How to avoid concerns with the interpretation of two primary endpoints if significant superiority in one is sufficient for formal proof of efficacy.

Formal proof of efficacy of a drug requires that in a prospective experiment, superiority over placebo, or either superiority or at least non-inferiority to an established standard, is demonstrated. Traditionally one primary endpoint is specified, but various diseases exist where treatment success needs to be based on the assessment of two primary endpoints. With co-primary endpoints, both need to be "significant" as a prerequisite to claim study success. Here, no adjustment of the study-wise type-1-error is needed, but sample size is often increased to maintain the pre-defined power. Studies that use an at-least-one concept have been proposed where study success is claimed if superiority for at least one of the endpoints is demonstrated. This is sometimes also called the dual primary endpoint concept, and an appropriate adjustment of the study-wise type-1-error is required. This concept is not covered in the European Guideline on multiplicity because study success can be claimed if one endpoint shows significant superiority, despite a possible deterioration in the other. In line with Röhmel's strategy, we discuss an alternative approach including non-inferiority hypotheses testing that avoids obvious contradictions to proper decision-making. This approach leads back to the co-primary endpoint assessment, and has the advantage that minimum requirements for endpoints can be modeled flexibly for several practical needs. Our simulations show that, if planning assumptions are correct, the proposed additional requirements improve interpretation with only a limited impact on power, that is, on sample size.

Using a Further Planning MRI after Neoadjuvant Androgen Deprivation Therapy Significantly Reduces the Radiation Exposure of Organs at Risk in External Beam Radiotherapy of Prostate Cancer.

Radiotherapy for prostate cancer is often preceded by neoadjuvant androgen deprivation therapy (ADT), which leads to a reduction in the size of the prostate. This study examines whether it is relevant for treatment planning to acquire a second planning magnetic resonance imaging (MRI) after ADT (=MRI 2) or whether it can be planned without disadvantage based on an MRI acquired before starting ADT (=MRI 1). The imaging data for the radiotherapy treatment planning of 17 patients with prostate cancer who received two planning MRIs (before and after neoadjuvant ADT) were analyzed as follows: detailed comparable radiation plans were created separately, each based on the planning CT scan and either MRI 1 or MRI 2. After ADT for an average of 17.2 weeks, the prostate was reduced in size by an average of 24%. By using MRI 2 for treatment planning, the V60Gy of the rectum could be significantly relieved by an average of 15% with the same coverage of the target volume, and the V70Gy by as much as 33% (compared to using MRI 1 alone). Using a second MRI for treatment planning after neoadjuvant ADT in prostate cancer leads to a significant relief for the organs at risk, especially in the high dose range, with the same irradiation of the target volume, and should therefore be carried out regularly. Waiting for the prostate to shrink after a few months of ADT contributes to relief for the organs at risk and to lowering the toxicity. However, the use of reduced target volumes requires an image-guided application, and the oncological outcome needs to be verified in further studies.