Interpretation of clinical trials Marije Hamaker & Martine Extermann

Disclosure Marije Hamaker Nothing to disclose Disclosure Martine Extermann

Program The relevance of trial participation of older patients Reasons for poor participation Validity of clinical trails Interpreting observational data Patient-centered outcome measures

Trials vs. reality ©Erna Beers 2013 Wetenschappelijke onderzoeken geven vaak niet de actuele werkelijkheid weer ©Erna Beers 2013

Elderly patients in cancer trials Patients 65 years of age or older were underrepresented overall in all 15 types of cancer except lymphoma 63% of cancer population > 65 years 25% of patients in cancer trials  LIMITED GENERALISABILITY OF TRIAL RESULTS N Engl J Med 1999;341:2061-7

Reasons for excluding elderly Competing causes of death Treatment discontinuation/reduced dosage due to toxicity Diminished treatment effect Requires greater sample size

Reasons for poor trial participation Physician-related factors Fear of toxicity, assumptions regarding benefit, preferences, time Patient-related factors Preferences, logistics Trial-related factors Ineligibility, complexity, time-restraints, randomization Tailored care vs. standardized care The Breast 2013;22:556-9 Cancer control 2014;21: 209-14

Possible solutions to improve participation Non-exclusive inclusion criteria Incorporation of dose escalation/de-escalation Parallel treatment arm for ineligible patients Registration of ineligible patients to address selection bias Trials specifically designed for elderly Education of patients and physicians Taking/making time to explain the relevance of a trial Observational studies

Internal validity of clinical trials The extend to which the observed effects are true for the study participants Affected by: Method of treatment assignment Blinding Loss to follow up

Randomized controlled trials Optimizing internal validity Demonstrate what can be achieved with a treatment with careful observations and under certain restrictions

External validity External validity The extend to which the results of the study are a true reflection of what can be expected in the target population Often at conflict with internal validity

Reasons for excluding elderly Competing causes of death Treatment discontinuation/reduced dosage due to toxicity Diminished treatment effect Requires greater sample size THIS DIMINISHED EFFECT IS AN ACCURATE ESTIMATION OF TRUE CLINICAL BENEFIT IN THE OLDER POPULATION

Example: CAIRO trial Trial on chemotherapy in metastatic colon cancer Subsequent comparison with real-life outcomes in: Patients fulfilling in- and exclusion criteria (eligible) Patients not eligible Group Median survival Hazard ratio Trial participants 17 months 1.00 Eligible non-participants 15.7 months 1.03 Non-eligible non-participants 9.3 months 1.70

Assessing external validity Only possible if key characteristics are recorded and reported Age distribution Cognitive and physical function (care dependence, mobility etc.) Reported in only a minority of studies Even in studies specifically addressing older patients!

Observational data Valuable in determining real life effects Phase IV trials

Risk of misattribution In a systematic review on observational studies in breast cancer, 71% were subject to confounding by indication!! Journal of Clinical Oncology 2003;21:3580-7

Instrumental variable A factor associated with treatment allocation but not with outcome If applied correctly, validity close to RCT Example: Geographical region, country, time-period Patient populations must be comparable, similar access to health care etc.

Behandelrichtlijnen bij ouderen minder goed gevolgd Example: year of diagnosis Behandelrichtlijnen bij ouderen minder goed gevolgd 75-80 yrs 80-84 yrs 85-90 yrs 90+ yrs De Glas et al. Br J Surg 2014

There is more to life than survival With aging come different priorities Older patients less accepting of toxicities Particularly when affecting independence, cognition or social situation Importance of patient-reported outcome measures

Patient-centered outcome measures Ann Oncol. 2014 Mar;25(3):675-81

When quality of life is included… Results are often not published Or “ignored” when effect on primary outcome shows opposite pattern of benefit

Take home messages (Frail) older patients need to be included in research Consider the external validity of trial data Beware of confounding in observational data There is more to life than survival

How to use clinical trial data in everyday practice Martine Extermann, MD Moffitt Cancer Center University of South Florida Tampa, FL, USA

Accrual into clinical trials 50% Median cancer age: 67 years 50% Data from NCI cooperative groups phase II and III trials Hurria et al., JCO 2014

How valid are guidelines in 80+ yo NSCLC? 760 NSCLC patients aged 80+ Mean age 85.2 y, 11.4% >90 NCCN guidelines v4.2014, ESMO guidelines early (2013) and metastatic (2014) NSCLC Studies cited: NCCN 244; ESMO early 67; ESMO metastatic 81. GRADE evidence. Evidence % “ 2+ studies eligible” 80+ yo patients Present >60% Partial 30-60% Limited <30% Battisti et al. Clin Lung Cancer, 2017

Evidence for localized stage Battisti et al. Clin Lung Cancer, 2017

Evidence for Metastatic 1st line Battisti et al. Clin Lung Cancer, 2017

Evidence for Targeted therapies and misc. Battisti et al. Clin Lung Cancer, 2017

Geriatric screening +/- CGA

Frailty Multiple tools, but as a rule, tools that incorporate ADL/IADL, comorbidity (typically severe CIRS-G), and geriatric syndromes perform well in oncology E.g. Tucci 2009, Rostoft-Kristjansson 2012, Ferrat 2017 etc…

Chemotherapy risk scores CRASH score (Extermann et al., Cancer 2012) CARG score (Hurria et al., JCO 2011, 2016)

Evaluate the validity of a study for your patient Read the methods section! Eligibility criteria Patient ages and condition Tumor size/type/stage Proportion of patients completing treatment Check drug metabolism: renal vs liver excretion Check drug interactions (e.g. amiodarone, dronedarone) Know comorbidity-related toxicities (e.g. diabetes and taxane neuropathy)

If you tune it well, it will work                                                                                                                                Jean Tinguely, Carnival Fountain, Basel, Switzerland