1. Interpretation of clinical trials Marije Hamaker & Martine Extermann

2. Disclosure Marije Hamaker
Nothing to disclose
Disclosure Martine Extermann

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

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

5. 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

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

7. 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:

8. 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

9. 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

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

11. 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

12. 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

13. 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

14. 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!

15. Observational data Valuable in determining real life effects
Phase IV trials

17. 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

18. 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.

19. 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

21. 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

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

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

24. 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

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

26. 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

27. 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

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

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

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

31. Geriatric screening +/- CGA

32. 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…

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

34. 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)

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