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 <65 65-69 70+ P

N (total 2390) 1654 491 245 -

% 70 21 9 -

H.R. (OS) - With chemo 0.86 1.01 0.90 .29

H.R. (EFS) 0.82 0.90 0.87 .42

Non-Lung Ca Deaths (%) 12 19 22 <.0001

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?

“Isn’t 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: <11, female: <10) 2.2 (1.1-4.3) 3

Creatinine Clearance (Jelliffe –ideal wt) <34 2.5 (1.2-5.6) 3

1 or more falls in last 6 months 2.3 (1.3-3.9) 3

Hearing impairment (fair or worse) 1.6 (1.0-2.6) 2

Limited in walking 1 block (MOS) 1.8 (1.1-3.1) 2

Assistance required in medication intake 1.4 (0.6-3.1) 1

Decreased social activity (MOS) 1.3 (0.9-2.0) 1

Possible score range: 0-25

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” “High”“Mid”

Chi-square test

p<.0001

Chi-square test

p=0.17

27%

53%

83%

0%

20%

40%

60%

80%

100%

0-5 6-10 11-21

Low

Mid

High

Gra

de

3-5

To

xic

itie

s

Model II score

MD KPS

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