Article

Overall survival: Still the gold standard: Why overall survival remains the definitive end point in cancer clinical trials

Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
The Cancer Journal (Impact Factor: 3.61). 09/2009; 15(5):401-5. DOI: 10.1097/PPO.0b013e3181bdc2e0
Source: PubMed

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.

1 Follower
 · 
87 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Enthusiasm for therapeutic cancer vaccines has been rejuvenated with the recent completion of several large, randomized phase III clinical trials that in some cases have reported an improvement in progression free or overall survival. However, an honest appraisal of their efficacy reveals modest clinical benefit and a frequent requirement for patients with relatively indolent cancers and minimal or no measurable disease. Experience with adoptive cell transfer-based immunotherapies unequivocally establishes that T cells can mediate durable complete responses, even in the setting of advanced metastatic disease. Further, these findings reveal that the successful vaccines of the future must confront: (i) a corrupted tumor microenvironment containing regulatory T cells and aberrantly matured myeloid cells, (ii) a tumor-specific T-cell repertoire that is prone to immunologic exhaustion and senescence, and (iii) highly mutable tumor targets capable of antigen loss and immune evasion. Future progress may come from innovations in the development of selective preparative regimens that eliminate or neutralize suppressive cellular populations, more effective immunologic adjuvants, and further refinement of agents capable of antagonizing immune check-point blockade pathways.
    Immunological Reviews 01/2011; 239(1):27-44. DOI:10.1111/j.1600-065X.2010.00979.x · 12.91 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: As nanotechnologies move closer to use in humans, quantitative imaging methods will play a vital role in answering questions of biodistribution. Accurate knowledge of the location and quantity of in vivo nanoconstructs and carriers is a challenging task, and new methods of quantitative imaging at appropriate resolutions are being developed and tested. Sustaining simultaneous advancement in both imaging development and nanotechnology research requires multidisciplinary research teams conducting experiments with interconnected goals. On an even greater scale, networks of multidisciplinary teams focused on similar issues of imaging and probe development offer opportunities for leveraging resources, as well as providing a forum for sharing ideas and creating consensus on solutions to common challenges. The Network for Translational Research (NTR): Optical Imaging in Multimodal Platforms from the National Cancer Institute is just such a network. Four multidisciplinary centers are accepting the challenges of developing and optimizing multimodal imaging hardware and software along with imaging probe development. These efforts are similar to the efforts that will be required for future studies of in vivo nanoparticle biodistribution. In addition to technology development and optimization, the network is organized to confront the challenges of validation of the imaging hardware and associated imaging agents, similar to the methods needed for validating nanomedicine.
    Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology 01/2011; 3(1):5-10. DOI:10.1002/wnan.117 · 4.24 Impact Factor
  • [Show abstract] [Hide abstract]
    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
Show more