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On optimal designs for clinical trials: An updated review
Optimization of clinical trial designs can help investigators achieve higher qualityresults for the given resource constraints. The present paper gives an overviewof optimal designs for various important problems that arise in different stages ofclinical drug development, including phase I doseâtoxicity studies; phase I/II studiesthat consider early efficacy and toxicity outcomes simultaneously; phase IIdoseâresponse studies driven by multiple comparisons (MCP), modeling techniques(Mod), or their combination (MCPâMod); phase III randomized controlled multiarmmulti-objective clinical trials to test difference among several treatment groups;and population pharmacokineticsâpharmacodynamics experiments. We find thatmodern literature is very rich with optimal design methodologies that can be utilizedby clinical researchers to improve efficiency of drug development
Interventions for the treatment of oral cavity and oropharyngeal cancer:chemotherapy
<b>Background:</b> Oral cavity and oropharyngeal cancers are frequently described as part of a group of oral cancers or head and neck cancer. Treatment of oral cavity cancer is generally surgery followed by radiotherapy, whereas oropharyngeal cancers, which are more likely to be advanced at the time of diagnosis, are managed with radiotherapy or chemoradiation. Surgery for oral cancers can be disfiguring and both surgery and radiotherapy have significant functional side effects, notably impaired ability to eat, drink and talk. The development of new chemotherapy agents, new combinations of agents and changes in the relative timing of surgery, radiotherapy, and chemotherapy treatments may potentially bring about increases in both survival and quality of life for this group of patients.<p></p>
<b>Objectives:</b> To determine whether chemotherapy, in addition to radiotherapy and/or surgery for oral cavity and oropharyngeal cancer results in improved survival, disease free survival, progression free survival, locoregional control and reduced recurrence of disease. To determine which regimen and time of administration (induction, concomitant or adjuvant) is associated with better outcomes.<p></p>
<b>Search strategy:</b> Electronic searches of the Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE, EMBASE, AMED were undertaken on 28th July 2010. Reference lists of recent reviews and included studies were also searched to identify further trials.<p></p>
<b>Selection criteria:</b> Randomised controlled trials where more than 50% of participants had primary tumours in the oral cavity or oropharynx, and which compared the addition of chemotherapy to other treatments such as radiotherapy and/or surgery, or compared two or more chemotherapy regimens or modes of administration, were included.<p></p>
<b>Data collection and analysis:</b> Trials which met the inclusion criteria were assessed for risk of bias using six domains: sequence generation, allocation concealment, blinding, completeness of outcome data, selective reporting and other possible sources of bias. Data were extracted using a specially designed form and entered into the characteristics of included studies table and the analysis sections of the review. The proportion of participants in each trial with oral cavity and oropharyngeal cancers are recorded in Additional Table 1.<p></p>
<b>Main results:</b> There was no statistically significant improvement in overall survival associated with induction chemotherapy compared to locoregional treatment alone in 25 trials (hazard ratio (HR) of mortality 0.92, 95% confidence interval (CI) 0.84 to 1.00). Post-surgery adjuvant chemotherapy was associated with improved overall survival compared to surgery +/- radiotherapy alone in 10 trials (HR of mortality 0.88, 95% CI 0.79 to 0.99), and there was an additional benefit of adjuvant concomitant chemoradiotherapy compared to radiotherapy in 4 of these trials (HR of mortality 0.84, 95% CI 0.72 to 0.98). Concomitant chemoradiotherapy resulted in improved survival compared to radiotherapy alone in patients whose tumours were considered unresectable in 25 trials (HR of mortality 0.79, 95% CI 0.74 to 0.84). However, the additional toxicity attributable to chemotherapy in the combined regimens remains unquantified.<p></p>
<b>Authors' conclusions:</b> Chemotherapy, in addition to radiotherapy and surgery, is associated with improved overall survival in patients with oral cavity and oropharyngeal cancers. Induction chemotherapy is associated with a 9% increase in survival and adjuvant concomitant chemoradiotherapy is associated with a 16% increase in overall survival following surgery. In patients with unresectable tumours, concomitant chemoradiotherapy showed a 22% benefit in overall survival compared with radiotherapy alone.<p></p>
On the almost sure convergence of adaptive allocation procedures
In this paper, we provide some general convergence results for adaptive
designs for treatment comparison, both in the absence and presence of
covariates. In particular, we demonstrate the almost sure convergence of the
treatment allocation proportion for a vast class of adaptive procedures, also
including designs that have not been formally investigated but mainly explored
through simulations, such as Atkinson's optimum biased coin design, Pocock and
Simon's minimization method and some of its generalizations. Even if the large
majority of the proposals in the literature rely on continuous allocation
rules, our results allow to prove via a unique mathematical framework the
convergence of adaptive allocation methods based on both continuous and
discontinuous randomization functions. Although several examples of earlier
works are included in order to enhance the applicability, our approach provides
substantial insight for future suggestions, especially in the absence of a
prefixed target and for designs characterized by sequences of allocation rules.Comment: Published at http://dx.doi.org/10.3150/13-BEJ591 in the Bernoulli
(http://isi.cbs.nl/bernoulli/) by the International Statistical
Institute/Bernoulli Society (http://isi.cbs.nl/BS/bshome.htm
Handling Covariates in the Design of Clinical Trials
There has been a split in the statistics community about the need for taking
covariates into account in the design phase of a clinical trial. There are many
advocates of using stratification and covariate-adaptive randomization to
promote balance on certain known covariates. However, balance does not always
promote efficiency or ensure more patients are assigned to the better
treatment. We describe these procedures, including model-based procedures, for
incorporating covariates into the design of clinical trials, and give examples
where balance, efficiency and ethical considerations may be in conflict. We
advocate a new class of procedures, covariate-adjusted response-adaptive (CARA)
randomization procedures that attempt to optimize both efficiency and ethical
considerations, while maintaining randomization. We review all these
procedures, present a few new simulation studies, and conclude with our
philosophy.Comment: Published in at http://dx.doi.org/10.1214/08-STS269 the Statistical
Science (http://www.imstat.org/sts/) by the Institute of Mathematical
Statistics (http://www.imstat.org
Efficient randomized-adaptive designs
Response-adaptive randomization has recently attracted a lot of attention in
the literature. In this paper, we propose a new and simple family of
response-adaptive randomization procedures that attain the Cramer--Rao lower
bounds on the allocation variances for any allocation proportions, including
optimal allocation proportions. The allocation probability functions of
proposed procedures are discontinuous. The existing large sample theory for
adaptive designs relies on Taylor expansions of the allocation probability
functions, which do not apply to nondifferentiable cases. In the present paper,
we study stopping times of stochastic processes to establish the asymptotic
efficiency results. Furthermore, we demonstrate our proposal through examples,
simulations and a discussion on the relationship with earlier works, including
Efron's biased coin design.Comment: Published in at http://dx.doi.org/10.1214/08-AOS655 the Annals of
Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical
Statistics (http://www.imstat.org
Asymptotic theorems of sequential estimation-adjusted urn models
The Generalized P\'{o}lya Urn (GPU) is a popular urn model which is widely
used in many disciplines. In particular, it is extensively used in treatment
allocation schemes in clinical trials. In this paper, we propose a sequential
estimation-adjusted urn model (a nonhomogeneous GPU) which has a wide spectrum
of applications. Because the proposed urn model depends on sequential
estimations of unknown parameters, the derivation of asymptotic properties is
mathematically intricate and the corresponding results are unavailable in the
literature. We overcome these hurdles and establish the strong consistency and
asymptotic normality for both the patient allocation and the estimators of
unknown parameters, under some widely satisfied conditions. These properties
are important for statistical inferences and they are also useful for the
understanding of the urn limiting process. A superior feature of our proposed
model is its capability to yield limiting treatment proportions according to
any desired allocation target. The applicability of our model is illustrated
with a number of examples.Comment: Published at http://dx.doi.org/10.1214/105051605000000746 in the
Annals of Applied Probability (http://www.imstat.org/aap/) by the Institute
of Mathematical Statistics (http://www.imstat.org
Preoperative chemoradiation versus radiation alone for stage II and III resectable rectal cancer
Background : Preoperative radiotherapy (RT) decreases local recurrence rate and improves survival in stage II and III rectal cancer patients. The combination of chemotherapy with RT has a sound radiobiological rationale, and phase II trials of combined chemoradiation (CRT) have shown promising activity in rectal cancer.
Objectives : To compare preoperative RT with preoperative CRT in patients with resectable stage II and III rectal cancer.
Search methods : We searched the Cochrane Register of Controlled Trials, Web of Science, Embase.com, and Pubmed from 1975 until June 2012. A manual search was performed of Ann Surg, Arch Surg, Cancer, J Clin Oncol, Int J Radiat Oncol Biol Phys and the proceedings of ASTRO, ECCO and ASCO from 1990 until June 2012.
Selection criteria : Relevant studies randomized resectable stage II or III rectal cancer patients to at least one arm of preoperative RT alone or at least one arm of preoperative CRT.
Data collection and analysis : Primary outcome parameters included overall survival (OS) at 5 years and local recurrence (LR) rate at 5 years. Secondary outcome parameters included disease free survival (DFS) at 5 years, metastasis rate, pathological complete response rate, clinical response rate, sphincter preservation rate, acute toxicity, postoperative mortality and morbidity, and anastomotic leak rate. Outcome parameters were summarized using the Odds Ratio (OR) and associated 95% confidence interval (CI) using the fixed effects model.
Main results : Five trials were identified and included in the meta-analysis. From one of the included trials only preliminary data are reported. The addition of chemotherapy to preoperative RT significantly increased grade III and IV acute toxicity (OR 1.68-10, P = 0.002) and marginally affected postoperative overall morbidity (OR 0.67-1.00, P = 0.05) while no differences were observed in postoperative mortality or anastomotic leak rate. Compared to preoperative RT alone, preoperative CRT significantly increased the rate of complete pathological response (OR 2.12-5.84, P < 0.00001) although this did not translate into a higher sphincter preservation rate (OR 0.92-1.30, P = 0.32). The incidence of local recurrence at five years was significantly lower in the CRT group compared to RT alone (OR 0.39-0.72, P < 0.001). No statistically significant differences were observed in DFS (OR 0.92-1.34, P = 0.27) or OS (OR 0.79-1.14, P = 0.58) at five years.
Authors' conclusions : Compared to preoperative RT alone, preoperative CRT enhances pathological response and improves local control in resectable stage II and III rectal cancer, but does not benefit disease free or overall survival. The effects of preoperative CRT on functional outcome and quality of life are incompletely understood and should be addressed in future trials
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