Temporal Trends and Predictors of PerioperativeChemotherapy Use in Elderly Patients With ResectedNonsmall Cell Lung Cancer

Jue Wang, MD1

Yong Fang Kuo, PhD2,3

Jean Freeman, PhD2,3

Avi B. Markowitz, MD2

James S. Goodwin, MD2,3

1 Department of Internal Medicine, Section ofOncology-Hematology, University of NebraskaMedical Center, Omaha, Nebraska.

2 Department of Internal Medicine, University ofTexas Medical Branch, Galveston, Texas.

3 Sealy Center on Aging, University of TexasMedical Branch, Galveston, Texas.

BACKGROUND. The authors assessed patterns of perioperative chemotherapy use

in elderly patients with resected stage I, II, or IIIA nonsmall cell lung cancer

(NSCLC) from 1992 to 2002.

METHODS. By using data from the Surveillance, Epidemiology, and End Results

Program, 11,807 patients were identified who had resected stage I, II, or IIIA

NSCLC between 1992 and 2002 and survived �120 days beyond diagnosis. The

rate of perioperative chemotherapy use was measured by calendar year, and the

association between clinical/demographic characteristics and the receipt of

chemotherapy was examined by using logistic regression.

RESULTS. In total, 957 patients with stage I, II, or IIIA NSCLC (8.1% of the study

population) received perioperative chemotherapy. The proportion of patients

receiving chemotherapy for stage I NSCLC changed little during the study period.

Of 3230 patients with stage II and IIIA NSCLC, 609 patients (18.9%) received

chemotherapy, 423 patients (13%) received chemotherapy combined with radia-

tion. 452 patients (15.6%) received adjuvant chemotherapy, and 66 patients

(2.3%) received neoadjuvant chemotherapy. The use of chemotherapy increased

significantly among patients who were diagnosed after 1994 relative to patients

who were diagnosed in 1992 after controlling for sociodemographic and treat-

ment characteristics (P < .001). There was significantly increased use of new-gen-

eration chemotherapy agents, such as carboplatin and taxanes (P < .001). The

proportion of patients receiving combined-modality therapy also increased signif-

icant (P < .001). Younger age, being married, having advanced-stage tumor or ad-

enocarcinoma, having a later diagnosis year, receiving radiation, and seeing an

oncologist were predictors for the receipt of chemotherapy (P < .001).

CONCLUSIONS. A substantial proportion of Medicare beneficiaries with NSCLC

received perioperative chemotherapy. Specifically designed prospective trials that

focus on older patients are needed. Cancer 2008;112:382–90. � 2007 American

Cancer Society.

KEYWORDS: Medicare beneficiaries, nonsmall cell lung cancer, chemotherapy,Surveillance, Epidemiology, and End Results-Medicare database.

L ung cancer is the most common malignancy and the leading

cause of cancer-related death in the U.S., with 174,470 new diag-

noses and 163,460 deaths in 2006.1 The majority of patients with

lung cancer have nonsmall cell lung cancer (NSCLC).2 The most

effective treatment for stage I, II, and IIIA NSCLC is surgical resec-

tion. Despite surgical resection, from 50% to 60% of patients relapse

and die from their lung cancer.3 Systemic recurrence has been

reported as the most frequent type of failure in patients with

NSCLC,4 and it is postulated that >75% of deaths are related to

Address for reprints: Jue Wang, MD, Departmentof Internal Medicine, Section of Oncology-Hema-tology, University of Nebraska Medical Center,Omaha, NE 68198-7680; Fax: (402) 559-6520;E-mail: juewang@unmc.edu

We acknowledge the efforts of the AppliedResearch Branch, Division of Cancer Preventionand Population Science, National Cancer Institute;the Office of Information Services, and the Officeof Strategic Planning, Health Care FinancingAdministration; Information Management Ser-vices, Inc; and the Surveillance, Epidemiology,and End Results (SEER) Program tumor registriesin the creation of the SEER-Medicare database.Interpretation and reporting of these data aresolely the responsibility of the authors. We alsothank Sarah Toombs Smith, PhD, for editorialassistance.

Received May 15, 2007; revision received July10, 2007; accepted August 15, 2007.

ª 2007 American Cancer SocietyDOI 10.1002/cncr.23181Published online 26 November 2007 in Wiley InterScience (www.interscience.wiley.com).

382

disease relapse, especially distant metastases.5

Because of these recurrences, the 5-year survival rate

of patients with early-stage NSCLC, despite complete

resection, ranges from 45% to 70%.5,6 After other

solid cancers (ie, breast, colon), effective adjuvant

therapy theoretically should include systemic chemo-

therapy. Many attempts have been made in the past

to reduce the risk of relapse and death from lung

cancer by administering adjuvant chemotherapy to

patients after surgical resection.

In 1995, a meta-analysis of postoperative chemo-

therapy in NSCLC by the British Medical Council

indicated a 13% reduction in the hazard of death,

leading to a 5% absolute improvement in survival

5 years after the start of adjuvant cisplatin-based

chemotherapy compared with observation only.7

Although this trend did not reach statistical signifi-

cance, the findings led to multiple national and

international trials that were powered adequately to

find an absolute benefit of 5% at 5 years. Results of

these trials have been reported in the last 5 years.8–16

In 2003, the abstract of the International Adju-

vant Lung Cancer Trial (IALT) study, which was pre-

sented at the Annual Meeting of American Society of

Clinical Oncology, first demonstrated a survival bene-

fit of adjuvant chemotherapy.8 In 2004, chemother-

apy became the standard of care in the U.S., when

the IALT trial demonstrated that, compared with

surgery alone, cisplatin-based adjuvant therapy

improved the 5-year survival rate by 40% to 44.5% in

patients with resected NSCLC.9

To our knowledge, there is little information

regarding the use of adjuvant chemotherapy in el-

derly patients with resectable NSCLC outside clinical

trials. It is known that the elderly are underrepre-

sented in clinical trials.17 For example, the median

age in the IALT trial was 59 years (range, 27–

77 years).8,9 We used data from the population-based

Surveillance, Epidemiology, and End Results (SEER)-

Medicare database to study the trend in receipt of

chemotherapy during the decade from 1992 to 2002

to investigate factors associated with use of perioper-

ative chemotherapy among elderly patients with

resected NSCLC.

MATERIALS AND METHODSData Source and CohortThe study cohort was comprised of patients who

were registered in the National Cancer Institute’s

SEER Program from 1992 to 2002. The SEER Program

collects uniformly reported data from 11 population-

based cancer registries covering approximately 14%

of the U.S. population.18 For each incident cancer,

the SEER registries collect information on patients’

tumor characteristics, demographic characteristics,

and month and year of diagnosis. Since 1991, SEER

data have been merged with Medicare administrative

data by a matching algorithm that has successfully

linked files for >94% of SEER registry patients who

were diagnosed at age �65 years. The Medicare

claims files contain extensive diagnostic, treatment,

and cost data for patients who are covered by Medi-

care. In 1993, these 2 databases were linked.19

We identified 34,511 patients aged >66 years

who were diagnosed with NSCLC between 1992 and

2002 (SEER codes 34.0–34.9 and International Classi-

fication of Diseases for Oncology, Second edition

[ICD-O-2] morphology codes 8010–8040, 8050–8076,

8140, 8250–8260, 8310, 8320, 8323, 8430, 8470–8490,

8550–8573, 8980, and 8981). We excluded patients

without Medicare Part A and Part B coverage during

the year before and the 120 days after diagnosis and

those who were members of a health maintenance

organization (n 5 9709 patients for both exclusions).

Identification of Staging and Surgical ProceduresWe defined resection surgery as wedge resection,

pneumonectomy, or lobectomy that occurred within

4 months after the diagnosis of NSCLC from both

the site-specific surgery code in SEER and Medicare

claims. The IDC ninth revision, clinical modification

(ICD-9-CM) and Current Procedural Terminology

(CPT) codes were taken from outpatient and inpati-

ent billing claims and were used to define the follow-

ing procedures: pneumonectomy (ICD9-CM codes

32.50 and 32.60; CPT codes 32,440, 32,442, and

32,445), lobectomy (ICD9-CM code 32.40; CPT codes

32,480, 32,482, 32,484, and 32,486), and wedge resec-

tion (ICD9-CM codes 32.29 and 32.30; CPT code

32,500). Of 24,802 patients who met the selection

criteria, 11,807 patients underwent resection.

Identification of Chemotherapy and Radiation TreatmentWe used the Health Care Financing Administration’s

Common Procedure Coding System (HCPCS) to

identify patients who received a specific chemothera-

peutic drug within 120 days after their NSCLC diag-

nosis according to their physician claims or their

hospital outpatient claims files. We chose the 120-

day window to differentiate initial adjuvant treatment

from treatment at relapse. In addition, using Level II

HCPCS codes (J9XXX, 96,400–96,549), ICD-9-CM

diagnostic codes (V581, V662, and V672), revenue

codes (0331, 0332, and 0335), and a procedure code

(9925) from physician claims files or outpatient or

admission hospital claims, we searched for evidence

of other chemotherapy delivery. Among patients

Chemotherapy for NSCLC in Elderly/Wang et al. 383

without specific J9XXX chemotherapy HCPCS codes,

these codes were used to capture evidence that an

unspecified chemotherapeutic drug had been given

during the 120 days after diagnosis. We defined

radiation therapy within 120 days after cancer diag-

nosis through the radiation code in SEER and Medi-

care claims.

Identification of Patients Seeing a Medical OncologistWe defined the patient as one who ‘‘saw a medical

oncologist’’ if the patient had a physician claim

within the 4-month period from the month of diag-

nosis and the physician specialty (primary or sec-

ondary) was medical oncology or hematology based

on data from the Centers for Medicare and Medicaid

Services (CMS). The physician claims have a 2-digit

CMS provider specialty code (90 for medical oncolo-

gist, 83 for hematology oncologist) that represents

the specialty reported to the carrier who processed

the claim.18

Definition of Explanatory VariablesOur analysis of use of adjuvant chemotherapy by

year was adjusted by the following patient-level vari-

ables: sex, race, marital status, age at diagnosis,

American Joint Committee on Cancer stage, tumor

grade, histology type, and SEER site. The socioeco-

nomic characteristics of each patient were based on

the percentage of adults with <12 years of education

and the percentage of residents living below the pov-

erty level from census tract data. To assess the preva-

lence of comorbid disease in our cohort, we

calculated the Charlson comorbidity index by identi-

fying billing codes for various conditions during the

year before diagnosis of cancer using the Deyo

implementation of the Charlson score applied to

both inpatient and outpatient claims.19 Hospital

affiliation with a medical school was available from

the SEER-Medicare Hospital file and was categorized

as no, limited, graduate, and major affiliation. The

number of beds at each hospital also was available

from the SEER-Medicare Hospital file.

Statistical AnalysisStatistical analyses were performed using SAS soft-

ware (version 9.13; SAS Inc., Cary, NC). We measured

the proportion of patients with resected NSCLC who

underwent adjuvant chemotherapy in each calendar

year stratified by stage. We performed univariate and

multivariate logistic regression analyses to evaluate

the association between other clinical and demo-

graphic characteristics and adjuvant chemotherapy

use. Covariates included sex, race, age, marital status,

SEER registry, median household income, tumor

stage at diagnosis, tumor grade, and histology.

RESULTSReceipt and Predictors of Perioperative ChemotherapyIn total, 11,807 patients with stage I, II, or IIIA

underwent surgical resection during the study pe-

riod. Among them, 957 patients (8.1% of the study

population) received perioperative chemotherapy.

The proportion of patients with stage I NSCLC

receiving chemotherapy changed little over the study

period (Fig. 1). Next, we focused our attention on the

3230 patients with stage II or IIIA NSCLC who under-

went resection. Table 1 shows the demographic and

clinical characteristics of those 3230 patients and the

percentage in each subgroupwho received chemother-

apy. Overall, 609 patients (18.9%) received peri-

operative chemotherapy. Chemotherapy was delivered

postoperatively to 15.6% of patients and preoperatively

to 2.3% of patients. Combined-modality therapy

(chemotherapy and radiation therapy) were delivered

to 423 patients (13%), and chemotherapy alone was

delivered to 186 patients (5.8%).

Younger patients were more likely than older

patients to receive chemotherapy. For patients ages

66 to 69 years and aged �80 years, chemotherapy

use declined from 25.8% to 9% (P < .0001). Among

patients who had stage II NSCLC, 13.3% received

chemotherapy compared with 24.5% of patients who

had stage IIIA NSCLC (P < .0001). In addition to age

and advanced stage, having an adenocarcinoma his-

tology (P < .0001), having a later diagnosis year

(P < .0001), being married (P < .0001), receiving

radiation (P < .0001), and seeing an oncologist

(P < .0001) were associated with chemotherapy use

FIGURE 1. Time trends in Medicare claims for perioperative chemotherapyby stage during the period from 1992 to 2002. AJCC indicates American

Joint Committee on Cancer.

384 CANCER January 15, 2008 / Volume 112 / Number 2

in univariate analysis (Table 1). Multivariate analyses

generally confirmed the results of the univariate

analyses (Table 2).

In univariate analysis, certain geographic loca-

tions also were associated with a higher rate of adju-

vant chemotherapy use, from a high of 24.2% in

Michigan to a low of 12.5% in Utah (Table 1). In

multivariate analyses, this variable became less sig-

nificant (Table 2).

Receiving care in a nonteaching hospital also

was associated with a higher rate of adjuvant chemo-

therapy use than receiving care in a teaching hospital

in univariate analysis (Table 1). However, this factor

became nonsignificant in multivariate analyses (Table

2). Sex, race, comorbidity, tumor grade, urban resi-

dence, income, education level, and hospital volume

were not associated with use of perioperative chemo-

therapy after adjusting for other variables in this cohort

of elderly patient with resected NSCLC (Table 2).

Trend and Frequency of Perioperative Chemotherapy UseThe proportion of patients who received periopera-

tive chemotherapy and combination therapy changed

TABLE 1Demographic and Clinical Characteristics of Patients With ResectedStage II, IIIA Nonsmall Cell Lung Cancer and the Percentage TreatedWith Adjuvant Chemotherapy During the Period 1992–2002

CharacteristicTotal no.of patients

Adjuvant

chemotherapy

PNo. ofpatients %

Total 3230 609 18.9

Age, y

66–69 938 242 25.8 <.0001

70–74 1148 227 19.8

75–79 787 108 13.7

�80 357 32 9

Sex

Men 1804 349 19.3 .4219

Women 1426 260 18.2

Race

White 2793 534 19.1 .4837

Black 164 33 20.1

Hispanic 99 15 15.2

Other/unknown 174 27 15.5

AJCC stage

II 1624 216 13.3 <.0001

IIIA 1606 393 24.5

Grade

Well differentiated 169 34 20.1 .1625

Moderate differentiated 953 167 17.5

Poorly differentiated 1788 334 18.7

Unknown 320 74 23.1

Histologic type

Squamous cell carcinoma 1025 157 15.3 .0003

Adenocarcinoma 1257 270 21.5

Bronchioalveolar 206 29 14.1

Others 742 153 20.6

SEER region

San Francisco 224 30 13.4 .0011

Connecticut 510 83 16.3

Michigan 574 139 24.2

Hawaii 86 13 15.1

Iowa 398 62 15.6

New Mexico 101 14 13.9

Seattle 362 73 20.2

Utah 56 7 12.5

Georgia 206 50 24.3

San Jose 161 35 21.7

Los Angeles 552 103 18.7

TABLE 1(continued)

Characteristic

Total no.

of patients

Adjuvantchemotherapy

P

No. of

patients %

Census tract education (% of adults with <12 y of education)

<11 694 141 20.3 .2164

11–18 696 137 19.7

18–26 673 124 18.4

�26 696 113 16.2

Census tract poverty level (% living below the poverty line)

<3.5 728 155 21.3 .1170

3.5–6.5 708 117 16.5

6.5–12 666 118 17.7

�12 657 125 19

Comorbidity index

0 2158 429 19.9 .1945

1 719 123 17.1

2 242 38 15.7

�3 111 19 17.1

Married

No 1223 194 15.9 .0007

Yes 2007 415 20.7

Metropolitan area

No 396 75 18.9 .9632

Yes 2834 534 18.8

Teaching hospital*

Major 1127 181 16.1 .0362

Limited/graduate 673 106 15.8

No affiliation 1098 216 19.7

No. of hospital beds*

<350 1231 226 18.4 .2209

�350 1667 277 16.6

Seeing oncologists

Yes 1540 485 31.5 <.0001

No 1690 124 7.3

AJCC indicates American Joint Committee on Cancer; SEER, Surveillance, Epidemiology, and End

Results Program.

* For 9% of patients, surgical procedures could not be found in inpatient claims from 1 month

before to 4 months after lung cancer diagnosis.

(continued)

Chemotherapy for NSCLC in Elderly/Wang et al. 385

significantly during the study period. The use of

chemotherapy increased significantly in patients who

were diagnosed in 1994 (odds ratio [OR], 1.89; 95%

confidence interval [95% CI], 1.41–3.12), 1995 (OR,

2.57; 95% CI, 1.57–4.21), 1996 (OR, 2.84; 95% CI,

1.75–4.63), 1997 (OR, 2.44; 95% CI, 1.48–4.03), 1998

(OR, 4.10; 95% CI, 2.50–6.72), 1999 (OR, 4.43; 95% CI,

2.66–7.38), 2000 (OR, 4.72; 95% CI, 2.85–7.83), 2001

(OR, 3.44; 95% CI, 1.85–6.38), and 2002 (OR, 4.22;

95% CI, 2.11–8.43) relative to the proportion of

patients who were diagnosed in 1992 after control-

ling for sociodemographic and treatment characteris-

tics (Table 2). Chemotherapy use initially increased

in the early 1990s, reached to its peak around 1997/

1998 for stage II and around 1999/2000 for stage IIIA,

and slowly declined afterward. The use of chemo-

therapy in patients with stage IIIA NSCLC increased

again around 2000 (Fig. 1). The time trend for the

proportion of patients who received combined-

modality therapy and chemotherapy alone is shown

in Figure 2.

TABLE 2Multivariate Logistic Regression Analysis of the Factors AssociatedWith the Receipt of Chemotherapy in Patients With Stage II, IIIANonsmall Cell Lung Cancer

Characteristic

Receiving adjuvant chemotherapy:

OR (95% CI)

Model I Model II

Age

Every 5 y 0.67 (0.60–0.75) 0.68 (0.61–0.77)

Sex

Men 1.00 1.00

Women 0.98 (0.80–1.21) 0.95 (0.76–1.18)

Race

White 1.00 1.00

Black 0.87 (0.55–1.37) 1.00 (0.62–1.62)

Hispanic 0.61 (0.33–1.12) 0.58 (0.30–1.09)

Other/unknown 0.69 (0.41–1.17) 0.72 (0.41–1.26)

AJCC stage

II 1.00 1.00

IIIA 1.79 (1.47–2.18) 1.74 (1.42–2.14)

Grade

Well differentiated 1.00 1.00

Moderate differentiated 0.78 (0.50–1.22) 0.91 (0.57–1.46)

Poorly differentiated 0.78 (0.51–1.20) 0.88 (0.56–1.38)

Unknown 0.99 (0.60–1.63) 1.09 (0.64–1.85)

Histologic type

Squamous cell carcinoma 1.00 1.00

Adenocarcinoma 1.57 (1.24–1.99) 1.42 (1.11–1.82)

Bronchioalveolar 0.98 (0.61–1.57) 0.90 (0.55–1.47)

Others 1.40 (1.07–1.84) 1.39 (1.04–1.85)

SEER region

Utah 1.00 1.00

San Francisco 1.47 (0.58–3.73) 2.03 (0.77–5.32)

Connecticut 1.70 (0.71–4.10) 2.31 (0.93–5.71)

Michigan 2.78 (1.17–6.57) 2.95 (1.22–7.15)

Hawaii 1.64 (0.52–5.14) 1.46 (0.44–4.78)

Iowa 1.68 (0.70–4.04) 1.61 (0.65–3.96)

New Mexico 1.44 (0.52–4.01) 1.44 (0.50–4.15)

Seattle 2.47 (1.03–5.95) 2.87 (1.16–7.07)

Georgia 2.88 (1.17–7.12) 2.28 (0.90–5.78)

San Jose 2.83 (1.12–7.15) 3.99 (1.53–10.43)

Los Angeles 2.59 (1.09–6.15) 2.37 (0.98–5.77)

TABLE 2(continued)

Characteristic

Receiving adjuvant chemotherapy:OR (95% CI)

Model I Model II

Year of diagnosis

1992 1.00 1.00

1993 1.43 (0.85–2.14) 1.29 (0.74–2.23)

1994 1.89 (1.14–3.12) 1.84 (1.08–3.11)

1995 2.57 (1.57–4.21) 1.90 (1.13–3.19)

1996 2.84 (1.75–4.63) 2.14 (1.28–3.57)

1997 2.44 (1.48–4.03) 1.77 (1.05–2.99)

1998 4.10 (2.50–6.72) 2.87 (1.71–4.84)

1999 4.43 (2.66–7.38) 3.40 (1.98–5.82)

2000 4.72 (2.85–7.83) 3.57 (2.09–6.09)

2001 3.44 (1.85–6.38) 2.30 (1.20–4.40)

2002 4.22 (2.11–8.43) 2.77 (1.33–5.76)

Comorbidity index

0 1.00 1.00

1 0.85 (0.67–1.08) 0.84 (0.65–1.07)

2 0.77 (0.52–1.14) 0.73 (0.49–1.10)

�3 0.85 (0.50–1.45) 0.81 (0.46–1.42)

Married

No 1.00 1.00

Yes 1.32 (1.07–1.64) 1.29 (1.03–1.61)

Census tract poverty level (% living below the poverty line)

<3.5 1.00 1.00

3.5–6.5 0.83 (0.62–1.11) 0.76 (0.56–1.04)

6.5–12 0.88 (0.65–1.19) 0.81 (0.59–1.12)

�12 1.02 (0.74–1.42) 1.06 (0.75–1.49)

Teaching hospital*

Major 1.00 1.00

Limited/graduate 1.02 (0.76–1.37) 1.06 (0.78–1.45)

No affiliation 1.20 (0.90–1.60) 1.12 (0.83–1.51)

No. of hospital beds*

<350 1.00 1.00

�350 0.92 (0.72–1.17) 0.88 (0.68–1.13)

Radiation

No 1.00 1.00

Yes 2.43 (1.98–2.98) 2.15 (1.74–2.66)

Seeing oncologists

No 1.00

Yes 5.63 (4.46–7.10)

OR indicates odds ratio; 95% CI, 95% confidence interval; AJCC, American Joint Committee on Can-

cer; SEER, Surveillance, Epidemiology, and End Results Program.

* For 9% of patients, surgical procedures could not be found in inpatient claims from 1 month

before to 4 months after lung cancer diagnosis.

(continued)

386 CANCER January 15, 2008 / Volume 112 / Number 2

Type of Chemotherapeutic Agents UsedThe proportion of patients receiving specific che-

motherapeutic agents also changed significantly dur-

ing the study period (Fig. 3), rising from 16.7% to

75% and from 0% to 65.4% for carboplatin and tax-

ane, respectively, and declining from 45% to 3.85%

and from 30% to 7% for etoposide and cisplatin,

respectively.

DISCUSSIONThe decision to use chemotherapy is complex in the

face of uncertain benefit. Surveys reveal that indivi-

dual physicians and types of specialists differ widely

in their beliefs regarding chemotherapy.20,21 Because

of the high risk of recurrence even in patients with

resected NSCLC, clinicians are motivated strongly to

add systemic therapy to surgery either preoperatively

or postoperatively even in patients with early-stage

disease.22,23 Some experts recommended adjuvant

chemotherapy for patients with resected NSCLC in

the absence of definitive data because of the great

risk of distant recurrence.22,23 Some patients prefer

aggressive treatment because of the perceived high

risk of recurrence.24

In a population-based sample of Medicare bene-

ficiaries with resected stage I, II, and IIIA NSCLC

between 1992 and 2002, we observed that 8.1%

of patients received perioperative chemotherapy.

The use of chemotherapy increased significantly in

patients who were diagnosed after 1994 relative to

patients who were diagnosed in 1992 after control-

ling for sociodemographic and treatment characteris-

tics. Our findings are consistent with recent studies

of patterns of care in patients NSCLC conducted in

the U.S. and other countries.25–27 A noteworthy ob-

servation from our study was that chemotherapy use

initially increased and reached to its peak around

1997/1998 for stage II, around 1999/2000 for stage

IIIA, and slowly declined afterward. Increased chem-

otherapy use in the 1990s corresponded temporally

with publication of the British Medical Council’s

meta-analysis, which demonstrated the moderate ef-

ficacy of adjuvant chemotherapy in patients with

resected NSCLC.7 The later decline in the use of

chemotherapy corresponded to the publication of

several randomized trials, which failed to demon-

strate the benefit of adjuvant chemotherapy,16,28 sug-

gesting that community practice is sensitive to new

findings from clinical trials. However, some of those

trials were criticized for being underpowered for

detecting small benefits of adjuvant chemotherapy in

this patient population.29

Chemotherapy use declined dramatically with

increasing age at diagnosis, consistent with previous

findings.30,31 This may be because of physicians’ per-

ception of decreased chemotherapy tolerance or

increased risks of toxicity in elderly patients.30 Older

patients with lung cancer often are compromised by

the surgery itself and have a prolonged recovery time

compared with other cancer operations, such as

mastectomy and colectomy. This may interfere with

the receipt of chemotherapy. Elderly patients also

may be reluctant to trade quality of life for a per-

ceived survival benefit31 and may be more likely to

refuse chemotherapy.32,33

We observed significant associations between

disease stage and the receipt of chemotherapy. For

patients with stage I disease, perioperative chemo-

therapy use was rare. This is in line with a recent

updated analysis of the Cancer and Leukemia Group B

trial, which failed to show a significant improvement

in overall survival in patients with stage IB NSCLC.11

For patients with stage II or IIIA disease, chemotherapy

use was greater and increased substantially by stage.

FIGURE 2. Time trends in Medicare claims for perioperative chemotherapyor combined-modality therapy during the period from 1992 to 2002.

FIGURE 3. Time trends in Medicare claims for specific chemotherapeuticagents for resected stage II, IIIA nonsmall cell lung cancer during the period

from 1992 to 2002.

Chemotherapy for NSCLC in Elderly/Wang et al. 387

This is consistent with the results from clinical trials in

which increasing benefit was reported with advanced

stage.5,6

We observed that married patients received

chemotherapy more often, consistent with findings

in other cancers.34,35 The reasons underlying treat-

ment differences by marital status are unclear but

may include encouragement or support from

patients’ spouses in seeking aggressive treatment36 or

the perception of a higher ‘‘value’’ of life in those

patients with a spouse and dependents.36 Clinicians

also may recommend aggressive therapies more of-

ten to married patients.

Patients who had a medical oncology referral

were more likely to receive adjuvant chemotherapy

(adjusted OR, 5.63; 95% CI, 4.46–7.10). This is in

agreement with other studies, which demonstrated

that the decision to get a medical oncology referral is

a key step in the eventual receipt of chemother-

apy.37–39

From 1992 to 2002, the combination of che-

motherapeutic agents also changed. Our results sug-

gest that carboplatin and paclitaxel came into wide

use as agents for patients with NSCLC in the U.S.

This shift occurred despite lack of definitive data on

the efficacy of these agents in the adjuvant setting.

Tolerance and toxicity of chemotherapy is a major

concern for elderly patient with lung cancer.40 Many

elderly patients with NSCLC have difficulty tolerating

cisplatin-based treatment because of its nephrotoxi-

city, ototoxicity, and neurotoxicity; cisplatin adminis-

tration requires aggressive hydration that may be

contraindicated in elderly patients because of their

comorbidities. Furthermore, cisplatin is also one of

the most emetogenetic drugs. The substitution of

carboplatin in elderly patients is appealing.22

Although carboplatin does not possess activity equiv-

alent to that of cisplatin in all platinum-sensitive

tumors,41–43 carboplatin still may be an alternative to

cisplatin in elderly patients who are poor candidates

for cisplatin. With both activity and tolerability de-

monstrated in the treatment of advanced NSCLC,44,45

the taxanes (paclitaxel and docetaxel) also became a

popular option in the U.S.; with the increased use of

newer chemotherapeutic agents, the use of older

agents (cyclophosphamide, etoposide, and cisplatin)

dropped to a low rate.

The best sequence of surgery and chemotherapy

remains controversial. The majority of patients re-

ceived chemotherapy postoperatively during the

study period. The advantage of adjuvant chemother-

apy includes no delay of tumor resection and precise

pathologic staging. In addition, chemotherapy gener-

ally is more effective in treating minimal-volume dis-

ease compared with grossly apparent disease.29 The

advantages of using neoadjuvant chemotherapy

include earlier commencement of systemic therapy,

allowing for the surgical resection of tumor that may

not have been suitable for surgery at diagnosis. The

potential disadvantages of neoadjuvant therapy

include delaying potentially curative surgery and

increasing postoperative morbidity and mortality.29

The patients in the current analysis were aged

�66 years. To our knowledge, there have been no

trials specifically assessing chemotherapy for NSCLC

in older patients. In a subgroup analysis of the

National Cancer Institute of Canada Clinical Trials

Group study JBR.10, adjuvant vinorelbine and cispla-

tin improved survival in patients aged >65 years with

acceptable toxicity, even though elderly patients

received less chemotherapy.46 The results from a

meta-analysis of NSCLC7 indicated that the benefit

of adjuvant chemotherapy was independent of age.

We examined the association of chemotherapy with

survival from lung cancer in the SEER-Medicare data.

There are major challenges to assessing treat-

ment outcomes in observational data, most of which

relate to selection biases. For example, a selection

bias may be expected for patients with better under-

lying health to be more likely to receive chemother-

apy.47 In our analyses, we used multivariable survival

analyses and also controlled for propensity to treat.

We also stratified the analyses into deaths from can-

cer versus deaths from other causes. In our analyses,

patients with lung cancer who received chemother-

apy experienced an approximate 33% lower mortality

from noncancer causes. This indicates that there

were strong residual selection biases that were not

eliminated after controlling for potential confounders

and propensity to receive chemotherapy. Conse-

quently, the survival analyses lack validity, and we

did not present them.

The current study has several strengths. First, the

nationwide Medicare claims data offer a unique op-

portunity to study the use of adjuvant chemotherapy

in elderly patients with NSCLC. Compared with clini-

cal trials data, which are known to underrepresent el-

derly patients, population studies are more likely to

represent all elderly patients in the real world. Sec-

ond, this large, population-based study conducted in

community-dwelling elderly patients accounted for

14% of the U.S. population. The sample size was

large enough to allow us to draw conclusions regard-

ing patterns of care in a diverse population and to

examine several potentially confounding variables.

Our study had some limitations. First, the study

findings may be applicable only to patients who

were diagnosed with NSCLC at age �66 years who

388 CANCER January 15, 2008 / Volume 112 / Number 2

were not health maintenance organization members

and had both Medicare Part A and Part B coverage.

Chemotherapy use most likely was greater in patients

aged <65 years. Second, administrative databases

have inherent problems with data collection and

coding. Another limitation is that we were unable to

address the role of patients’ performance status in

perioperative chemotherapy use. Although the diag-

noses included in Medicare claims data do allow for

an assessment of comorbidity, previous studies indi-

cate that comorbidity may not be associated with

performance status.48,49

Our results demonstrated a trend toward the

increased use of chemotherapy and combined-mo-

dality therapy in elderly patients with resected

NSCLC during the decade from 1992 to 2002. The

most frequent use of chemotherapeutic agents also

changed. Our analysis assessed practice patterns that

existed before the publication of a large clinical trial

that confirmed the survival benefits of adjuvant

chemotherapy. Consequently, the proportion of

patients receiving chemotherapy today may be

higher. Better understanding of the biology of lung

cancer, the introduction of less toxic regimens, and

better supportive care are likely to impact treatment

patterns further in elderly patients with NSCLC. Our

findings may be used as a baseline against which the

benefit of new therapies can be compared.

REFERENCES1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun

MJ. Cancer statistics, 2006. CA Cancer J Clin. 2006;56:106–

130.

2. Parkin DM. Global cancer statistics in the year 2000. Lancet

Oncol. 2001;2:533–543.

3. Spira A, Ettinger DS. Multidisciplinary management of lung

cancer. N Engl J Med. 2004;350:379–392.

4. Immerman SC, Vanecko RM, Fry WA, Head LR, Shields TW.

Site of recurrence in patients with stages I and II carci-

noma of the lung resected for cure. Ann Thorac Surg.

1981;32:23–27.

5. Rosell R, Felip E, Maestre J, et al. The role of chemotherapy

in early non-small-cell lung cancer management. Lung

Cancer. 2001;34(suppl 3):S63–S74.

6. Mountain CF. Revisions in the International System for Sta-

ging Lung Cancer. Chest. 1997;111:1710–1717.

7. Chemotherapy in non-small cell lung cancer: a meta-anal-

ysis using updated data on individual patients from 52 ran-

domised clinical trials. Non-small Cell Lung Cancer

Collaborative Group. BMJ. 1995;311:899–909.

8. Le Chevalier T, for the IALT Investigators. Results of the

Randomized International Adjuvant Lung Cancer Trial

(IALT) cisplatin-based chemotherapy (CT) versus no CT in

1867 patients with resected non-small cell lung cancer

(NSCLC). Proc Am Soc Clin Oncol. 2003:22. Abstract 6.

9. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon

JP, Vansteenkiste J;International Adjuvant Lung Cancer Trial

Collaborative Group. Cisplatin-based adjuvant chemother-

apy in patients with completely resected non-small-cell

lung cancer. N Engl J Med. 2004;350:351–360.

10. Winton TL, Livingston R, Johnson D, et al. Vinorelbine and

cisplatin vs observation in resected non-small-cell lung

cancer. N Engl J Med. 2005;352:2589–2597.

11. Strauss GM, Herndon JE, MaddausMA, et al. Adjuvant chem-

otherapy in stage IB non-small cell lung cancer (NSCLC):

update of Cancer and Leukemia Group B (CALGB) Protocol

9633 [abstract]. Proc AmSoc Clin Oncol. 2006;24:365.

12. Douillard J, Rosell R, Delena M, et al. ANITA: phase III ad-

juvant vinorelbine (N) and cisplatin (P) versus observation

(OBS) in completely resected (stage I-III) non-small-cell

lung cancer (NSCLC) patients (pts); final results after 70-

month median follow-up [abstract]. Proc Am Soc Clin

Oncol. 2005;24:619.

13. Scagliotti GV, Fossati R, Torri V, et al. Randomized study of

adjuvant chemotherapy for completely resected stage I, II,

or IIIA non-small cell lung cancer. J Natl Cancer Inst.

2003;95:1453–1461.

14. Waller D, Peake MD, Stephens RJ, et al. Chemotherapy for

patients with non-small cell lung cancer: the surgical set-

ting of the Big Lung Trial. Eur J Cardiothorac Surg.

2004;26:173–182.

15. Tada H, Tsuchiya R, Ichinose Y, et al. A randomized trial

comparing adjuvant chemotherapy versus surgery alone

for completely resected pN2 non-small cell lung cancer

(JCOG9304). Lung Cancer. 2004;43:167–173.

16. Keller SM, Adak S, Wagner H, et al. A randomized trial of

postoperative adjuvant therapy in patients with completely

resected stage II or IIIA non-small-cell lung cancer. Eastern

Cooperative Oncology Group. N Engl J Med. 2000;343:

1217–1222.

17. Goodwin JS, Hunt WC, Humble CG, Key CR, Samet JM.

Cancer treatment protocols. Who gets chosen? Arch Intern

Med. 1988;148:2258–2260.

18. Baldwin LM, Adamache W, Klabunde CN, et al. Linking

physician characteristics and Medicare claims data: issues

in data availability, quality, and measurement. Med Care.

2002;40(8 suppl):IV-82–IV-95.

19. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new

method of classifying prognostic comorbidity in longitudi-

nal studies: development and validation. J Chronic Dis.

1987;40:373–383.

20. Mackillop WJ, O’Sullivan B, Ward GK. Non-small cell lung

cancer: how oncologists want to be treated. Int J Radiat

Oncol Biol Phys. 1987;13:929–934.

21. PalmerMJ, O’Sullivan B, Steele R, Mackillop WJ. Controversies

in the management of non-small cell lung cancer: the results

of an expert surrogate study.RadiotherOncol. 1990;19:17–28.

22. Greco FA, Hainsworth JD. Paclitaxel-based therapy in non-

small-cell lung cancer: improved third generation chemo-

therapy. Ann Oncol. 1999;10(suppl 5):S63–S67.

23. Greco FA, Burris HA 3rd, Gray JR, et al. Paclitaxel and car-

boplatin adjuvant therapy alone or with radiotherapy for

resected nonsmall cell lung carcinoma: a feasibility study

of the Minnie Pearl Cancer Research Network. Cancer.

2001;92:2142–2147.

24. Fagerlin A, Zikmund-Fisher BJ, Ubel PA. Cure me even if it

kills me: preferences for invasive cancer treatment. Med

Decis Making. 2005;25:614–619.

25. Langer CJ, Moughan J, Movsas B, et al. Patterns of care

survey (PCS) in lung cancer: how well does current U.S.

practice with chemotherapy in the non-metastatic setting

follow the literature? Lung Cancer. 2005;48:93–102.

Chemotherapy for NSCLC in Elderly/Wang et al. 389

26. Chien CR, Lai MS. Trends in the pattern of care for lung

cancer and their correlation with new clinical evidence:

experiences in a university-affiliated medical center. Am J

Med Qual. 2006;21:408–414.

27. Mahmud SM, Reilly M, Comber H. Patterns of initial man-

agement of lung cancer in the Republic of Ireland: a popu-

lation-based observational study. Lung Cancer. 2003;41:57–

64.

28. Logan DM, Lochrin CA, Darling G, Eady A, Newman TE,

Evans WK. Adjuvant radiotherapy and chemotherapy for

stage II or IIIA non-small-cell lung cancer after complete

resection. Provincial Lung Cancer Disease Site Group. Can-

cer Prev Control. 1997;1:366–378.

29. Choong NW, Vokes EE. Adjuvant and neoadjuvant therapy

for early-stage non-small-cell lung cancer. Clin Lung Can-

cer. 2005;7(suppl 3):S98–S104.

30. Brown JS, Eraut D, Trask C, Davision AG. Age and treat-

ment of lung cancer. Thorax. 1996;51:564–568.

31. de Rijke JM, Schouten LJ, ten Velde GP, et al. Influence of

age, comorbidity and performance status on the choice of

treatment for patients with non-small cell lung cancer;

results of a population-based study. Lung Cancer. 2004;46:

233–245.

32. Earle CC, Venditti LN, Neumann PJ, et al. Who gets chem-

otherapy for metastatic lung cancer? Chest. 2000;117:1239–

1246.

33. Goodwin JS, Hunt WC, Samet JM. Determinants of cancer

therapy in elderly patients. Cancer. 1993;72:594–601.

34. Goodwin JS, Hunt WC, Samet JM. A population-based

study of functional status and social support networks of

elderly patients newly diagnosed with cancer. Arch Intern

Med. 1991;151:366–370.

35. Goodwin JS, Hunt WC, Key CR, Samet JM. The effect of

marital status on stage, treatment, and survival of cancer

patients. JAMA. 1987;258:3125–3130.

36. Stiggelbout AM, Jansen SJ, Otten W, Baas-Thijssen MC, van

Slooten H, van de Velde CJ. How important is the opinion

of significant others to cancer patients’ adjuvant chemo-

therapy decision-making? Support Care Cancer. 2007;15:

319–325.

37. Earle CC, Neumann PJ, Gelber RD, Weinstein MC, Weeks

JC. Impact of referral patterns on the use of chemotherapy

for lung cancer. J Clin Oncol. 2002;20:1786–1792.

38. Luo R, Giordano SH, Freeman JL, Zhang D, Goodwin JS.

Referral to medical oncology: a crucial step in the treat-

ment of older patients with stage III colon cancer. Oncolo-

gist. 2006;11:1025–1033.

39. Luo R, Giordano SH, Zhang DD, Freeman J, Goodwin JS.

The role of the surgeon in whether patients with lymph

node-positive colon cancer see a medical oncologist. Can-

cer. 2007;109:975–982.

40. Gridelli C, Perrone F, Monfardini S. Lung cancer in the el-

derly. Eur J Cancer. 1997;33:2313–2314.

41. Rosell R, Gatzemeier U, Betticher DC, et al. Phase III ran-

domised trial comparing paclitaxel/carboplatin versus

paclitaxel/cisplatin in patients with advanced non-small-

cell lung cancer: a cooperative multinational trial. Ann

Oncol. 2002;13:1539–1549.

42. Lokich J, Anderson N. Carboplatin versus cisplatin in solid

tumors: an analysis of the literature. AnnOncol. 1998;9:13–21.

43. Schiller JH, Harrington D, Belani CP, et al. Comparison of 4

chemotherapy regimens for advanced non-small cell lung

cancer. N Engl J Med. 2002;346:92–98.

44. Simon GR, Bunn PA Jr. Taxanes in the treatment of

advanced (stage III and IV) non-small cell lung cancer

(NSCLC): recent developments. Cancer Invest. 2003;21:87–

104.

45. Ramalingam S, Belani CP. Taxanes for advanced non-small

cell lung cancer. Expert Opin Pharmacother. 2002;3:1693–

1709.

46. Pepe C, Hasan B, Winton TL, et al.; National Cancer Insti-

tute of Canada, Intergroup Study JBR.10. Adjuvant vinorel-

bine and cisplatin in elderly patients: National Cancer

Institute of Canada and Intergroup Study JBR. J Clin Oncol.

2007;25:1553–1561.

47. Giordano SH, Duan Z, Kuo YF, Hortobagyi GN, Goodwin

JS. Use and outcomes of adjuvant chemotherapy in older

women with breast cancer. J Clin Oncol. 2006;24:2750–

2756.

48. Extermann M, Overcash J, Lyman GH, Parr J, Balducci L.

Comorbidity and functional status are independent in

older cancer patients. J Clin Oncol. 1998;16:1582–1587.

49. Repetto L, Venturino A, Vercelli M, et al. Performance sta-

tus and comorbidity in elderly cancer patients compared

with young patients with neoplasia and elderly patients

without neoplastic conditions. Cancer. 1998;82:760–765.

390 CANCER January 15, 2008 / Volume 112 / Number 2