# Chemotherapy Administration during Pelvic  Radiation for Cervical Cancer Patients Aged ≥ 55 Years in  the SEER-Medicare Population

Authors: Charles Kunos; Heidi Gibbons; Fiona Simpkins; Steven Waggoner
Journal: Journal of Oncology
 (2008)

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## Abstract

Our study evaluated whether 1999 National Cancer Institute (NCI) chemoradiation guidelines for cervical cancer impacted treatment of women ≥55 years. We identified 385 women ≥55 years (median, 72 years) diagnosed with stage II-IVA cervical cancer between January, 1998 and December, 2002 in the United States Surveillance, Epidemiology, and End Results (SEER)-Medicare registries. Chemoradiation frequency tables were constructed for age, race, community setting, socioeconomic status, and comorbidity index. Of 385 women, 166 (43%) received chemoradiation as primary treatment. Prior to the 1999 NCI clinical alert, 5/43 (12%) in 1998 and 24/54 (44%) in 1999 received chemoradiation. The chemoradiation proportion was 41% (36/87) in 2000, 48% (51/107) in 2001, and 53% (50/94) in 2002 (trend,P<.01). Women ≥71 years had significantly lower odds of chemoradiation (P=.04). While SEER-Medicare data indicated an increasing trend for chemoradiation after the 1999 NCI clinical alert, chemoradiation was less frequent in elderly women with cervical cancer.


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## Body

## 1. Introduction

Cervical cancer is the second most frequently
diagnosed cancer among women worldwide, with nearly 80 percent arising among
women in developing countries [1]. Despite effective
screening modalities, nearly 40 percent of women in the United States present
with locally advanced stage
II-IVA cervical cancers extending beyond the cervix to invade
vaginal or parametrial, pelvic sidewall, bladder, or rectal tissues [1].In women with locally advanced cervical cancer, three
randomized trials have shown concurrent pelvic radiation and platinum-based
chemotherapy meaningfully contribute to improved disease-free survival [2–4]. These compelling
clinical results prompted the National
Cancer Institute (NCI) to issue a publicized national clinical alert in February,
1999 advising concurrent
platinum-based chemotherapy and radiation for women with locally advanced cervical
cancer [5].According to the United States Surveillance,
Epidemiology, and End-Results (SEER) cancer registries between January, 1998
and December, 2002, 35 percent of annual incident cervical cancer patients
arose in women aged 55 years or older (≥55).
However, women ≥55 years accounted for 55 percent of cervical cancer-related
mortality during this time period. Widening disparity between cervical cancer
incidence and mortality among women ≥55 years questions whether chemoradiation
has been implemented as a national practice pattern in this patient population.
Population-based studies are needed to evaluate the national impact of the 1999
NCI clinical alert advising chemoradiation for locally advanced cervical cancer.
The merged SEER-Medicare dataset
offers a population-based cohort of women ≥55 years longitudinally tracked over the course of
cancer diagnosis, treatment, and follow-up [6]. The utility of SEER-Medicare data to identify chemotherapy administration
has been validated [7]. This study determines the frequency of chemoradiation administration in women ≥55 years diagnosed with cervical cancer immediately before and after
the 1999 NCI clinical alert using the population-based SEER-Medicare dataset. Secondary aims included identifying
factors in women aged ≥55 years
associated with decreased chemotherapy administration during radiation.


## 2. Methods

### 2.1. Data Source.

Data were abstracted from the NCI-sponsored SEER-Medicare
program using the SEER 11-registries plus Alaska 1998–2003 dataset (July, 2006
edition, [8]). Because SEER data contain no
unique personal identifiers and thus are available for public use and research,
approval by an ethics committee or informed consent is not necessary to perform
our analyses. In general, SEER data cover
26 percent of the US population, and therefore, are considered representative
of the whole US population [8]. The SEER program
registries routinely collect data on patient demographics (i.e.,
age, race [Caucasian, African-American, Asian, Hispanic, or other], patient
residence, and socioeconomic status [income per census tract]), primary tumor
site (i.e., cervix), tumor morphology and stage at diagnosis, first course of
treatment, and follow-up for vital status. The SEER program does not record
chemotherapy administration.To identify claims for chemotherapy administration [7], data were abstracted from three merged
SEER-Medicare files: Medicare provider analysis and review (MEDPAR), carrier claims
(NCH), and outpatient claims (OUTSAF). MEDPAR files record all calendar year part
A short stay, long stay, and skilled nursing facility claims. NCH files contain
calendar year Center for Medicare and Medicaid
Services (CMS) physician/supplier part B claims. OUTSAF files list calendar
year claims for hospital outpatient departments, rural health clinics, renal
dialysis facilities, outpatient rehabilitation facilities, comprehensive
outpatient rehabilitation facilities, and community mental health centers [9]. Procedure
codes for chemotherapy administration made within 3 months after diagnosis of
cervical cancer were ascertained [10].


### 2.2. Study Population.

The study population consisted of all female
patients, without previous or synchronous invasive cancers, who were diagnosed
with stage II, III, or IVA cervical cancer between 1998 and 2002 (n=3,601). Stage
I patients (n=1,363) were excluded because they are not reliably substaged
(i.e., IB1 or IB2) in the SEER-Medicare database and the majority underwent
definitive surgery (1,044 of 1,363 [76.6%]). Women with unknown stage (n=357), stage
0 (n=47), and stage IVB
(n=402) cervical cancers were excluded. To ensure that chemotherapy claims
coincided with radiation and are not missed secondary to payment by private
insurance (n=431), included women must have had Medicare parts A and B coverage
for the duration of their cancer care (n=1,001) [7]. For determination of chemoradiation administration, included
women ≥55 years must have undergone radiation (external pelvic and brachytherapy
implant) for primary treatment of their cervical cancer (n=385).


### 2.3. Comorbidity Index.

The Charlson comorbidity index is a summary
measure of 19 comorbid conditions, each assigned a weighting factor according
to its potential for influencing mortality [11]. Charlson comorbidity indices [11] were calculated by abstracting Medicare ICD-9-CM diagnosis
and procedure codes relating to cardiovascular, cerebrovascular, hepatic,
renal, diabetic, connective tissue, or neoplastic disease among inpatient and
outpatient claims made for each woman one year prior to the diagnosis of
cervical cancer [12–14]. Women diagnosed with chronic end-stage renal disease or
listed in the SEER-Medicare dataset as having diagnosis codes for renal
disease, renal failure, or renal insufficiency were considered women as having renal
disease comorbidity [10].


### 2.4. Statistical Analysis.

For this analysis, the day of diagnosis in SEER was
arbitrarily assigned as the 15th of the month. Women were considered to have
received concurrent chemoradiation therapy if there was at least one submitted
billing claim for chemotherapy within a three-month period after diagnosis and
radiation treatment. Chi-square tests for categorical variables and Student'st-tests for continuous variables were
used to compare differences in demographic and tumor variables by chemoradiation
administration. Adjusted odds ratios for chemoradiation were generated using multivariate
logistic regression models sequentially controlling age, race, residence,
socioeconomic status, comorbidity, tumor stage, and histology as defined in
Table 1. A P-value α<0.05
(two-sided) was used to determine statistical significance. Computer programing
and statistical analyses were performed using SAS software version 9.1 (SAS
Institute, Cary, NC).Table 1
Patient demographics (n=385).
Age*73.3±0.37 (55–94 years)StageII213 (55.3%)III163 (42.3%)IVA9 (2.3%)Year of diagnosis199843 (11.2%)199954 (14.0%)200087 (22.6%)2001107 (27.8%)200294 (24.4%)HistologySquamous289 (75.1%)Adenocarcinoma55 (14.3%)Adenosquamous13 (3.4%)Other28 (7.3%)RaceCaucasian237 (61.6%)African-American74 (19.2%)Asian34 (8.8%)Hispanic25 (6.5%)Other15 (3.9%)LocationBig metropolitan (≥250,000)235 (61.0%)Metropolitan (20,000 to 249,999)94 (24.4%)Urban (2,500–19,999, adjacent metropolitan area)17 (4.4%)Less urban (2,500–19,999, not adjacent metro area)32 (8.3%)Rural (<2,500)7 (1.8%)Socioeconomic status (median income per census tract)*$44,540 ±$1,125Comorbidity index, Charlson0274 (71.2%)163 (16.4%)228 (7.3%)3+20 (5.2%)*Mean ±Standard Error of Mean.


## 2.1. Data Source.

Data were abstracted from the NCI-sponsored SEER-Medicare
program using the SEER 11-registries plus Alaska 1998–2003 dataset (July, 2006
edition, [8]). Because SEER data contain no
unique personal identifiers and thus are available for public use and research,
approval by an ethics committee or informed consent is not necessary to perform
our analyses. In general, SEER data cover
26 percent of the US population, and therefore, are considered representative
of the whole US population [8]. The SEER program
registries routinely collect data on patient demographics (i.e.,
age, race [Caucasian, African-American, Asian, Hispanic, or other], patient
residence, and socioeconomic status [income per census tract]), primary tumor
site (i.e., cervix), tumor morphology and stage at diagnosis, first course of
treatment, and follow-up for vital status. The SEER program does not record
chemotherapy administration.To identify claims for chemotherapy administration [7], data were abstracted from three merged
SEER-Medicare files: Medicare provider analysis and review (MEDPAR), carrier claims
(NCH), and outpatient claims (OUTSAF). MEDPAR files record all calendar year part
A short stay, long stay, and skilled nursing facility claims. NCH files contain
calendar year Center for Medicare and Medicaid
Services (CMS) physician/supplier part B claims. OUTSAF files list calendar
year claims for hospital outpatient departments, rural health clinics, renal
dialysis facilities, outpatient rehabilitation facilities, comprehensive
outpatient rehabilitation facilities, and community mental health centers [9]. Procedure
codes for chemotherapy administration made within 3 months after diagnosis of
cervical cancer were ascertained [10].


## 2.2. Study Population.

The study population consisted of all female
patients, without previous or synchronous invasive cancers, who were diagnosed
with stage II, III, or IVA cervical cancer between 1998 and 2002 (n=3,601). Stage
I patients (n=1,363) were excluded because they are not reliably substaged
(i.e., IB1 or IB2) in the SEER-Medicare database and the majority underwent
definitive surgery (1,044 of 1,363 [76.6%]). Women with unknown stage (n=357), stage
0 (n=47), and stage IVB
(n=402) cervical cancers were excluded. To ensure that chemotherapy claims
coincided with radiation and are not missed secondary to payment by private
insurance (n=431), included women must have had Medicare parts A and B coverage
for the duration of their cancer care (n=1,001) [7]. For determination of chemoradiation administration, included
women ≥55 years must have undergone radiation (external pelvic and brachytherapy
implant) for primary treatment of their cervical cancer (n=385).


## 2.3. Comorbidity Index.

The Charlson comorbidity index is a summary
measure of 19 comorbid conditions, each assigned a weighting factor according
to its potential for influencing mortality [11]. Charlson comorbidity indices [11] were calculated by abstracting Medicare ICD-9-CM diagnosis
and procedure codes relating to cardiovascular, cerebrovascular, hepatic,
renal, diabetic, connective tissue, or neoplastic disease among inpatient and
outpatient claims made for each woman one year prior to the diagnosis of
cervical cancer [12–14]. Women diagnosed with chronic end-stage renal disease or
listed in the SEER-Medicare dataset as having diagnosis codes for renal
disease, renal failure, or renal insufficiency were considered women as having renal
disease comorbidity [10].


## 2.4. Statistical Analysis.

For this analysis, the day of diagnosis in SEER was
arbitrarily assigned as the 15th of the month. Women were considered to have
received concurrent chemoradiation therapy if there was at least one submitted
billing claim for chemotherapy within a three-month period after diagnosis and
radiation treatment. Chi-square tests for categorical variables and Student'st-tests for continuous variables were
used to compare differences in demographic and tumor variables by chemoradiation
administration. Adjusted odds ratios for chemoradiation were generated using multivariate
logistic regression models sequentially controlling age, race, residence,
socioeconomic status, comorbidity, tumor stage, and histology as defined in
Table 1. A P-value α<0.05
(two-sided) was used to determine statistical significance. Computer programing
and statistical analyses were performed using SAS software version 9.1 (SAS
Institute, Cary, NC).Table 1
Patient demographics (n=385).
Age*73.3±0.37 (55–94 years)StageII213 (55.3%)III163 (42.3%)IVA9 (2.3%)Year of diagnosis199843 (11.2%)199954 (14.0%)200087 (22.6%)2001107 (27.8%)200294 (24.4%)HistologySquamous289 (75.1%)Adenocarcinoma55 (14.3%)Adenosquamous13 (3.4%)Other28 (7.3%)RaceCaucasian237 (61.6%)African-American74 (19.2%)Asian34 (8.8%)Hispanic25 (6.5%)Other15 (3.9%)LocationBig metropolitan (≥250,000)235 (61.0%)Metropolitan (20,000 to 249,999)94 (24.4%)Urban (2,500–19,999, adjacent metropolitan area)17 (4.4%)Less urban (2,500–19,999, not adjacent metro area)32 (8.3%)Rural (<2,500)7 (1.8%)Socioeconomic status (median income per census tract)*$44,540 ±$1,125Comorbidity index, Charlson0274 (71.2%)163 (16.4%)228 (7.3%)3+20 (5.2%)*Mean ±Standard Error of Mean.


## 3. Results

### 3.1. Patient Demographics.

After exclusions, 385 women aged ≥55 years
underwent pelvic radiation and intracavitary brachytherapy for primary
treatment of cervical cancer between January, 1998 and December, 2002. Median
age was 72 years (range 55–94 years). Table1 presents patient demographic and tumor
variables for the 385 women included in this analysis. The majority of cases
were stage II squamous cell cancers diagnosed in Caucasian women who had minimal comorbidities
and who resided in large metropolitan areas.


### 3.2. Concurrent Chemoradiation.

Among women aged ≥55 years identified in the SEER-Medicare dataset, 166 of 385
(43%) received chemoradiation. Cisplatin chemotherapy was specifically claimed
in 129 of 166 (78%) women. Before the 1999 NCI clinical alert, 30 percent of
women aged ≥55 years (29 of 97 women) identified in the SEER-Medicare registry received at least one
chemotherapy dose during radiation (see Table2). In the year 2000 and after
the 1999 NCI clinical alert, the proportion receiving chemoradiation was 41
percent of women aged ≥55 years (36 of 87 women). Afterwards, the
proportion receiving chemoradiation was greater than 50 percent (see Table 2).
Between 1998 and 2002, a significant increasing trend for chemoradiation administration
was observed among women aged ≥55 years registered in the SEER-Medicare dataset (P<.01). The
median number of chemotherapy claims during radiation was four (mean 4.2,
standard deviation 1.9, Table 2). Among women treated with chemoradiation, 78
of 166 (47%) received five or more cycles of chemotherapy. Table 3 compares variables
in univariate analyses evaluating patients who received concurrent chemotherapy
and radiation compared to those who received radiation alone. The mean age of
women receiving chemoradiation was significantly younger (Table 3, P<.001). The proportion of women residing
in urban, less urban, and rural areas receiving chemoradiation was
significantly higher than receiving radiation alone (20% versus 10%, P=.03). Chemotherapy
use during radiation was not associated with race, socioeconomic
status, tumor histology or stage, or comorbidity index. The proportion of women
diagnosed with renal disease comorbidity was similar among chemoradiation (18/166, 11%)
and radiation alone (21/219, 10%) treatment groups (P=.73).Table 2
Concurrent chemoradiation by year of treatment and and by number of claims
(cycles) within ±3 months of radiation.
Year*# Chemoradiation/Total # Women19985/43 (11.6%)199924/54 (44.4%)200036/87 (41.4%)200151/107 (47.7%)200250/94 (53.2%)CyclesTotal # Women1202 to 4685 to 6697 or more9*MH Chi-square = 15.83; P<.001 for trend.Table 3
Univariate comparison of patients who received chemoradiation treatment versus those who received radiation treatment alone.
Chemoradiation (n=166)RT alone (n=219)P value*Age71.7±0.4874.4±0.53<.001Stage.393II89 (53.6%)124 (56.6%)III74 (44.6%)89 (40.6%)IVA3 (1.8%)6 (2.7%)Histology.628Squamous129 (77.7%)160 (73.1%)Adenocarcinoma23 (13.8%)32 (14.6%)Adenosquamous4 (2.4%)9 (4.1%)Other10 (6.0%)18 (8.2%)Race.445Caucasian97 (58.4%)140 (63.9%)African-American34 (20.5%)40 (18.3%)Hispanic6 (3.6%)9 (4.1%)Asian14 (8.4%)20 (9.1%)Other15 (9.0%)10 (4.6%)Location.028Big metropolitan (≥250,000)88 (53.0%)147 (67.1%)Metropolitan (20,000  to 249,999)44 (26.5%)50 (22.8%)Urban (2,500–19,999, adjacent metro area)11 (6.6%)6 (2.7%)Less urban (2,500–19,999, not adjacent metro area)19 (11.4%)13 (5.9%)Rural (<2,500)4 (2.4%)3 (1.4%)Socioeconomic status (median income per census tract)$44,308  ± $1,512$44,715  ± $1,614.858Comorbidity index, Charlson.6410116 (69.9%)158 (72.1%)131 (18.7%)32 (14.6%)210 (6.0%)18 (8.2%)3+9 (5.4%)11 (5.0%)*Student's t-test or chi-square for frequency data.Table4 presents multivariate analyses for odds
of receiving concurrent chemoradiation adjusting for patient demographic and tumor
differences. Women aged 71 years or older had a significantly decreased odds of
undergoing chemoradiation treatment as compared to women aged 55 to 70 years (P=.04).
For women 71 years or older, the proportion of women with renal disease who
received chemoradiation (9 of 95, 10%) and radiation alone (7 of 138, 5%) was
similar (P=.19). In multivariate analyses, women residing
in urban, less urban, and rural areas had significantly increased odds of
undergoing chemoradiation treatment as compared to women residing in
metropolitan areas (P<.001). The
proportion of women 71 years or older in big metropolitan, metropolitan, and
urban/less urban/rural areas was 42 percent (99 of 235), 35 percent (33 of 61),
and 36 percent (20 of 56), respectively (P=.41). Race,
socioeconomic status, comorbidity index, and tumor histology or stage were not
significant confounders for chemoradiation treatment.Table 4
Multivariate analysis for chemoradiation administration within 3 months after diagnosis in women with stages II-IVA cervical cancer from 1998 to 2002.
Patient  and tumor characteristicsnumber of cases (n=385)Odds  ratio* of chemoradiation95% Confidence intervalAge55–70 years152 (39.5%)1—>71 years233 (60.5%)0.620.42–0.94StageII213 (55.3%)1—III163 (42.3%)0.960.63–1.47IVA9 (2.3%)0.590.14–2.50HistologySquamous289 (75.1%)1—Adenocarcinoma55 (14.3%)0.840.45–1.57Adenosquamous13 (3.4%)0.530.16–1.78Other28 (7.3%)0.610.26–1.43RaceCaucasian237 (61.6%)1—African-American74 (19.2%)1.220.72–2.06Other74 (19.2%)1.280.75–2.18ResidenceBig Metropolitan area235 (61.0%)1—Metropolitan area94 (24.4%)1.480.89–2.45Urban, less urban, rural56 (14.5%)2.631.41–4.91Socioeconomic status, median income<30,70094 (24.4%)1—30,701–39,42593 (24.2%)0.770.47–1.2839,426–53,707102 (26.5%)0.720.43–1.20>53,70896 (24.9%)1.180.70–1.98Comorbidity index, Charlson0274 (71.2%)1—163 (16.4%)1.090.61–1.94228 (7.3%)0.720.31–1.653+20 (5.2%)0.80.31–2.10*Adjusted for variables listed in the tables.


## 3.1. Patient Demographics.

After exclusions, 385 women aged ≥55 years
underwent pelvic radiation and intracavitary brachytherapy for primary
treatment of cervical cancer between January, 1998 and December, 2002. Median
age was 72 years (range 55–94 years). Table1 presents patient demographic and tumor
variables for the 385 women included in this analysis. The majority of cases
were stage II squamous cell cancers diagnosed in Caucasian women who had minimal comorbidities
and who resided in large metropolitan areas.


## 3.2. Concurrent Chemoradiation.

Among women aged ≥55 years identified in the SEER-Medicare dataset, 166 of 385
(43%) received chemoradiation. Cisplatin chemotherapy was specifically claimed
in 129 of 166 (78%) women. Before the 1999 NCI clinical alert, 30 percent of
women aged ≥55 years (29 of 97 women) identified in the SEER-Medicare registry received at least one
chemotherapy dose during radiation (see Table2). In the year 2000 and after
the 1999 NCI clinical alert, the proportion receiving chemoradiation was 41
percent of women aged ≥55 years (36 of 87 women). Afterwards, the
proportion receiving chemoradiation was greater than 50 percent (see Table 2).
Between 1998 and 2002, a significant increasing trend for chemoradiation administration
was observed among women aged ≥55 years registered in the SEER-Medicare dataset (P<.01). The
median number of chemotherapy claims during radiation was four (mean 4.2,
standard deviation 1.9, Table 2). Among women treated with chemoradiation, 78
of 166 (47%) received five or more cycles of chemotherapy. Table 3 compares variables
in univariate analyses evaluating patients who received concurrent chemotherapy
and radiation compared to those who received radiation alone. The mean age of
women receiving chemoradiation was significantly younger (Table 3, P<.001). The proportion of women residing
in urban, less urban, and rural areas receiving chemoradiation was
significantly higher than receiving radiation alone (20% versus 10%, P=.03). Chemotherapy
use during radiation was not associated with race, socioeconomic
status, tumor histology or stage, or comorbidity index. The proportion of women
diagnosed with renal disease comorbidity was similar among chemoradiation (18/166, 11%)
and radiation alone (21/219, 10%) treatment groups (P=.73).Table 2
Concurrent chemoradiation by year of treatment and and by number of claims
(cycles) within ±3 months of radiation.
Year*# Chemoradiation/Total # Women19985/43 (11.6%)199924/54 (44.4%)200036/87 (41.4%)200151/107 (47.7%)200250/94 (53.2%)CyclesTotal # Women1202 to 4685 to 6697 or more9*MH Chi-square = 15.83; P<.001 for trend.Table 3
Univariate comparison of patients who received chemoradiation treatment versus those who received radiation treatment alone.
Chemoradiation (n=166)RT alone (n=219)P value*Age71.7±0.4874.4±0.53<.001Stage.393II89 (53.6%)124 (56.6%)III74 (44.6%)89 (40.6%)IVA3 (1.8%)6 (2.7%)Histology.628Squamous129 (77.7%)160 (73.1%)Adenocarcinoma23 (13.8%)32 (14.6%)Adenosquamous4 (2.4%)9 (4.1%)Other10 (6.0%)18 (8.2%)Race.445Caucasian97 (58.4%)140 (63.9%)African-American34 (20.5%)40 (18.3%)Hispanic6 (3.6%)9 (4.1%)Asian14 (8.4%)20 (9.1%)Other15 (9.0%)10 (4.6%)Location.028Big metropolitan (≥250,000)88 (53.0%)147 (67.1%)Metropolitan (20,000  to 249,999)44 (26.5%)50 (22.8%)Urban (2,500–19,999, adjacent metro area)11 (6.6%)6 (2.7%)Less urban (2,500–19,999, not adjacent metro area)19 (11.4%)13 (5.9%)Rural (<2,500)4 (2.4%)3 (1.4%)Socioeconomic status (median income per census tract)$44,308  ± $1,512$44,715  ± $1,614.858Comorbidity index, Charlson.6410116 (69.9%)158 (72.1%)131 (18.7%)32 (14.6%)210 (6.0%)18 (8.2%)3+9 (5.4%)11 (5.0%)*Student's t-test or chi-square for frequency data.Table4 presents multivariate analyses for odds
of receiving concurrent chemoradiation adjusting for patient demographic and tumor
differences. Women aged 71 years or older had a significantly decreased odds of
undergoing chemoradiation treatment as compared to women aged 55 to 70 years (P=.04).
For women 71 years or older, the proportion of women with renal disease who
received chemoradiation (9 of 95, 10%) and radiation alone (7 of 138, 5%) was
similar (P=.19). In multivariate analyses, women residing
in urban, less urban, and rural areas had significantly increased odds of
undergoing chemoradiation treatment as compared to women residing in
metropolitan areas (P<.001). The
proportion of women 71 years or older in big metropolitan, metropolitan, and
urban/less urban/rural areas was 42 percent (99 of 235), 35 percent (33 of 61),
and 36 percent (20 of 56), respectively (P=.41). Race,
socioeconomic status, comorbidity index, and tumor histology or stage were not
significant confounders for chemoradiation treatment.Table 4
Multivariate analysis for chemoradiation administration within 3 months after diagnosis in women with stages II-IVA cervical cancer from 1998 to 2002.
Patient  and tumor characteristicsnumber of cases (n=385)Odds  ratio* of chemoradiation95% Confidence intervalAge55–70 years152 (39.5%)1—>71 years233 (60.5%)0.620.42–0.94StageII213 (55.3%)1—III163 (42.3%)0.960.63–1.47IVA9 (2.3%)0.590.14–2.50HistologySquamous289 (75.1%)1—Adenocarcinoma55 (14.3%)0.840.45–1.57Adenosquamous13 (3.4%)0.530.16–1.78Other28 (7.3%)0.610.26–1.43RaceCaucasian237 (61.6%)1—African-American74 (19.2%)1.220.72–2.06Other74 (19.2%)1.280.75–2.18ResidenceBig Metropolitan area235 (61.0%)1—Metropolitan area94 (24.4%)1.480.89–2.45Urban, less urban, rural56 (14.5%)2.631.41–4.91Socioeconomic status, median income<30,70094 (24.4%)1—30,701–39,42593 (24.2%)0.770.47–1.2839,426–53,707102 (26.5%)0.720.43–1.20>53,70896 (24.9%)1.180.70–1.98Comorbidity index, Charlson0274 (71.2%)1—163 (16.4%)1.090.61–1.94228 (7.3%)0.720.31–1.653+20 (5.2%)0.80.31–2.10*Adjusted for variables listed in the tables.


## 4. Discussion

The present data from the US population-based SEER-Medicare database indicate that the 1999 NCI clinical
alert for platinum-based chemoradiation has had an impact on chemoradiation use
for locally advanced stage
II-IVA cervical cancers diagnosed in women ≥55 years. Eighteen
months before the NCI clinical alert, less than 30 percent of women ≥55
years received chemoradiation.
However, within 18 months of the NCI clinical alert, the proportion of women ≥55
years with locally advanced cervical cancer receiving chemoradiation
significantly rose to 50 percent. Since chemoradiation use has steadily risen
through the last SEER-Medicare cohort available for study (i.e., 2002), the
recommendation has been followed but a substantial fraction of women ≥55 years
still did not receive concurrent chemoradiation in 2002 three years after the
NCI clinical alert.Age is a risk factor for pelvic and distant relapse as
well as death after treatment for cervical cancer. In multivariate analyses
conducted by the Gynecologic Oncology Group evaluating radiation and chemotherapeutic
radiation sensitizers [15], older patient age at diagnosis significantly
conferred less cervical cancer recurrence or death. These findings led to the
controversial suggestion that younger patient age at diagnosis was associated
with high mortality; and yet, the inferior mortality outcomes attributable to
younger patient age have vanished in the era of platinum-based chemoradiation
as no contemporary Gynecologic Oncology Group or cooperative group study
identifies age as a significant confounder upon survival outcomes [2–4]. While platinum-based chemoradiation appears to have
decreased mortality in younger women, it remains unknown whether older women
are deriving full survival benefit from chemoradiation treatment. Perceived and
actual hematological, renal, gastrointestinal, and neural toxicities of platinum
chemotherapy perhaps influence physicians to not consider coadministration of
chemotherapy during radiation in older women. These data indicate that
significantly fewer women older than 71 years who have locally advanced
cervical cancer receive chemoradiation—even though the
survival of these older patients who receive chemoradiation approaches that of
younger patients who undergo chemoradiation treatment [2–4, 16]. This study is not the first to
identify this age trend.In a pattern of care study [17], it was reported that 63 percent
of all women captured in this survey underwent concurrent chemotherapy and radiation in 1999, as
compared to 26 percent in 1998. Twenty-five percent of women 60 years or older
received chemoradiation as compared to 48 percent among women aged 40 years or
less (P=.02) [17]. In an earlier analysis of the SEER-Medicare database
controlling for racial and socioeconomic factors, increasing age was strongly
associated (P<.0001) with
receiving neither chemoradiation nor radiation treatment for cervical cancer [18]. However, both studies capture only those women treated
through 1999, study periods ending when the 1999 NCI clinical alert were released. Thus, a true assessment of the
impact of the NCI clinical alert is essentially unknown.The present data are the
first assessment of chemoradiation treatment after the 1999 NCI clinical alert for
chemoradiation treatment of locally advanced cervical cancer in women aged ≥55 years.
The US SEER-Medicare dataset is an NCI-sponsored cancer registry that reflects
a wide range of race/ethnic, demographic, and socioeconomic diversity and that
avails itself to cancer health service delivery analyses in women aged ≥55
years. The data presented herein reflect
prospectively collected but not randomized practice and usage of
chemoradiation. These data measure the impact of randomized clinical trials in
cervical cancer, as popularized by the national 1999 NCI clinical alert, on
clinical chemoradiation practices for the treatment of cervical cancer. Thus, these
data conveniently sample a small proportion of the total number of women with
locally advanced cervical cancer treated in the US
each year. Consequently, analyses
on these nonrandomly treated women can only be considered as an interpretive
guide for changing trends in chemoradiation usage for locally advanced cervical
cancer. Indeed, the present data suggest that women ≥55 years with locally advanced cervical cancer are
increasingly likely to receive chemoradiation. Data also suggest that
chemoradiation use has significantly lagged behind in women 71 years or
older compared to women 55 to 70 years. Perhaps physicians applied the NCI recommendations to
some groups of women more consistently than others.In this study of the
SEER-Medicare population, age emerges as an important factor influencing
whether patients receive chemoradiation. While the NCI clinical alert has
strongly endorsed use of chemoradiation for all patients with locally advanced
cervical cancer, it is worth considering the causes of disparity in
chemoradiation use among younger and older women. The exact regimen of
chemotherapy administration, patient-specific chemotherapy dosage, and adverse
effects of treatment cannot be abstracted reliably from the SEER-Medicare
database. While reluctance of older patients to receive chemotherapy due to
perceived toxicities, tolerability, or an apathetic attitude often are
difficult to enumerate, physical limitations such as comorbid disease may be
more reliably estimated in a population-based database that records these
factors. In the current study, a high Charlson comorbidity index was not
associated with more infrequent chemoradiation treatment. Comorbid renal
disease, as identified by diagnosis codes for renal disease, renal failure, or
renal insufficiency, also was not associated with infrequent chemoradiation
treatment.Demographic variables of
race, socioeconomic status, and tumor variables of histology and clinical stage
were not associated with more infrequent chemoradiation treatment, a reassuring
finding of this study. However, a significant disparity in the proportion of
women ≥55 years in metropolitan and nonmetropolitan residencies was observed
in this study. Only 40 percent of the women residing in metropolitan areas as
compared to 60 percent of women residing in urban, less urban, and rural residencies
received chemoradiation during the entire 1998 to 2002 period under study (P=.03). Disparity in age cohorts among
residences does not account for this difference as the proportion of women aged
71 years or older among big metropolitan, metropolitan, and urban/less
urban/rural areas is similar (P=.41). The issues surrounding the more frequent use of radiation alone in metropolitan
residencies are difficult to abstract but perhaps are related to unreported
comorbid disease, patient refusal, and perceived toxicities/tolerability of the
combined treatment regimen. The data cannot exclude the possibility that
healthcare-system-related factors, such as access to care or differences in
referrals for chemotherapy consultation, could explain the findings of the
current study. The reasons why older women do not receive chemotherapy remain
elusive, and perhaps, future population-based studies may provide more
meaningful insight.Our study is not without
interpretative criticism. The population
covered by SEER program representing 26 percent of the general population compares
favorably to US census population data with regard to measures of poverty and
education, but has a higher
proportion of urban and foreign-born persons in the registry as compared
to the general US population. Census population estimates for the year 2000 [19] suggest that 73 percent of women aged ≥55 years live in metropolitan areas as compared to
85 percent registered in the SEER-Medicare dataset. There may also be
differences in the underlying racial distribution of the SEER-Medicare dataset
compared to the US population comprising new incident cases of cervical cancer [20]. This
SEER-Medicare dataset used to analyze the impact of the NCI clinical alert is limited to women aged ≥55 years that must have been enrolled in Medicare
Part A and B coverage for the duration of their cervical cancer treatment. Thus,
by limiting the dataset by an age criterion of ≥55 years, this analysis does not capture
chemoradiation treatment in young women who comprise the majority of new incident cases in
the US. Moreover, identification of chemoradiation in the SEER-Medicare population
follows the Centers for Medicare and Medicaid Services’ coverage policies
relating to chemotherapy administration. Current Centers for Medicare and
Medicaid Services policy permits fee-for-service reimbursement for intravenous
chemotherapy [7], including cisplatin chemotherapy administration. As
Medicare billing claims for chemotherapy administration are often coded within
six months of initial cancer diagnosis [7], this analysis’ three-month
timeframe for coincident chemotherapy and radiation treatment in the
SEER-Medicare dataset is reasonable. Women simultaneously enrolled by a private
insurer were excluded as chemotherapy administration may have been paid by this
entity rather than Medicare, and thus falsely skewing results toward treatment
with radiation alone. Another limitation is that comorbid disease documentation
in a population-based dataset is derived from claims-based administrative coding,
which may generally be less complete than data obtained from direct medical
chart review. Interpretative criticism also concerns the timeliness of the
SEER-Medicare cohort under study, as these patients may be poorly reflective of
modern chemoradiation practice; and yet, SEER data and Medicare data are
infrequently merged. As such, the 1998–2002 SEER-Medicare
patient population represents the most contemporary cohort in which to study
concurrent SEER radiation and Medicare chemotherapy recorded administration.The current analysis of 1998–2002 SEER-Medicare
data indicates increased utilization of chemoradiation treatment since the 1999
NCI clinical alert strongly
advocating for concurrent chemotherapy and radiation for locally advanced
cervical cancer. Older age has been considered a barrier to chemotherapy. Between
1998 and 2002, the population-based SEER-Medicare registry identifies 43
percent of the women ≥55 years with locally advanced cervical
cancer receiving chemoradiation despite published guidelines to the contrary. While
our study is provocative, it is unable to definitively assess current national
chemoradiation practice patterns. To further corroborate our findings, it would
be interesting to analyze NCI-sponsored
clinical trials enrolling women aged ≥55 years to determine if the number of chemotherapy cycles
given during radiation impacts clinical outcome. Further analysis of national
practice patterns from future US Surveillance, Epidemiology, and End-Results-Medicare
mergers is warranted to identify contributing factors leading to the disparity
in incidence and mortality among women ≥55 years with locally advanced cervical
cancer.



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*Source: 931532-2008-08-27.xml*