The important study reported from Stanford University was predicated on disease-free survival, and thus was closed early by its Data Safety and Monitoring Committee, and there were insufficient cases to provide a meaningful overall survival analysis Unfortunately the situation has been confused by a well-publicized but flawed meta-analysis 42which ignored the various problems of individual published and unpublished trials and dj el diablo swiss anti aging them together into a comparison of observed versus expected outcomes.
This study erroneously concluded that there is a statistically significant survival benefit from adjuvant chemotherapy.
While in the future this may be proven to be correct, this specific meta-analysis did not prove the point. The EORTC has attempted to address this issue in a well-designed, randomized trial, in which standard local therapy has been compared to standard local therapy plus the addition of adjuvant chemotherapy.
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Perhaps relevant to this issue is the study from Stadler and colleagues 23mentioned above. While this study was not designed to address the utility of adjuvant chemotherapy per se, and was restricted to patients with mutant P53 tumors, stage pT, it is noteworthy that the patients who received 3 cycles of adjuvant MVAC did not appear to have improved overall survival, compared with those who were treated with surgery alone Although this may simply have reflected the population of patients with Pmutant urothelial cancer, this study clearly did not provide any additional data to support the routine use of adjuvant chemotherapy for invasive bladder cancer.
We still believe that 80 a randomized trial testing the use of adjuvant chemotherapy is needed to resolve the issue, and that adjuvant chemotherapy cannot be regarded as standard-of-care in Newer Approaches to Systemic Treatment Combined with Local Therapy Although some phase I-II studies focused on novel agents used in the neoadjuvant or adjuvant setting for bladder cancer have been reported, there is very little level 1 information about whether these innovations produce a real survival benefit.
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In clinical practice, gemcitabinecisplatin has been used widely in association with local therapy, either in a neoadjuvant or adjuvant fashion, based on the thought that the results achieved are similar to those from MVAC; in reality, the only well-powered study demonstrating this was in the metastatic setting, and revealed a hazard ratio of 1.
To my knowledge, no definitive trial has proven that gemcitabine-cisplatin provides a survival benefit when added to definitive treatment in either the neoadjuvant or adjuvant setting, nor that it is equivalent to MVAC. The problems of historical, non-randomized or under-powered comparisons, including the potential for case selection bias or follow-up bias, preclude any valid statistical assessment of the published data.
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In fact, Cognetti and colleagues, in a randomized trial assessing the role of adjuvant gemcitabine-cisplatin in one of two schedules, reported non-significantly inferior survival from the chemotherapy arm, compared to cystectomy alone H. If I see a patient who is not sufficiently robust to tolerate the MVAC or CMV regimens, I firstly question whether that fact is likely to reflect limited potential for safe radical cystectomy. If I conclude that cystectomy is likely to be feasible and safe, and that the MVAC regimen poses too much risk because of its direct toxic side effects, I will occasionally propose neoadjuvant gemcitabinecisplatin, after explaining carefully the limitations of the published data.
Another regimen that was recently reported in a randomized comparison against MVAC for metastatic disease is the combination of gemcitabine, cisplatin and paclitaxel GCP Although there was a modest increment in response rate from GCP against metastatic urothelial cancer, there was no significant difference in survival. Nonetheless, a Spanish cooperative group recently reported a survival benefit from adjuvant GCP after cystectomy in a presentation at the Annual Scientific Meeting of the American Society of Clinical Oncology However, there are two important caveats to this Derek Raghavan observation a the same group initially reported very impressive results with GCP for metastatic disease in an early report at the ASCO meeting, but subsequent follow up indicated a much less impressive true result, indicating the importance of mature follow-up and adequate sample size 53 ; b I rarely implement data presented only at clinical meetings without presentation as a peer-reviewed manuscript, and it has been some years since the initial presentation of this study without a followup peer-reviewed paper.
There have been recent reports of the use of targeted therapies, such as erlotinib or lapatinib targeting the epidermal growth factor receptorin patients with relapsed disease, with disappointing results 54and this concept has been extended to the neoadjuvant setting for invasive bladder cancer These studies represent clinical modeling and really are not definitive, and it is not yet possible to make any recommendations produs facial anti-imbatranire the use of targeted therapy in a neo-adjuvant context.
That said, it seems reasonable to consider the neoadjuvant setting for clinical trial modeling, provided that patients are not put at risk of unnecessary or prolonged delay of definitive treatment.
Similarly, there is no published level 1 evidence that confirms the utility of gemcitabine, the taxanes, any novel platinum complexes in this context, and thus no recommendations can be made about their use, other than in the context of clinical trials, at the present time.
The risk in testing such novel approaches is that an established paradigm, with defined survival benefit, will be replaced by inferior experimental therapy when cure is at stake.
The Future It seems likely that molecular prognostication and prediction will increasingly influence the selection of treatment for invasive bladder cancer in the future. In the treatment of bladder cancer, we appear to have reached a plateau with surgical and radiation techniques to control local disease, and our progress in cytotoxic chemotherapy has been slow since the introduction of the taxanes and gemcitabine.
However, there may be potential in leveraging the panoply of targeted therapies, provided that this is done in well-structured clinical trials that are designed to avoid losing the gains that we have won since Of importance, we must be mindful of the promiscuity dj el diablo swiss anti aging some targeted therapies in their interaction with their purported targets, and we should be cautious in the use of Bayesian randomized discontinuation designs, which may incorrectly omit agents that have modest activity, especially if it is manifested after a time lag.
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Despite the failure of the P53 trial to achieve its goals 23its study design may provide a useful paradigm for future research. The idea of designing trials based on defined gene targets makes sense, but these studies may require additional patient information to improve recruitment and compliance.
It also will be important to remind patients and physicians about the progress that has been made, to avoid nihilism and a return to the ways of the past, and also to emphasize the importance of randomized clinical trials in demonstrating real, but incremental, progress.
In the absence of a quantum leap forward, clinical trials will allow us to improve survival, unlike the myriad of under-powered phase I-II trials of the past 20 years. Conflict of Interests: None.
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