Overall survival (OS) in contemporary randomized clinical trials (RCT) in advanced breast cancer (ABC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1002-1002
Author(s):  
A. Katz ◽  
E. D. Saad ◽  
M. E. Buyse
Keyword(s):  
Randomized Clinical Trials ◽  
Statistical Significance ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Primary Study ◽  
Medical Subject Headings ◽  
Study Objective ◽  
Phase Iii Trials ◽  
Primary Study Objective ◽  
The One

1002 Background: OS has been considered an elusive endpoint, while progression-free survival (PFS), time to tumor progression (TTP), and time to treatment failure (TTF) have been used frequently and often interchangeably as primary endpoints (PE) in ABC (Saad, Ann Oncol 2009). Methods: We searched PubMed using the medical subject headings “breast neoplasms” and “drug therapy,” limiting the search to phase III trials on systemic antineoplastic therapies published between 1/2000 and 12/2007 in 8 leading medical journals (Ann Oncol, BCRT, BJC, Cancer, EJC, JCO, Lancet Oncol, and NEJM). PE was the one stated explicitly, used for N calculation, or listed first. Significant PE (SigPE) was considered as P <0.05 for superiority trials (N=47), or proven non-inferiority/equivalence otherwise. Results: We retrieved 58 RTCs, with a median sample size of 329 evaluable patients. The table shows the breakdown of these trials by size and PE, and the number of trials that reached statistical significance on their PE and on OS. Overall, a statistically significant gain in OS was reported in 11 of 58 RCTs (19%). In 30 RCTs with gain in PE, 26 favored the experimental arm. Conclusions: While publication and journal selection biases may not be excluded, our review suggests that gain in OS, although seldom a primary study objective, is not infrequent in contemporary RCTs in ABC. However, the majority of RCTs are underpowered for OS, which remains a secondary or exploratory endpoint in most cases. [Table: see text] No significant financial relationships to disclose.

scholarly journals Eligibility criteria and endpoints in metastatic renal cell carcinoma trials.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 465-465
Author(s):  
Sarah Wong ◽  
David I. Quinn ◽  
Georg A. Bjarnason ◽  
Scott A. North ◽  
Srikala S. Sridhar
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Phase Iii Trials ◽  
The One ◽  
Meta Analyses

465 Background: Treatments for metastatic renal cell carcinoma (mRCC) are often compared across trials, but trial eligibility criteria and endpoints differ. In Sept 2015, DATECAN published recommendations for time-to-event endpoints in mRCC trials. The success of their efforts to harmonize endpoints has not yet been assessed. Methods: We assessed eligibility criteria and endpoints from 18 Phase III mRCC trials starting from 2003 onwards. We also assessed 4 Phase III trials submitted after Sept. 2015 for compliance with DATECAN recommendations. Results: Among the 18 trials, consistent criteria were: absolute neutrophil count ≥1,500/µL, platelet count ≥100,000/µL, and bilirubin ≤1.5xULN. However, the following differed in requirements and measures used: see table.The 4 newer trials did not entirely follow DATECAN’s recommendations. Although their primary endpoint is progression free survival (PFS) as recommended, 3/4 trials do not define PFS, and the one that does includes death from any cause instead of DATECAN’s “death from kidney cancer.” Conclusions: Key eligibility criteria were somewhat inconsistent across phase III mRCC trials, and newer trials’ endpoints did not align with DATECAN’s recommendations. Not only is greater standardization needed to facilitate meta-analyses and cross-trial comparisons, but as evident from lack of adherence to DATECAN’s recommendations, greater promotion and enforcement of recommendations is needed to harmonize trial design and improve comparability.[Table: see text]

Does progression-free-survival (PFS) correlate with overall- and cancer-specific survival (OS/CSS) in randomized clinical trials (RCTs) exploring the addition of hormonal therapy (HT) to radiotherapy (RT) for early prostate cancer (EPC)? Analysis of six RCTs

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5056-5056
Author(s):  
E. M. Ruggeri ◽  
E. Bria ◽  
P. Carlini ◽  
F. Cuppone ◽  
M. Milella ◽  
...  
Keyword(s):  
Sample Size ◽  
Randomized Clinical Trials ◽  
Progression Free Survival ◽  
Outcome Data ◽  
Phase Iii ◽  
Cancer Specific Survival ◽  
End Point ◽  
Target Sample Size ◽  
Phase Iii Trials ◽  
Beta Coefficient

5056 Background: Although PFS is considered the standard primary end-point in EPC, the correlation with OS has never been explored in RCTs randomizing patients (pts) to HT plus radiotherapy (RT) versus RT. Given the relatively long prognosis in this disease setting, the correlation between PFS and CSS should be investigated as well. Methods: All phase III trials reporting all outcome’ data were considered eligible. The correlation has been explored according to a linear regression model considering both each single outcome pair (PFS, OS and CSS rates) for all arms, and each reported Hazard Ratio (HRs). The correlation was estimated according to both the Pearson- (r) and R2-coefficient (parametric) and the Spearman coefficient (Rho, non-parametric). A sensitivity analysis in 2 subgroups (long- and short-term HT) to test for effect robustness has been accomplished as well. A model to determine the target sample size to determine CSS benefit of 3%, 4%, 6% and 7% months, respectively, was calculated as well. Results: Six RCTs (4,212 pts) were collected (follow-up range: 4.5–7.6 years). In the overall population, when considering the crude rates, a linear stronger correlation was found between PFS and CSS (r=0.71, R2=0.51, p=0.003; Rho=0.75, p=0.005), rather than with OS (r=0.55, R2=0.30, p=0.06; Rho=0.78, p=0.11). Again, when considering HRs, a linear stronger correlation was found between PFS and CSS (r=0.87, R2=0.76, p=0.02; Rho=0.94, p=0.005), rather than with OS (r=0.75, R2=0.56, p=0.08; Rho=0.77, p=0.07). Similar correlations were found whatever subgroups was explored. The sample size model (on the basis of the beta-coefficient=0.71), calculate 4,575, 2,006, 1,115 and 700 pts to improve PFS of 4%, 6%, 8%, and 10% months, which means to improve CSS of 2.8%, 4.3%, 5.7% and 7.1%, respectively. Conclusions: The correlation between PFS and CSS in RCTs exploring the benefit of adding HT to RT for EPC is significant, and suggests its further investigation as surrogate end-point. The natural history of the disease clearly explains the stronger correlation of PFS with CSS rather than with OS. No significant financial relationships to disclose.

Assessing analgesia equivalence and appetite following alfaxalone- or ketamine-based injectable anesthesia for feline castration as an example of enhanced recovery after surgery

2017 ◽  
Vol 20 (2) ◽  
pp. 73-82 ◽  
Author(s):  
Tatum Armstrong ◽  
Marika C Wagner ◽  
Jagjit Cheema ◽  
Daniel SJ Pang
Keyword(s):  
Enhanced Recovery ◽  
Statistical Significance ◽  
Pain Scale ◽  
Primary Study ◽  
Rescue Analgesia ◽  
Study Objective ◽  
Scale Scores ◽  
The Difference ◽  
Primary Study Objective ◽  
Species Specific

Objectives The primary study objective was to assess two injectable anesthetic protocols, given to facilitate castration surgery in cats, for equivalence in terms of postoperative analgesia. A secondary objective was to evaluate postoperative eating behavior. Methods Male cats presented to a local clinic were randomly assigned to receive either intramuscular ketamine (5 mg/kg, n = 26; KetHD) or alfaxalone (2 mg/kg, n = 24; AlfHD) in combination with dexmedetomidine (25 μg/kg) and hydromorphone (0.05 mg/kg). All cats received meloxicam (0.3 mg/kg SC) and intratesticular lidocaine (2 mg/kg). Species-specific pain and sedation scales were applied at baseline, 1, 2 and 4 h postoperatively. Time taken to achieve sternal recumbency and begin eating were also recorded postoperatively. Results Pain scale scores were low and showed equivalence between the treatment groups at all time points (1 h, P = 0.38, 95% confidence interval [CI] of the difference between group scores 0–0; 2 h, P = 0.71, 95% CI 0–0; 4 h, P = 0.97, 95% CI 0–0). Four cats crossed the threshold for rescue analgesia (KetHD, n = 1; AlfHD, n = 3). At 1 h, more cats in the KetHD (65%) group than in the AlfHD (42%) group were sedated, but statistical significance was not detected ( P = 0.15, 95% CI −1 to 0). Most AlfHD cats (88%) began eating by 1 h vs 65% of KetHD cats ( P = 0.039). Time to recover sternal recumbency did not differ between groups ( P = 0.86, 95% CI −14.1 to 11.8). Conclusions and relevance These results show that AlfHD and KetHD provide equivalent analgesia as part of a multimodal injectable anesthetic protocol. Alfaxalone is associated with an earlier return to eating.

Trial design from a clinical perspective

ESC CardioMed ◽  
2018 ◽  
pp. 3067-3071
Author(s):  
John G. F. Cleland ◽  
Ian Ford
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Trial Design ◽  
Statistical Significance ◽  
Well Being ◽  
Phase Iii ◽  
Practical Significance ◽  
Commercial Company ◽  
Phase Iii Trials ◽  
General Guidance

This chapter is written primarily from the perspective of investigators with limited resources designing clinical trials to assess the effects of interventions on patient well-being and outcomes with the hope that the results might influence clinical practice and guidelines. Other perspectives should be taken into account. The advice may be less applicable when resources are abundant (e.g. phase III trials sponsored by a large commercial company). Much research is funded by commercial companies hoping for a return on investment; they will design clinical trials to increase the chance of a statistically positive result. Many investigators will do the same although their motivation may differ. However, practising clinicians, patients, and health services want trials that help inform their daily clinical practice rather than merely achieving statistical significance. Large studies may be statistically positive but of dubious practical significance. This chapter gives some general guidance on selecting patients, comparators, endpoints, and study design.

scholarly journals Anti-Angiogenic Agents in Management of Sarcoma Patients: Overview of Published Trials

2020 ◽  
Vol 10 ◽  
Author(s):  
Pierre-Yves Cren ◽  
Loïc Lebellec ◽  
Thomas Ryckewaert ◽  
Nicolas Penel
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Double Blind ◽  
Multikinase Inhibitors ◽  
Randomized Phase Ii ◽  
Phase Iii Trials

We reviewed all fully published clinical trials assessing anti-angiogenic agents in sarcoma patients (last issue, January 13, 2020). Anti-angiogenic macromolecules (e.g., bevacizumab or ombrabulin) provide disappointing results. Many multikinase inhibitors have been assessed with non-randomized phase II trials with limited samples and without stratification according to histological subtypes, therefore interpretation of such trials is very challenging. On the contrary, pazopanib, regorafenib, and sorafenib have been assessed using double-blind placebo-controlled randomized phase II or phase III trials. Compared to placebo, sorafenib demonstrates activity in desmoid-type fibromatosis patients. Based on results of phase 3 trial, pazopanib had obtained approval for treatment of pretreated non-adipocytic soft tissue sarcoma. Regorafenib is currently assessed in several clinical settings and provides significant improvement of progression-free survival in pre-treated non-adipocytic soft tissue sarcoma and in advanced pretreated osteosarcoma. Multikinase inhibitors are a breakthrough in sarcoma management. Many trials are ongoing. Nevertheless, predictive factors are still missing.

scholarly journals P14.15 Benefit of Bevacizumab for recurrent glioblastoma. Results of 81 patients from a single institution

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii69-iii69
Author(s):  
O Absalyamova ◽  
G Kobiakov ◽  
G Agabekyan ◽  
A Poddubsky ◽  
A Belyashova ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Recurrent Glioblastoma ◽  
Phase Iii ◽  
Rapid Progression ◽  
Concomitant Disease ◽  
Free Survival ◽  
Phase Iii Trials ◽  
Continuous Application

Abstract BACKGROUND No standard of care has been established for patients with progressive glioblastoma (rGBM). Previous studies suggested that bevacizumab (BEV) is safe and produces responses that result in a decreased use of glucocorticoids and increased progression-free survival (PFS) with an unclear effect on overall survival (OS). Crossover to BEV in the control arm is the possible reason why the advantage of BEV has not been proven in Phase III trials. We retrospectively analyzed own results of BEV treatment in rGBM. MATERIAL AND METHODS 81 patients progressed after radiotherapy plus concomitant and maintenance temozolomide (TMZ) and undergo BEV as monotherapy (BevMo, 11 patients) or in combinations (Irinotecan (BevI) - 53, lomustine (BevL)- 11, TMZ (BevT) - 6. Median age 54 years. Among them 33 patients were re-irradiated: 11 - radiosurgery (RS), 20 fractionated irradiation (RT), 2 - RS+RT. 33 patients continued BEV after progression with changing or adding cytostatic. PFS was calculated from the date of verification, PFS1 - from the date of 1-st progression, PFS2 - from the date of 2-nd progression. RESULTS Median PFS was 9.0 ([CI] 7.0–10.9) months. Median PFS1 was 10.5 ([CI] 8.1–12.9) months. In the BevMo, BevI, BevL, BevT group PFS1 was 15.7, 10.1, 10.5, 13.2 months, respectively, p=0.7. Objective response (OR) was reached in 34%, stable disease (SD) in 28%, progression (PD) in 37% patients. 16 patients stopped BEV without progression (4-patient`s decision, 7- doctor`s decision, 2 - adverse event, 3 - concomitant disease). Median time of BEV treatment was 11.6 months. Median BEV-free interval till progression was 3.7 months. 33 patients continued or restarted BEV after progression. Median PFS2 was 8.0 ([CI] 4.9–11.1) months. The median OS from the date of 1-st progression was 23.5 months ([CI] 18.7–27.4). In groups with RT, RS, RS+RT and no re-irradiarion OS was 24.6 ([CI] 17.6–31.5), 35.4 ([CI] 35.0–35.8), 17.8, 20.6 ([CI] 15.2–26.0), respectively, p=0.2. CONCLUSION OS in our group is outrageously high. Maintaining BEV after progression was effective. In our group BEV discontinuation led to rapid progression. The resumption of Bev with progression was effective, which indicates the advisability of its continuous application.

Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial

2020 ◽  
Vol 38 (3) ◽  
pp. 193-202 ◽  
Author(s):  
Richard S. Finn ◽  
Baek-Yeol Ryoo ◽  
Philippe Merle ◽  
Masatoshi Kudo ◽  
Mohamed Bouattour ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Interim Analysis ◽  
Statistical Significance ◽  
Study Drug ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Double Blind ◽  
Previously Treated

PURPOSE Pembrolizumab demonstrated antitumor activity and safety in the phase II KEYNOTE-224 trial in previously treated patients with advanced hepatocellular carcinoma (HCC). KEYNOTE-240 evaluated the efficacy and safety of pembrolizumab in this population. PATIENTS AND METHODS This randomized, double-blind, phase III study was conducted at 119 medical centers in 27 countries. Eligible patients with advanced HCC, previously treated with sorafenib, were randomly assigned at a two-to-one ratio to receive pembrolizumab plus best supportive care (BSC) or placebo plus BSC. Primary end points were overall survival (OS) and progression-free survival (PFS; one-sided significance thresholds, P = .0174 [final analysis] and P = .002 [first interim analysis], respectively). Safety was assessed in all patients who received ≥ 1 dose of study drug. RESULTS Between May 31, 2016, and November 23, 2017, 413 patients were randomly assigned. As of January 2, 2019, median follow-up was 13.8 months for pembrolizumab and 10.6 months for placebo. Median OS was 13.9 months (95% CI, 11.6 to 16.0 months) for pembrolizumab versus 10.6 months (95% CI, 8.3 to 13.5 months) for placebo (hazard ratio [HR], 0.781; 95% CI, 0.611 to 0.998; P = .0238). Median PFS for pembrolizumab was 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 2.5 to 4.1 months) for placebo at the first interim analysis (HR, 0.775; 95% CI, 0.609 to 0.987; P = .0186) and 3.0 months (95% CI, 2.8 to 4.1 months) versus 2.8 months (95% CI, 1.6 to 3.0 months) at final analysis (HR, 0.718; 95% CI, 0.570 to 0.904; P = .0022). Grade 3 or higher adverse events occurred in 147 (52.7%) and 62 patients (46.3%) for pembrolizumab versus placebo; those that were treatment related occurred in 52 (18.6%) and 10 patients (7.5%), respectively. No hepatitis C or B flares were identified. CONCLUSION In this study, OS and PFS did not reach statistical significance per specified criteria. The results are consistent with those of KEYNOTE-224, supporting a favorable risk-to-benefit ratio for pembrolizumab in this population.

scholarly journals Blinded Independent Central Review of Progression-Free Survival in Phase III Clinical Trials: Important Design Element or Unnecessary Expense?

2008 ◽  
Vol 26 (22) ◽  
pp. 3791-3796 ◽  
Author(s):  
Lori E. Dodd ◽  
Edward L. Korn ◽  
Boris Freidlin ◽  
C. Carl Jaffe ◽  
Lawrence V. Rubinstein ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Treatment Effectiveness ◽  
Progression Free Survival ◽  
Informative Censoring ◽  
Phase Iii ◽  
General Strategy ◽  
Design Element ◽  
Free Survival ◽  
Using Data

Progression-free survival is an important end point in advanced disease settings. Blinded independent central review (BICR) of progression in randomized clinical trials has been advocated to control bias that might result from errors in progression assessments. However, although BICR lessens some potential biases, it does not remove all biases from evaluations of treatment effectiveness. In fact, as typically conducted, BICRs may introduce bias because of informative censoring, which results from having to censor unconfirmed locally determined progressions. In this article, we discuss the rationale for BICR and different ways of implementing independent review. We discuss the limitations of these approaches and review published trials that report implementing BICR. We demonstrate the existence of informative censoring using data from a randomized phase II trial. We conclude that double-blinded trials with consistent application of measurement criteria are the best means of ensuring unbiased trial results. When such designs are not practical, BICR is not recommended as a general strategy for reducing bias. However, BICR may be useful as an auditing tool to assess the reliability of marginally positive results.

Current Strategies in Treatment of Oligodendroglioma: Evolution of Molecular Signatures of Response

2006 ◽  
Vol 24 (8) ◽  
pp. 1246-1252 ◽  
Author(s):  
Kurt A. Jaeckle ◽  
Karla V. Ballman ◽  
Ravi D. Rao ◽  
Robert B. Jenkins ◽  
Jan C. Buckner
Keyword(s):  
Regulatory Protein ◽  
Radiation Therapy Oncology Group ◽  
Specific Treatment ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Molecular Signatures ◽  
Molecular Events ◽  
Therapeutic Decisions ◽  
Phase Iii Trials ◽  
Prognostic Group

Oligodendroglioma frequently (≥ 70%) responds to radiation and chemotherapy, and is the first CNS neoplasm in which a genetic signature (1p and 19q deletion) has been associated with outcome within the context of large clinical trials. Current translational investigations focus on deletions or mutations of potential tumor suppressor genes, epigenetic alterations, amplification or mutation of growth factor and regulatory genes, and characterization of signaling events and regulatory protein expression. The most compelling data has involved 1p and 19q loss, which is observed in over 50% of anaplastic oligodendrogliomas. In two randomized phase III trials (Radiation Therapy Oncology Group 9402 and European Organisation for Research and Treatment of Cancer 26951), the addition of neoadjuvant or adjuvant procarbazine, lomustine, and vincristine (PCV; respectively) to radiotherapy did not produce superior survival as compared with radiotherapy alone. A modest increase in progression-free survival was observed with the addition of PCV, but at the cost of increased toxicity. Combined 1p and 19q loss identified a favorable prognostic group in both studies, which appeared to be independent of treatment arms. However, it is unclear whether these deletions represent surrogate markers of a favorable biologic tumor behavior, or are predictive of outcome after specific treatment. Currently, there is insufficient data to allow therapeutic decisions to be made solely on the basis of 1p and 19q gene deletion status. Future phase III trials are evaluating other chemotherapeutic and targeted agents, including temozolomide, and include correlative investigations of aberrant molecular events in these neoplasms, which may lead to future therapeutic strategies that are based on specific molecular signatures.

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

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

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

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