How do multi-stage, multi-arm trials compare to the traditional two-arm parallel group design – a reanalysis of 4 trials

<p>Abstract</p> <p>Background</p> <p>To speed up the evaluation of new therapies, the multi-arm, multi-stage trial design was suggested previously by the authors.</p> <p>Methods</p> <p>In this paper, we evaluate the performance of the two-stage, multi-arm design using four cancer trials conducted at the MRC CTU. The performance of the design at fictitious interim analyses is assessed using a conditional bootstrap approach.</p> <p>Results</p> <p>Two main aims are addressed: the error rate of correctly carrying on/stopping the trial at an interim analysis as well as quantifying the gains in terms of resources by employing this design. Furthermore, we make suggestions for the best timing of this interim analysis.</p> <p>Conclusion</p> <p>Multi-arm, multi-stage trials are an effective way of speeding up the therapy evaluation process. The design performs well in terms of the type I and II error rates.</p

TP53 status and taxane-platinum versus platinum-based therapy in ovarian cancer patients: A non-randomized retrospective study

<p>Abstract</p> <p>Background</p> <p>Taxane-platinum therapy (TP) has replaced platinum-based therapy (PC or PAC, DNA damaging chemotherapy) in the postoperative treatment of ovarian cancer patients; however, it is not always effective. TP53 protein plays a differential role in response to DNA-damaging agents and taxanes. We sought to define profiles of patients who benefit the most from TP and also of those who can be treated with PC.</p> <p>Methods</p> <p>We compared the effectiveness of PC/PAC (n = 253) and TP (n = 199) with respect to tumor TP53 accumulation in ovarian cancer patients with FIGO stage IIB-IV disease; this was a non-randomized retrospective study. Immunohistochemical analysis was performed on 452 archival tumors; univariate and multivariate analysis by the Cox's and logistic regression models was performed in all patients and in subgroups with [TP53(+)] and without TP53 accumulation [TP53(-)].</p> <p>Results</p> <p>The advantage of taxane-platinum therapy over platinum-based therapy was seen in the TP53(+), and not in the TP53(-) group. In the TP53(+) group taxane-platinum therapy enhanced the probability of complete remission (p = .018), platinum sensitivity (p = .014), platinum highly sensitive response (p = .038) and longer survival (OS, p = .008). Poor tumor differentiation diminished the advantage from taxane-platinum therapy in the TP53(+) group. In the TP53(-) group PC/PAC was at least equally efficient as taxane-platinum therapy and it enhanced the chance of platinum highly sensitive response (p = .010). However, in the TP53(-) group taxane-platinum therapy possibly diminished the risk of death in patients over 53 yrs (p = .077). Among factors that positively interacted with taxane-platinum therapy in some analyses were endometrioid and clear cell type, FIGO III stage, bulky residual tumor, more advanced age of patient and moderate tumor differentiation.</p> <p>Conclusion</p> <p>Our results suggest that taxane-platinum therapy is particularly justified in patients with TP53(+) tumors or older than 53 years. In the group of patients ≤53 yrs and with TP53(-) tumors platinum-based therapy is possibly equally efficient. We provide hints for planning randomized trials to verify these observations.</p

Defining the surgical management of suspected early-stage ovarian cancer by estimating patient numbers through alternative management strategies

&lt;p&gt;Objective: To establish the optimal management strategy for women with suspected stage 1 ovarian cancer.&lt;/p&gt; &lt;p&gt;Design:  We created a flowchart to illustrate each of six hypothetical management strategies. These considered two surgical approaches (systematic lymphadenectomy versus no lymph node dissection at all) in combination with three different policies for giving adjuvant chemotherapy.&lt;/p&gt; &lt;p&gt;Setting:  Gynaecological cancer centre, London, UK.&lt;/p&gt; &lt;p&gt;Data sources:  Patient data and published papers.&lt;/p&gt; &lt;p&gt;Methods:  We developed a deterministic model that uses information from multiple sources to estimate patient flow through each level of a hypothesised decision tree.&lt;/p&gt; &lt;p&gt;Results:  We estimated that for every 100 cases of suspected early-stage ovarian cancer, there would be 37 cases with ‘apparent’ stage 1 disease and that of these, two (6%) would be denied potentially life-saving adjuvant treatment if systematic lymphadenectomy was not performed. The number of women given chemotherapy would not, according to our estimates, differ greatly between the two surgical approaches, the 7% increase with systematic lymphadenectomy being because of cases identified as having nodal metastases.&lt;/p&gt; &lt;p&gt;Conclusions: We present a model of the intraoperative decision-making process that determines the extent of the staging procedure to be performed within our department when early-stage ovarian cancer is suspected. Unless adjuvant chemotherapy is prescribed for all, systematic pelvic and para-aortic node dissection is required to optimise survival. However, in our department, this would result in 32% of women with suspected early-stage ovarian cancer undergoing systematic node dissection. This flexible focused model may facilitate multidisciplinary team discussion when this part of the surgical staging procedure is considered within the context of the population presenting to the team, the morbidity of the procedure within the department and the predictive values of frozen section within that department. As the model is not disease-specific, it may be useful for decision making in other medical disciplines.&lt;/p&gt

Why i.p. therapy cannot yet be considered as a standard of care for the first-line treatment of ovarian cancer:a systematic review

A National Cancer Institute (NCI) clinical announcement recommended i.p. therapy for women with optimally debulked ovarian cancer. Its basis was a summary of eight randomised controlled trials and two systematic reviews, which appear to indicate benefit of i.p. therapy. However, the systematic reviews that inform the recommendations have been inappropriately presented and interpreted. The systematic reviews inappropriately pooled results from 'confounded' trials in which different drugs and different doses of drugs were given in the control and i.p. treatment arms. Therefore, it is not possible to assess which component of treatment is responsible for improving outcome. In addition, none of the trials use a control arm of the internationally accepted standard of care. Using just the unconfounded trials, indirect comparisons show that the magnitude of benefit observed when i.p. regimens are compared with older i.v. regimens [hazard ratio (HR) for overall survival (OS) 0.75; 95% confidence interval (CI) 0.60-0.92, P = 0.006] is smaller than the magnitude of benefit achieved with modern day standard of i.v. treatment compared with the same i.v. regimen used as control in the unconfounded i.p. trials (HR for OS 0.68; 95% CI 0.58-0.80, P <0.001). A further difficulty is that the reviews cannot recommend an i.p. regimen for standard use. Drug-related toxicity and catheter complications that occur with i.p. therapy are considerable. The NCI recommendations have major implications for the treatment of women with ovarian cancer and for the next generation of clinical trials. We do not believe that the body of evidence currently available supports the recommendation that i.p. therapy should form part of routine care. The choice of treatment of women with newly diagnosed, optimally debulked, ovarian cancer, where therapy has the best chance of influencing OS, is too important to be left with this uncertainty. A clinical trial that investigates a practical and acceptable regimen which gives some or all chemotherapy by the i.p. route and compares this with standard i.v. chemotherapy should be a priority for those who wish to promote its use