THE FRAILTY SYNDROME AND CANCER TREATMENT IN THE ELDERLY

1. THE FRAILTY SYNDROME AND CANCER TREATMENT IN THE ELDERLY Judith Leibovici, Orit Itzhaki, Tatiana Kaptzan, Raida Asfour, Monica Huszar, Judith Sinai, Ehud Skutelsky and Moshe Michowitz Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, 69978 Tel-Aviv, Israel International Federation on Ageing (IFA) 11th Global Conference on Ageing, Prague 2012

2. About 60% of cancers appear in people aged over 65 years. Nevertheless, elderly cancer patients are not receiving the same standard of oncological careas younger patients.

3. Treatment of aged cancer patients constitutes a yet unsolved problem, particularly for those who are frail. Cancer treatments now in use most often include aggressive procedures which are particularly harmful to elderly frail individuals.

4. Treatment of cancer in elderly patients is extremely problematic due to their increased tendency to: Frailty Comorbidities Polypharmacy Increased sensitivity to drug toxicity In view of the aggressiveness of anti-cancer therapies in use, not all aged patients are fit for these treatments.

5. Frailty confers high risk of falls, fractures, disability, hospitalization and mortality.

6. Mortality is a function of frailty

7. Until recently, a clear definition of frailty remained elusive. The American Medical Association characterized the term “frailty” as: "The most complex and challenging problem to the physician and all health care professionals".

8. A large variety of properties have been attributed to the frailty syndrome, up to 75, by the group of Rockwood.

9. The definition of FRAILTY now mostly adopted, that of Fried et al. (2001), includes 5 items: • Unintentional weight loss or sarcopenia • Weakness as measured by grip strength • Poor endurance resulting in self-reported exhaustion • Slowness as measured by walking speed • Self-reported low physical activity • Patients with 3 or more of these criteria are considered FRAIL. Patients with 1 or 2 of these signs are considered PRE-FRAIL.

10. Frailty depends on: • Age • Gender • Socio-economic conditions • Level of education

11. Very recently Shamliyan et al. calculated the pooled prevalence of frailty in function of age of the two types of groups: those who define frailty according to phenotype (Fried-like) and those who define it by accumulation of deficits (Rockwood- like). Shamliyan et al. Ageing Res Rev, 2012

12. Pooled prevalence of frailty in function of age Age Fried-like Rockwood-like 65-70 3-6% 5-15% 70-80 5-12% 8-17% 80-84 >16% >16% >85 26% 50-56% Shamiylian et al. 2012

13. Elderly cancer patients were traditionally under-treated or not treated at all. Moreover, the under-treatment was not evidence- based, since aged cancer patients were most often not included in clinical trials.

14. Cancer treatment in the aged was viewed differently by different groups. Balducci stressed the idea that age per se should not preclude"classical" cancer treatment and this should include the "fit" elderly patients who, he considered, constitute the majority of the elderly population. Balducci L. Aging, frailty and chemotherapy. Cancer Control 14: 7-12, 2007

15. According to Balducci, "Most older patients appear to benefit from cancer treatment to an extent comparable to that of younger individuals and only a minority should be excluded from treatment due to reduced tolerance" Balducci, 2007

16. Santos-Eggimann et al. reported the prevalence of frailty and pre-frailty in 10 European countries. The frailty phenotype was assessed in this study for more than 16,000 participants.

17. Santos- Eggiman 2009

18. One notable result of this study was that the proportion of frailty was higher in Southern than in Northern European countries. Frailty was more frequent in Spain, Italy and Greece than in Sweeden and Switzerland. The data suggested that socio-economic factors and education level contribute to this difference.

19. Comparison of frail and pre-frail prevalence in different countries

20. The range of frailty prevalence is situated between 4.3-21.1 % (mean 11.9) However, the prevalence of pre-frailty is very high, ranging between 40.0-84.1 (mean 49.0 ), most values being situated around 50%. The dimension of the prevalence of non-fit individuals in the aged population is definitely very high. The prevalence of pre-frail plus frail reaches in certain populations 75-80 percent!

21. Indeed, the percentage of those considered to be frail among the elderly is low in many Western countries (4-8%). However, they may constitute more than 20-30% in countries such as those in Southern Europe. (Data concerning developing countries are very few and they risk to be much higher). In addition, the percentage of pre-frail individuals is very high (closeto50%), in all European countries. Importantly, pre-frail individuals are expected to become in 3-4 years frail .

22. It follows that up to 70%-80% of elderly patients (frail+ pre-frail) are non-fit and thus have to undergo milder treatments.

23. The fraction of non-fit elderly people constitutes thus a majority in the aged population, indicating that cancer treatment in the old is even more complicated than previously thought.

24. Thus, only a minority of elderly people are "fit" (about 30%) and can be treated "traditionally". For the majority of aged cancer patients (about 70%), milder treatments have thus to be adopted.

25. We suggest, moreover, that the usually aggressive anti-cancer proceduresmay even precipitatethe transit from pre-frail to frail status.

26. The social aspects of the frailty problem (the need of elevating the socio-economic status and education level), may finally be more efficient, less expensive and - most important - entail less suffering to aged cancer patients than the treatment of frailty.

27. Treatment of frail cancer patients: New suggestions Only recently, treatment of the main types of cancer, adapted for the different stages of frailty (and beyond -disability- ) have been suggested (Monfardini S, Int Emerg Med 6: S115 –S118, 2011). The new suggestions include: 1) Reduced doses of chemotherapy 2) Use of less toxic drugs 3) Administration of cytotoxics at hospital 4) Supervised conditions of post-treatment

28. With reference to Balducci’ s statement: Numerous studies were published in recent years showing that selected fit elderly individuals are able to undergo the same aggressive therapies as successfully as young cancer patients.

29. It is therefore true that chronological age alone should not prevent elderly cancer patients from receiving usual anti-cancer treatment. In addition, whenever a less aggressivetherapy is discovered (minimally invasive surgery, for instance), it might also be appropriate for less fit senior patients.

30. The question is, what is the percentage of those elderly fit patients in the aging population. According to Balducci, they constitute the majority. We contend that, on the contrary, they constitute a minority in the elderly population.

31. Based on the published prevalence of frailty and pre-frailty in the elderly population, we suggest that most elderlypatients are not fit for the now existing anti-neoplastic treatment modalities. Therefore, novel approaches, adapted to the aging host and to the specific biology of tumors in the old, should be investigated.

32. Balducci states that the very concept of frailty has prevented life-saving interventions in anti-neoplastic treatment in older patients. However, frailty – though complex – does exist and may, moreover, be fatal.