Responder Identification in Clinical Trials

The thesis gives an overview of the techniques used up to now for responder identification and it proposes a new method for systematic search for responders. The responder identification method consists of the following three steps: 1. Identification of prognostic factors (e.g. via Cox-PH model on the standard treatment arm) 2. Identification of patients in the new treatment arm, who's survival is badly estimated by the prognostic model (e.g. via search for outliers in the deviance or martingale residuals) 3. Identification of predictive factors, which describe common features of the patients with residual outliers, namely the positive and negative responders (e.g. via regression tree or bump hunting analysis, or via the suggested stabilized bump hunting procedure) The method is evaluated with a simulation study and applied on the EMIAT data s

Categorical versus continuous circulating tumor cell enumeration as early surrogate marker for therapy response and prognosis during docetaxel therapy in metastatic prostate cancer patients

Background: Circulating tumor cell (CTCs) counts might serve as early surrogate marker for treatment efficacy in metastatic castration-resistant prostate cancer (mCRPC) patients. We prospectively assessed categorical and continuous CTC-counts for their utility in early prediction of radiographic response, progression-free (PFS) and overall survival (OS) in mCRPC patients treated with docetaxel. Methods: CTC-counts were assessed in 122 serial samples, as continuous or categorical (= 5 CTCs) variables, at baseline (q0) and after 1 (q1),4 (q4) and 10 (q10) cycles of docetaxel (3-weekly, 75 mg/m2) in 33 mCRPC patients. Treatment response (TR) was defined as non-progressive (non-PD) and progressive disease (PD),by morphologic RECIST or clinical criteria at q4 and q10. Binary logistic and Cox proportional hazards regression analyses were used as statistical methods. Results: Categorical CTC-count status predicted PD at q4 already after one cycle (q1) and after 4 cycles (q4) of chemotherapy with an odds ratio (OR) of 14.9 (p = 0.02) and 18.0 (p = 0.01). Continuous CTC-values predicted PD only at q4 (OR 1.04, p = 0.048). Regarding PFS, categorical CTC-counts at q1 were independent prognostic markers with a hazard ratio (HR) of 3.85 (95 % CI 1.1-13.8, p = 0.04) whereas early continuous CTC-values at q1 failed significance (HR 1.02, 95 % CI 0.99-1.05, p = 0.14). For OS early categorical and continuous CTC-counts were independent prognostic markers at q1 with a HR of 3.0 (95 % CI 1.6-15.7, p = 0.007) and 1.02 (95 % CI 1.0-1.040, p = 0.04). Conclusions: Categorical CTC-count status is an early independent predictor for TR, PFS and OS only 3 weeks following treatment initiation with docetaxel whereas continuous CTC-counts were an inconsistent surrogate marker in mCRPC patients. For clinical practice, categorical CTC-counts may provide complementary information towards individualized treatment strategies with early prediction of treatment efficacy and optimized sequential treatment

How Do Persons with Young and Late Onset Dementia Die?

Background: End of life symptoms and symptom management as well as the quality of dying (QoD) of persons with advanced dementia (PWAD) have not yet been systematically studied in Germany. Objective: 1) To investigate symptoms, treatment and care at the end of life, advance care planning, and circumstances of death of recently deceased PWAD;2) To determine whether there are differences between young and late onset dementia (YOD and LOD). Methods: The study was performed in the context of the project EPYLOGE (IssuEs in Palliative care for persons in advanced and terminal stages of Young-onset and Late-Onset dementia in Germany). Closest relatives of recently deceased patients with advanced YOD (N = 46) and LOD (N = 54) living at home or in long term care were interviewed. Results: Circumstances of death, symptoms, and treatment appeared to be similar between YOD and LOD, except that persons with LOD had significantly more somatic comorbidities and were admitted to hospital in the last three months of life more often than persons with LOD. At end of life, 60% of PWAD appeared to be at peace. Difficulty swallowing, gurgling, shortness of breath, and discomfort were observed most frequently. Large interindividual differences in suffering and QoD were present. Determinants of QoD were not identified. Conclusion: Our findings suggest that low QoD was caused by inadequate recognition and/or insufficient treatment of burdensome physical and emotional symptoms. PWADs' needs should be assessed regularly, and strategies focusing on treatment and implementing support for both the patient and caregiver must be established

Systematic Review and Narrative Summary: Treatments for and Risk Factors Associated with Respiratory Tract Secretions (Death Rattle) in the Dying Adult

AimTo identify effective treatments and risk factors associated with death rattle in adults at the end of life.BackgroundThe presence of noisy, pooled respiratory tract secretions is among the most common symptoms in dying patients around the world. It is unknown if ‘death rattle’ distresses patients, but it can distress relatives and clinicians. Treatments appear unsatisfactory, so prophylaxis would be ideal if possible.DesignQuantitative systematic review and narrative summary following Cochrane Collaboration guidelines.Data sourcesCINAHL, MEDLINE, Health Source Nursing and Web of Science were searched for international literature in any language published from 1993 - 2016 using MeSH headings and iterative interchangeable terms for ‘death rattle’.Review MethodsRandomised controlled trials were appraised using the Cochrane Collaboration’s tool for assessing risk of bias. Non-randomised studies were assessed using ROBINS-I tool for assessing risk of bias in non-randomised studies of interventions. Instances of treatment and risk were extracted and relevant key findings extracted in line with Cochrane methods.ResultsFive randomised trials and 23 non-randomised studies were analysed. No pharmacological or non-pharmacological treatment was found superior to placebo. There was a weak association between lung or brain metastases and presence of death rattle, but otherwise inconsistent empirical support for a range of potential risk factors.ConclusionsClinicians have no clear evidence to follow in either treating death rattle or preventing it occurring. However, several risk factors look promising candidates for prospective analysis, so this review concludes with clear recommendations for further research

Responder Identification in Clinical Trials with Censored Data 2 Summary

We present a newly developed technique for identification of positive and negative responders to a new treatment which was compared to a classical treatment (or placebo) in a randomized clinical trial. This bump-hunting-based method was developed for trials in which the two treatment arms do not differ in survival overall. It checks in a systematic manner if certain subgroups, described by predictive factors do show difference in survival due to the new treatment. Several versions of the method were discussed and compared in a simulation study. The best version of the responder identification method employs martingale residuals to a prognostic model as response in a stabilized through bootstrapping bump hunting procedure. On average it recognizes 90 % of the time the correct positive responder group and 99 % of the time the correct negative responder group

Summary

Clinical trials often judge the efficacy of a new treatment by comparing the survival patterns of patients who are randomly assigned to undergo the new or a standard/placebo treatment. Usually, the entire groups are analyzed, although certain subgroups of patients may react differently to the new treatment than others. Some patients taking the new treatment might benefit from it (the positive responders) while others may be harmed by it (the negative responders). We applied a newly developed responder identification method (Kehl & Ulm, 2003) on the doubleblinded placebo controlled European Myocardial Infarction Amiodarone Trial (EMIAT). The method, which is based on bump hunting, proceeds to find the so called predictive factors, which describe positive and negative trends in survival in special subgroups of patients, solely due to Amiodarone. Factors found to be predictive were: age, previous infarction, beta-blocker treatment, onset, NYHA classification, and sex. Negative responders to Amiodarone, i.e. patients taking Amiodarone who survived shorter than a similar group under placebo, were patients who were older than 65 years, have had a previous infarction, and were not on beta-blockers. Positive responders to Amiodarone, (longer survival time), were male patients who were not negative responders, had NYHA classification greater than or equal to two, and onset greater than one. Further studies are needed to investigate this hypothesis.