GERIATRIC ONCOLOGY Chemotheraphy : Risks and Benefit

Eko A PangarsaHematology –Medical Oncology

Internal Medicine Department-Kariadi Hospital

CURRICULUM VITAE

Name : Eko Adhi Pangarsa MD, Hematology – Medical Oncology Consultant

Occupation : Haematologi-Medical Oncology Internal Medicine Department -Karyadi Hospital- Semarang- Indonesia

Recent Courses : ESMO Preceptorchip Colorectal Cancer, Singapore 2014

ESMO Preceptorchip Lung Cancer, Singapore 2015

ESMO Academy , Oxford - United Kingdom , 2015

Lymphoma Working Party Education Course -European Bone Marrow Transplant,Ireland ,2016

Preceptorchip Breast Cancer in Premenopouse Women , Taipeh 2018

International Congress Malignant Lymphoma, Lugano 2019

Organization :

IDI : Indonesian Medical Association PAPDI : Indonesian Internal Medicine Association

ESMO : European Society Medical Oncology ASCO : American Society Clinical Oncology

CACA : Chinese Anti Cancer Association ISHMO : The Indonesia Society of Hematology and Medical Oncology

YKI : Indonesian Cancer Foundation

Introduction

• Life expectancy has increased the number of elderly patients.

• Globally, the number of older adults is increasing at a rapid pace (estimated 524

million in 2010 to nearly 1.5 billion in 2050), taking place in developing regions.

• More than 60% pts who are newly diagnosed with cancer are age ≥ 65 years or

older, which makes this the most common population seen in an oncology

practice

• Chemotherapy is an important component of treatment for many cancers.

• The side effects of chemotherapy affect an individual's physical health, quality of

life and emotional state.

• The side-effects and long-term sequelae of

anti-cancer chemotherapy remain a major concern for

both patients and clinicians.

• The management of a side effect can include a reduction

in the dose intensity ; but there is evidence..patients

with low dose chemotherapy have reduced

survival rates.

• Older adults are heterogeneous. Each patient needs to be captured and integrated in the decision-

making process of cancer treatment

• Treating older patients can be challenging ,as other comorbid conditions may limit life expectancy and

the ability to tolerate oncologic treatment.

Demography• Currently, the proportion of older adults is highly variable across regions, ranging

from 17.9% in Europe to 3.5% in Africa, but this will also increase globally

Soto-Perez-de-Celis, E. et al. Global geriatric oncology: Achievements and challenges. J. Geriatr.

Oncol. 8, 374–386 (2017)

Demography

Indonesia, approximately 23,66 million (9,03%) adult elder (2017)

KEMENKES. Analisis Situasi Lansia Di Indonesia. (2017).

• Cancer incidence and mortality rates in older adults are higher in developed country than developing country.

Soto-Perez-de-Celis, E. et al. Global geriatric oncology: Achievements and challenges. J. Geriatr. Oncol. 8, 374–386 (2017)

CANCER AND AGING

• Increasing age is one of the strongest risk factors for cancer development

• The link between them is complex and the foundamental factors are

unanswered.

• Cancer and aging seem to share common etiologies such as genomic

instability / DNA Damage is stimulus for cancer and aging .

• Another explanatory model views cancer and aging as stem cell diseases

Senescence as a central hallmark

Mchugh, D. & Gil, J. Senescence and aging : Causes , consequences , and therapeutic avenues. 217, 65–77 (2018).

• Why cancer is common in elderly people? Methylation analysis

Klutstein, M., Nejman, D., Green, R. & Cedar, H. DNA

Methylation in Cancer and Aging. 76, 3446–3451 (2016)

Why cancer is common in elderly people?

• The accumulation of mutations along an extended lifespan

• Reduced fitness of intracellular mechanisms that protect from cancer

• A pro-tumorigenic tissue environment

• Immunosuppression

Zinger, A., Cho, W. C. & Ben-yehuda, A. Cancer and Aging - the Inflammatory Connection. 8, 611–627 (2017)

The aging process –Impact on organs and systems

• Heart: Decreased heart rate, decreased responsiveness to adrenergic stimuli, increased afterload

• Brain: Neuronal loss, changes in synaptic function, hyperactivation of microglial cells

• Immune system: Reduced immune response to aggressors

• Lungs: Decreasing lung volumes and maximal rates of airflow; decreasing forced vital capacity; decreased diffusing capacity

• Kidney: Increasing renal cortical loss; progressive decrease in glomerular filtration rate and renal blood flow

The end result = Increased risk of acute illness and of complications during cancer treatment

Geriatric Assesment Tools

Complexity of Elderly Patients

Comprehensive Geriatric Assessment –Principles

• Reason :

1. CGA can identifies problems that are not identified by routine patient history and physical examination,

identify areas of vulnerability may otherwise be missed in routine oncology visits.

2. CGA geriatric assessment can predict survival and adverse events of treatment to assist clinical decision

3. CGA identifies areas where interventions can be performed, such as dietary advice, physical therapy,

and social support, which can help patients tolerate

• CGA is classically divided into “domains”, with each domain corresponding to one aspect of aging-related

issues. Each domain is evaluated through one (or more) validated tools.

• There is no definitive evidence to determine the specific use of a set of tools over another.

Comprehensive Geriatric Assessment

• Comprehensive Geriatric Assessment (CGA) should be the standard form of evaluation and follow-up for elderly patients before and during cancer treatment

Korc-Grodzicki, B., Shahrokni, A. & Holmes, H. M. Geriatric assessment for oncologists. Cancer Biol. Med. 12, 261–274 (2015)

Assessment of comorbidities

• Commonly used indices are the Charlson Comorbidity Index (CCI)

• Comorbidities:

o increase the risk of complications,

o modify cancer behavior, or mask symptoms with subsequent delays in cancer diagnosis,

o cancer treatment may worsen comorbidities or

o increase the frequency of drug interactions.

Korc-Grodzicki, B., Shahrokni, A. & Holmes, H. M. Geriatric assessment

for oncologists. Cancer Biol. Med. 12, 261–274 (2015)

Cognitive Assessment

• MMState Exam

• impaired cognition :

o difficulties in understanding and remembering treatment instructions,

o delayed diagnosis of complications

o less compliance with oral therapies and supportive treatments.

Korc-Grodzicki, B., Shahrokni, A. & Holmes, H. M. Geriatric

assessment for oncologists. Cancer Biol. Med. 12, 261–274

(2015).

POSSIBLE CONTRIBUTORS TO COGNITIVE DIFFICULTIES IN ELDERLY CANCER PATIENTS

M. Lange et al. Cancer Treatment Reviews 40 (2014) 810–817

Assessment of physical function

• Physical function = performance, including

gait speed, grip strength, balance,

and lower extremity strength

• A commonly used test for gait speed is

the timed up and go (TUG)

• Grip strength is a measure that correlates with sarcopenia, and has been shown to be

associated with adverse outcomes in patients with cancer, and associated with mortality

in general populations.

Medication Management and Polypharmacy

• Very complex due to age related physiologic changes,

multiple comorbidities and multiple medications.

• Chemotherapy Risk Assessment Scale for High-Age

Patients (CRASH) and the Cancer and Aging Research

Group (CARG) chemotherapy toxicity calculator, have

been developed to assist in the prediction of

chemotherapy toxicity.

• These two calculators, which can be freely accessed

online, use patient, tumor, and geriatric assessment

information to predict the probability of experiencing

grade ≥ 3 toxicities

Age-related physiologic changes in organ function affect pharmacokinetics and pharmacodynamics

Predict toxicity with chemotherapy administration : Cancer and Aging Research Group (CARG)

HurriaA, et al. J Clin Oncol. 2016;34(20):2366-71.

Risk strata versus toxicity percentage for the (A) development and (B) validation cohorts

Chemotherapy Side Effects in Elderly patients

0-3 : Low4-6 : Int Low

7-9 : Int High≥ 9 : High

Chemotherapy regimens are given a numerical value from 0 to 2 based on their potential for chemotherapy toxicities. This is called a Chemotox score. This score is calculated using the MAX2 index.

Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH)

Social issues and quality of life

• Cancer has a substantial impact on quality of life

and on social function at any age.

• Increased social isolation is also a risk factor for

poor tolerance of adverse effects of cancer

treatment.

• Social isolation and low levels of social support

have been associated with higher mortality risk.

Functional status• Needs any assistance on

instrumental activities of daily living (IADLs) or activities of daily living (ADLs).

• IADLs: include shopping, transportation, using the telephone, managing finances, medication management, cooking, cleaning, and laundry

• ADLs (basic self-care skills): include bathing, dressing, grooming, toileting, transferring, feeding, and continence

• Performance status (ECOG or Karnofsky) lacks reliability as a form of functional evaluation in elderly patients

Chavan PP, Kedia SK, Yu X (2017) Physical and Functional Limitations in US Older Cancer Survivors. J Palliat Care Med 7: 312. doi: 10.4172/2165-7386.1000312

Psychological status

• Depression is highly prevalent in older persons

with cancer, with a range of 10%-65% across

different GA studies.

• The distress thermometer (DT) is a single item

that asks patients to rate their distress in the

past week on a 0 (“no distress”) to 10

(“extreme distress”) scale

Nutritional status

• Disease-related malnutrition has been defined as a condition that results from

the activation of systemic inflammation by an underlying disease such as cancer

• Cachexia is a multifactorial wasting syndrome : ongoing loss of skeletal muscle

mass with or without loss of fat mass, and may lead to functional impairment

• Sarcopenia is low lean body mass (mostly muscle); fatigue is common, strength

may be lessened, and physical function limited.

Malnutrition is a significant problem among elderly persons

General population data using Mini Nutritional Assessment (MNA)

Kaiser MJ, et al., J Am GeriatrSoc2010;58(9):1734–8 © 2010, Copyright the Authors. Journal compilation. © 2010, The American Geriatrics Society

Pathophysiology and Metabolism Malnutrition in the presence of a tumor

J. Arends et al. / Clinical Nutrition 36 (2017) 1187e1196

Cachexia as a multi-organ syndrome. In addition to skeletal muscle and adipose tissue, other organs are affected by the cachectic process. (NATURE REVIEWS | CANCER (14) 2014 : 754-62)

ROUND TABLE DISCUSSION 22 8 2019

The strong impact that cancer cachexia on cancer patiens’ outcome and quality of life, suggests that nutritional issues should be taken into consideration from the beginning of natural history of

cancer.

The need for “parallel pathway”

ROUND TABLE DISCUSSION 22 8 2019

Estimating life expectancy

• CGA is a long process, multiple screening tools –shortened forms of CGA, which select patients who need full CGA or not – are available.

• The G8 has been the best studied with highest sensitivity, the choice of screening tools depends on context, and no tool is recommended over another.

• An abnormal G8, VES-13, and Triage Risk Screening Tool have been associated with functional decline and poorer survival. GS provide a rough but objective, view of patients’ underlying health status, and results of the screening tools may unmask underlying impairment.

Screening Tool

Selected Geriatric Screening Tools

The choice of screening tool depends on the clinical resources that are available at a center, the goals of screening, and familiarity with the tool.

Screening Tools –G8• According to the conventional

classification a score: > 14 was defined as normal

≤ 14 was defined as abnormal

Takahashi, M., Takahashi, M., Komine, K. & Yamada, H. The G8 screening tool enhances prognostic value to ECOG performance status in

elderly cancer patients : A retrospective , single institutional study. 1–14 (2017)

A. Scoring SystemElement of Assessment ScoreAge•75–84 1• ≥85 3Self-Reported Health• good or excellent 0• fair or poor 1ADLs/IADLsNeeds helps in:• shopping 1• managing money 1• doing light housework 1• transferring 1•bathing 1ActivitiesNeeds help in:• stooping, crouching, or kneeling 1• lifting or carrying 10 lbs 1• writing of handling small objects 1• reaching or extending arm above shoulder 1• walking 1/4 mile 1• doing heavy housework 1

Screening Tools The Vulnerable Elderly Survey (VES) 13

The Vulnerable Elderly Survey 13 (VES-13) isa 13-item questionnaire .Patients who screen +( a score of 3 or higher) should undergo a complete CGA.

GENERAL APPROACH

Assesment Tree and Treatment Strategy for Elderly

Low-resource setting or if time is limited : Geriatric screening tools + chemotherapy toxicity risk ( CARG or CRASH ).Referral to geriatrician if screened positive for impairment on geriatric screening tools.If a geriatrician is not available, consider other tests on the basis of clinical impression and health areas at riskas indicated by screening tool

Consideration Chemotheraphyin elderly

Consideration Chemotheraphyin elderly

Consideration Chemotheraphyin elderly

Consideration Chemotheraphyin elderly

Diagram depicting age-related effects of respective cancer therapiesCupit-Link MC, et al. ESMO Open 2017;2:e000250.

Examples Consideration

Step 1

Assess frequency of FN associated with the planned chemotherapy regimen

Step 2

Assess factors that increase the frequency/risk of FN

FN risk > 20% FN risk 10 - 20% FN risk <10%

High risk Age > 65 years

Increased risk(level I and II evidence)

Advanced diseaseHistory of prior FNNo antibiotic prophylaxis, no G-CSF use

Other factors(level III and IV evidence)

Poor performance and/or nutritional statusFemale genderHaemoglobin < 12g/dlLiver, renal or cardiovascular disease

Step 3

Define the patient’s overall FN risk for planned chemotherapy regimen

Overall FN risk > 20% Overall FN risk < 20%

Prophylactic G-CSF recommended G-CSF use not indicated

ASCO-EORTC

High Risk Regiment FN (>20%)

Intermediate Risk FN (10-20%)

Moreau et al. In: Ann of Onc 2009 (20) : 513-9

MASCC Risk Stratification in Neutropenia

Scoring System

Characteristic Weight

Burden of illness: no or mild symptoms 5Intermediate 3

No hypotension 5No chronic obstructive pulmonary disease 4Solid tumor or no previous fungal infection 4No dehydration 3Burden of illness: moderate symptoms 3Outpatient status 3Age , 60 years 2

NOTE. Points attributed to the variable “burden of illness” are not cumulative. The maximum theoretical score is therefore 26

MASCC risk score >=21 : low; <21 : high

MASCC=MULTINATIONAL ASSOCIATION OF SUPPORT CARE IN CANCER

Antiemetic Risk Groups

Antiemetic risk groups1-3

Emetic risk group % pts

High emetic risk 90 % or more of patients experience acute emesis

Moderate emetic risk 30 % to 90 % of patients experience acute emesis

Low emetic risk 10 % to 30 % of patients experience acute emesis

Minimal emetic risk fewer than 10 % of patients experience acute emesis

1.Roila F. et al. Ann Oncol. 2016 Sep;27(suppl 5):v119-v133. MASCC/ESMO Antiemetic Guideline 2016 V.1.2. Available at:

http://www.mascc.org/;

2. NCCN: National Comprehensive Cancer Network; NCCN Clinical Practice Guidelines in Oncology; Version 1.2018. Available at: www.nccn.org

3. Hesketh P. J. et al. J Clin Oncol. 2017 Oct 1;35(28):3240-3261. doi: 10.1200/JCO.2017.74.4789. Epub 2017 Jul 31.

EMETOGENIC RISK OF IV AGENTS

EMETOGENIC RISK OF ORAL AGENTS

Care of Elderly (with cancer)

Early Stage Cancers

NATURAL JOURNEY IN CANCER PATIENTS

Conclusion• Most older patients have the same benefits

from cancer treatments as younger patients

and should not be excluded from treatment

based solely on age.

• Comprehensive Geriatric Assessment (CGA) is a

multi-dimensional, interdisciplinary evaluation,

used as a tool to guide future diagnostic / tx

• Collaboration between Oncologist and Geriatrician

to identify the presence of “frail” with validated tools.

• Elderly persons may have different priorities when making decisions – such as maintaining

functionality and independence –that may, to them, be more important than living longer

POWER OF TEAM WORK

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