Overall survival: still the gold standard: why overall survival remains the definitive end point in cancer clinical trials.
ABSTRACT Overall survival (OS) is the gold standard primary end point to evaluate the outcome of any drug, biologic, intervention, or procedure that is assessed in oncologic clinical trials. OS is universally recognized as being unambiguous, unbiased, with a defined end point of paramount clinical relevance, and positive results provide confirmatory evidence that a given treatment extends the life of a patient. Clinical trialists relentlessly attempt to devise more easily measured, cost-effective, and readily available event-driven end points as predictive surrogates of a definitive outcome, such as OS, and reduce the time with which clinical trials deliver definitive results. For some treatment modalities used in a limited number of cancer types, certain event-driven surrogates, eg, progression-free survival or time-to-progression may predict OS benefit. Biologic, cell-based, and vaccine-generated treatments are rapidly expanding the oncologist's armamentarium to combat cancers and pose a dilemma in that response may not be reflected by progression-free survival, time-to-progression, or other surrogates? As targeted therapies march forward, will each new therapy require a unique biomarker validated for every disease indication? Moreover, adjuvant treatments have demonstrated efficacy and given the current limited possibility of cure in the metastatic setting, should other end points, eg, quality-of-life, emerge as valid outcomes to demonstrate benefit. Clinical trials must continue to assess OS until biologically plausible measures are developed and emerge as valid early end point surrogates to replace the gold standard.
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ABSTRACT: To perform the first external validation of a recently identified association between disease-free survival at two years (DFS2) or three years (DFS3) and overall survival at five years (OS5) in patients after radical cystectomy (RC) for muscle-invasive urothelial carcinoma of the bladder (UCB). Records of 2483 patients who underwent RC for UCB at eight European centers between 1989 and 2008 were reviewed. The cohort included 1738 patients with pT2-4a tumors and negative soft tissue surgical margins (STSM) according to the selection criteria of the previous study (study group (SG)). In addition, 745 patients with positive STSM or other tumor stages (pT0-T1, pT4b) that were excluded from the previous study (excluded patient group (EPG)) were evaluated. Kappa statistic was used to measure the agreement between DFS2 or DFS3 and OS5. The overall agreement between DFS2 and OS5 was 86.5% (EPG: 88.7%) and 90.1% (EPG: 92.1%) between DFS3 and OS5. The kappa values for comparison of DFS2 or DFS3 with OS5 were 0.73 (SE: 0.016) and 0.80 (SE: 0.014) respectively for the SG, and 0.67 (SE: 0.033) and 0.78 (SE: 0.027) for the EPG (all p-values <0.001). We externally validated a correlation between DFS2 or DFS3 and OS5 for patients with pT2-4a UCB with negative STSM that underwent RC. Furthermore, this correlation was found in patients with other tumor stages regardless of STSM status. These findings indicate DFS2 and DFS3 as valid surrogate markers for survival outcome with RC.European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 03/2012; 38(7):637-42. DOI:10.1016/j.ejso.2012.02.187 · 2.89 Impact Factor
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ABSTRACT: Purpose of review: Recent advances in survival for patients with newly diagnosed and recurrent brain tumors, combined with the development of an ever-increasing number of potential treatments, has led to significant growth in the number of clinical trials for patients with brain tumors. Suitable clinical trial design and endpoints are vital for successfully evaluating these new treatments that may continue to improve outcome. However, inadequacies of clinical trial endpoints have challenged how best to evaluate promising new therapeutics. Recent findings: Pseudoprogression and pseudoresponse confound imaging-based endpoints, including overall radiographic response and progression-free survival. Overall survival is still regarded as the definitive endpoint, but recently identified active salvage agents such as bevacizumab may diminish the association between presalvage therapy and overall survival, making interpretation of clinical trial results difficult. Novel imaging and the assessment of patient function, quality of life (QOL), and cognition are more frequently employed as endpoints. Summary: An awareness of the benefits and imperfections of clinical trial endpoints will lead to improved clinical trial design and results. Validated endpoints of patient function, QOL, and cognition are available and increasingly valued as secondary endpoints.Current Opinion in Neurology 01/2012; 25(6):780-785. DOI:10.1097/WCO.0b013e328359b45e · 5.73 Impact Factor
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ABSTRACT: The current enhanced permeability and retention (EPR)-based approved nanomedicines have had little impact in terms of prolongation of overall survival in patients with cancer. For example, the two Phase III trials comparing Doxil®, the first nanomedicine approved by the US Food and Drug Administration, with free doxorubicin did not find an actual translation of the EPR effect into a statistically significant increase in overall survival but did show less cardiotoxicity. In the current work, we used a two-factor factorial experimental design with intraperitoneal versus intravenous delivery and nanomedicine versus free drug as factors to test our hypothesis that regional (intraperitoneal) delivery of nanomedicine may better increase survival when compared with systemic delivery. In this study, we demonstrate that bypassing, rather than exploiting, the EPR effect via intraperitoneal delivery of nanomedicine harboring a sustained-release function demonstrates dual pharmacokinetic advantages, producing more efficient tumor control and suppressing the expression of stemness markers, epithelial-mesenchymal transition, angiogenesis signals, and multidrug resistance in the tumor microenvironment. Metastases to vital organs (eg, lung, liver, and lymphatic system) are also better controlled by intraperitoneal delivery of nanomedicine than by standard systemic delivery of the corresponding free drug. Moreover, the intraperitoneal delivery of nanomedicine has the potential to replace hyperthermic intraperitoneal chemotherapy because it shows equal efficacy and lower toxicity. In terms of efficacy, exploiting the EPR effect may not be the best approach for developing a nanomedicine. Because intraperitoneal chemotherapy is a type of regional chemotherapy, the pharmaceutical industry might consider the regional delivery of nanomedicine as a valid alternative pathway to develop their nanomedicine(s) with the goal of better tumor control in the future.International Journal of Nanomedicine 03/2015; 10:2485—2502. DOI:10.2147/IJN.S78321 · 4.20 Impact Factor