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Adjuvant Chemotherapy in Older Adults with Lung Cancer Ajeet Gajra MD FACP Upstate Cancer Center, SUNY Upstate Medical University Syracuse, NY

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  • Adjuvant Chemotherapy in Older Adults with Lung Cancer

    Ajeet Gajra MD FACP

    Upstate Cancer Center,

    SUNY Upstate Medical University

    Syracuse, NY

  • Introduction: Early Stage NSCLC More older adults safely undergo surgery given improved

    surgical techniques and peri-operative care

    Cisplatin-based adjuvant chemotherapy (ACT) is standard of care in early stage resected NSCLC though no trials specific to older adults

    The evidence is limited to: Sub-group analyses of studies in age-unselected populations Retrospective analyses from population databases

    It is challenging to administer cisplatin to older adults

  • Adjuvant Chemotherapy in Older Adults with NSCLC: Questions

    1. What proportion of older adults receive surgery for stage I-IIIA NSCLC?

    2. What is the representation of elderly in ACT trials?(IALT, JBR, ANITA and CALGB 9633/ LACE)

    Example of database studies: SEER, Ontario, VA

    3. Decision making in the clinic

    4. Is carboplatin as good as cisplatin?

    5. Is some chemotherapy better than none i.e. chemotherapy dose?

    7. Can Geriatric Assessment help?

  • Surgical Treatment of Early Stage NSCLC

    The Impact of Age

  • Surgical Treatment of NSCLC in Older Adults

    How often are older adults offered curative

    surgery compared to younger patients?

    Is the Overall Survival the same amongst

    older adults treated with curative surgery as

    younger patients?

    What about lung cancer specific survival?

  • Surgical Treatment in the Elderly:SEER review of > 14000 adults

    Overalln 14,555

    < 65n 5057

    65-74n 6073

    75n 3425

    p value

    Treated with

    Curative Surgery (%)

    92 86 70 < .0001

    Median Survival

    (mo)

    71 47 28 < .0001

    Adapted from Mery et al. Chest 2005

    Overall Survival Lung cancer Related Survival

  • Early Stage Lung Cancer: Surgical Treatment

    Overall Mortality H.R. Lung Ca related Mortality H.R.

    Age 65-74 years 1.38 1.23

    Age 75 years 1.82 1.56

    Overalln 10,923

    66-69 yn 1408

    70-74 yn 2055

    75-79 yn 1907

    80 yn 1161

    Treated with

    Lobectomy (%)

    60 73 68 61 41

    Recent Results

    Adapted from Shrivani et al. Intl J Rad Onc Biol Phys 2012

    Adapted from Mery et al. Chest 2005

    Thus, older adults are less likely to be offered curative surgery for

    early stage NSCLC.

  • But my surgeon said they got it all so why do I need chemo?

    .but they even got the lymph nodes that the cancer traveled to!

  • Surgeons can cut out everything

    except cause.

    Herbert M. Shelton

  • Adjuvant Chemotherapy in Stage I-III NSCLC

    Data from Prospective Randomized Clinical Trials

  • Outcomes in Clinical Trials

  • Positive Phase III Trials

    ANITA IALT JBR.10 All Cis CALGB9633

    Total patients 840 1867 482 4584 344

    Age 65-69: n

    (%)

    170 (20) 328 (18) 84 (17) 901 (20 ) NA

    Age > 70: n (%) 64 (8) 168 (9) 71 (15) 414 (9) 72 (21)

    Upper Age limit 75 75 None - None

    Stage IB-IIIA I-III IB-II I- IIIA IB

    PS 0-2 0-2 0,1 NA 0, 1

    Cisplatin

    Planned Dose

    (mg/sqm)

    400 300-400 400 150-400 None;

    Cb AUC6

    OS increase at

    5 years (%)

    8.6 4.1 15 5.4 None

  • Lung Adjuvant Cisplatin Evaluation (LACE)

    5 trials - 4,584 patients

    Median follow-up: 5.1 years

    OS HR 0.89 [0.82-0.96], p= .005

    Stage IA HR 1.40 [0.95, 2.06]

    Stage IB HR 0.93 [0.78, 1.10]

    Stage II/III HR 0.83 [0.73, 0.95]

  • As to diseases, make a habit of two things to help, or at least, to do no harm

    Hippocrates

  • Toxicity of Adjuvant Chemotherapy

    Stage N Chemotherapy Grade 3/4 Neutropenia

    Therapy related mortality

    ALPI I-IIIA 1 209 C + Mito/Vds 28% 0.5%

    BLT I III 381 C + Etop/Vinca 40% 3%

    IALT I III 1 867 C + Etop/Vinca 18% (G4) 0.8%

    NCIC-JBR10 IB IIB 482 C + Vrb 73% 0.8%

    ANITA IB III A 840 C + Vrb 85% 2%

    LACE-

    Metaanalysis*

    IB - IIIA 1 190 Cisplatin-based 37% 0.9%

  • Adjuvant Trials in NSCLC: Summary

    No trials specific to older adults to date

    Older adults are under-represented in existing trials

    JBR.10- 15%

    LACE 9%

    Older adults may be at significant risk of chemotherapy toxicity

  • Limitations of Available Data

    Trial Median Age

    (2 arms)

    Pts PS2

    IALT 59 7

    BR.10 61 0

    CALGB 9633 61-62 1

    ANITA 59 3

    US Population 70 34-48%*

    How can the results of trials conducted in younger, healthier patients be applied to older, sicker patients in our clinics?

    What is the evidence specific to older adults?

  • In the absence of PRCTs specific to older adults

    Post-hoc Subset Analyses

    JBR.10

    LACE

    Population Database studies

    SEER

    VA Cancer Registry

  • Subset Analysis by Age: JBR.10Overall Survival

    Age > 65 Age 65

  • JBR.10: Disease Specific Survival

    Age > 65 Age 65

  • JBR.10 Subset Analysis

    Elderly had worse PS

    No significant

    differences in overall

    grade III/IV toxicity

    Elderly patients

    received significantly

    less chemotherapy

    More elderly patients

    refused treatment

    Age

    65

    Age

    >65

    p

    Vb 53 40 .0004

    Cis 72 56 .001

    Chemotherapy Dose Intensity mg/m2/week

  • Pooled analysis of Elderly in Adjuvant Trials

    No differences in severe toxicity rates were observed.

    Older patients received significantly lower first and total

    cisplatin doses, and fewer chemotherapy cycles (P < .0001)

    Older patients derived benefit from ACT but had competing

    causes for mortality

    Age Groups

  • Population Database Studies

    SEER Database

    Veterans Administration Cancer Registry

  • Population Database Analyses: SEER (Age > 65)

    Observational cohort study of 3324 patients with resected stages II-IIIA lung NSCLC

    Only 21% received platinum based ACT

    ACT assoc with improved OS: H.R. 0.78-0.81

    ACT not beneficial age 80: HR 1.32-1.46

    ACT was associated with: Increased odds of SAEs: O.R. 2.0

    Increased likelihood of hospital admission (13 vs. 7%)

    A 3.1% risk of death within 12 weeks

    Wisnivesky et al BMJ 2011

  • Population Study: Veterans Administration

    Williams C, et al, Cancer 2014

    3

    10

    2224

    39 40

    17

    47 46

    0

    10

    20

    30

    40

    50

    60

    70

    80

    90

    100

    IB II III

    % R

    ecei

    vin

    g A

    C

    Stage

    AC use among patients with Stages IB-III

    surgically resected NSCLC, by time period

    2001-20032004-20052006-2008

    (N=1674) (N=2482)

  • The Role of Carboplatin- VA Study

    0

    10

    20

    30

    40

    50

    60

    70

    80

    90

    100

    01 02 03 04 05 06 07 08

    % R

    ecei

    vin

    g p

    lati

    nu

    m-b

    ased

    AC

    Year

    Proportion of patients receiving

    carboplatin vs cisplatin, by year

    CARBO

    CIS

    Ganti AK, et al, ASCO 2013

  • Type of adjuvant chemotherapy by age (VA Study)

    Ganti et al, ASCO 2013

    0

    10

    20

    30

    40

    50

    60

    70

    80

    90

    100

    Carboplatin Cisplatin Non platinum

    < 70 Years

    70 Years

  • VA Study: Impact of Chemotherapy on OS

    Ganti et al, ASCO 2013

  • SEER Database: Type of Chemotherapy

  • Conclusions by authors:

  • Chemotherapy dose

    Even though older adults tolerate and receive lower doses, they still derive benefit

    Need to develop definitive guidelines for chemotherapy dose modification in older adults

  • Decision-making in the Clinic

    Communication is key

    Consider medical, psychological, and social issues: Pain, impaired breathing, or fatigue from thoracotomy. Debility due to smoking-related illness Depression Lung cancer related social stigma Nicotine withdrawal Social support- family, friends, caregivers.

    The elderly, are more susceptible to the toxic adverse effects of chemotherapy.

    More likely to die of something other than lung cancer than a younger patient with similar stage disease

    What are their goals for themselves?

  • Isnt it a bit unnerving that doctors

    call what they do practice?

    George Carlin

  • A GA-based approach

    Can Geriatric Assessment help identify those at greatest risk of

    chemotherapy toxicity?

  • Ideal Tool to Risk Stratify

    Identification of vulnerable older adult

    To stratify by toxicity risk for cytotoxic therapy

    Outcomes depend on not just age but other

    factors:

    Comorbidity,

    Physiologic function,

    Nutrition

    Functional status

    Social support

  • Predictive Model (CARG)

    Risk factors for Gr. 3-5 Toxicity OR (95% CI) Score

    Age 73 yrs 1.8 (1.2-2.7) 2

    GI/GU cancer 2.2 (1.4-3.3) 3

    Standard dose 2.1 (1.3-3.5) 3

    Poly-chemotherapy 1.8 (1.1-2.7) 2

    Hemoglobin (male:

  • Model Performance:Prevalence of Toxicity by Score

    Gra

    de

    3-5

    To

    xic

    itie

    s

    Total ScoreN=39 N=64 N=123 N=36N=50N=161

    0%

    20%

    40%

    60%

    80%

    100%

    0 to 4 5 6 to 8 9 to 11 12 to 13 14

    Low 27%(0 to 5)

    31%21%

    Mid 53%(6 to 11)

    45%

    63%

    High 83%( 12)

    76%

    92%

    ROC: 0.72

  • MD-rated KPS vs. Model II

    50% 51%

    62%

    0%

    20%

    40%

    60%

    80%

    100%

    90-100 80 70

    Low HighMid

    Chi-square test

    p

  • Future Directions

    Use of GA to guide adjuvant treatment. While the fit elderly may be offered the same therapies as

    younger patients, for the vulnerable elderly, alternative treatment strategies need to be explored.

    Study the role of non-cisplatin based regimens in the older adults

    Lower dose and altered schedule of cisplatin

    Care of octagenerarians offers particular challenges. No evidence thus far that ACT offers benefit.

    It is vital to discern the goals and expectations of the individual

  • Conclusions

    Assess interest in adjuvant chemotherapy.

    While absolute improvement in OS is 5.4% based on

    meta-analysis, the magnitude of benefit it is likely lower

    for older adults.

    If the patient is interested and at low risk for

    chemotherapy toxicity consider cisplatin based therapy.

    If the patient has contraindication to cisplatin, consider

    carboplatin based therapy.

    Data do not support the use of adjuvant chemotherapy

    in those over age 80 years.

  • The art of medicine consists of

    amusing the patient while nature cures

    the disease.

    Voltaire

    Thank You