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Rocha, Anderson, and Siome Goldenstein. "Progressive randomization: Seeing the unseen." Computer Vision and Image Understanding 114, no. 3 (2010): 349–62. http://dx.doi.org/10.1016/j.cviu.2009.10.002.
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Zhang, Jiameng, Emmanuelle Waubant, Gary Cutter, Jerry S. Wolinsky, and Robert Glanzman. "EDSS variability before randomization may limit treatment discovery in primary progressive MS." Multiple Sclerosis Journal 19, no. 6 (2012): 775–81. http://dx.doi.org/10.1177/1352458512459685.
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Background: Baseline Expanded Disability Status Scale (EDSS) is usually based on a single measurement. Here we evaluated whether using a baseline EDSS derived from two pre-treatment measurements improves the detection of progression events and the ability to demonstrate a therapeutic effect in delaying MS disability progression. Methods: Real data from OLYMPUS, a phase II/III randomized, placebo-controlled trial of rituximab in patients with primary progressive multiple sclerosis (PPMS), as well as simulated data were analyzed. Several definitions of baseline EDSS were used to capture sustained disability progression (SDP) events. Variations in the EDSS were estimated by linear mixed-effect models. Results: Selecting the higher of two baseline EDSS scores lowered the number of SDP events in both treatment groups, so decreasing sensitivity, and reduced the number of false SDP events, so increasing specificity. Conversely, selecting the lower of two baseline scores increased sensitivity but decreased specificity. Increased power (~7% based on the simulation study) was observed when the average of screening and Week 0 EDSS scores was used for baseline. Conclusion: Baseline EDSS derived from two pre-treatment EDSS measurements may enhance the ability of detecting a therapeutic effect in slowing disability progression in PPMS. This strategy could be implemented in future clinical trials of patients with MS.
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Duffaud, F., I. Ray-Coquard, B. Bui, et al. "Time to secondary resistance (TSR) after interruption of imatinib: Updated results of the prospective French Sarcoma Group randomized phase III trial on long-term survival." Journal of Clinical Oncology 27, no. 15_suppl (2009): 10508. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.10508.
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10508 Background: We previously demonstrated that imatinib mesylate (IM, Gleevec/Glivec; Novartis Pharma) must not be interrupted after 1 and 3 years (yr) in responding patients (pts) and has to be given continuously until disease progression (PD) or intolerance. The impact of IM re-introduction at progression remains unknown regarding the impact of the interruption on the TSR. Methods: This prospective national multicenter BFR14 study was initiated in June 2002. After 1, 3, and 5 yrs of IM 400mg/day, pts free from progression were randomly offered to continue (C arm) or interrupt (I arm) IM. Pts allocated to the I arm could restart IM (same dose) in case of PD. Primary endpoint was PFS. Pts declining randomization proceed with IM. Results: As of December 2008, 415 pts were included in this trial. Fifty-eight, 50 and 12 (ongoing) non progressive pts at 1, 3 and 5 yrs respectively were randomized in the I and C arm. Pt characteristics were well balanced between the two arms. The median time to progression (TTP) were 7.3 months (m) (rate of relapse: 91% of pts) and 9.4 m (rate of relapse: 84%) in the I arms after 1 and 3 years of treatment. In contrast the median TTP were 31.4 m and not reached in the C arms after 1 and 3 yrs of IM treatment respectively. IM reintroduction in the I arm after a re-progression allowed again a tumor control in 93% (43/46) of pts. The median follow-up from randomization is 56 m and 25 m at 1 and 3 yrs respectively. TSR after randomization to IM (first progression in the C arm, 2nd progression in the I arm) was not significantly different between the two arms (the 2-yrs TSR is similar in both arms 63% and 62% in the I and C arm respectively for the 1-yr randomization, 83.5% and 84.3% for the 3-yr randomization) but the rate of secondary resistance decrease over time in both arms: 40% or relapse in the 2 yrs following the 1 yr randomization vs less than 20% or relapse in the 2 yrs following the 3-yrs randomization. Conclusions: The majority of responding pts relapsed when IM was stopped after 1 and 3 yrs of treatment but response is reinduced in 93% of patients after IM reintroduction. TSR was not significantly affected by treatment interruption in this series of pts. [Table: see text]
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Bertucci, François, Isabelle Laure Ray-Coquard, Binh Bui Nguyen, et al. "Effect of five years of imatinib on cure for patients with advanced GIST: Updated survival results from the prospective randomized phase III BFR14 trial." Journal of Clinical Oncology 30, no. 15_suppl (2012): 10095. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.10095.
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10095 Background: We previously demonstrated that interruption of imatinib (IM) after 1, 3, and 5 yrs in responding patients (pts) with advanced GIST is associated with rapid relapse but reintroduction of IM allowed tumor control in almost all pts. Here, we examined the outcome of patients randomized in the interruption arm (I arm), and notably the characteristics of those not yet progressing. Methods: This prospective multicenter BFR14 study was initiated in June 2002 and closed for inclusion in July 2009. Seventy-one non-progressing patients were randomized in the I arm after 1 (N=32), 3 (N=25) and 5 years (N=14) of IM 400 mg/day. IM (same dose) was reintroduced in case of progressive disease (PD). Results: The median follow-up (FU) from randomization was 74, 48 and 22 months for pts randomized at 1, 3 and 5 yrs of IM treatment respectively. Updated survival data (January 2012) are summarized in the table. Out of the 3 pts not progressing in the I arm at 1 yr, 1 pt had refused to stop IM and 1 pt had a localized GIST with small residual disease at inclusion. Out of the 3 pts not progressing in the I arm at 3 yrs, 1 pt had refused to stop IM and 2 pts were included after complete resection of both primary tumor and metastases with a small residual disease. The FU of pts randomized at 5 yrs was short but out of the 5 non progressive pts, 2 are considered in PD on functional imaging (January 2012), 2 had a locally advanced GIST subsequently operated during IM and before randomization, and 1 had no target lesion at inclusion (resection of synchronous metastases). Conclusions: All but one pts with residual masses under IM and randomized in the I arm have relapsed. Six out of 7 patients not yet progressing in the I arm had reached complete remission following surgery at inclusion or before randomization (initial resection/debulking of metastases). [Table: see text]
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Peterson, P., M. Zwitter, M. Krzakowski, et al. "Delay in time to worsening of symptoms (TWS) of advanced non-small cell lung cancer (NSCLC) using gemcitabine (gem) maintenance therapy." Journal of Clinical Oncology 24, no. 18_suppl (2006): 7140. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.7140.
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7140 Background: Palliation of disease-related symptoms is an important clinical benefit. For advanced disease, this may be relief or delay of worsening of symptoms. Since benefit evaluation in clinical trials is usually focused on radiological assessments, development is needed to establish symptom improvement as an efficacy endpoint. Methods: To determine if gem maintenance therapy delayed the worsening of symptoms, retrospective analyses were performed using symptom data reported by patients (pts) with advanced NSCLC from a randomized trial of gem plus cisplatin followed by gem maintenance therapy plus best supportive care (GBSC) or best supportive care (BSC) (Krzakowski, ASCO 2004). Pts rated 6 symptoms using the Lung Cancer Symptom Scale (LCSS) at baseline and every cycle. Symptom worsening was retrospectively defined as a 15-mm increase in the severity score for any symptom (based on 100-mm scales) from randomization (start of maintenance therapy). Analyses were repeated for 10- and 20-mm increases. Data were analyzed using Kaplan-Meier (KM) plots and Cox regression, with censoring at the last LCSS for pts with no worsening. Results: At randomization, 73% were stage IV and 48% had Karnofsky performance status >80. Of the 206 pts randomized, 171 were included in the symptom analyses. Although not significant, the KM plot for TWS based on the 15-mm definition (defn) showed a separation between arms in favor of GBSC beginning ∼2.5 months after randomization (p = 0.24, HR = 0.79). TWS results for the 20-mm defn were significant in favor of GBSC (p = 0.013, HR = 0.59). When the same analysis was applied to individual symptoms, all symptoms showed the same numerical trend (HR<0.77) in favor of GBSC, with significant TWS advantage for GBSC (HR<0.56) for appetite loss and fatigue (15- and 20-mm defn) and for pain (20-mm defn). Additional analyses suggested a strong correlation between TWS and time to progressive disease. Conclusions: In addition to prolonging time to disease progression, gem maintenance therapy delays pt-reported worsening of symptoms. Correlation of TWS with time to progression suggests that delayed TWS may be a clinical benefit of delayed onset of progressive disease. [Table: see text]
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Hohol, Marika J., Michael J. Olek, E. John Orav, et al. "Treatment of progressive multiple sclerosis with pulse cyclophosphamidel methylprednisolone: Response to therapy is linked to the duration of progressive disease." Multiple Sclerosis Journal 5, no. 6 (1999): 403–9. http://dx.doi.org/10.1177/135245859900500i606.
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Objective: To determine if there are variables linked to responsiveness to pulse cyclophosphamide/methylprednisolone therapy in progressive Multiple Scerosis (MS). Background: MS is a presumed autoimmune disease of the CNS in which immunosuppressive and immunomodulatory treatments are being used. We have treated patient with the progressive form of MS using a regimen consisting of pulse cyclophosphamide/methylprednisolone that is given as an outpatient at 4-8 week intervals similar to lupus nephritis protocols. Design/Methods: We investigated a series of 95 consecutive progressive MS patient treated in an open label fashion in an effort to identify factors linked to response to treatment. Clinical outcome measures included status at 12 months and time to failure determined by EDSS change and global physician impression. For each endpoint associations were examined between outcome and patient characteristics including gender age at onset of disease and treatment, EDSS 1 year previously and at start of treatment, duration of MS, previous treatment, age at onset and duration of progression, and primary vs secondary progressive MS. Result: Of the variables studied, age, gender, age at onset, and age at treatment did not correlate with response to therapy. The most significant variable that correlated with response was length of time the patient was in the progressive phase (P=0.048, 12 month change in EDSS; P=0.017, risk for time to failure). Patient that improved on therapy at 12 months had progressive disease for an average of 2.1 years prior to treatment, whereas those stable or worse had progressive disease for 5.0 and 4.1 years respectively. There was a trend (P=0.08) favoring positive clinical responses in secondary progressive as opposed to primary progressive patients. Conclusions: Our data suggest that progressive MS may become refractory to immunosuppressive therapy with time and early intervention when patient enter the progressive stage should be considered. Furthermore, in trials of immunosuppressive agent for progressive MS, duration of progression should be considered as a randomization and analysis variable.
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McCarthy, Philip L., Kouros Owzar, Edward A. Stadtmauer, et al. "Phase III Intergroup Study of Lenalidomide (CC-5013) Versus Placebo Maintenance Therapy Following Single Autologous Stem Cell Transplant for Multiple Myeloma (CALGB 100104): Initial Report of Patient Accrual and Adverse Events." Blood 114, no. 22 (2009): 3416. http://dx.doi.org/10.1182/blood.v114.22.3416.3416.
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Abstract Abstract 3416 Poster Board III-304 Relapse and/or progression of disease are the primary causes of treatment failure after autologous hematopoietic stem cell transplant (ASCT) for multiple myeloma (MM). The primary objective of CALGB 100104 was to investigate whether adding maintenance therapy would improve the time to progression (TTP). The study was powered to detect an improvement of 9.6 months (prolongation of TTP from 24 months to 33.6 months) in MM patients undergoing a single ASCT. Secondary objectives were the Complete Response conversion rate following maintenance initiation, the Overall Survival and the feasibility of long term lenalidomide maintenance therapy. Eligible MM patients were Durie-Salmon Stage I-III patients within 1 year of diagnosis, receiving at least 2 months of any induction therapy with response (Stable Disease (SD) or better) and ≤ 70 years of age. Patients with progressive disease prior to ASCT were not eligible for study. Patients underwent stem cell mobilization followed by Melphalan 200 mg/m2 and ASCT with a minimum of 2 × 106 CD34 cells/kg for stem cell infusion. Responding patients with SD or better were randomized at day 100 to 110 post ASCT to study drug versus placebo. Patients with progressive disease were not randomized. Randomized patients were stratified by elevated β2 microglobulin at diagnosis and prior thalidomide or lenalidomide use during induction therapy. The starting dose was 10 mg daily with an escalation at 3 months to 15 mg if tolerated. Study drug could be de-escalated by 5 mg daily if not tolerated. Patients could be maintained at 5, 10 or 15 mg as tolerated and were followed with monthly complete blood counts. Drug was held for neutropenia (Absolute Neutrophil Count (ANC) < 500/μl or thrombocytopenia (<30,000/ μl) and restarted after resolution of cytopenia(s). Patients were re-staged by blood and urine testing every 3 months, by skeletal survey and bone marrow testing yearly and remained on maintenance therapy until progression. A total of 568 pts were registered at centers from the following cooperative groups: CALGB (n=377), ECOG (n=132), and BMT-CTN (n=59). The study opened in 12/2004 with increasing annual accrual: 2005, n=33, (6%); 2006, n=62, (11%); 2007, n=137, (24%); 2008, n=214, (38%); 2009, n=122, (21%) and study closure on 07/03/09. The drop out rate before randomization at day 100 to 110 was projected to be 10-15% with an expected randomization of 462 patients. Among the 568 registered patients, 424 have been randomized, 81 have dropped out pre-randomization and 63 are pending randomization as of 08/06/09. Projected final randomization is approximately 475. Pooled Hematologic and Non-Hematologic Adverse Events (AEs) are available from 275 patients in both arms. Individual patients experiencing Hematologic AEs are as follows: Grade 3 (severe) n=43 (16%); Grade 4 (life-threatening) n=26 (9%); and no Grade 5 (lethal). Individual patients experiencing Non-Hematologic AEs are as follows: Grade 3 n=74 (27%); Grade 4 n=9 (3%); Grade 5 n=5 (2%). The most common Non-Hematologic AEs were infection, fever, rash and fatigue. The Data Safety and Monitoring Board (DSMB) will continue to monitor the study for AEs and determination of progression. This large Phase III study has successfully completed patient registration and is nearing completion of patient randomization at day 100 to 110 post ASCT through the cooperation of the Intergroup oncology and transplant clinical research groups. Further analysis will determine if maintenance therapy with lenalidomide (CC-5013) is of benefit for MM patients following single ASCT. Disclosures McCarthy: Celgene: Speakers Bureau. Off Label Use: Lenalidomide for maintenance therapy following autotransplant for multiple myeloma. Stadtmauer:Celgene: Speakers Bureau. Richardson:Millenium (Research Funding and Advisory Board), Celgene, Keryx, BMS, Merck, Johnson and Johnson (All Advisory Board): Membership on an entity's Board of Directors or advisory committees, Research Funding. Anderson:Millenium: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.
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Koeberle, Dieter, Daniel C. Betticher, Roger Von Moos, et al. "Bevacizumab continuation versus no continuation after first-line chemo-bevacizumab therapy in patients with metastatic colorectal cancer: A randomized phase III noninferiority trial (SAKK 41/06)." Journal of Clinical Oncology 31, no. 15_suppl (2013): 3503. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.3503.
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3503 Background: Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after stop of first-line chemotherapy. Methods: In an open-label, phase 3 multicenter study conducted in Switzerland, patients with unresectable metastatic colorectal cancer having non-progressive disease after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned in a 1:1 ratio to continuing bevacizumab (7.5 mg/kg every 3 weeks) or no treatment. CT scans were done every 6 weeks between randomization and disease progression. The primary endpoint was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significant level of 10% and a statistical power of 85%. Results: The per-protocol population comprised 262 patients. Median follow-up is 28.6 months (range, 0.6-54.9 months). Median TTP was 17.9 weeks (95% CI 13.3-23.4) for bevacizumab continuation and 12.6 weeks (95% CI 12.0-16.4) for no continuation; HR 0.72 (95% CI 0.56-0.92). Median progression free-survival and overall survival, both measured from start of first-line treatment, was 9.5 months and 24.9 months for bevacizumab continuation and 8.5 months (HR 0.73 (95% CI 0.57 - 0.94)) and 22.8 months (HR 0.87 (95% CI 0.64 – 1.18)) for no continuation. Median time from randomization to second-line treatment was 5.9 months for bevacizumab and 4.8 for no continuation. Grade 3-4 adverse events in the bevacizumab continuation arm were uncommon. Conclusions: Non-inferiority could not be demonstrated. The 95% confidence intervals for the TTP HR indicate superiority of bevacizumab continuation after stop of first-line chemotherapy. The median differences in TTP and in time between randomization and start of second-line treatment were of moderate magnitude being less than 6 weeks. The results of an accompanying cost analysis will be presented at the meeting. Clinical trial information: NCT00544700.
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Silverman, M. P. "Progressive Randomization of a Deck of Playing Cards: Experimental Tests and Statistical Analysis of the Riffle Shuffle." Open Journal of Statistics 09, no. 02 (2019): 268–98. http://dx.doi.org/10.4236/ojs.2019.92020.
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Le Cesne, A., I. Ray-Coquard, B. Bui, et al. "Continuous versus interruption of imatinib (IM) in responding patients with advanced GIST after three years of treatment: A prospective randomized phase III trial of the French Sarcoma Group." Journal of Clinical Oncology 25, no. 18_suppl (2007): 10005. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.10005.
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10005 Background: IM the first-line targeted therapy for advanced GIST, must not be interrupted after one year (yr) in responding patients (pts) and has to be given continuously until disease progression (PD) or intolerance (Blay, Le Cesne et al, ASCO 2004 and 2005). The impact on progression free survival (PFS) of IM discontinuation in long lasting responding pts is unknown. Methods: This prospective national multicenter BFR14 study was initiated in June 2002. After 3 yrs of IM 400mg/day, pts free from progression were randomly offered to continue (C arm) or interrupt (I arm) IM, with the exception of pts initially randomized in the I arm after 1 yr of IM (32 pts). Pts allocated to the I arm could restart IM (same dose) in case of PD. Primary endpoint was PFS. Pts declining randomization proceed with IM. Results: As of december 2006, 286 pts were included in this trial and up to date, 35 non progressive pts at 3 yrs were randomized, 19 and 16 in the I anc C arm respectively. Pt characteristics were well balanced between the two arms. Nine progressions were reported after a median follow-up of 5.3 months (range 0–14) in this cohort of patients. IM reintroduction in the I arm after a re-progression allowed again a tumor control (OR or SD) in all evaluable pts so far. Conclusions: An increase in the rate of PD was observed in patients randomized after 3 years of IM. The final analysis will be performed after the randomization of 50 pts. Updated results including mutational analysis will be presented at the meeting. No significant financial relationships to disclose.
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Attal, Michel, Valerie cances Lauwers, Gerald Marit, et al. "Maintenance Treatment with Lenalidomide After Transplantation for MYELOMA: Final Analysis of the IFM 2005-02." Blood 116, no. 21 (2010): 310. http://dx.doi.org/10.1182/blood.v116.21.310.310.
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Abstract Abstract 310 High dose therapy with autologous stem cell transplantation (ASCT) is a standard treatment for young patients with myeloma. Some residual disease responsible for relapse is always present after ASCT. Effective maintenance treatment would be required to prevent relapse. However, such treatment is still to be defined. This phase 3, placebo-controlled trial investigated the efficacy of lenalidomide (LEN) for maintenance after transplantation. Patients, under 65 years of age, with non-progressive disease after a first line ASCT (performed within the last 6 months) were randomized to receive consolidation with LEN (25 mg/d, 21 days/month, for 2 months) followed by maintenance with either placebo (Arm A) or LEN (10 to 15 mg/d) until relapse (Arm B). From July 2006 to August 2008, 614 patients were randomized. Patient's characteristics of each group were similar with regard to age (57 years), ISS stage, FISH analysis, induction regimen (VAD / bortezomib-dex / others = 49%/44%/7%), diagnosis-randomization interval (10 months), and response at time of randomization. The first pre-planned interim analysis was performed on the 4th of September 2009 with a median follow up of 24 months from randomization (ASCO 2010, abstract 8018). The independent data and safety monitoring committee recommended to unblind the trial due to the PFS superiority of arm B (primary end point). On the 6th of July 2010, the trial was unblinded and the final analysis was performed with a median follow up of 34 months from randomization and 44 months from diagnosis. Consolidation with LEN improved the very good partial response rate (VGPR) (p<0.0001). Maintenance with LEN improved the progression-free survival: median 24 months from randomization and 34 months from diagnosis in arm A, versus 42 months from randomization and 52 months from diagnosis in arm B (HR=0.5, p<10−8). This benefit was observed across all stratified subgroups of patients including beta-2 microglobulin level, (< or > 3 mg/l) cytogenetic profile (del 13, + or -), and response after transplantation (CR/VGPR or not). In multivariate analysis, PFS was related to maintenance with LEN (p<0.0001), and to the achievement of CR/VGPR after consolidation with LEN (p<0.01). Maintenance treatment with LEN was not associated with resistance of the disease at time of progression: the median interval between progression and death was similar in both arms (12 months). With the current follow-up, the 5-year post diagnosis overall survival remains extremely high and similar in the 2 treatment groups: 83%. Maintenance treatment with LEN was well tolerated. The definitive interruption rate for serious adverse events during maintenance was similar in both arms (Arm A=5%, Arm B=8%, NS). The IFM 2005-02 trial demonstrates that lenalidomide is an effective and well tolerated maintenance treatment after transplantation for multiple myeloma patients. Disclosures: Attal: celgene: Consultancy, Research Funding; johnson and johnson: Consultancy, Research Funding. Off Label Use: maintenance treatment with Revlimid. Facon:celgene: Consultancy, Research Funding; johnson and johnson: Consultancy. Roussel:celgene: Consultancy; johnson and johnson: Consultancy. Avet-Loiseau:celgene: Consultancy, Research Funding; johnson and johnson: Consultancy, Research Funding. Harousseau:celgene: Consultancy; johnson and johnson: Consultancy.
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Rittmeyer, Achim, Arnaud Scherpereel, Vera A. Gorbunova, et al. "Effect of maintenance bevacizumab (Bev) plus pemetrexed (Pem) after first-line cisplatin/Pem/Bev in advanced nonsquamous non-small cell lung cancer (nsNSCLC) on overall survival (OS) of patients (pts) on the AVAPERL (MO22089) phase III randomized trial." Journal of Clinical Oncology 31, no. 15_suppl (2013): 8014. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.8014.
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8014 Background: Maintenance monotherapy has been associated with improved survival for NSCLC pts. AVAPERL was designed to evaluate the safety and efficacy of bevacizumab with or without pemetrexed as continuation maintenance treatment and demonstrated improved progression-free survival (PFS) (Barlesi, JCO in press). Methods: Pts with advanced nsNSCLC received first-line Bev (7.5 mg/kg), cisplatin (75 mg/m2), and Pem (500 mg/m2) every 3 weeks (q3w) for 4 cycles. Those non progressing were randomized to maintenance Bev (7.5 mg/kg) +/-Pem (500 mg/m2) q3w until progressive disease or unacceptable toxicity. The primary end point (PFS) was met. An independent update analysis has been conducted to assess OS. Results: A total of 376 pts receive induction treatment; 125 and 128 were randomized to the Bev-alone and Bev+Pem arms, respectively. Induction therapy resulted in confirmed disease control in 71.9% of pts. After a median follow-up of 14.8 months, PFS for the Bev+Pem arm was significantly improved both from induction (10.2 v 6.6 m, HR 0.58 [0.45-0.76], p<.0001) and randomization (7.4 v 3.7 m, HR 0.57 [0.44-0.75], p<.0001). With 58% of events, OS for the Bev+Pem arm was also improved both from induction (19.8 v 15.9 m, HR 0.88 [0.64-1.22], p=.32) and randomization (17.1 v 13.2 m, HR 0.87 [0.63-1.21], p=.29). The PFS and OS improvements were comparable across age, PS, smoking status, and response to induction (SD vPR/CR) subgroups. No new safety signal was observed during this updated analysis. Conclusions: Continuation maintenance with Bev+Pem in an unselected population of nsNSCLC pts who had achieved disease control after induction was associated with an increase by almost 4 months in OS benefit over standard Bev alone. Clinical trial information: NCT00961415.
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Wang, Jennifer, Shi-Ming Tu, Lance C. Pagliaro, et al. "A prospective randomized phase III trial comparing consolidation therapy with or without strontium-89 following induction chemotherapy in androgen-independent prostate cancer." Journal of Clinical Oncology 32, no. 4_suppl (2014): 90. http://dx.doi.org/10.1200/jco.2014.32.4_suppl.90.
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90 Background: New therapies have shown benefit for advanced prostate cancer, but are not curative. Bone metastases cause significant prostate cancer morbidity. Preliminary studies showed that bone-targeted therapy with strontium-89 (Sr-89) with doxorubicin was feasible in patients with stable or responding metastatic castration-resistant prostate cancer (mCRPC) after KAVE (ketoconazole and doxorubicin alternating with estramustine and vinblastine) induction with promising time to progression (13.9 vs. 7.0 months) and overall survival (27.7 vs. 16.8 months). We conducted this phase III, randomized, double-blind, multicenter study to determine the effectiveness of consolidation therapy with or without Sr-89. Methods: Patients with progressive mCRPC with bone disease received induction with KAVE or docetaxel/prednisone (D) chosen by the treating physician. Patients with stable or responding disease were randomized at week 16 to receive doxorubicin with either one dose (4 mCi) or no Sr-89. Primary endpoint was overall survival (OS). Results: This study was activated in April 2002 with planned randomization of 480 patients (240 patients per study arm). The trial closed early with a total of 265 patients: median age 67; median prostate-specific antigen (PSA) 71.2; 109 received KAVE; 155 received D, 127 (47.9%) patients went on to randomization, 43 (39.4%) from the KAVE arm, and 84 (54.2%) from the D arm. Multivariate Cox proportional hazards regression was used to control for induction regimen, Eastern Cooperative Oncology Group (ECOG) status, and number of bone metastases. Median survival from times of registration and randomization in the no-Sr-89 arm were 26.5 months (95% CI: 21.1, 29.9) and 22.8 months (95% CI: 17.7, 26.1), respectively, compared to 27.9 months (95% CI: 23.6, 34.2) and 24.3 (95% CI:19.8, 29.9) months in the Sr-89 arm. OS from registration (p=0.61) and randomization (p=0.62) were not statistically significant on univariate or multivariate analyses. Conclusions: The addition of Sr-89 to consolidation chemo did not improve OS in this study. This community-based, multicenter study closed prematurely due to slow accrual, demonstrating challenges in conducting trials in the US that combine radionuclide therapy with chemotherapy. Clinical trial information: MDA 3410.
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Sabbah, H. N., H. Shimoyama, V. G. Sharov, et al. "Effects of ACE inhibition and beta-blockade on skeletal muscle fiber types in dogs with moderate heart failure." American Journal of Physiology-Heart and Circulatory Physiology 270, no. 1 (1996): H115—H120. http://dx.doi.org/10.1152/ajpheart.1996.270.1.h115.
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The proportion of slow-twitch, fatigue-resistant type 1 skeletal muscle (SM) fibers is often reduced in heart failure (HF), while the proportion of fatigue-sensitive type-II fibers increases. This maladaptation may be partially responsible for the exercise intolerance that characterize HF. In this study, we examined the effects of early monotherapy with the angiotensin-converting enzyme inhibor, enalapril, and the beta-blocker, metoprolol, on SM fiber type composition in 18 dogs with moderate HF produced by intracoronary microembolizations. HF dogs were randomized to 3 mo therapy with enalapril (10 mg twice daily), metoprolol (25 mg twice daily), or no treatment. Triceps muscle biopsies were obtained at baseline, before randomization, and at the end of 30 mo of therapy. Type I and type II SM fibers were differentiated by myofibrillar adenosinetriphosphatase (pH 9.4). In untreated dogs, the proportion of type I fibers was 27 +/- 1% before randomization and decreased to 23 +/- 1% (P < 0.05) at the end of 3 mo of follow up. In dogs treated with enalapril or metoprolol, the proportion of type I fibers was 30 +/- 4 and 28 +/- 2% before randomization and 33 +/- 4 and 33 +/- 1%, respectively, after 3 mo of therapy. In conclusion, in dogs with moderate HF, early therapy with enalapril or metoprolol prevents the progressive decline in the proportion of type I SM fibers.
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Galsky, M. D., D. D. Von Hoff, M. Neubauer, et al. "Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors." Journal of Clinical Oncology 27, no. 15_suppl (2009): 3541. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.3541.
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3541 Background: The current paradigm of histology-specific drug development may not be optimal in the era of targeted therapeutics. We sought to explore the activity of lapatinib, an oral tyrosine kinase inhibitor of HER2, with a trial design focused on the target rather than on tumor-type. Methods: Patients (pts) with HER2-amplified treatment-refractory metastatic gastro- esophageal (G/E), bladder (B), ovarian (O), or uterine (U) tumors were enrolled into a double-blinded randomized discontinuation study of lapatinib 1500 mg PO daily (malignancies selected based on reported frequencies of HER2 amplification). The planned sample size was 250 HER2+ pts, with the goal of then randomizing 100 pts with SD at week (wk) 12 to either lapatinib or placebo until progressive disease (PD). Pts who responded at wk 12 (CR or PR) continued on lapatinib; those who progressed were discontinued from study. Primary objectives were response rate at 12 wks and percentage of pts who remain progression free at 24 wks. Secondary objectives were duration of response, progression free survival (PFS) after randomization, and determination of the incidence of HER2 amplification in multiple tumor types. Futility analyses were preplanned to ensure feasibility of screening and of randomization (i.e. a sufficient rate of non- progression at 12 wks). Results: A total of 145 pts were screened (G/E=47, B=35, O=58, U=5); 42 were HER2-amplified (G/E=16, B=13, O=13, U=0) and 32 (G/E=13, B=9, O=10) were enrolled. At wk 12, 1 (3%) patient had a CR, 10 (31%) had SD, 19 (59%) had PD, and 2 (6%) were unknown. Median time to progression during open-label lapatinib was 78 days, 95% CI (42, 92). Only 7 pts with SD underwent randomization. Two pts with esophageal cancer remain on study; one (CR at wk 12) remains a CR at wk 60 and the other (SD at wk 12) remains with SD at wk 36. Low response rate coupled with slow screening and enrollment led to early study closure. Conclusions: Basing trial eligibility on a target, versus histologic classification, is challenging. While HER2 amplifications appear to be prevalent in select non-breast tumors, lapatinib monotherapy in refractory disease is associated with a low level of objective responses. [Table: see text]
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Nasr, Fadi, Reem El Khoury, Intissar Yehia, Saada Diab, Ahmad Al Ghoche, and Lewis Nasr. "Small cell lung cancer: Real-world data from two institutions in Lebanon for patients receiving carboplatin etoposide or atezolizumab in first line of treatment." Journal of Clinical Oncology 39, no. 15_suppl (2021): e20578-e20578. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e20578.
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e20578 Background: Small-cell lung cancer (SCLC), accounts for approximately 15% to 17% of all diagnosed lung cancers. It is an aggressive high-grade neuroendocrine carcinoma, diagnosed during advanced stages in the majority of patients. Despite the fact that first line treatment provides response rates of up to 80%, the majority of patients relapse within 6 months after completion of initial treatment. Few advances have been made in the management of recurrent disease and treatments patterns are poor and limited in each line of the disease. The aim of this study is to present real world data regards survival outcomes such as progression free survival and overall survival in SCLC patients receiving carboplatine etoposide or tecentriq carboplatin etoposide regimens as first line of treatment. Methods: This is a retrospective (descriptive) study on 56 patients aged ≥ 18 years and with confirmed histological SCLC. Patients with extensive stage of SCLC were enrolled in this cohort study from 2 health institutions in Lebanon from July 2007 to December 2019 and followed up until progression or death. Primary end points were overall survival (time from randomization to death from any cause) and progression free survival at 6 and 12 months (time from randomization to disease progression). Secondary endpoints included objective response rate and the duration of response. Exploratory analyses included the assessment of survival outcomes of each type of treatment according to liver and brain metastasis. Results: Overall, 56 SCLC patients, diagnosed between 2003 and 2019, were observed (age <65: (27.0%, 10 patients); ≥65 (73.0%, 41 patients)). Most often prescribed treatment were etoposide-carboplatyl (80.8%, 42 patients) and atezolizumab (19.2%10 patients). Regarding metastasis at diagnosis, liver and brain metastasis were respectively (26.8%, 11 patients) and (17.1%, 7 patients). 27patients (71.1%) were alive at 6 months without progressive disease and 13 patients (34.21 %) alive at 12 months without PD. Median progression free survival incidence since diagnosis was 8.8 months. Overall survival was 10.86 months. Objective response rate after first line was 84.2%. In a cox regression analysis, liver metastasis, brain metastasis, survival at 6 or 12 months without progressive disease did not decrease significantly PFS or OS since diagnosis. Conclusions: To our knowledge, this is the first real world clinical data on SCLC in Lebanon. This study showed limited treatment options and short survival outcomes with PFS= 8.8months and OS= 10.86 months respectively for carboplatin etoposide regimen and tecentriq carboplatin etoposide regimen. There is an essential needs for clinical comparative studies in real world practicing between treatments at each line, specially for novel treatment like atezolizumab that may present new hope and directions for SCLC.
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Moehler, Markus H., Mikhail Dvorkin, Mustafa Ozguroglu, et al. "Results of the JAVELIN Gastric 100 phase 3 trial: avelumab maintenance following first-line (1L) chemotherapy (CTx) vs continuation of CTx for HER2− advanced gastric or gastroesophageal junction cancer (GC/GEJC)." Journal of Clinical Oncology 38, no. 4_suppl (2020): 278. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.278.
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278 Background: We report the primary analysis of JAVELIN Gastric 100, which compared avelumab (anti–PD-L1) maintenance after 1L CTx vs continued CTx in patients (pts) with GC/GEJC. Methods: In this global, open-label, phase 3 trial (NCT02625610), eligible pts had previously untreated, unresectable, locally advanced/metastatic (LA/M) HER2− GC/GEJC. Pts without progressive disease (PD) after 12 weeks of 1L oxaliplatin/fluoropyrimidine induction were randomized 1:1 to avelumab 10 mg/kg Q2W switch maintenance or continued CTx, stratified by region (Asia vs non-Asia). Primary endpoint was overall survival (OS) post induction in all randomized or PD-L1+ (≥1% of tumor cells, 73-10 assay) pts. Results: 805 pts received induction CTx and 499 pts were randomized (avelumab, n = 249; CTx, n = 250). At data cutoff (Sep 13, 2019), minimum follow-up was 18 months. In the avelumab and CTx arms, median OS post induction/randomization was 10.4 months (95% CI 9.1-12.0) vs 10.9 months (95% CI 9.6-12.4), hazard ratio (HR) 0.91 (95% CI 0.74-1.11; p = 0.1779); 24-month OS rates were 22.1% (95% CI 16.8-28.0) vs 15.5% (95% CI 10.8-20.9), respectively. The HR for OS in PD-L1+ pts (n = 54) was 1.13 (95% CI 0.57-2.23). No OS trend was seen in Asian pts (n = 114; HR 0.90 [95% CI 0.59-1.36]) or other subgroups, except for a potential benefit with avelumab in pts with no metastatic sites at randomization (n = 60; HR 0.52 [95% CI 0.28-0.98]). Progression-free survival was similar between arms (HR 1.04 [95% CI 0.85-1.28]). In the avelumab vs CTx arms, objective response rates (post randomization only) were 13.3% (95% CI 9.3-18.1) vs 14.4% (95% CI 10.3-19.4), and 12-month rates for duration of response were 62.3% (95% CI 40.9-77.9) vs 28.4% (95% CI 13.2-45.7), respectively. Treatment-related adverse event rates (all grades/grade ≥3) were 61.3%/12.8% with avelumab and 77.3%/32.8% with CTx. Conclusions: Avelumab maintenance showed clinical activity and favorable safety vs continued CTx in pts with LA/M GE/GEJC; however, JAVELIN Gastric 100 did not meet its primary objective of demonstrating superior OS in the randomized or PD-L1+ population. Clinical trial information: NCT02625610.
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Nakamura, Masato, Yoshinori Munemoto, Masazumi Takahashi, et al. "SAPPHIRE: A randomized phase II study of mFOLFOX6 + panitumumab versus 5-FU/LV + panitumumab after 6 cycles of frontline mFOLFOX6 + panitumumab in patients with colorectal cancer." Journal of Clinical Oncology 36, no. 4_suppl (2018): 729. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.729.
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729 Background: FOLFOX therapy, an infusion of 5-fluorouracil (5-FU) with leucovorin in combination with oxaliplatin (OXA), is a common first-line chemotherapy regimen for unresectable, advanced or recurrent colorectal carcinoma (CRC). However, long-term administration of OXA is associated with peripheral neuropathy (PN); decreasing treatment length of OXA may be beneficial without reducing its efficacy. Methods: Chemotherapy-naïve pts aged ≥20 yrs with RAS wild-type advanced/recurrent CRC were enrolled to receive 6 cycles of panitumumab (Pmab) + mFOLFOX6 once every 2 wks. Pts who completed 6 cycles of Pmab + mFOLFOX6 and confirmed no progressive disease were subsequently randomized 1:1 to continue to receive Pmab + mFOLFOX6 (arm 1) or Pmab + 5-FU/LV (arm 2). The primary endpoint was progression-free survival (PFS) rate at 9 mos after randomization. The threshold PFS rate was defined as 30%, and the expected rate was set at 50%, with a 90% power and a 1-sided alpha value of 0.10. In the primary analysis, a binomial test was conducted separately for each arm. This study was designed as a phase II randomized screening comparison study which does not use direct comparison for the primary analysis. Results: Of 164 enrolled pts who received initial Pmab + mFOLFOX6 treatment, 56 were randomized to arm 1 and 57 to arm 2. PFS rates at 9 mos after randomization were significantly higher than the defined threshold at 44.6% (80% CI, 36.4–53.2) in arm 1 and 47.4% (39.1–55.8) in arm 2. Median PFS after randomization was 9.1 (8.6–11.2) and 9.3 (6.0–13.0) mos, respectively. Grade ≥2 PNs occurred in 6 (10.7%) and 1 (1.8%) pts in arms 1 and 2, respectively. Serious AEs occurred in 14 (25.0%) pts in arm 1 and in 9 (16.7%) pts in arm 2. Conclusions: The results of this trial suggest that Pmab + 5-FU/LV after 6 fixed-cycles of Pmab + mFOLFOX6 may be a treatment option in pts with RAS wild type chemotherapy-naïve advanced/recurrent CRC. Pts treated with Pmab + 5-FU/LV had a lower occurrence of grade ≥2 PNs compared with Pmab + mFOLFOX6. Clinical trial information: NCT02337946.
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Pejčić, Ivica, Ivan Petković, Ana Cvetanović, and Irena Conić. "Single Center Experience Study with Pembrolizumab in Patients with BRAF Mutant Negative Metastatic Melanoma." Acta Facultatis Medicae Naissensis 35, no. 4 (2018): 267–72. http://dx.doi.org/10.2478/afmnai-2018-0028.
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Abstract The aim of the paper was to determine the efficacy, toxicity and progression free survival with anti-PD-1 immunotherapy pembrolizumab in BRAF wild type metastatic melanoma patients with good performance status (ECOG PS 0-1). From February 2017 to April 2018, 17 patients with BRAF mutant wild type metastatic melanoma were enrolled in the study. Only 3/17 patient had received chemotherapy previously. The aim of the study was to confirm the efficacy of pembrolizumab immunotherapy in patients with good performance status (ECOG 0-1). Treatment consisted of pembrolizumab 2 mg/kg Q3 weeks continued until disease progression or intolerable toxicity. Secondary end points included toxicity and progression-free survival (defined as the time from randomization to documented disease progression according to RECIST). The overall response rate (ORR) was 11/17 (53.0 %), with complete response (CR) 0, partial response (PR) 3 (18 %), stable disease (SD) 8 (47%), and progressive disease (PD) 6 (35%). A total number of 97 consecutive cycles were administered. Adverse effects were mild. The most common toxicity was pneumonitis grade 1. None of the patients in the study demonstrated grade 2, 3 and 4 toxicity. No treatment-related deaths occurred. The median time to disease progression was 5.8 months. Anti-PD-1 pembrolizumab immunotherapy appeared to be a beneficial therapeutic approach with less toxicity for metastatic BRAF wild type melanoma patients with good PS.
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Michallet, Mauricette, Peter Dreger, Laurent Sutton, et al. "Autologous Hematopoietic Stem Cell Transplantation (autoHSCT) in CLL: First Results of An EBMT Randomized Trial Comparing Autotransplant Versus Wait and Watch." Blood 114, no. 22 (2009): 877. http://dx.doi.org/10.1182/blood.v114.22.877.877.
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Abstract Abstract 877 This phase-III randomized EBMT-intergroup trial studied the impact of a consolidating autoHSCT vs no consolidation for patients with CLL in Binet stage A progressive, B or C , in CR, nodular PR or VGPR after first or second line therapy. The primary objective was to show that autoHSCT increased the 5-year progression-free survival (PFS) by 30%. Although it had been calculated that 270 patients were to be randomized, the study was terminated by the steering committee in July 2007 due to poor accrual. Here we present a first analysis based on 69% of expected follow-up forms. Results: Between November 2001 and July 2007, 223 patients were enrolled (SFGM-TC/FCLLG n=98, MRC n=62, GCLLSG n=32, SAKK n=10, other EBMT centers n=17). There were 74% males and 26% females. Binet stages were progressive A 13%, B 67%, C 20%; 59% were in CR, and 41% in very good or nodular PR. Of note, SFGM-TC/FCLLG included only patients in CR. 82% of the patients were enrolled in 1st, and 18% in 2nd remission. Patients were randomized between group 1 (autoHSCT n=112) and group 2 (observation n=111) after an induction treatment which was left at the discretion of the investigators. Median PFS was 43 months in the observation group but not reached in the autoHSCT group; 5-year PFS was 48% and 65%, respectively (p=0.005). Accordingly, autoHSCT halved the relapse risk (5-year relapse incidence 25% vs. 51%; HR 0.4 [0.23-0.71], p=0.002). Cox modeling for randomization arm, Binet stage, disease status, line of treatment, contributing group (country), and the interaction between randomization arm and contributing group confirmed that autoHSCT significantly improved PFS (HR 0.41 [0.23-0.75] p=0.004). The beneficial effect of autoHSCT was stable over all contributing groups although patients accrued by SFGM-TC/FCLLG overall had a significantly better PFS than patients from other countries (HR 0.2 [0.08-0.55], p=0.001). At 5 years, the probability of OS was 92% and 91% for autoHSCT and observation, respectively. Significant differences in terms of non-relapse death were not observed. At the last follow up, among 205 evaluable patients, 186 are alive (147CR, 39 relapse), 19 died (14 from relapse and 5 from non-relapse causes) . In conclusion, in patients with CLL in first or second remission, consolidating autoHSCT reduces the risk of progression (PFS) by more than 50%, but has no effect on overall survival. Disclosures: No relevant conflicts of interest to declare.
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Suttmann, Henrik, Jochen Gleissner, Andreas Huebner, et al. "Adherence Measures for Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone Acetate plus Prednisone: Results of a Prospective, Cluster-Randomized Trial." Cancers 12, no. 9 (2020): 2550. http://dx.doi.org/10.3390/cancers12092550.
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Residual androgen production causes tumor progression in metastatic, castration-resistant prostate cancer (mCRPC) patients. Abiraterone acetate (AA), a prodrug of abiraterone, is an oral CYP-17 inhibitor that blocks androgen production. It was hypothesized that adherence-enhancing measures (AEM) might be beneficial for mCRPC patients receiving abiraterone acetate plus prednisone (AA + P). This multicenter, prospective, 2-arm trial allocated mCRPC patients who were progressive after docetaxel-based chemotherapy or asymptomatic/mildly symptomatic after failure of an androgen deprivation therapy to Arm A (with AEM) or Arm B (without AEM) by center-based cluster-randomization. The primary objective was to assess the influence of AEM on discontinuation rates and medication adherence in mCRPC patients treated with AA + P. A total of 360 patients were allocated to Arm A, and 315 patients to Arm B. At month 3, the rate of treatment discontinuation, not due to disease progression or the start of new cancer therapy, was low in both arms (A: 9.0% vs. B: 7.3%, OR = 1.230). Few patients had a medium/low Morisky Medication Adherence Scale (MMAS-4) score (A: 6.4% vs. B: 9.1%, OR = 0.685). The results obtained did not suggest any clear adherence difference between Arm A and Arm B. In patients with mCRPC taking AA + P medication, adherence seemed to be generally high.
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Matthews, Philip J., Charles H. Knowles, Yang C. Chua, Claire Delaney, Anthony R. Hobson, and Qasim Aziz. "Effects of the concentration and frequency of acid infusion on the development and maintenance of esophageal hyperalgesia in a human volunteer model." American Journal of Physiology-Gastrointestinal and Liver Physiology 294, no. 4 (2008): G914—G917. http://dx.doi.org/10.1152/ajpgi.00445.2007.
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Previous studies have demonstrated that a single 30-min distal esophageal infusion of concentrated (0.15 M, pH 0.8) hydrochloric acid (HCl) induces hyperalgesia to an electrical stimulus in a human model. The aim of this study was to refine this model using physiological acid concentrations (pH 1.8–4) in repeated short exposures. Two different cohorts of 10 volunteers underwent two studies. Study 1: randomization to four 5-min distal esophageal infusions of acid (0.15 M) or saline, 1 h apart. Double-blind measurements of baseline and postexposure proximal esophageal and chest wall pain thresholds (PTs) were performed to electrical stimulation at 30-min intervals throughout the study. Study 2: randomization to four 15-min infusions of 0.15, 0.075, and 0.01 M HCl and saline. In study 1, with multiple acid infusions, a significant progressive drop in PTs was observed in both areas tested ( P ≤ 0.0001). In study 2, increasing acid concentrations had a significant effect over multiple time points, P ≤ 0.0001. Similar initial reductions in PTs were observed for all acid concentrations compared with saline; however, hypersensitivity was shorter lasting with 0.01 M acid. In healthy subjects, esophageal hypersensitivity can be induced and maintained up to 4 h by repeated short-duration acid infusion and at physiological pH levels. This has implications for future model design and pathophysiological understanding of acid-related esophageal hypersensitivity.
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Loehrer, P. J., R. Birch, S. D. Williams, F. A. Greco, and L. H. Einhorn. "Chemotherapy of metastatic seminoma: the Southeastern Cancer Study Group experience." Journal of Clinical Oncology 5, no. 8 (1987): 1212–20. http://dx.doi.org/10.1200/jco.1987.5.8.1212.
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From 1978 to 1984, 62 patients with advanced seminoma of testicular or extragonadal origin were entered on two consecutive Southeastern Cancer Study Group (SECSG) protocols. All patients had progressive disease and were stratified according to tumor burden. Randomization on SEG 78-GU240 was cisplatin, vinblastine, and bleomycin (PVB), with or without doxorubicin; on SEG 81-GU332, randomization was to PVB or cisplatin, etoposide (VP-16), and bleomycin (PVP16B). Dosages of etoposide, vinblastine, and doxorubicin were decreased by 25% in patients who had received prior radiotherapy. Thirty patients (55%) had received prior chest and/or abdominal radiotherapy. Overall, 41 of 60 evaluable patients (68%) achieved a complete remission (CR) and 37 patients are alive and free of disease. CR was obtained in 13 of 15 patients (87%) with minimal disease, 13 of 16 (81%) with moderate disease, and 15 of 29 (52%) with advanced disease. Patients with no prior radiotherapy or limited-field (chest or abdomen) radiotherapy were more likely to achieve CR than those with prior chest and abdominal radiotherapy (75% v. 42%). Using univariate analysis, the extent of disease is the only significant prognostic factor, whereas both extent of disease and extent of prior radiotherapy are significant in a multivariate analysis. This study confirms the chemosensitivity of metastatic seminoma in a cooperative group setting and defines prognostic factors useful for comparison of other chemotherapeutic trials in seminoma.
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Attal, Michel, Valérie Lauwers-Cances, Gérald Marit, et al. "Lenalidomide Maintenance After Stem-Cell Transplantation For Multiple Myeloma: Follow-Up Analysis Of The IFM 2005-02 Trial." Blood 122, no. 21 (2013): 406. http://dx.doi.org/10.1182/blood.v122.21.406.406.
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Abstract Methods and Patients This randomized, placebo-controlled, phase 3 trial investigated the efficacy of lenalidomide (LEN) maintenance after transplantation for multiple myeloma. Patients, under 65 years of age, with non-progressive disease after a first-line autologous stem-cell transplant (ASCT) were randomized to receive maintenance with placebo or LEN (10 to 15 mg/d) until disease progression or unacceptable toxic effects. From July 2006 to August 2008, 614 patients were randomized. In January 2011, the DSMB recommended to stop LEN due to the increased incidence of second primary malignancies (SPMs). The median duration of maintenance treatment with LEN was 2 years (IQ range= 1-3). We previously reported this trial with a median follow-up of 45 months (Attal et al, N Engl J Med 2012). Results As of May 2013, median follow-up was 70 months from diagnosis and 60 months from randomization. LEN maintenance improved the 5-year progression-free survival (PFS) post randomization: 42%, versus 18% with placebo (p<0.0001), respectively. Overall, 403 patients had disease progression and 364 have started a second line therapy. The median 2nd PFS for the treated patients (time from progression in first-line to the second progression or last follow-up or death) was 10 months within the LEN arm versus 18 months within the placebo arm (p<0.0001), respectively. The median 2nd PFS in the LEN and placebo groups were 9 and 8 months (NS) for patients treated with a bortezomib-based regimen, 8 months and 18 months (p<0.01) for patients treated with an IMiD-based regimen, 14 months and 28 months (p=0.03) for patients treated with a regimen without new agents or with a second line ASCT, respectively. The 5-year post randomization overall survival (OS) was similar in the 2 groups: 68% in the LEN group versus 67% in the placebo group (HR=1). In the multivariate analysis, the OS was significantly related to age (p=0.001), International Staging System (p=0.03), and poor cytogenetics (t(4;14) or chromosome 17 deletion; p=0.008). The median survival after the first progression was 29 months in the LEN group versus 48 months in the placebo group (p< 0.0001). An increased incidence of SPMs was observed in the LEN group: 44 SPMs (hematologic: 20, non-hematologic: 24) in 35 patients were reported in the LEN group versus 28 SPMs (hematologic: 6, non-hematologic: 22) in 20 patients in the placebo group. The incidence of SPMs (excluding non melanoma skin cancers) was 2.3 per 100 patient-years in the LEN group versus 1.3 in the placebo group (p=0.03). Conclusion This new analysis confirms that lenalidomide is an effective treatment to prolong PFS after transplantation for multiple myeloma patients. However, this impressive benefit is not currently associated with an improved overall survival, due to a shorter survival after the first progression. Disclosures: Attal: CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau. Off Label Use: FRONTLINE THERAPY WITH CARFILZOMIB IN MULTIPLE MYELOMA. Facon:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Hulin:JANSSEN: Honoraria; CELGENE: Honoraria. Moreau:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Roussel:JANSSEN: Honoraria; CELGENE: Honoraria. Avet-Loiseau:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau.
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Robak, Tadeusz, Jerzy Blonski, Krzysztof Jamroziak, et al. "Cladribine Alone and in Combination with Cyclophosphamide or Cyclophosphamide and Mitoxantrone in Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL): Long-Term Follow-up of the the Polish Adult Leukemia Group (PALG CLL2) Study,." Blood 118, no. 21 (2011): 3915. http://dx.doi.org/10.1182/blood.v118.21.3915.3915.
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Abstract Abstract 3915 Purpose. In 2006 we have published an early report of the prospective, randomized, multicenter study (PALG CLL2) comparing the efficacy and toxicity of cladribine alone and in combination with cyclophosphamide (CC) or cyclophosphamide plus mitoxantrone (CMC) in 508 previously untreated patients with progressive and advanced CLL (Blood. 2006;108:473–9). In this early analysis we found that CMC induced higher CR rate than CC (36% vs. 21%, p=0.004), but no differences in overall response (OR), progression-free survival (PFS) and overall survival (OS) among treatment groups were observed. The aim of the present study was to verify whether long-term follow-up might change originally published data on PFS or/and OS as well as to compare the rate of late complications including secondary neoplasms and Richter's syndrome. Methods. In PALG CLL2 study PFS was defined as the time from the end of first–line therapy to disease progression or death from any cause. OS was measured from the time of randomization to death or last contact. OS and PFS were calculated according to the method of Kaplan and Meier and compared between groups by the log-rank test. Only patients with pathologically-proven tumours diagnosed after chemotherapy initiation were considered as having secondary neoplasms or Richter's syndrome. Frequencies of secondary tumours were compared by chi2 test. Results. The median time of follow-up as of Januar y 2011 was 45.6 months (95% CI: 39.9–51.4). The results of comparison of survival times and late complications in different study arms are shown in Table 1 and Figure 1. Conclusions. Long term results for 508 r andomized patients confirm that cladribine alone, CC and CMC regimens produce comparable PFS and OS in previously untreated progressive CLL. The risk of secondary tumours does not differ in the investigated treatment groups. Disclosures: No relevant conflicts of interest to declare.
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Chi, Kim N., Ur Metser, Johannes Czernin, et al. "Study evaluating metastatic castrate resistant prostate cancer (mCRPC) treatment using 177Lu-PNT2002 PSMA therapy after second-line hormonal treatment (SPLASH)." Journal of Clinical Oncology 39, no. 15_suppl (2021): TPS5087. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps5087.
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TPS5087 Background: Treatment options with minimal toxicity and novel mechanisms of action are urgently needed to improve clinical outcomes from mCRPC. Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) represents a new treatment for patients with PSMA-avid mCRPC. 177Lu-PNT2002 (also known as [Lu-177]-PSMA-I&T) is a PSMA-targeting agent and studies have shown demonstrable promising initial data. This trial seeks to prospectively evaluate the efficacy of 177Lu-PNT2002 for men with progressive mCRPC after androgen receptor axis-targeted (ARAT) therapy. Methods: This is a multi-center, open-label, phase III study. All patients must be at least 18 years of age, have documented progressive mCRPC at time of screening, high PSMA expression by PSMA PET/CT per blinded independent central review (BICR), chemotherapy naïve for CRPC and unfit or unwilling to receive chemotherapy. The study will commence with a 25-patient dosimetry lead-in. In the dosimetry phase, patients will receive up to four cycles of 177Lu-PNT2002 at 6.8 GBq every 8 weeks. In the randomization phase, approximately 390 patients will be randomized in a 2:1 ratio to receive 177Lu-PNT2002 (Arm A) versus enzalutamide or abiraterone (with prednisone or dexamethasone) (Arm B). Patients randomized to Arm B have an option to crossover to 177Lu-PNT2002 treatment after BICR-assessed radiologic progression. The primary endpoint is Radiological progression-free survival (rPFS) assessed by BICR using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG3) (bone) criteria. Key secondary endpoints include objective response rate, duration of response, PSA response, and overall survival. The study is powered at 90% to test the alternative hypothesis of a hazard ratio (HR) ≤ 0.66 at an α of 0.025. ClinicalTrials.gov identifier: NCT04647526. Clinical trial information: NCT04647526.
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De La Fouchardiere, Christelle, Yann Godbert, Cécile Dalban, et al. "Final results of the multicenter, open-label, randomized phase II trial PAZOTHYR evaluating continuous versus intermittent administration of pazopanib in radio-iodine-refractory thyroid cancers (NCT01813136)." Journal of Clinical Oncology 38, no. 15_suppl (2020): 6540. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.6540.
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6540 Background: Multikinase inhibitors (MKI) targeting angiogenesis, including pazopanib (P), have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC) but are accompanied by adverse effects, leading to dose adjustments/interruptions. We aimed to investigate the efficacy and tolerance of a discontinuous scheme of pazopanib administration in this situation. Methods: This randomized phase II study enrolled RAIR-TC patients (pts) in first or second-line of MKI with documented disease progression within 12 months (m). After a 6-m pazopanib continuous induction phase, pts with stable disease (SD) or tumor response were randomly assigned in a 1:1 ratio to receive continuous pazopanib (CP) or intermittent pazopanib (IP) until progression and restart. They were stratified by best tumor response [stable disease vs. objective response] and prior MKI treatment [yes vs. no]). Primary endpoint was time to treatment failure (TTF) defined as time between randomization and permanent discontinuation of pazopanib (either for disease progression or intolerance); secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and safety. Results: 168 pts (66.5 years median age; 51.8% female) were included and 100 pts randomized (CP: 50, IP: 50). The median number of metastatic sites was 2.0 (1-7) and 50 pts (29.8%) were pretreated with MKI. With a median follow-up of 31.3 m, we did not show any statistically significant difference in the TTF, 80% (66.0-88.7%)] of the pts being under P at 6 m after randomization in the IP arm versus 78% (63.8-87.2%) in the CP arm. Median TTF was 14.7 m 95% CI [9.3; 17.4] and 11.9 m 95% CI [7.5; 15.6] respectively (HR 0.79 [0.49-1.27]). The best response with P was 35.6% (95% CI [28.2; 43.6]) and the disease control rate was 89.4% 95% CI [83.5; 93.7]. Median time to progression under P was not statistically different between 2 arms (5.7m 95% CI [4.8;7.8] in the IP arm vs. 9.2m 95% CI [7.3;11.1] in the CP arm (HR 1.36 [0.88; 2.12]). 36/100 pts (36%) experienced pazopanib-related grade 3/4 AEs (CP:17; IP: 19) mainly represented by gastrointestinal disorders, hypertension, cardiac disorders and asthenia. Five pazopanib-related deaths were reported (CP:1;IP: 4). Conclusions: The intermittent administration of pazopanib study did not significantly demonstrate superiority in efficacy or tolerance over continuous treatment. Continuous administration of MKI remains the standard in RAIR-TC. Clinical trial information: NCT01813136 .
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Kimmelman, Jonathan. "Better to be in The Placebo Arm for Trials of Neurological Therapies?" Cell Transplantation 27, no. 4 (2018): 677–81. http://dx.doi.org/10.1177/0963689718755708.
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Patients with progressive neurodegenerative diseases often pursue trial entry seeking to access cutting edge therapies. However, cutting edge therapies for neurodegenerative diseases tend to have higher adverse event rates and underperform placebo. This essay argues that patients seeking trial entry are probably better off, medically, by being assigned to the placebo arm. Because trials involve extra clinic visits and research procedures, patients may be still better off medically by skipping trial participation altogether. I close by arguing that the Neurology research community might better honor the contributions of research subjects by pressing sponsors to promptly publish the results of non-positive trials, minimizing the use of uneven randomization ratios that favor assignment to the investigational treatment, and by fostering systematic collection of data on the risk/benefit balance of trial participation.
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Van Cutsem, E., J. F. Seitz, J. Raoul, et al. "Evaluation of progression-free survival by blinded independent central review in patients with progressive, well-differentiated pancreatic neuroendocrine tumors treated with sunitinib or placebo." Journal of Clinical Oncology 29, no. 4_suppl (2011): 249. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.249.
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249 Background: Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor with antiangiogenic activity. In a phase III, double-blind, placebo-controlled, randomized trial in patients with advanced, well-differentiated progressive pancreatic neuroendocrine tumors (NET), sunitinib 37.5 mg continuous daily dosing significantly improved investigator-assessed progression-free survival (PFS) compared with placebo (median, 11.4 months vs. 5.5 months; hazard ratio [HR] 0.418; 95% CI: 0.263, 0.662; P=0.0001). To evaluate the possibility that recognizable treatment- associated adverse events (AEs) might have impacted the efficacy results by unblinding the investigators, we conducted a retrospective blinded independent central review (BICR) of the tumor imaging scans. Methods: PFS was defined as the time from randomization to the first objective progression of disease or death due to any cause, whichever occurred first. Baseline and on-study CT/MRI scans were evaluated independently according to a two-reader, two-time point lock, followed by a sequential locked read, batch mode paradigm, by independent, third party radiologists. Reading radiologists were blinded to investigator tumor assessments and AEs; discrepancies were adjudicated by a similarly blinded and independent third radiologist. Results: Overall, 171 patients were randomized to treatment (sunitinib, n=86, placebo, n=85). Scans were collected retrospectively for 170 (99.4%) patients. Complete scan sets/time points were available for 160 patients (93.6%). Median PFS based on BICR of scans was 12.6 months for sunitinib and 5.8 months for placebo with an HR of 0.315 (95% CI: 0.181, 0.546; p=0.000015), consistent with the investigator- assessed PFS results. Conclusions: This BICR of tumor scans confirms the investigator-assessed, clinically meaningful PFS benefit of sunitinib in patients with pancreatic NET, and provides evidence against the presence of any systematic bias favoring sunitinib. [Table: see text]
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Del Campo, Jose Maria, Mansoor Raza Mirza, Jonathan S. Berek, et al. "The successful phase 3 niraparib ENGOT-OV16/NOVA trial included a substantial number of patients with platinum resistant ovarian cancer (OC)." Journal of Clinical Oncology 35, no. 15_suppl (2017): 5560. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.5560.
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5560 Background: Niraparib is a highly selective poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor (PARPi); in preclinical studies, it concentrates in the tumor relative to plasma to deliver durable, near complete PARP inhibition and persistent antitumor effects.Niraparib demonstrated significantly longer progression free survival (PFS) vs placebo in patients (pts) with recurrent OC who were randomized following a complete response (CR) or partial response (PR) to platinum based chemotherapy in the controlled, double-blind phase 3 ENGOT-OV16/NOVA trial. To more fully characterize the NOVA trial population, we assessed platinum resistance status, defined as a duration of response to platinum < 6 months to the most recent (ultimate) platinum regimen. Analysis was limited to pts in the placebo arm, as inclusion of pts receiving active treatment (niraparib) would have confounded the ability to determine duration of response to platinum alone. Methods: Pts with recurrent OC, no prior PARPi use, ≥2 prior courses of platinum based chemotherapy, and CR or PR to the most recent platinum based chemotherapy were eligible. Pts were assigned to one of two cohorts based on g BRCA testing (g BRCAmut or non-g BRCAmut) and randomized 2:1 within each cohort to niraparib 300 mg or placebo qd until progressive disease (PD). Randomization occurred up to 8 weeks following the last dose of the most recent platinum based chemotherapy. PFS was measured from time of randomization to death or earliest PD as assessed by independent review committee. Estimated probability of pts having disease progression in each cohort and pooled across cohorts 6 months after the last dose of their most recent platinum therapy was calculated using the Kaplan-Meier methodology. Results: 181 pts were randomized to placebo (65 g BRCAmut and 116 non-g BRCAmut). Platinum resistance rate estimates for the g BRCAmut, non-g BRCAmut, and pooled cohorts were 42%, 53%, and 49%, respectively. Conclusions: Approximately half of the pts in the NOVA study, where niraparib treatment met its primary endpoint of prolonging PFS following a response to platinum, had developed platinum resistance to their last line of chemotherapy. Clinical trial information: NCT01847274.
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Morris, Michael J., Glenn Heller, Alan Haruo Bryce, et al. "Alliance A031201: A phase III trial of enzalutamide (ENZ) versus enzalutamide, abiraterone, and prednisone (ENZ/AAP) for metastatic castration resistant prostate cancer (mCRPC)." Journal of Clinical Oncology 37, no. 15_suppl (2019): 5008. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.5008.
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5008 Background: Androgen receptor (AR) signaling is an important growth mechanism in mCRPC, providing the rationale for treatment with AR axis inhibitors such as ENZ and AAP. Targeting AR with anti-androgens such as ENZ can result in compensatory autocrine and paracrine androgenic stimulation. Therefore, using ENZ with the androgen biosynthesis inhibitor AAP to dampen these resistance mechanisms could improve clinical outcomes relative to ENZ alone. Methods: Men with progressive mCRPC by Prostate Cancer Working Group 2 criteria were eligible. Prior treatment with taxanes for mCRPC and any prior treatment with ENZ or AAP was exclusionary. Patients (pts) were randomized 1:1 to ENZ or ENZ/AAP at standard FDA-approved doses. Randomization was stratified by prior chemotherapy and Halabi prognostic three risk groups. Castrating therapy was maintained. The primary endpoint was overall survival (OS) defined as the date of randomization from date of death or last follow-up. The log-rank test had 90% power to detect a hazard ratio for OS of 0.77 with a one-sided type I error rate of 0.025. Secondary endpoints included radiographic progression free survival (rPFS) and on-treatment PSA declines. Exploratory endpoints included imaging changes, and changes in serum biomarkers such as androgens, angiokines, and circulating microRNA and RNA. The primary analysis was based on the stratified log-rank test adjusting on the stratification factors. Results: Between January 2014 and August 2016, 1311 men were randomized: 657 to ENZ and 654 to ENZ/AAP. Groups were well balanced between arms, including stratification variables. 15.6% of pts were high risk, 35.3% intermediate, and 48.1% low. Median OS was 33.6 mo (95% CI 30.5-36.4) and 32.7 mo (29.9-35.4) respectively, two-sided p = 0.53. Fifty percent PSA decline rate was 80% vs. 76.5%. Grade 3-5 adverse events (AE) (all attributions) were 55.6% and 68.8% respectively. Treatment discontinuation due to AEs occurred in 5% and 12%, pt withdrawal in 5% and 13%, and progression or death in 57% and 48% of pts respectively. Conclusions: Addition of abiraterone acetate to enzalutamide did not prolong survival in men with mCRPC. The combination resulted in more AEs than enzalutamide alone. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01949337.
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Takayama, Yoshimasa, Eizo Kimijima, Eiji Harunari, and Hideo Watanabe. "Changes in Crystallographic Orientation Distribution during Superplastic Deformation in Aluminum Alloys." Materials Science Forum 838-839 (January 2016): 72–77. http://dx.doi.org/10.4028/www.scientific.net/msf.838-839.72.
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Changes in crystallographic orientation distribution during superplastic deformation in a fine-grained Al-Zn-Mg-Cu alloy and an Al-Mg-Mn alloy consisting of the coarse-grained surface and the fine-grained center layers have been reviewed in order to reveal contribution of dislocation slips to deformation. The strain rate and grain size dependences of the deformation behavior were examined by SEM/EBSD (scanning electron microscopy/ electron back scatter diffraction) analysis. Intragranular misorientation increases after deformation at high strain rates, presumably due to dislocation activity, while it was low in the specimen deformed at a low strain rate in the early stage of 35% strain. Progressive randomization of the initial texture was also found during deformation at the low strain rate. Further, grain structure and grain boundary character are analyzed in detail to discuss the deformation mechanism.
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Naik, Jyoti, Dirk R. de Waart, Karina Utsunomiya, et al. "ATP8B1 and ATP11C: Two Lipid Flippases Important for Hepatocyte Function." Digestive Diseases 33, no. 3 (2015): 314–18. http://dx.doi.org/10.1159/000371665.
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P4 ATPases are lipid flippases and transport phospholipids from the exoplasmic to the cytosolic leaflet of biological membranes. Lipid flipping is important for the biogenesis of transport vesicles. Recently it was shown that loss of the P4 ATPases ATP8B1 and ATP11C are associated with severe Cholestatic liver disease. Mutation of ATP8B1 cause progressive familial Intrahepatic Cholestasis type 1 (PFIC1)and benign recurrent intrahepatic cholestasis type 1 (BRIC 1). From our observations we hypothesized that ATP8B1 deficiency causes a phospholipids randomization at the canalicular membrane, which results in extraction of cholesterol due to increase sensitivity of the canalicular membrane. Deficiency of ATP11C causes conjugated hyperbilirubinemia. In our preliminary result we observed accumulation of unconjugated bile salts in Atp11c deficient mice probably because of regulation in the expression or function of OATP1B2. Similar to ATP8B1, ATP11C have regulation on membrane transporters.
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Goodin, Douglas S., Anthony T. Reder, Anthony L. Traboulsee, et al. "Predictive validity of NEDA in the 16- and 21-year follow-up from the pivotal trial of interferon beta-1b." Multiple Sclerosis Journal 25, no. 6 (2018): 837–47. http://dx.doi.org/10.1177/1352458518773511.
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Background: Long-term follow-up from the randomized trial of interferon beta-1b (IFNB-1b) permitted the assessment of different definitions of no evidence of disease activity (NEDA) for predicting long-term outcome in multiple sclerosis (MS). Objective: To examine the predictive validity of different NEDA definitions. Methods: Predictive validity for negative disability outcomes (NDOs) at 16 years and survival at 21 years post-randomization were assessed. NEDA in the first 2 years was defined as follows: clinical NEDA: no relapses or Expanded Disability Status Scale (EDSS) progression from baseline to Year 2; NEDA-3a: no relapses, no confirmed ⩾1-point EDSS progression, and no new T2-active lesions; NEDA-3b: no relapses, no EDSS progression, and no increase in T2 burden of disease (T2-BOD); and NEDA-4: no relapses, no EDSS progression, and no increase in T2-BOD or atrophy. NDOs were defined as death, need for wheelchair, EDSS ⩾6, or progressive MS. Results: A total of 245 and 371 patients were evaluated at 16 and 21 years, respectively. Clinical NEDA predicted NDOs ( p = 0.0029), as did baseline EDSS ( p < 0.0001), baseline T2-BOD ( p < 0.0001), and change in T2-BOD ( p = 0.0033). IFNB-1b treatment ( p = 0.0251), relapse rate in the 2 years before study start ( p = 0.0260), T2-BOD at baseline ( p = 0.0014), and change in T2-BOD ( p = 0.0129) predicted survival at 21 years. Conclusion: Clinical NEDA predicted long-term disability outcome. By contrast, definitions of NEDA that included on-therapy changes in magnetic resonance imaging variables did not increase the predictive validity.
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Young, Lufei, Kathleen Healey, Mary Charlton, Kendra Schmid, Rana Zabad, and Rebecca Wester. "A home-based comprehensive care model in patients with Multiple Sclerosis: A study pre-protocol." F1000Research 4 (September 18, 2015): 872. http://dx.doi.org/10.12688/f1000research.7040.1.
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Background Disability is prevalent in individuals with multiple sclerosis (MS), leading to difficulty in care access, significant caregiver burden, immense challenges in self-care and great societal burden. Without highly coordinated, competent and accessible care, individuals living with progressive MS experience psychological distress, poor quality of life, suffer from life-threatening complications, and have frequent but avoidable healthcare utilizations. Unfortunately, current healthcare delivery models present severe limitations in providing easily accessible, patient-centered, coordinated comprehensive care to those with progressive MS. We propose a home-based comprehensive care model (MAHA) to address the unmet needs, challenges, and avoidable complications in individuals with progressive MS with disabling disease.Objective The article aims to describe the study design and methods used to implement and evaluate the proposed intervention. Method The study will use a randomized controlled design to evaluate the feasibility of providing a 24-month, home-based, patient-centered comprehensive care program to improve quality of life, reduce complications and healthcare utilizations overtime (quarterly) for 24 months. A transdisciplinary team led by a MS-Comprehensivist will carry out this project. Fifty MS patients will be randomly assigned to the intervention and usual care program using block randomization procedures. We hypothesize that patients in the intervention group will have fewer complications, higher quality of life, greater satisfaction with care, and reduced healthcare utilization. The proposed project is also expected to be financially sustainable in fee-for-service models but best suited for and gain financial success in valued-based care systems. Discussion This is the first study to examine the feasibility and effectiveness of a home-based comprehensive care management program in MS patients living with progressive disability. If successful, it will have far-reaching implications in research, education and practice in terms of providing high quality but affordable care to population living with severe complex, disabling conditions.
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Wick, Wolfgang, Andriy Krendyukov, Klaus Junge, Thomas Höger, Claudia Kunz, and Harald Fricke. "Longitudinal analysis of quality of life following treatment with asunercept plus reirradiation versus reirradiation in progressive glioblastoma patients." Journal of Clinical Oncology 37, no. 15_suppl (2019): 2022. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.2022.
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2022 Background: Palliation of symptoms and the maintenance of quality of life (QoL) are important goals in cancer treatment.1,2 Beyond progression free survival (PFS) and overall survival (OS), health related QoL was one of the secondary endpoints in the asunercept plus irradiation Phase II trial (NCT01071837) in recurrent glioblastoma.3 Current analysis presents time to deterioration (TtD) of QoL using data from this study. Methods: Data from patients (pts) with a baseline and ≥1 post-baseline QoL assessment were included in this analysis. TtD was defined as the time from randomization to the first deterioration in the EORTC QLQ-C15, PAL EORTC QLQ-BN20 and Medical Research Council (MRC)-Neurological status. Deterioration was defined as a decrease of ≥10 points from baseline in the QLQ-C15 PAL overall QoL and functioning scales, an increase of ≥10 points from baseline in the QLQ-C15 PAL fatigue scale and the QLQ-BN20 total sum of score, and a rating of “Worse” in the MRC-Neurological status. Pts without a deterioration were censored at the last QoL assessment. Kaplan-Meier estimates were used to describe TtD and both treatment groups compared using the logrank test. The relationship between progression of disease (PD) and QoL deterioration has been investigated. Results: Compared to reirradiation alone, treatment with asunercept + reirradiation was associated with significant improvement of TtD (P≤0.01; Table). PD was a key driver for QoL deterioration and the median TtD was comparable with PFS in favour of the asunercept treatment arm. Conclusions: Treatment with asunercept plus irradiation significantly prolongs TtD and maintains QoL, versus reirradiation alone in progressive glioblastoma patients. Clinical trial information: NCT01071837. References: 1. NCCN. Central Nervous System Cancers. Version 2018.2; 2. Stupp R et al. Ann Oncol 2014;25(S3):iii93-iii101; 3. Wick et al. Clin Cancer Res 2014;20:6304–13.[Table: see text]
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Teel, Elizabeth F., Stephen W. Marshall, L. Gregory Appelbaum, et al. "A Randomized Controlled Trial Investigating the Feasibility and Adherence to an Aerobic Training Program in Healthy Individuals." Journal of Sport Rehabilitation 28, no. 7 (2019): 692–98. http://dx.doi.org/10.1123/jsr.2018-0007.
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Context:Concussion management is moving from passive rest strategies to active interventions, including aerobic exercise therapy. Little information is available regarding the feasibility and adherence of these programs.Objectives:To determine whether an aerobic exercise training program intended for rehabilitation in people with concussion is feasible. Healthy, nonconcussed subjects were studied in this phase 1 trial.Design:Phase 1 parallel-group, randomized controlled trial in a sample of healthy (nonconcussed), recreationally active university students.Setting:Laboratory.Patients:40 healthy university students.Methods:Participants were equally randomized to acute concussion therapy intervention (ACTIVE) training or nontraining groups. All participants completed maximal cardiopulmonary exercise tests on a stationary cycle ergometer at 2 test sessions approximately 14 days apart. During this 2-week study period, ACTIVE training participants completed six 30-minute cycling sessions, progressing from 60% to 80% of the participant’s individualized maximal oxygen consumption. A subset of participants (NACTIVE = 12, Nnontraining = 11) wore physical activity monitors throughout the 2-week study period.Main Outcomes Measures:Study protocol and randomization effectiveness, exercise safety and adherence, and progressive intensity of the ACTIVE training procedures.Results:No adverse events occurred during any exercise sessions. Twelve ACTIVE training participants (60%) completed all training sessions, and every participant completed at least 4 sessions. Heart rate increased throughout the training period (P < .001), but symptom changes and training adherence remained stable despite the progressively increasing workload. ACTIVE training participants completed approximately 30 additional minutes of physical activity on training sessions days, although that was not statistically significant (P = .20).Conclusions:University-aged students were adherent to the ACTIVE training protocol. Future research should investigate the safety and feasibility of aerobic training programs in acutely concussed individuals to determine their appropriateness as a clinical rehabilitation strategy.
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Aziz Ismail, Nemat Ismail Abdel, and Wafaa Taha Ibrahim Elgzar. "The Effect of Progressive Muscle Relaxation on Post Cesarean Section Pain, Quality of Sleep and Physical Activities Limitation." International Journal of Studies in Nursing 3, no. 3 (2018): 14. http://dx.doi.org/10.20849/ijsn.v3i3.461.
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Background: Pain, sleep disturbances, and physical activity limitation are the most tiresome complains of the women post caesarian section (Cs). Progressive muscle relaxation is a promising intervention for these complains. This study aimed to determine the effect of progressive muscle relaxation technique on post-cesarean section pain, quality of sleep and physical activities limitation. Research design: Randomized controlled clinical trial. Setting: post-partum unit at Damanhour National Medical Institute. Sample: A purposive sample of 80 women undergoing Cs was recruited. Randomization block was done to randomly assign 40 women for the study group and 40 for the control group. Tools: Four tools were used for data collection: structured interview schedule, short-form McGill Pain Questionnaire, Physical activities limitation Questionnaire and Groningen Sleep Quality Scale. Results: After the intervention, PMR significantly decreased pain severity among study group in Pain Rating Index scale, Visual analogue pain scale, and Present Pain Intensity scale compared to the control group. The severe physical activities limitation significantly absent from the entire study group, while it was significantly present among 70% of the control group. About two-thirds (62.5%) of the study group had a good quality of sleep compared to 5% of the control group. Conclusion: PMR significantly decreased pain, improved physical activities and quality of sleep among women after Cs. Recommendation: PMR should be incorporated in the nursing intervention protocols post-Cs.
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Sartor, A. Oliver, Michael J. Morris, and Bernd J. Krause. "VISION: An international, prospective, open-label, multicenter, randomized phase 3 study of 177Lu-PSMA-617 in the treatment of patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC)." Journal of Clinical Oncology 37, no. 15_suppl (2019): TPS5099. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.tps5099.
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TPS5099 Background: The novel therapeutic drug 177Lu-PSMA-617 is a prostate specific membrane antigen (PSMA) targeting agent to deliver radionuclide therapy for the treatment of pts with metastatic castration resistant prostate cancer. Based on preclinical data that demonstrated high PSMA binding affinity & compound internalization, prolonged tumor uptake, rapid kidney clearance, & high tumor-to-background ratio, 177Lu-PSMA-617 proceeded into clinical development. Preliminary clinical evidence indicates 177Lu-PSMA-617 may demonstrate clinical benefit in pts with mCRPC in a setting where pts had no recommended standard of care. This Phase 3 study will assess the efficacy of 177Lu-PSMA-617 in patients with progressive PSMA-positive mCRPC by measuring overall survival (OS) and radiographic progression free survival (rPFS) in a randomized, prospective, open-label trial. Methods: The primary objective of this study is to compare the 2 alternative endpoints of rPFS & OS in pts with progressive PSMA-positive mCRPC who receive 177Lu-PSMA-617 in addition to best supportive/standard of care vs pts treated with best supportive/best standard of care alone. Eligibility criteria are: PSMA expressing tumor; prior exposure to a taxane and novel androgen axis drug. Pts will be randomized in a 2:1 ratio in favor of the investigational arm with stratification factors of LDH, liver disease, ECOG score, and use of NAAD at time of randomization as a standard of care. Under the alternative hypothesis, median OS on active is assumed to be 13.7 mo for a HR of 0.7306 and rPFS on the active is assumed to be 6 mo for a HR of 0.67. Planned enrollment for this study is 750 patients. Enrollment began in June 2018 and continues; the IDMC last reviewed the trial for safety in January 2019 and suggested that the trial continue as planned. Clinical trial information: NCT03511664.
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Bergsland, Emily K., Michelle R. Mahoney, Timothy R. Asmis, et al. "Prospective randomized phase II trial of pazopanib versus placebo in patients with progressive carcinoid tumors (CARC) (Alliance A021202)." Journal of Clinical Oncology 37, no. 15_suppl (2019): 4005. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.4005.
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4005 Background: Patients (pts) with progressive advanced well-differentiated neuroendocrine tumors arising outside of the pancreas have limited systemic treatment options. Pazopanib (PZ) is an oral multi-kinase inhibitor with activity against VEGFR-2,-3, PDGFR-α, and β, and c-KIT, with initial data suggesting efficacy in CARC. Methods: This was a multicenter, randomized, double-blind, phase II study of PZ (800 mg/day) versus placebo (PL) in progressive CARC. Key eligibility: low-intermediate grade CARC, radiologic progressive disease (PD) < 12 months (mo), and adequate end-organ function. Prior somatostatin analog (SSA) mandated for midgut tumors. Concurrent SSA allowed if previous PD on SSA documented. Primary endpoint was progression-free survival (PFS), defined as time from randomization to PD by central review or death. Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. The trial had 85% power to detect a difference in median PFS of 14 v 9 mo (hazard ratio [HR] 0.64) at one-sided alpha = 0.1. A stratified log-rank test based on the intend-to-treat (ITT) principle was used. Unblinding and crossover were allowed if PD confirmed by central review. Results: 171 (97 PZ, 74 PL) pts were randomized between 6/2013-10/2015: median age 63; 56% female; 66% small bowel primary; 87% concurrent SSA. Median follow-up of 31 mo; 112 (56 PZ, 56 PL) PFS events observed. 6 pts (4 PZ, 2 PL) remain on initial treatment. Median PFS was 11.6 and 8.5 mo in PZ and PL, respectively (HR = 0.53, 1-sided 90% upper confidence limit [UCL] 0.69, p = 0.0005) which crossed the pre-specified protocol efficacy boundary. 49 PL pts received PZ after PD. Median OS was 41 and 42 mo in PZ and PL, respectively (HR = 1.13, 1-sided 90% UCL 1.51, p = 0.70). RR data will be presented. Notable grade 3+ adverse events were (PZ v. PL %) hypertension (35 v. 8), fatigue (11 v. 4), ALT (10 v. 0), AST (10 v. 0), and diarrhea (7 v. 4). Conclusions: PZ compared to PL was associated with significant improvement in PFS in patients with progressive CARC. The results confirm that VEGF signaling pathway is a valid target for therapy in CARC. Support: U10CA180821, U10CA180882 https://acknowledgments.alliancefound.org . Clinical trial information: NCT01841736.
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Lesosky, Maia, Molebogeng X. Rangaka, Cara Pienaar, et al. "Plasma Biomarkers to Detect Prevalent or Predict Progressive Tuberculosis Associated With Human Immunodeficiency Virus–1." Clinical Infectious Diseases 69, no. 2 (2018): 295–305. http://dx.doi.org/10.1093/cid/ciy823.
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Abstract Background The risk of individuals infected with human immunodeficiency virus (HIV)-1 developing tuberculosis (TB) is high, while both prognostic and diagnostic tools remain insensitive. The potential for plasma biomarkers to predict which HIV-1–infected individuals are likely to progress to active disease is unknown. Methods Thirteen analytes were measured from QuantiFERON Gold in-tube (QFT) plasma samples in 421 HIV-1–infected persons recruited within the screening and enrollment phases of a randomized, controlled trial of isoniazid preventive therapy. Blood for QFT was obtained pre-randomization. Individuals were classified into prevalent TB, incident TB, and control groups. Comparisons between groups, supervised learning methods, and weighted correlation network analyses were applied utilizing the unstimulated and background-corrected plasma analyte concentrations. Results Unstimulated samples showed higher analyte concentrations in the prevalent and incident TB groups compared to the control group. The largest differences were seen for C-X-C motif chemokine 10 (CXCL10), interleukin-2 (IL-2), IL-1α, transforming growth factor-α (TGF-α). A predictive model analysis using unstimulated analytes discriminated best between the control and prevalent TB groups (area under the curve [AUC] = 0.9), reasonably well between the incident and prevalent TB groups (AUC &gt; 0.8), and poorly between the control and incident TB groups. Unstimulated IL-2 and IFN-γ were ranked at or near the top for all comparisons, except the comparison between the control vs incident TB groups. Models using background-adjusted values performed poorly. Conclusions Single plasma biomarkers are unlikely to distinguish between disease states in HIV-1 co-infected individuals, and combinations of biomarkers are required. The ability to detect prevalent TB is potentially important, as no blood test hitherto has been suggested as having the utility to detect prevalent TB amongst HIV-1 co-infected persons.
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Chevreau, C., I. Ray-Coquart, B. Bui, et al. "Outcome of patients with advanced GIST achieving a complete remission (CR) with imatinib (IM) before interruption: Pooled analysis of two consecutive prospective randomizations of the French Sarcoma Group BFR14 phase III trial." Journal of Clinical Oncology 27, no. 15_suppl (2009): 10549. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.10549.
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10549 Background: Patients (pts) experiencing a major response under IM treatment seem to have a better outcome than others (Cioffi, ASCO 08). IM interruption in responding patients after 1 and 3 yrs of treatment results in a high risk of rapid progression after a few months. The influence of pattern of response on PFS before IM discontinuation is unknown. Methods: Since June 2002, 415 pts were included in this trial. Fifty-eight, 50 and 12 (ongoing) non progressive pts at 1, 3 and 5 yrs respectively were randomly offered to continue (C arm) or interrupt (I arm) IM. Sixty-four pts were randomized in the I arm, 32, 25 and 7 after 1, 3 and 5 yrs of IM treatment respectively. Time to progression (TTP) of pts achieving a CR or a major PR (residual tumor < 10mm) before IM interruption was compared to outcome of pts experiencing others patterns of response. Results: Twenty-three pts achieving a CR or a major PR (36%) before randomization in the I arm, 9 after 1 yr, 10 after 3 yrs and 4 after 5 yrs of IM treatment. As of December 2008, 15 relapses were observed in the CR group (65%) versus 36 in the other cohort of pts (90%). The median TTP were 10.5 months (IC95%: 9–16 months) for the CR group and 6.1 months (IC95%: 4–9.2 months) for the non CR group (p=0.058). The median TTP were 9.4 months for the CR group vs 6 months for pts randomized after 1 yr of treatment, 12.3 months versus 5.7 months for pts randomized after 3 yrs of treatment respectively. One third of pts achieving a CR before randomization in the I arm was free of disease in December 2008. Conclusions: A CR achieved under IM is not a prerequisite for a prolonged disease-free survival in advanced GIST after 1 or 3 yrs of treatment. Despite a trend for a favourable outcome, prognosis of pts with a CR or a major PR is similar to those achieving a PR or a disease stabilisation. A selected group of advanced GIST pts in CR could be cured with IM alone. New radiological assessments or response critera have to be implemented in order to define a real CR. [Table: see text]
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Ward, J. E., S. Limvorasak, T. Karrison, et al. "A randomized phase II study of pazopanib in castrate-sensitive prostate cancer: A University of Chicago phase II consortium/DoD Prostate Cancer Clinical Trials Consortium study." Journal of Clinical Oncology 29, no. 7_suppl (2011): 170. http://dx.doi.org/10.1200/jco.2011.29.7_suppl.170.
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170 Background: Intermittent androgen suppression (IAS) has been studied as a way of minimizing toxicity from long term androgen deprivation therapy (ADT). Based on previous studies with similar agents, we hypothesized that inhibition of VEGFR would result in prolonged time to PSA progression (TTPP) and allow for longer periods off ADT. Methods: Men with biochemically recurrent, progressive prostate cancer and no evidence of macroscopic metastases were enrolled. They received 6 months of ADT. If at the end of that time the PSA was <0.5 ng/mL (with castrate testosterone levels), they were randomized to pazopanib 800 mg/d or observation. The primary outcome was TTPP, defined as time to a PSA >4.0 ng/mL, at which time they were restarted on ADT. Results: 37 pts met randomization criteria. 18 were randomized to pazopanib. Only 4 pts met the endpoint criteria of TTPP, whereas 13 (72%) pts went off study for other reasons with 1 pt on treatment at study closure. Reasons for discontinuation included drug toxicity (grade 1/2, 9 pts) and patient preference (2 pts). No grade 3/4 toxicity was noted. 1 pt was removed due to pulmonary embolus, 1 pt due to MD discretion and 1 pt due to noncompliance. 19 pts were randomized to observation of which 12 were off treatment when the study was stopped. Only 5 pts met criteria for TTPP, whereas 7 of 12 (58%) dropped out for other reasons, including the frequency of protocol related blood draws and visits (3 pts) and randomization to observation (2 pts), 1 pt was removed per MD discretion and 1 pt transferred care. Due to high dropout rates in both arms, accrual was halted as the primary endpoint could not be measured robustly. Conclusions: Minimizing the long term toxicities of ADT is an unmet need in prostate cancer therapy. Hence clinical interventions in concert with IAS represent an attractive area for drug development. This trial has outlined several barriers that exist in studying this patient population and might help to optimize future studies. Future trial design in this arena should investigate drugs with minimal toxicity and employ a design that maximizes patient convenience while anticipating the low threshold for patient drop out. No significant financial relationships to disclose.
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Crump, Michael, John Kuruvilla, C. Tom Kouroukis, et al. "A Randomized Trial Of Rituximab Vs Observation Following Autologous Stem Cell Transplantation (ASCT) For Relapsed Or Refractory CD20-Positive B Cell Lymphoma: Final Results Of NCIC CTG LY.12." Blood 122, no. 21 (2013): 155. http://dx.doi.org/10.1182/blood.v122.21.155.155.
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Abstract Background NCIC CTG LY.12 was an international randomized trial evaluating two treatment strategies for patients (pts) with aggressive lymphoma relapsing after or with progressive disease following primary therapy. The first randomization demonstrated that gemcitabine, dexamethasone, cisplatin (GDP) was non-inferior to and significantly less toxic than dexamethasone, cytarabine, cisplatin (DHAP) as salvage therapy (ASH 2012). Here we report the results of the second randomization, testing the ability of the CD20 antibody rituximab (R) administered post-ASCT to improve event-free survival (EFS) compared to no further therapy. Methods Pts with CD20-positive aggressive lymphoma who underwent ASCT after GDP or DHAP who had recovered from ASCT-related toxicities and who remained clinically progression-free within 3-5 weeks post-transplant were stratified by centre, salvage regimen received, response to salvage therapy (CR vs PR/SD) and prior treatment with R, and were randomized using a minimization algorithm to receive R 375 mg/m2every 2 months for 6 doses, or observation. Response assessment by CT scanning was required at 3,7,13 and 25 mos post-ASCT or as needed to evaluate possible disease recurrence. The primary endpoint of the second randomization was 2 year EFS; to detect an improvement by 15% (from 50 to 65%, hazard ratio 0.62) required 142 events, with a 2-sided α 0.05 and power 0.80. Because of the low event rate over the last year and a projected time of many years to reach the protocol specified event rate, the Data Safety Monitoring Committee approved a request for study closure and analysis, with 118 events recorded. Results 230 patients were randomized to R maintenance (115) or observation (115). Baseline patients and disease characteristics were well balanced between treatment arms: median age was 53 yrs, 28% were age >65 and 40% were female; 52% received GDP and 48% DHAP; 55% had an IPI score of 2 or more at relapse/progression, and 17% had transformed (TR) from previous indolent lymphoma. Response to salvage pre-ASCT: CR 24%, PR 58%; 70% had received R with chemotherapy prior to study enrolment, and 69% received R with protocol salvage treatment. All analyses are by intention to treat (ITT). To date, there have been 118 EFS events (R 53, observation 65). After a median follow-up of 63 months, 2 year EFS was 64% for pts treated with maintenance R vs 51% for those on observation (HR 0.74, 95% CI 0.48-1.14, p= 0.11); there was no difference in overall survival (OS) at 4 years (R 69%, observation 68%, p=0.64). Grade 3-4 neutropenia was reported in 36% of pts on R maintenance vs 25% during observation; and Gr 3-4 thrombocytopenia in 11% and 16%, respectively. Febrile neutropenia occurred in 10 pts (9%) on R maintenance and 2 pts (2%) on observation. Two year EFS was similar in subsets defined by stratification variables at randomization: GDP salvage therapy: R 57.0% vs observation 45.9% (HR 0.84, 95% CI 0.52-1.36), DHAP: R 70.0% vs observation 57.1% (HR 0.68, 0.39-1.18); response to salvage CR/CRu: R 69.0% vs 52.9% (HR 0.71, 0.32-1.6), PR: R 64.5% vs observation 57.4% (HR 0.90, 0.55-1.46); R use with prior treatment: R 53.7% vs observation 42.0% (HR 0.81, 0.54-1.22); no prior R: R 83.3% vs observation 70.6% (HR 0.64, 0.29-1.38). In multivariable analysis, only age >60 was significantly associated with EFS; ECOG performance status, treatment arm, stage and extra-nodal disease were not significant. Conclusion This evaluation of rituximab maintenance treatment every 2 mos for one year after ASCT for aggressive lymphoma failed to meet the study endpoint of improved EFS, compared to observation. Disclosures: Crump: Roche: Honoraria; Jansen-Ortho: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Novartis: Research Funding; Seattle Genetics: Honoraria. Off Label Use: rituximab for maintenance therapy post autolgous transplant for lymphoma. Kuruvilla:Roche Canada Seattle Genetics, Janssen, Celgene, Lundbeck, Karyopharm: Honoraria. Kouroukis:Roche: Honoraria. Federico:MedImmune: Research Funding. Meyer:Lilly: Consultancy; Celgene: Consultancy.
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Qiao, Mengyuan, Chongli Chen, Yuqing Liang, Yuxi Luo, and Wenbin Wu. "The Influence of Serum Uric Acid Level on Alzheimer’s Disease: A Narrative Review." BioMed Research International 2021 (June 2, 2021): 1–8. http://dx.doi.org/10.1155/2021/5525710.
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As a powerful antioxidant in the human body, uric acid (UA) has been the subject of increasing research that focused on its influence on Alzheimer’s disease (AD) in recent years. The latest literature was gathered to describe the influence of serum uric acid (SUA) level on the onset and progression of AD and to analyze the possibility that SUA is a biomarker of Alzheimer’s disease. A large number of existing studies suggested that the SUA level was lower or tended to decrease in patients with AD, and increased SUA level may have a protective effect in AD, which could reduce the risk of onset and slowing the course of the disease. However, some Mendelian randomization analyses suggested that genetically determined uric acid was not associated with AD risk. Existing research results are contradictory due to the high inconsistency of the studies, the selection of subjects, and other factors. UA also showed a strong association with cognitive function, and there appeared to be a gender-selective neuroprotective action. Due to its potent antioxidant properties, the low uric acid level may contribute to oxidative stress to accelerate disease progression. But some preclinical data showed a possibility that in some special cases, UA had a prooxidant properties. The possibility was raised in the discussion of the underlying mechanism that both the low uric acid level and the rapidly progressive course of the disease were the consequence of malnutrition. This paper reviews recent advances in the study of SUA and AD which offers the possibility of new biomarker, new prevention, and treatment strategies for Alzheimer’s disease.
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Kimby, Eva, Sandra Lockmer, Harald Holte, et al. "The PRIMA-Prognostic Index (PI) Is Valid in Follicular Lymphoma (FL) Patients with Rituximab Chemo-Free First-Line Treatment." Blood 132, Supplement 1 (2018): 4150. http://dx.doi.org/10.1182/blood-2018-99-114866.
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Abstract Background: Follicular lymphoma (FL) is a heterogenous disease. The optimal timing, sequence and choice of therapy remain matters of debate and there is no optimal prognostic tool. The FLIPI (Follicular Lymphoma International Prognostic Index) is based on five bio-clinical parameters and is widely used, but not as guide for choice of treatment. Recently a new prognostic score (PRIMA-PI), based solely on two parameters, bone marrow involvement and serum beta2 microglobulin (ß2m) was proposed for patients treated with immunochemotherapy (Bachy E., Blood 2018). The Nordic Lymphoma Group (NLG) performed two randomized trials including patients with symptomatic/progressive indolent CD20+ lymphoma, with rituximab monotherapy or rituximab in combination with interferon (IFN)-α2a as primary treatment, without maintenance (Kimby E., 2008, 2015). The 10 years follow-up of these patients showed a good survival with no major safety issues and no need for later chemotherapy in 38% of FL patients (Lockmer S, JCO 2018). Aim/Purpose: To evaluate two different prognostic systems (the new PRIMA-PI and the FLIPI), for overall survival (OS) and time to treatment failure (TTF) in a cohort of symptomatic/progressive FL patients treated with a rituximab-containing first-line regimen without chemotherapy. Methods: Previously untreated patients with a confirmed FL diagnosis (n=269) or indolent lymphoma not otherwise specified (n=22, most FLs with insufficient material for grading), treated in the NLG randomized trials with two cycles rituximab (375 mg/m2 x 4 weeks), with or without IFN-α2a, were classified into the three PRIMA-PI categories: high-risk: ß2m> 3mg / L, intermediate-risk: ß2m ≤ 3 mg / L with bone marrow involvement and low-risk: ß2m ≤ 3 mg / without bone marrow involvement. The FLIPI scores were also assessed. TTF, defined as the interval between randomization and either initiation of new lymphoma therapy due to relapse or intolerance, or death from any cause, as well as OS were estimated using the Kaplan Meier method. The log-rank test was used for comparison between risk groups. Results: Out of 291 patients, 252 had complete data on PRIMA-PI and FLIPI (at the time of randomization in the original trials) and were available for analyses of TTF and OS. Patient characteristics are shown in Table 1. PRIMA-PI seemed to identify a true high-risk group of 47 patients, 32 of them being high risk also according to FLIPI, while a larger patient group (n=117) was classified as FLIPI high-risk. After a long follow-up time, median 9.9 years (0.4 -18.8) from randomization, median 10.6 years for the 214 patients (74%) still alive, 76 patients (26%) were failure-free and 108 (37%) without need of any chemotherapy, Patients with PRIMA-PI high showed a shorter TTF compared to PRIMA-PI intermediate and low (Fig 1a), whereas the FLIPI risk-groups were not significantly separated (Fig 1b). Evidence of transformation to aggressive disease was seen in 55 patients, with no significant difference in frequency between the PRIMA-PI groups, nor between FLIPI groups. Both PRIMA-PI and FLIPI were of significant value for predicting OS, most evident after a long follow-up time (Fig 1c and d). In 41 patients the cause of death was progressive disease or therapy complications, regarded as lymphoma-related death, whereas 21 died of other causes. The lymphoma-specific survival was related to the PRIMA-PI (log-rank p=0.03), but not to the FLIPI (n.s). Prognosis was worse for the PRIMA-PI high-risk group than the for the low-risk, also when adjusted for sex, high age (>60 years), diagnosis, stage, ECOG and FLIPI risk-group; TTF HR 1.82 (95% CI 1.16-2.85, p=0.01) and OS HR 2.3 (95% CI 1.00-5.38, p=0.05). Conclusion: FL patients included in two NLG trials with complete clinical data and a median follow-up of >10 years after randomization have been assessed for validation of different prognostic indices. In these patients, all with chemo-free first-line therapy, the PRIMA-PI was shown a valid predictor of both TTF and OS and seemed more useful than the FLIPI. The PRIMA-PI high risk identified a group of patients (19% of all) with true poor prognosis. Disclosures Kimby: Roche: Honoraria; Roche: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees. Holte:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Roche, Norway: Research Funding. Wahlin:Roche: Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Hagberg:Roche: Honoraria.
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Zweegman, Sonja, Fredrik H. Schjesvold, Bronno van der Holt, et al. "Ixazomib-Thalidomide-Low Dose Dexamethasone (ITd) Induction Followed By Maintenance Therapy with Ixazomib or Placebo in Newly Diagnosed Multiple Myeloma Patients Not Eligible for Autologous Stem Cell Transplantation; Results from the Randomized Phase II HOVON-126/Nmsg 21#13 Trial." Blood 132, Supplement 1 (2018): 800. http://dx.doi.org/10.1182/blood-2018-99-111650.
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Abstract Introduction A triplet combination including a proteasome inhibitor (PI) and an IMiD has shown significant efficacy in newly diagnosed multiple myeloma (NDMM) patients. A role for maintenance therapy with the PI bortezomib has been suggested in non-head to head comparisons. Therefore, we investigated the efficacy and feasibility of an oral regimen including induction therapy with ixazomib in combination with thalidomide and dexamethasone, followed by a randomization between maintenance therapy with ixazomib or placebo in elderly non-transplant eligible (nte) NDMM. We here report the final analysis of induction therapy and preliminary results of the randomization phase of the study. This trial was registered at www.trialregister.nl as NTR4910. Methods In this prospective multicenter phase II trial nte-NDMM 143 patients were treated with 9 28 day-cycles consisting of ixazomib 4 mg (day 1, 8, 15), thalidomide 100 mg (day 1-28) and dexamethasone 40 mg (day 1, 8, 15, 22) followed by randomization between either ixazomib or placebo (both day 1, 8, 15/28 days) until progression. Primary objectives were comparison of progression free survival (PFS) between maintenance therapy with ixazomib or placebo (hypothesized hazard ratio (HR) 0.39) and to determine the overall response rate (ORR) of induction therapy. Frailty was assessed by a modification of the IMWG frailty index based on age, the Charlson Comorbidity Index and the WHO performance as a proxy for (instrumental) Activities of Daily Living (scoring WHO 0 as 0 points, WHO 1 as 1 point, and WHO 2-3 as 2 points). High risk cytogenetics was defined as del17p, t(4;14) and/or t(14;16). Results The median follow up (FU) from registration is 26.4 months (range 0.9-41.0 months). Patient characteristics are presented in table 1. Following induction treatment ORR (i.e. ≥PR) was 81% (95% confidence interval (CI) 74-87%), ≥ VGPR 47% (95% CI 38-55%) and ≥ CR 9% (95% CI 5-15%). Age ≥76 years, frailty (unfit or frail) or high cytogenetic risk did not affect the rate and quality of response. Median PFS from registration for all patients was 14.3 months (95%-CI 11.8-16.8). Frailty did not affect PFS. The median PFS for high risk and standard risk disease was comparable; 12.4 months (95%-CI 7.3-20.0) versus 14.6 months (95%-CI 11.5-17.4) respectively. The OS from registration at 18 months was 85% (95% CI 77-90). This was 90% (95% CI 72-97), 92% (95% CI 78-97) and 74% (95% CI 61-84) for fit, unfit and frail patients respectively. Seventy-eight patients (55%) were randomized. The reasons for not being randomized were toxicity (17% [24/143]), progressive disease (15% [21/143]), death (3% [5/143]) and other reasons (10% [15/143]). Median FU from randomization is 18.6 months (range 9.0-31.5 months). Baseline characteristics of randomized patients separately are presented in table 1. Upgrade of response occurred in 13% of patients receiving placebo and 10% of patients receiving ixazomib. The median PFS from randomization was 8.4 months (95%-CI 3.0-13.8) in the placebo arm and 10.1 months (95%-CI 5.6-24.1) in the ixazomib arm (p=0.47, figure 1). The OS from randomization at 18 months was 92% (95%-CI 77-97) in the placebo arm and 100% in the ixazomib arm (p=0.85). Toxicity is presented in table 2. The incidence of neuropathy was low; 8% grade 3 (mainly during thalidomide treatment; 5%) and no grade 4. There was no new onset neuropathy during ixazomib maintenance. During induction 24/143 (17%) patients discontinued therapy due to toxicity; 11 thalidomide-related neurotoxicity, 3 infection, 3 skin toxicity, 2 gastro-intestinal (GI) toxicity and 5 other. During maintenance 4/38 (11%) in the placebo (3 neurotoxicity and 1 other) versus 4/39 (10%) in the ixazomib arm (3 neurotoxicity and 1 GI) discontinued therapy due to toxicity. Discontinuation due to toxicity was comparable across age and frailty groups. Conclusion Induction treatment with 9 cycles of ITd in nte NDMM results in a high ORR of 81%, with 47% ≥ VGPR, independent of age, frailty status and cytogenetic risk. Our placebo controlled randomized phase II trial did not show an improvement in response and PFS with ixazomib maintenance therapy until progression. Ixazomib maintenance did not result in additional toxicity as compared to placebo. Disclosures Zweegman: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schjesvold:Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy; Bayer: Consultancy; Adaptive: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy; Abbvie: Honoraria; Novartis: Honoraria. Levin:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Sonneveld:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Abildgaard:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding.
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McCarthy, Philip L., Sarah A. Holstein, Sin-Ho Jung, et al. "CALGB/ECOG 100104 (Alliance) study: Lenalidomide (LEN) vs placebo (PBO) maintenance (maint) after stem cell transplant (SCT) for patients (pts) with multiple myeloma—Overall survival (OS) and progression-free survival (PFS) adjusted for treatment (tx) crossover (XO)." Journal of Clinical Oncology 35, no. 15_suppl (2017): 8037. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.8037.
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8037 Background: At a prespecified interim analysis (Dec 2009), the phase 3 CALGB study results surpassed the prespecified superiority boundary (significantly improved PFS for LEN maint vs PBO after SCT) and the majority of PBO arm pts without progressive disease (PD) crossed over to LEN maint. An updated analysis (cutoff Mar 2015), showed significantly longer OS with LEN maint (HR, 0.56; 95% CI, 0.42-0.76). We examined the effect of LEN vs PBO on OS and PFS from randomization, adjusting for XO effects. Methods: The rank-preserving structural failure time model (RPSFTM; Robins, Commun Stat Theory Methods, 1991) was used for XO adjustment; the iterative parameter estimation (IPE; Branson, Stat Med, 2002) algorithm was used as validation. Survival was portioned assuming a residual LEN effect after discontinuation. A landmark analysis was also performed at the Dec 2009 interim for pts who remained on Tx. Results: Pts were randomized to LEN maint (n = 231) and PBO (n = 229) (intent-to-treat [ITT] population); 76 pts without PD crossed over from PBO to LEN. Median time from randomization to XO was 11.5 mos. The relative Tx effect for OS and PFS increased for LEN vs PBO when adjusting for XO using RPSFTM and IPE (Table). The landmark analysis at the Dec 2009 interim (PBO XO, n = 76; No XO, n = 34) showed the Tx effect is not dissimilar to the ITT analysis (HR 0.53; 95% CI, 0.25-1.13). Sensitivity analyses showed consistent results. Conclusions: Adjusting for the potential diluting effects of XO reduced median OS and PFS with PBO, and improved the Tx effect in the ITT analyses for OS and PFS for LEN vs PBO maint after SCT. The statistical significance of the ITT analyses was maintained throughout. Support: U10CA180821, U10CA180882, CA180820. Clinical trial information: NCT00114101. [Table: see text]
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Mathew, P., P. F. Thall, M. M. Johnson, et al. "Preliminary results of a randomized placebo-controlled double-blind trial of weekly docetaxel combined with imatinib in men with metastatic androgen-independent prostate cancer (AIPC) and bone metastases (BM)." Journal of Clinical Oncology 24, no. 18_suppl (2006): 4562. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.4562.
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4562 Background: To further examine preclinical (Uehara, JNCI 2003) and clinical (Mathew, JCO 2004) evidence that the platelet-derived growth factor receptor (PDGFR) inhibitor, Imatinib, may modulate taxane activity in AIPC with BM, a randomized trial was conducted. Methods: 144 men with progressive AIPC with BM, no prior taxane, ECOG Performance Score (PS) ≤ 2, stratified by PS, hemoglobin, alkaline phosphatase and number of prior regimens, were planned for equal randomization to i.v. Docetaxel 30mg/m2 D 1, 8, 15, 22 q42 + Imatinib 600 mg daily (DI) or placebo (DP) for an improvement in time-to-progression (TTP) from 4.5 to 7.0 months (two-sided α = 0.05,β = 0.20). Secondary endpoints included toxicity, tumor response and phospho-PDGFR expression. An IRB review of gastrointestinal adverse events led to a recommendation to halt accrual early. Results: 104 evaluable men (52/arm) accrued between April 2003 and July 2005 were followed for a median of 7 months (range 0.5–23.4). The median TTP was 4.4 months (95% CI: 3.2–8.7) for DI and 5.3 months (95% CI: 3.4–11.3) for DP (p = 0.49, log-rank test). Median overall survival was 21.3 months for DI and not attained for DP (p = 0.56). Partial response was observed in 11 (3 DI, 8 DP), stable disease in 23 (14 DI, 9 DP), progressive disease in 56 (27 DI, 29 DP). Excess Grade 3 AEs with DI were principally fatigue (16 vs 6), gastrointestinal (11 vs 6), and arrhythmia (5 vs 1). Five cases of perforated sigmoid diverticulitis (4 DI, 1 DP; one death) were associated with high-dose steroid use (Fisher’s exact test p < 0.0001). Expression of phospho-PDGFR on tumor cells (≥2+ intensity) was established by immunohistochemistry in 12/14 (86%) of informative bone marrow biopsies. After cross-over to DI from DP, 5/23 (22%) patients were progression-free at 12 weeks without partial response. Conclusion: Notwithstanding the likely high prevalence of activated PDGFR in AIPC BM, Imatinib does not detectably modulate Docetaxel activity and excess toxicity was noted in this population. In-vivo monitoring of p-PDGFR and bone markers will qualify these findings. [Table: see text]
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Michallet, Mauricette, Peter Dreger, Laurent Sutton, et al. "Autologous hematopoietic stem cell transplantation in chronic lymphocytic leukemia: results of European intergroup randomized trial comparing autografting versus observation." Blood 117, no. 5 (2011): 1516–21. http://dx.doi.org/10.1182/blood-2010-09-308775.
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Abstract We present results of a phase 3 randomized trial of autografting in chronic lymphocytic leukemia versus observation for responding patients after first- or second-line treatment. The primary objective was to demonstrate that autografting improves the 5-year event-free survival (EFS) from 30% to 50%. There were 223 enrolled patients, 72% men and 28% women, 83% after first and 17% after second-line treatment. Binet stages were progressive A 13%, B 67%, C 20%; at randomization, 59% were in complete remission, and 41% in less than complete remission. Patients were randomized between autografting (n = 112) and observation (n = 111). Median EFS was 24.4 months (range, 16.7-32 months) in the observation group and 51.2 months (39.8-62.5 months) in the autografting group; the 5-year EFS was 24% and 42%, respectively (P < .001). Accordingly, the 5-year relapse incidence was 76% versus 54% (P < .001). Median time to relapse requiring therapy or death was 40 months (25-56 months) in the observation arm and 65 months (59-71 months) after autografting (P = .002). Cox modeling confirmed that autografting significantly improved EFS (hazard ratio 0.44, 95% confidence interval 0.30-0.65; P < .001). At 5 years, the probability of OS was 85.5% and 84.3% for autografting and observation, respectively (P = .77). In chronic lymphocytic leukemia, consolidating autografting reduces the risk of progression by more than 50% but has no effect on overall survival.