55 years (range = 29–70 years). According to Lauren’s classification, 215 patients (33%) showed intestinal type. After a median follow-up period of 61.6 months (range = 2.6–113.9 months), the 5-year RFS and OS rates were 55.0% (95% CI = 51.2–58.9%) and 59.9% (95% CI = 56.2–63.6%), respectively. Intraoperatively assessed macroscopic serosal changes were identified in 432 patients (66%). This was significantly associated with multifocal or diffuse gastric cancer (p = 0.001), Borrmann type IV (p = 0.005), advanced pathological T stage (p < 0.001), advanced pathological N stage (p < 0.001), advanced pathological stage (p < 0.001), and total gastrectomy (p < 0.001). In multivariate analyses, which included prognostic factors of localized gastric cancer, macroscopically serosal changes were significantly associated with poor RFS (hazard ratio [HR] = 2.0, 95% CI 1.4–2.7; p < 0.001) and OS (HR = 2.1, 95% CI 1.5–3.0; p < 0.001). It was also significantly related with shorter time-to-peritoneal recurrence (HR = 2.9; 95% CI = 1.7–5.0; p< 0.001). Conclusions: Intraoperatively assessed macroscopic serosal changes confer a poor prognosis and increased peritoneal recurrence in patients with curatively resected GC. Macroscopic assessment of serosal changes may be a useful indicator that allows better risk stratification of patients with resected GC in terms of prognosis and peritoneal recurrence.

CVP alternating with fludarabine (CVP/F) chemotherapy prior to idiotype vaccination for follicular lymphoma (FL)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8065-8065
Author(s):  
W. Z. Ai ◽  
F. J. Hsu ◽  
J. M. Timmerman ◽  
D. Czerwinski ◽  
B. Taidi ◽  
...  
Keyword(s):  
Opportunistic Infections ◽  
Tumor Burden ◽  
Phase Iii ◽  
The Novel ◽  
Effective Immune Response ◽  
Best Response ◽  
Time To Treatment Failure ◽  
Phase Iii Trials ◽  
Idiotype Vaccine

8065 Background: Reducing the tumor burden prior to vaccination facilitates an effective immune response (IR) against the idiotype in FL. In this context, we evaluated the efficacy and toxicity of a novel cytoreductive regimen, CVP/F. Methods: Newly diagnosed, advanced stage FL patients (pt) were treated with CVP (cyclophosphamide 400 mg/m2 PO d1–5, vincristine 2 mg d 1, prednisone 100 mg/m2 d1–5) alternating with F (25 mg/m2 IV d1–5) every 21 days for 2 cycles beyond best response (maximum 8). Pt judged to be cytoreduced adequately were vaccinated monthly × 5 with idiotype protein made from their FL. Results: Among 34 enrolled pt, median age was 45 years (yr), and FLIPI scores were: 18% low, 71% intermediate and 12% high. 38% pt had grade 1 and 62% had grade 2 FL. There were no toxic deaths or opportunistic infections. With 233 cycles (117 CVP and 116 F) given to 33 evaluable pt, neutropenic fever occurred in 7 cycles (3%). 20 cycles (17%) of CVP and 29 cycles (25%) of F were dose reduced for leukopenia. 18 pt (53%) achieved a CR (16) or CRu (2), and 13 pt (38%) had a PR. 22 pt (65%) treated with CVP/F proceeded to vaccination; 10 additional pt (29%) were vaccinated after secondary chemotherapy was given for further cytoreduction. At median follow-up of 11.2 yr, 15-yr overall survival (OS) was 85%. Two of 5 deaths occurred without lymphoma progression. TTF (time to treatment failure = second treatment, relapse, death) at 11 yr was 38%. Anti-idiotype antibody and T cell IR were seen in 44% and 31% pt, respectively. There were no differences in TTF or OS according to IR. Conclusions: CVP/ F was effective in advanced FL, comparing favorably with our historical experience with CVP in terms of CR rate, proportion proceeding to vaccination, TTF and OS after vaccination. This favorable outcome may have been due to the novel alternating CVP/F cytoreductive regimen, idiotype vaccination or both. The idiotype vaccine is now being tested in phase III trials. The CVP/F regimen also warrants further evaluation. No significant financial relationships to disclose.

Evaluation of the absolute lymphocyte count as a biomarker for melanoma patients treated with the commercially available dose of ipilimumab (3mg/kg).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8575-8575 ◽  
Author(s):  
Michael Andrew Postow ◽  
Jianda Yuan ◽  
Katherine Panageas ◽  
Kita Bogatch ◽  
Margaret Callahan ◽  
...  
Keyword(s):  
Survival Data ◽  
Lymphocyte Count ◽  
Preliminary Finding ◽  
Absolute Lymphocyte Count ◽  
Phase Iii ◽  
Cancer Center ◽  
Karnofsky Performance Score ◽  
Phase Iii Trials ◽  
Pre Treatment

8575 Background: Ipilimumab (ipi) has demonstrated an overall survival (OS) benefit in 2 phase III trials. Only ~30% of patients (pts) achieve clinical benefit, and factors that determine which pts benefit are unclear. For pts treated with 10mg/kg of ipi, we previously reported that an absolute lymphocyte count (ALC) ≥1000/μL prior to dose 3 [week (wk) 7] was associated with improved OS. Since the mean increase in ALC during ipi treatment correlates with dose, we investigated if ALC is also associated with improved OS at 3mg/kg, the currently FDA approved, commercially available dose. Methods: In an IRB-approved analysis, we evaluated landmark survival data from 137 pts treated with 3mg/kg of ipi at Memorial Sloan-Kettering Cancer Center. 67 pts were treated on an expanded access protocol (CA 184-045). 70 pts were treated per FDA approval (commercial ipi) with 4 standard induction doses. These 2 groups were analyzed separately because some pts in CA 184-045 received re-induction ipi. ALC was determined at first ipi dose (baseline, wk 1) and at subsequent doses (wks 4, 7, and 10). Results: Pts treated with 3mg/kg on CA 184-045 with a wk 7 (prior to dose 3) ALC ≥1000/µL had significantly improved OS compared to pts with an ALC at wk 7 <1000/μL (Median OS: not reached vs. 4.24 mos, p<0.001). This OS difference was also seen for pts treated with commercial ipi (Median OS: not reached vs. 4.44 mos, p<0.01). This difference remained significant in a multivariable model accounting for Karnofsky performance score, LDH, M-stage, and number of prior therapies for pts in the CA 184-045 group and commercial ipi group (p=0.01 and p=0.05, respectively). Baseline ALC ≥1000/µL was associated with improved OS (p=0.02) for pts in the commercial ipi group, though follow-up is limited. Conclusions: At the FDA approved dose of ipi, 3mg/kg, ALC at wk 7 remains significantly associated with improved OS. Our preliminary finding of improved OS for pts treated with commercial ipi whose pre-treatment baseline ALC ≥1000/µL deserves confirmation with longer follow-up and prospective validation. Baseline or on treatment ALC may be a marker of overall prognosis, regardless of therapy.

Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration.

2017 ◽  
Vol 35 (18_suppl) ◽  
pp. LBA1-LBA1 ◽  
Author(s):  
Qian Shi ◽  
Alberto F. Sobrero ◽  
Anthony Frank Shields ◽  
Takayuki Yoshino ◽  
James Paul ◽  
...  
Keyword(s):  
Cox Model ◽  
Disease Free Survival ◽  
Standard Of Care ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Stage Iii ◽  
Differential Outcomes ◽  
Phase Iii Trials ◽  
Stratified Cox Model

LBA1 Background: Since 2004, 6 months (m) of oxaliplatin (oxali)-based treatment has been the standard of care as adjuvant therapy for stage III CC. Since oxali is associated with cumulative neurotoxicity, shorter duration of adjuv therapy could spare pts toxicity and lead to substantial saving in health expenditures. Methods: A prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials (SCOT, TOSCA, Alliance/SWOG 80702, IDEA France (GERCOR/PRODIGE), ACHIEVE, HORG) was performed to evaluate the non-inferiority (NI) of 3m compared with 6m (ref) of adjuv FOLFOX/XELOX. The primary endpoint was disease-free survival (DFS), defined as time from enrolment to relapse, 2nd CRC, and death (all causes). NI was to be declared if the 2-sided 95% confidence interval (CI) for DFS hazard ratio (HR 3m v 6m) estimated by a stratified Cox model was below 1.12. NI was examined within regimen and stage subgroups as pre-planned. Results: The analysis included 12,834 pts from 12 countries, accrued from 6/07 to 12/15. Stage distribution: 13% T1-2, 66% T3, 21% T4; 28% N2; 40% received XELOX. G3+ neurotoxicity was higher in the 6m v 3m arm (16 v 3% FOLFOX, 9 v 3% XELOX, p<0.0001). With a median follow-up of 39 mos, 3263 DFS events were observed. Overall, the 3 year DFS rate was 74.6% (3m) and 75.5% (6m), with estimated DFS HR of 1.07 (95%CI, 1.00-1.15). The 3m v 6m DFS HRs were 1.16 (95%CI, 1.06-1.26) and 0.95 (95% CI, 0.85-1.06) for FOLFOX and XELOX treated pts, respectively. The 3m v 6m DFS HRs were 1.01 (95%CI, 0.90-1.12) in T1-3 N1, and 1.12 (95%CI, 1.03-1.23) for T4 or N2 pts. Conclusions: While NI was not established for the overall cohort, NI of 3m v 6m oxali-based adjuv therapy was supported for XELOX. As each IDEA trial treated varying proportions of pts with XELOX (0 to 75%), the regimen interaction likely produced the differential outcomes observed between individual studies. Certain substages (T1-3 N1) also showed NI for 3m v 6m. These data provide a framework for discussions on risks and benefits of individualized adjuv therapy approaches. Support: U10CA180821, U10CA180882, U10CA180888, U10CA180835, INCA, PHRC2009, EME 09/800/34, HTA 14/140/84, CRUK C1348/A15960, JFMC. Clinical trial information: NCT01150045.

Prolongation of the average survival time in pancreatic cancer (a new measure of effect): Pooled analysis of adjuvant chemotherapy trials.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16723-e16723
Author(s):  
Eduardo Ceballos Barbancho ◽  
Galo Sánchez Robles
Keyword(s):  
Pancreatic Cancer ◽  
Adjuvant Treatment ◽  
Area Under The Curve ◽  
Pooled Analysis ◽  
National Institutes Of Health ◽  
Phase Iii ◽  
Processing Application ◽  
Average Survival ◽  
Phase Iii Trials

e16723 Background: With the aim of improving the prognosis of the disease, in recent years attempts have been made to optimize the adjuvant treatment of pancreatic cancer, having demonstrated the usefulness of chemotherapy in several phase III trials: CONKO-001, JASPAC-01, ESPAC -4 and PRODIGE. Methods: The method to measure the Area Under the Curve (AUC) is universally known. When the curve is not homogeneous, the AUC is calculated using the traditional method of breaking down the total area into a sum of many polygons. We have calculated the AUC through pixel counting using Image J, which is an image processing application, programmed in Java, developed in the National Institutes of Health and free to access. To estimate the consistency between the pixels and the sum of polygons, we have performed several curves with linear edges to measure the AUC through the sums of the polygons, and then by counting pixels with the Image J application. We have verified that the results are similar, so the pixel count can be used to replace the sum of polygons, especially when the curves are not homogeneous. Entering the areas obtained with Image J in the worksheet, made for this purpose, and available for free at evalmed.es, the measures of the effect are automatically obtained: prolongation of the average surival time (PtS), prolongation of the average event free time (PtSLEv) and time lived without an event (PtvSEV). Results: The median follow-up in all studies was 60 months, with the exception of CONKO-001, for which we have data at an average follow-up time of 136 months, however for our comparative purpose we cite the results in the first 60 months. -CONKO-001: PtS was 5.1 months (24.2 observation vs 29.3 gemcitabine). PtSLEv was 9.6 months (13 observation vs 22.6 gemcitabine). PtvSEv was 22.57 months. -JASPAC-01: PtS was 9.04 months (32.4 gemcitabine vs 41.5 gemcitabine + S1). PtSLEv was 9.75 months (21.6 gemcitabine vs 31.4 gemcitabine + S1). PtvSEv was 31.38 months. -ESPAC-4: PtS was 3.2 months (34 gemcitabine vs 37.2 gemcitabine + capecitabine). PtSLEv was 2.7 months (25.6 gemcitabine + 28.3 gemcitabine + capecitabine). PtvSEv was 24.92 months. -PRODIGE: PtS was 6 months (37 gemcitabine vs 43 FOLFIRINOX). PtSLEv was 8.9 months (22.4 gemcitabine vs 31.2 FOLFIRINOX). PtvSEv was 31.23 months. Conclusions: In the adjuvant treatment with chemotherapy in pancreatic cancer, the transit from observation to gemcitabine, and from here to the most intensive schedules, has meant or contributed an important advance for patients in terms of PtS, PtSLEv and PtvSEv.

Prolonged Overall Survival with Lenalidomide Plus Dexamethasone Compared with Dexamethasone Alone in Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 412-412 ◽  
Author(s):  
Donna Weber ◽  
Robert Knight ◽  
Christine Chen ◽  
Andrew Spencer ◽  
Zhinuan Yu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Prior Treatment ◽  
Phase Iii ◽  
P Value ◽  
Double Blind ◽  
Prior Therapy ◽  
Phase Iii Trials

Abstract Introduction: Lenalidomide (Len), an analog of thalidomide (Thal) is a novel, oral, immunomodulatory agent that is effective against multiple myeloma (MM). In 2 prospective, randomized, double-blind, placebo-controlled phase III trials, Len with dexamethasone (Dex) induced a significantly higher overall response (OR) rate and complete remission (CR) rate, as well as longer time-to-progression (TTP) in comparison with Dex alone. Here, we investigate the long-term overall survival (OS) with Len/Dex. Methods: We evaluated the pooled results from both randomized trials (MM-009, MM-010) of 704 patients who had relapsed or refractory MM, without prior resistance to Dex, who received either Len (25 mg daily for 3 weeks every 4 weeks), or placebo. Dex was given at 40 mg on days 1–4, 9–12, 17–20 every 4 weeks for 4 cycles. From cycle 5 onwards, Dex was given at 40 mg on days 1–4 only. Response rate and TTP are based on data obtained before unblinding (June 2005 [MM-009] and August 2005 [MM-010]). Follow-up data on OS were obtained up to January 2007. Forty-seven percent of patients who received placebo/Dex crossed over to receive Len +/− Dex. Results: Of 704 patients, 353 were treated with Len/Dex and 351 with Dex alone. Baseline characteristics were well balanced between patients receiving Len/Dex and those receiving Dex alone. Median TTP, OR, and CR were significantly improved in patients treated with Len/Dex compared with Dex alone (Table). Of patients who progressed on Dex alone prior to unblinding, or were found to be receiving Dex alone after unblinding, 47% crossed over to Len +/− Dex. Despite these patients crossing over to Len +/− Dex at progression or at the time of unblinding, the OS was significantly improved in patients treated with Len/Dex compared with Dex alone (hazard ratio 1.295; 95% confidence interval 1.040–1.614; p=0.02). Median OS in the Len/Dex group was 35 months and 31 in the Dex alone group (p<0.05). Median OS was also significantly longer with Len/Dex compared with Dex alone in patients with more than 1 prior therapy (32.4 months versus 27.3 months, p<0.05). Similar median OS was observed with Len/Dex and Dex alone in patients with 1 prior therapy (median OS not yet reached and 35.3 months, p=0.24). Conclusion: With increased follow-up and despite cross-over, patients treated first with Len/Dex had significantly improved OS compared with those treated with Dex alone. Len/Dex (n=353) Dex alone (n=351) P value OR, % 60.6 21.9 <0.001 CR, % 15.0 2.0 <0.001 Median TTP, months 11.2 4.7 <0.001 Median OS, months 35.0 31.0 <0.05 Median OS in patients with 1 prior treatment, months not yet reached 35.3 0.24 Median OS in patients with >1 prior treatment, months 32.4 27.3 <0.05

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