El 3 de noviembre de 2015, la Fundación Ramón Areces organizó en su sede en Madrid (C/ Vitruvio, 5) una jornada sobre ‘El cáncer como consecuencia del envejecimiento: posibles soluciones’. Coordinado por la investigadora María Vallet Regí, del Departamento de Química Inorgánica y Bioinorgánica de la Universidad Complutense de Madrid, contó con la presencia, entre otros científicos, de Mariano Barbacid, Lodovico Balducci y Theresa Guise.

1. CANCER & AGEING:
COLORECTAL CANCER
TREATMENT APPROACH
Alfredo Carrato Mena
Servicio de Oncología Médica
Hospital Universitario Ramón y Cajal,
Universidad Alcalá
EL CÁNCER Y EL
ENVEJECIMIENTO:
POSIBLES SOLUCIONES
Madrid, 3 Noviembre 2015

3. COLORECTAL CANCER INCIDENCE AND
MORTALITY RATES
Median age of 69 years at diagnosis and 74 years at death

4. LIFE EXPECTANCY IN SPAIN AT AGE 65 YEARS

5. Prognostic Factors* 5-Year Relapse-Free Survival (%)
T3N0M0 (11-20 nodes analyzed) 79
T3N0M0 low grade 73
T3N0M0 (≤10 lymph nodes examined) 72
T3N0M0 high grade 65
T4N0M0 low grade 60
T4N0M0 high grade 51
T3N1M0 49
T3N2M0 15
* Results were derived from the Mayo Clinic calculator
http://www.mayoclinic.com/calcs, using a referent age of 60-69 years old.
Survival results did not consider treatment benefits. Good quality of surgery
and >10 nodes are crucial requirements.
CRC SELECTED PROGNOSTIC FACTORS AND FIVE-
YEAR RELAPSE-FREE SURVIVAL (JCO 2005;23:8512)

6. REVISED TNM CLASSIFICATION FOR STAGE III CRC
(N=50,042)
59.8%
42.0%
27.3%
0
10
20
30
40
50
60
70
IIIA IIIB IIIC
Node-positive subgroups
Observed 5-
year
survival (%)
p<0.0001
IIIA: T1/2, N1 IIIB: T3/4, N1 IIIC: Any T, N2
Greene et al (2002)(http://www.mayoclinic.com/calcs)

7. MOSAIC 10 year OS
JCO 2015; Nov 2

8. Adjuvant Colon Cancer Chemotherapy in patients ≥ age 75 years
Sanoff HK et al. J Clin Oncol 30:2624-2634.Stage III, 2004 -2007
44%
34%

9. Adjuvant Colon Cancer Chemotherapy in patients ≥ age 75 years
Sanoff HK et al. J Clin Oncol 30:2624-2634.

10. XELOX vs FU/LV as adj. tt. for Patients with Stage III Colon
CancerSchmoll HJ et al J Clin Oncol 2015 Aug 31. pii: JCO.2015.60.9107. [Epub ahead of print]

11. NSABP C07: FLOX vs FU/LV in Patients With Stage II/III Colon
Cancer
Yothers G et al J Clin Oncol 29:3768-3774

12. Impact of Age on the Efficacy of Newer Adjuvant Therapies in
Patients With Stage II/III Colon Cancer
McCleary NJ et al J Clin Oncol 31:2600-2606

13. STRATEGIC CRC DISEASE MANAGEMENT
• Long-term strategic planning is needed for each patient:
• To control disease
• Prolong survival
• Improve quality of life
• Improve treatment of elderly and poor PS patients
• Attempt a cure in highly selected patients
First-line
1st-
line
2nd-
line
AdjuvantDiagnosis
Neo-
adjuvant/
Surgery
Secondary resection?
Palliative therapy
Cure
Recurrence
etc.
Cure

14. PATIENT GROUPS IN METASTATIC CRC
Group 3
Patients with
less aggressive
disease or who are
unable to tolerate
standard CT regimens
Schmoll H-J, Sargent D. Lancet 2007;370:105–107
Group 1
Patients with
potentially resectable
metastases
Group 2
Patients with
non-resectable
metastases, high
tumor burden, and
tumor-related
symptoms
Aggressive therapy Less aggressive therapy
CT=chemotherapy

16. POOLED FOLFOX IN ELDERLY CRC TRIALS. Goldberg R. J Clin Oncol
2006;24:4085-4091
3,742 colorectal cancer patients (614 age 70)
OS Forest plots by study for bimonthly
FOLFOX vs control by age
DFS Forest plots by study for bimonthly
FOLFOX vs control by age

17. RANDOMIZED FU or CAPE vs FOLFOX or CAPOX IN ELDERLY
mCRC
Seymour M et al. Lancet. 2011 May 21; 377(9779): 1749–1759

18. RANDOMIZED PHIII TRIAL FULV vs FOLFIRI in ELDERLY mCRC
Aparicio T et al. Ann Oncol 2015; Oct 20
Cognitive and
functional
impairment were
predictive of severe
toxicity or
unexpected
hospitalization

19. POOLED BEVACIZUMAB FOLFOX IN ELDERLY mCRC TRIALS
Cassidy J et al. J Cancer Res Clin Oncol 2010;136:737–743
Confirmed by the AVEX randomized phase III trial. Cunningham D. Lancet Oncol
2013;14:1077

20. CANCER TREATMENT IN THE ELDERLY
• 50% of cancer cases are diagnosed in patients over 70
years of age
• The life expectancy of a 70-year-old men is 10 years and
that of women it is 15 years
• Older persons with cancer are under-screened, under-
staged and under-treated or not treated at all.
• They are under-represented in clinical trials
• The results of therapy in older patients are seldom
reported separately.

21. INFLUENCE OF AGE ON PHARMACOKINETICS
• Decreased GI tract absorption (↓gastric motility, ↓secretions,
↓absorptive surface, ↓hepatic blood flow).
• Decreased volume of distribution for water soluble drugs
(↓water content, ↓serum albumin, ↓hemoglobin)
• Reduced hepatic drug metabolism (↓liver volume, ↓hepatic
blood flow)
• Biliary excretion, probably unchanged.
• Reduced renal excretion (↓GFR)
• Decrements of cardiac and marrow reserves
• Decrements in bone and muscle mass

22. MORE FREQUENT AND SEVERE COMPLICATIONS OF
CHEMOTHERAPY IN THE ELDERLY
• Myelosuppression
• Mucositis
• Delayed nausea and vomiting
• Cardiomyopathy
• Renal injury
• Peripheral or central neurotoxicity

23. ANTICANCER TREATMENTS
• Surgery
• Radiation therapy
• Chemotherapy
• Hormonotherapy
• Immunotherapy
• Biological therapy
• others …(50% cancer patients are receiving alternative
or additional treatments)

24. ATTITUDES TOWARDS CHEMOTHERAPY
(SLEVIN M ET AL. BMJ 1990;300:1450-60)
acceptation medical oncologists cancer
rate and radiaton-oncologists patients
--------------------------------------------------------------------------
- low possibility of cure 24 % 60 %
- survival > 3 months 15.3 % 47.9 %
- low symptomatic benefit 4.5 % 50.5 %

25. DECISION PROCESS
Health professionals, patients, families and friends
• Is the patient going to die of the disease?
• Is the patient going to suffer from the disease?
• Is the patient going to tolerate the treatment with no fatal
complication?
• Are there competing issues affecting life expectancy and cancer
outcome?
• To define who is considered fit for treatment should be based on
a combination of functional changes related to the aging process
and other factors such as social support.

26. COMPREHENSIVE GERIATRIC ASSESSMENT
• Estimates of life expectancy:
– Functional Status
– The number of comorbid conditions
– The presence of geriatric syndromes
– Cognition
– Depression.
• Patients at high risk for complications of Chemo:
– Dependent in any instrumental activity of daily living
– Poor social support (live alone or with an older person)

27. COMPREHENSIVE GERIATRIC ASSESSMENT
• Unrecognized medical problems may be revealed and
properly treated. CGA may minimize the complications of
cancer treatment.
• Frail Patients:
– Age 85 and older
– Dependent in any activity of daily living
– Three or more comorbid conditions
– One or more geriatric syndromes.
• Frail patients has no functional reserve and are susceptible
to any insignificant stress.
• Frail patients are mainly candidates for palliation.

28. SYSTEMATIC GERIATRIC SCREENING RESULTS
Kenis C et al. Annals of Oncology 2013;24:1306–1312,

29. SUGGESTED TREATMENT FOR THE ELDERLY
• GROUP 1: Healthy and god PS -> Standard treatment
• GROUP 2: Partially dependent, two or less comorbid
conditions:
– Life expectancy is shortened by cancer
• If they can tolerate treatment: Standard Treatment
• If they cannot tolerate treatment: Palliation
– Life expectancy not shortened by cancer: Palliation
• GROUP 3: Totally dependent, weakened, three or more
comorbid conditions or one geriatric syndrome:
Palliation

30. MANAGEMENT SUGGESTIONS FOR ELDERLY PATIENTS
• Adjust first CT doses to GFR or hepatic function. Successive doses
should be modified according to the toxicity observed.
• Hgb should be around 12 g/dl. Erythropoietic agents:
– reduce RBC transfusion rates,
– improve fatigue scores, cognitive function, and patient QoL
• G-CSF should be used with moderately toxic CT (10% risk of febrile
neutropenia) in order to:
– Decrease incidence of neutropenia and febrile neutropenia
– Decrease infection-related mortality
– Maintain chemotherapy dose intensity and density
• Palliation (goal with frail patients) may include some mild form of CT
(UFT, CI 5-FU, capecitabine, etc).

31. THE PHYSICIAN’S VOCATION
• To cure sometimes
• To relieve often
• To comfort always
– Traditional saying

32. SYMPTOMS IN ELDERLY CANCER PATIENTS
RECEIVING PALLIATIVE CARE
PAUTEX S ET AL. CROH 2003;47:281-286
42 pts, 72 +/- 9y (52-88)
% intensity (VAS)
• fatigue 84 5.7
• somnolence 77 4.4
• appetite loss 79 4.3
• dyspnoea 77 4.2
• pain 62 4.8 / 10
• anxiety 58 3.9
• depression 50 3.9
• nausea 26 3.8

33. curative
treatments
life prolonging
treatments
symptomatic
treatments
terminal
care
grief,
mourning
time
LIFE SPAN OF NON CURABLE CANCER PATIENTS
palliative carecontinuous care

34. Cancer history
Functional
Status
time (months or years)
relapse
Acute failure
death
diagnosis
metastasis

35. CLINICAL CASES
N°1
• 83 years old male with severe Parkinson’s disease, past
history of abdominal surgery due to bullet wound, colon
cancer, osteoarthrosis and right hip prosthesis
N°2
• 78 years old male with mild cognitive impairment and severe
deafness, and past history of colon and skin cancers,
prostatectomy and subdural hematoma

36. Karol Wojtyla,
pope John Paul II,
1978-2005
Ronald Reagan,
40th USA
president, 1981-89
N°1 N°2

37. Clinical Settings
Clinical services
CARE COORDINATION:
MAKING THE CONNECTION
Provider
Patient at Home
Technology
Supportive care:
•Rehabilitation
•Nutrition
•Social Services
•Palliative care
•Pharmacy
• Geriatrics
• Clinical
Oncology
• Primary care
Optimal patient outcome

38. BACKGROUND
Common tumors can have:
• Molecular subtypes
• Therapeutics to match
Rare cancers can have driver mutations
with therapeutics to match
Rapidly evolving evidence for new
driver and pathway mechanisms c
(with potential therapeutics)
Molecular subtypes of lung cancers a
a
Pao and Hutchinson Nature Medicine 18: 349-351, 2012
Basal cell – PTCH mutation b
b
Von Hoff et al. NEJM 361:1164-1172, 2009
c
TCGA Nature 497: 67-73, 2013; NEJM May 1st
2013
Gatalica et al. ASCO 2013

39. METHODS
A very robust analysis of the tumor’s biology and
potential clinically actionable targets can be
enabled by a Multi-platform, technology
independent analysis
• Mutational Analysis by Sanger Sequencing, Next
Generation Sequencing, FISH and PCR
• Gene Copy Number by Fluorescent in Situ Hybridization /
Chromogenic In Situ Hybridization (FISH / CISH)
• MGMT Methylation by PCR
• Protein Expression Analysis by Immunohistochemistry
(IHC) (n=17 biomarkers)
Gatalica et al. ASCO 2013

40. SOME PREDICTIVE BIOMARKERS IN ONCOLOGY
1-8: European Public Assessment Reports, available at www.ema.europa.eu for: 1. Herceptin®
; 2. Tyverb®
; 3. Glivec®
; 4. Iressa®
; 5. Tarceva®
; 6. Vectibix®
; 7. Erbitux®
;
8. Zelboraf®
; 9. Crinò L, et al. J Clin Oncol 2011;29(Suppl):7514.
Tumour type Biomarker Drug
Breast cancer HER-2 overexpression Trastuzumab1
, lapatinib2
, pertuzumab, TDM1
Gastric cancer HER-2 overexpression Trastuzumab1
CML BCR/ABL fusion gene Imatinib3
GIST c-KIT mutation Imatinib3
NSCLC EGFR mutation Gefitinib4
, erlotinib5
mCRC RAS gene mutation status Panitumumab6
, cetuximab7
Melanoma BRAF V600 Vemurafenib8
NSCLC EML4/ALK Crizotinib9*
aCRC MMR Fluopyrimidines
*approved by FDA as of September 2011; not approved by EMA as of September 2012.

41. Identification and validation of miRNAs useful for CRC patient stratification
IDENTIFICATION: Hybridization arrays in paraffin-embedded CRC biopsies:
1437 miRNAs analyzed in 8 samples
Samples
1 Healthy control
2,3 CRC<45 years
4,5,6 Lynch
7,8 CRC>50 years
Statistical and functional analyses: Selection of 17 miRNAs to be validated by qRT-PCR
miRNAs associated to age of diagnosis
(65 years): miR-1, miR-27, miR-193,
SNORD4
miRNAs associated to differentiation
stage, stroma, to inflammatory infiltrates,
TNM, tumor localization (right/left),
positive ganglia, mucoid component

43. CONCLUSSIONS
• Age specific cancer incidence rates increase through the
oldest age groups
• An Oncology and Geriatrics integrated approach is useful for
the elderly cancer patient
• CGA has significant impact on treatment decisions
• Frailty predicts negative outcomes
• Screening is advisable if QoL & life expectancy is long enough
• Retrospective results of non-geriatric trials are not
reproducible in the general geriatric population
• Prospective trials and translational research is a must for
innovation in Geriatric Oncology & better patient’s outcome.

44. ¡MUCHAS