Original Study
Geographic Variation and Sociodemographic Disparity in the Use of Oxaliplatin-Containing Chemotherapy in Patients With Stage III Colon Cancer Janki M. Panchal, David R. Lairson, Wenyaw Chan, Xianglin L. Du Abstract This study examined the geographic variation and sociodemographic disparities in the use of oxaliplatin chemotherapy, which has not been widely studied in the past. Our results suggest that chemotherapy use varies across geographic regions. Patterns of use that relate specifically to oxaliplatin-containing chemotherapy can inform providers and researchers how newer regimens are being used as standard chemotherapy in a real-world setting. Background: According to the National Cancer Comprehensive Network (NCCN), oxaliplatin with 5-fluorouracil and leucovorin (5-FU/LV) is the recommended adjuvant chemotherapy for patients with resected stage III colon cancer. Age and race are considered strong predictors of chemotherapy receipt, whereas geographic disparity has received minimal attention. The purpose of this study was to examine geographic variation and sociodemographic disparity in the use of chemotherapy in patients with stage III colon cancer, focusing specifically on oxaliplatin. Methods: A retrospective cohort of 4106 Medicare patients was identified from the Surveillance, Epidemiology and End Results (SEER)/Medicare linked database. Descriptive statistics show how oxaliplatin-containing chemotherapy was used in various geographic regions among different age and racial groups. Multiple logistic regression analysis was performed to examine the relationship between receipt of oxaliplatin-containing chemotherapy and geographic region while adjusting for other sociodemographic and tumor characteristics. Results: Only 49% of the patients with stage III disease received adjuvant chemotherapy within 3 to 6 months of colon cancer–specific surgery. Patients aged 66 to 70 years were 78% more likely to receive chemotherapy than were those aged 80 years and older (P ⬍ .001). Patients in less urban regions were approximately 42% less likely to receive oxaliplatin chemotherapy than those residing in a big metro region (odds ratio [OR], 0.58; P ⫽ .008). Conclusion: Chemotherapy use varies across geographic regions, especially for new chemotherapy drugs like oxaliplatin. Further research is needed to identify the causes of this geographic disparity and ways to provide high-quality cancer care to all patients according to their preferences and needs. Clinical Colorectal Cancer, Vol. 12, No. 2, 113-21 © 2013 Elsevier Inc. All rights reserved. Keywords: Age disparity, Chemotherapy, Colon cancer, Geographic disparity, Oxaliplatin
Introduction Adjuvant chemotherapy has been the standard of care for patients with stage III colon cancer since 1990. Until the late 1990s, the standard chemotherapy regimen was a combination of 5-fluorouracil
Division of Management, Policy, and Community Health, The University of Texas School of Public Health, Houston, TX Submitted: Jul 26, 2012; Revised: Sep 27, 2012; Accepted: Sep 28, 2012; Epub: Nov 6, 2012 Address for correspondence: Janki M. Panchal, PhD, Division of Management, Policy and Community Health, The University of Texas School of Public Health, 1200 Herman Pressler, Reuel A. Stallones Bldg., E307, Houston, TX 77030 E-mail contact:
[email protected]
1533-0028/$ - see frontmatter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clcc.2012.09.007
and leucovorin (5-FU/LV).1-3 The US Food and Drug Administration (FDA) approved a few new chemotherapeutic agents for use as adjuvant chemotherapy in resected colon cancer in the past decade. These agents varied in their efficacy and survival benefits. One such chemotherapeutic drug among the newly approved drugs is oxaliplatin. In the European MOSAIC trial and a phase III trial of the National Surgical Adjuvant Breast and Bowel Project (NSABP), oxaliplatin and 5-FU/LV combination therapy (5-fluorouracil, leucovorin [folinic acid], oxaliplatin [FOLFOX]) have shown significant improvement in disease-free survival rates at 3 to 5 years when compared with 5-FU/LV therapy.4-6 In 2004, soon after oxaliplatin received US FDA approval for use in adjuvant settings, the National Comprehensive Cancer Network (NCCN) panel recommended the
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Geographic Disparity in Chemotherapy Use combination of oxaliplatin and 5-FU/LV for standard adjuvant chemotherapy for stage III resected colon cancer.7,8 However some patient subgroups do not receive the recommended chemotherapy treatment.9 As a result, there have been unequal burdens of colon cancer, primarily in older patients, patients from certain minority racial/ethnic groups, patients with lower socioeconomic status (SES), and patients from certain geographic locations.10-13 Little is known about nonmedical factors that determine the variation in chemotherapy use in patients with stage III colon cancer. Age and race are considered strong predictors of chemotherapy receipt,11,14,15 whereas geographic disparity has received minimal attention despite the fact that quality of and access to cancer care varies widely across the nation.13,16,17 Data from the US Working Group on Cancer Statistics reported that the incidence and mortality rate associated with colon cancer treatment show a wide geographic variation, yet geographic disparity in colon cancer care is not well studied.18,19 Existing studies on geographic disparity have shown that the odds of receiving adjuvant chemotherapy for urban and suburban patients with stage III colon cancer are higher than for patients from rural regions; even after adjusting for sociodemographic variables, geographic disparity in the use of chemotherapy remained.13,16,17 However newly approved oxaliplatin-containing chemotherapy was not studied. The present study examined geographic variation and sociodemographic disparities in the use of oxaliplatin-containing adjuvant chemotherapy in patients with stage III colon cancer in 18 areas of the United States, which accounted for 26% of the total US population.
Patients and Methods Data Source We performed a retrospective cohort study of geographic disparities associated with the use of oxaliplatin-containing chemotherapy in Medicare patients with stage III resected colon cancer, using the 2003 to 2005 SEER/Medicare database. This database links 2 large components: (1) clinical data from Surveillance, Epidemiology, and End Results (SEER) and (2) Medicare claims data for covered health care services. The SEER program of the National Cancer Institute is an authoritative source for information on cancer incidence and survival in the United States. Since its establishment in 1973, the SEER program continued to expand to include more regions and state registries. We used the SEER 17 program, which includes cancer registries from Atlanta, Georgia; Connecticut; Detroit, Michigan; Hawaii; Iowa; New Mexico; San Francisco/Oakland, California; Seattle/Puget Sound, Washington; Utah; Los Angeles, California; San Jose/Monterey, California; rural Georgia; the Alaska Native Tumor Registry; greater California; Kentucky; Louisiana; and New Jersey,20 which covers approximately 28% of the US population. SEER areas are found to be generalizable to the US population,21 although this generalizability has been questioned by others.22,23 Patients from the Alaska Native registry were not included because of small samples, leaving 16 SEER areas in the final analysis. Medicare is the primary health insurer for elderly and disabled patients in the United States. All Medicare enrollees are covered under Part A; approximately 95% of Medicare Part A beneficiaries are estimated to be enrolled in Medicare Part B, which covers physician services, outpatient clinic care,
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durable medical equipment, and certain drugs such as chemotherapeutic agents.24
Study Population The study cohort consists of all the patients with stage III colon cancer in the SEER/Medicare database who were diagnosed with stage III colon cancer between 2003 and 2005. The patients were selected having initiated chemotherapy within 3 to 6 months after surgery. The inclusion criteria required that patients had continuous Medicare Part A and B enrollment without health maintenance organization (HMO) enrollment during the 12 months before diagnosis until the end of the study period. Patients were required to be at least 66 years of age, which provided 1 year after becoming eligible for Medicare to check for comorbidity before diagnosis. We excluded cases with any missing data or cases identified from death certificates.
Key Study Variables and Outcome Measures SEER uses the rural-urban continuum codes developed by the Economic Research Service; the codes are grouped based on population size according to the official metropolitan status by the Office of Management and Budget in June 2003.25 The codes are defined as follows: (1) “big metro”—ie, metropolitan area counties of 1 million population or more; (2) “metro”—ie, metro area countries of less than 1 million population; (3) “urban”—ie, urban population of 20,000 or more; (4) “less urban”—ie, urban population of 2500 to 19,999; (5) “rural”—ie, urban population of less than 2500. In addition to geographic variations, we examined patient age, race, sex, SES, marital status, and comorbidity, as well as tumor characteristics such as tumor size, tumor grade, node involvement, and year of diagnosis to evaluate potential confounding effects. The SES variable is neighborhood SES at the census tract level but not individual SES and is obtained from assigning patients to a census tract. The primary outcome is the use of oxaliplatin-containing chemotherapy within 3 to 6 months of colon cancer–specific surgery. The surgery codes were identified using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) classification system (45.71-45.76, 45.79, and 45.8) from the Medicare file. The date of surgery was missing from the SEER/Medicare linked database; therefore we used date of admission from Medicare hospital files as a proxy for the date of surgery, assuming that the patient received surgery within 1 to 2 days of the date of hospitalization. The Healthcare Common Procedure Coding System (HCPCS) was used to identify the chemotherapy-related drug information. The HCPCS code is J9263 for oxaliplatin chemotherapy, J9190 for fluorouracil chemotherapy, and J0640 for leucovorin. The chemotherapy administration codes are also given by HCPCS codes, ie, Q0083 to Q0085 as well as by ICD-CM procedural code, ie, 99.25.
Statistical Analysis Descriptive statistics and the 2 test for contingency were carried out to show how oxaliplatin-containing chemotherapy was used in various geographic regions among different age and racial groups. We performed multiple logistic regression analysis to examine the relationship between receipt of oxaliplatin-containing chemotherapy and geographic region while adjusting for patient and tumor characteristics. The dependent variable was the receipt of oxaliplatin within 3 to 6 months of colon cancer–specific surgery (binary outcome
Janki M. Panchal et al Table 1 Descriptive Statistics of Patients With Stage III Colon Cancer Receiving Chemotherapy n Age (y)
Chemotherapy (%)
No Chemotherapy (%)
Total (%)
2040 (100)
2066 (100)
4106 (100)
66-70
546 (26.76)
177 (8.57)
723 (17.61)
71-75
585 (28.68)
292 (14.13)
877 (21.36)
76-80
538 (26.37)
435 (21.06)
973 (23.70)
81 and older
371 (18.19)
1162 (56.24)
1533 (37.34)
White
1732 (84.90)
1697 (82.14)
3429 (83.51)
African
147 (7.21)
211 (10.21)
358 (8.72)
American
160 (7.84)
153 (7.41)
313 (7.62)
⌾2 P Valuea ⬍ .0001
Race 0.002
Other Sex Male
932 (45.69)
736 (35.62)
1668 (40.62)
Female
1108 (54.31)
1330 (64.38)
2438 (59.38)
Single
138 (6.76)
173 (8.37)
311 (7.57)
Married
1205 (59.07)
781 (37.80)
1986 (48.37)
Other
697 (34.17)
1112 (53.82)
1809 (44.06)
791 (38.77)
604 (29.24)
1395 (33.97)
⬍ .0001
Marital Status ⬍ .0001
Year of Diagnosis 2003 2004
691 (33.87)
682 (33.01)
1373 (33.44)
2005
558 (27.35)
780 (37.75)
1338 (32.59)
Big metro
1113 (54.56)
1187 (57.45)
2300 (56.02)
⬍ .0001
Geographic Location
Metro
588 (28.82)
529 (25.61)
1117 (27.20)
Urban
116 (5.69)
120 (5.81)
236 (5.75)
Less urban
183 (8.97)
190 (9.20)
373 (9.08)
Rural
40 (1.96)
40 (1.94)
80 (1.95)
Quintile 1
359 (17.60)
435 (21.06)
794 (19.34)
Quintile 2
380 (18.63)
445 (21.54)
825 (20.09)
Quintile 3
398 (19.51)
424 (20.52)
822 (20.02)
Quintile 4
434 (21.27)
415 (20.09)
849 (20.68)
Quintile 5
469 (22.99)
347 (16.80)
816 (19.87)
1083 (53.09)
770 (37.27)
1853 (45.13)
0.237
Median Household Income ⬍ .0001
Comorbidity None 1
582 (28.53)
615 (29.77)
1197 (29.15)
2
248 (12.16)
374 (18.10)
622 (15.15)
3 or more
127 (6.23)
307 (14.86)
434 (10.57)
⬍ .0001
Tumor Grade 98 (4.80)
97 (4.70)
195 (4.75)
Moderately differentiated
Well differentiated
1306 (64.02)
1269 (61.42)
2575 (62.71)
Poorly differentiated
569 (27.89)
598 (28.94)
1167 (28.42)
67 (3.28)
102 (4.94)
169 (4.12)
17 (0.83)
66 (3.19)
83 (2.02)
Unknown Node Involvement Not examined
.039
b
⬍ .0001
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115
Geographic Disparity in Chemotherapy Use Table 1 (Continued) n
Chemotherapy (%)
No Chemotherapy (%)
Total (%)
1-3
1369 (67.11)
1383 (66.94)
2752 (67.02)
4 or more
654 (32.06)
617 (29.86)
1271 (30.95)
⬍ 45 mm
1093 (53.58)
1043 (50.48)
2136 (52.02)
⬎ 45 mm
947 (46.42)
1023 (49.52)
1970 (47.98)
None
1978 (96.96)
2023 (97.92)
4001 (97.44)
Some
34 (1.67)
15 (0.73)
49 (1.19)
Unknown
28 (1.37)
28 (1.36)
56 (1.36)
⌾2 P Valuea
Tumor Size .047
Radiation Therapy
a b
Indicates distribution differences (P ⬍ .05 is significant) between chemotherapy and nonchemotherapy groups using 2 test statistic. For this particular table, we combined the “unknown” category with the “not examined” category to avoid n ⬍ 11, as required by the SEER/Medicare data user agreement.
yes/no). The primary predictors for the receipt of oxaliplatin were geographic region (using “big metro” as the reference group), race (using white race as the reference group), and age (using patients aged 66-70 years as the reference group). Important covariates were tumor characteristics (size, grade, node involvement, year of diagnosis), patient characteristics (sex, marital status, SES, and comorbidity) and treatment characteristics (radiation therapy or not). A two-sided P value of ⬍ 0.05 was considered statistically significant. The analysis was conducted using SAS, version 9.2 (SAS Institute, Cary NC).
Results All 7995 patients who were diagnosed with stage III colon cancer were selected from the SEER database between the years 2003 and 2005; of those colon cancer cases, members of HMOs and patients not covered by Medicare Part A and Part B (2136 patients), 220 patients younger than 66 years of age, and 619 patients who did not receive colon cancer–specific surgery were excluded from the sample. We also excluded patients who started using chemotherapy longer than 6 months after colon cancer–specific surgery; thus the final study cohort consisted of 4106 patients with stage III colon cancer. Patient characteristics and tumor characteristics between patients treated with chemotherapy and those who were not are shown in Table 1.
Geographic Variations and Other Patient Characteristics Only 49.6% of the patients with stage III colon cancer received adjuvant chemotherapy within 3 to 6 months after colon cancer– specific surgery, and more patients in “big metro” and “metro” regions received chemotherapy than did patients in “less urban” and “rural” regions. Younger patients were more likely to receive chemotherapy than were those aged 80 years and older (P ⬍ .001); similarly, white patients were more likely to receive chemotherapy than were African American patients (Table 1). The year of diagnosis also produced major distribution differences between patients treated with chemotherapy and those who were not, with most differences found in 2005. Chemotherapy patients were more likely to be in the higher median household income group quintile 5 and more likely to be married. Tumor characteristics showed significant distribution
116
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differences between patients who received chemotherapy and those who did not. Radiation therapy was seldom used for patients with stage III colon cancer. Table 2 shows the patient characteristics and tumor characteristics according to 5 geographic regions for both 5-FU/LV– only chemotherapy and oxaliplatin-containing chemotherapy. Approximately 23% of those who received any type of chemotherapy received oxaliplatin-containing chemotherapy (n ⫽ 886). Patients in the oldest age group were more likely to receive chemotherapy in “big metro” regions than in “rural” regions (25.79% in “big metro” regions vs. 13.33% in “rural” regions). Interestingly, with increasing rurality, the use of chemotherapy in African American individuals and in the single unmarried cohort decreased. Patients in the lowest quintile of SES, ie, quintile 1, were more likely to receive chemotherapy as rurality increased; there were no or very few patients found in quintile 4 and quintile 5 in “less urban” or “rural” regions. These observations were consistent even if only the oxaliplatin-containing chemotherapy cohort was observed.
Odds of Receiving Oxaliplatin-Containing Chemotherapy Table 3 shows the odds of receiving oxaliplatin-containing chemotherapy in patients with resected stage III colon cancer. Age was the most powerful predictor of receiving oxaliplatin-containing chemotherapy; odds of receiving oxaliplatin chemotherapy in patients aged 81 years or older is 76% less than in those aged 66 to 70 years (unadjusted OR, 0.24; P ⬍ .001; adjusted OR, 0.22; P ⬍ .0001). Patients aged 76 to 80 years were almost half as likely to receive oxaliplatin chemotherapy as those aged 66 to 70 years (unadjusted OR, 0.49; P ⬍ .001; adjusted OR, 0.48; P ⬍ .0001). Several other predictors from the independent associations were sex, marital status, median household income, comorbidity, node involvement, and tumor size, which showed significant association with the receipt of oxaliplatin-containing chemotherapy. The odds of receiving oxaliplatin chemotherapy were 7 times higher if the patient was diagnosed in 2005 vs. 2003 (P ⬍ .0001). The unadjusted OR suggests that the odds of receiving oxaliplatin-containing chemotherapy were higher in a “big metro” region and 23% less if the patient resided in a “less urban” region.
Janki M. Panchal et al Table 2 Use of 5-FU/LV Chemotherapy and Oxaliplatin-Containing Chemotherapy in Patients With Stage III Colon Cancer According to Geographic Regions and Other Patient Characteristics % of 5-FU/LV and Oxaliplatin Containing Chemotherapy Rates According to Geographic Regions Variable
Big Metro
Metro
Urban
Less Urban
Rural
5-FU/LV Oxaliplatin 5-FU/LV Oxaliplatin 5-FU/LV Oxaliplatin 5-FU/LV Oxaliplatin 5-FU/LV Oxaliplatin (n ⴝ 694) (n ⴝ 419) (n ⴝ 383) (n ⴝ 205) (n ⴝ 79) (n ⴝ 37) (n ⴝ 125) (n ⴝ 58) (n ⴝ 30) (n < 11) Age (y) 66-70
19.16
34.13
22.19
35.12
26.58
48.65
29.60
41.38
23.33
60.00
71-75
26.22
32.70
26.63
31.71
29.11
32.43
32.00
24.14
26.67
20.00
76-80
28.82
23.15
27.68
24.39
30.38
18.92
23.20
22.41
36.67
10.00
81 and older
25.79
10.02
23.50
8.78
13.92
—
15.20
12.07
13.33
10.00
82.85
80.19
86.42
90.24
89.87
83.78
88.8
91.38
96.67
100.00
Race White African American
7.78
9.31
5.22
4.88
5.06
5.41
9.60
8.62
3.33
—
Other
9.22
10.50
8.36
4.88
5.06
10.81
1.60
—
—
—
Male
42.36
49.40
43.60
47.32
50.63
56.76
47.20
44.83
46.67
70.00
Female
57.64
50.60
56.40
52.68
49.37
43.24
52.80
55.17
53.33
30.00
Sex
Marital Status Single
8.07
6.44
7.05
5.85
3.80
10.81
6.40
—
3.33
—
Married
50.58
63.48
56.66
69.27
65.82
70.27
63.20
70.69
73.33
90.00
Other
41.35
30.07
36.29
24.88
30.38
18.92
30.40
29.31
23.33
10.00
2003
51.01
17.90
49.87
20.00
53.16
21.62
44.00
18.97
40.00
20.00
2004
32.28
37.95
33.94
34.15
34.18
24.32
32.80
24.14
46.67
30.00
2005
16.71
44.15
16.19
45.85
12.66
54.05
23.20
56.90
13.33
50.00
Year of Diagnosis
Median Household Income Quintile 1
11.10
9.55
18.28
13.66
29.11
24.32
46.40
50.00
66.67
50.00
Quintile 2
14.55
13.37
18.54
22.44
32.91
32.43
31.20
32.76
16.67
50.00
Quintile 3
19.31
16.47
23.76
18.05
22.78
18.92
21.60
17.24
16.67
—
Quintile 4
26.22
23.87
20.37
26.34
13.92
21.62
0.80
—
—
—
Quintile 5
28.82
36.75
19.06
19.51
1.27
2.70
—
—
—
—
None
51.01
58.71
50.13
55.12
49.37
59.46
50.40
56.90
53.33
50.00
1
29.39
24.58
31.07
31.22
25.32
29.73
26.40
31.03
23.33
30.00
2
12.39
11.22
12.01
10.73
20.25
5.41
15.20
6.90
16.67
10.00
3 or more
7.20
5.49
6.79
2.93
5.06
5.41
8.00
5.17
6.67
10.00
Well differentiated
4.76
4.06
5.48
4.39
6.33
2.70
8.00
1.72
3.33
—
Moderately differentiated
65.71
63.48
62.66
60.00
63.29
70.27
69.6
51.72
70.00
70.00
Poorly differentiated
25.94
29.83
27.15
33.17
30.38
24.32
21.60
39.66
23.33
20.00
Unknown
3.60
2.63
4.70
2.44
—
2.70
0.80
6.90
3.33
10.00
Comorbidity
Tumor Grade Differentiation
Node Involvement Not examined
1.29
0.24
77.02
59.02
—
5.41
—
3.45
—
—
1-3
68.44
58.95
22.45
40.49
75.95
56.76
68.00
55.17
90.00
60.00
4 or more
30.26
40.81
0.52
0.49
24.05
37.84
32.00
41.38
10.00
40.00
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Geographic Disparity in Chemotherapy Use Table 2 (Continued) % of 5-FU/LV and Oxaliplatin Containing Chemotherapy Rates According to Geographic Regions Variable
Big Metro
Metro
Urban
Less Urban
Rural
5-FU/LV Oxaliplatin 5-FU/LV Oxaliplatin 5-FU/LV Oxaliplatin 5-FU/LV Oxaliplatin 5-FU/LV Oxaliplatin (n ⴝ 694) (n ⴝ 419) (n ⴝ 383) (n ⴝ 205) (n ⴝ 79) (n ⴝ 37) (n ⴝ 125) (n ⴝ 58) (n ⴝ 30) (n < 11) Tumor Size ⬍ 45 mm
53.31
52.98
52.74
56.59
55.70
67.57
52.80
48.28
46.67
60.00
⬎ 45 mm
46.69
47.02
47.26
43.41
44.30
32.43
47.20
51.72
53.33
40.00
None
96.83
98.33
97.91
98.54
96.20
100.00
92.00
87.93
93.33
100.00
Some
2.16
1.43
1.04
0.98
2.53
—
2.40
1.72
3.33
—
Unknown
1.01
0.24
1.04
0.49
1.27
—
5.60
10.34
3.33
—
Radiation Therapy
However after controlling for the confounding variables, the association between the receipt of oxaliplatin-containing chemotherapy and geographic regions became statistically significant. Patients in the “less urban” regions were approximately 42% less likely to receive oxaliplatin chemotherapy than were those residing in “big metro” regions (adjusted OR, 0.58; P ⫽ .008). We also performed additional analyses using different classification of geographic regions. In 1 scenario, we divided geographic regions into “urban,” “less urban,” and “rural” regions. The results remained the same, with patients in “rural” regions being 39% less likely to receive oxaliplatin-containing chemotherapy. However in another scenario, we divided geographic regions into “rural” and “nonrural” regions, and the results became insignificant. Other predictors of oxaliplatin chemotherapy receipt showed no major difference, except for the quintile 4 and quintile 5 of median household income variable, which became statistically insignificant in the multiple logistic regression model. Race remained statistically insignificant in the adjusted model. We did not include radiation therapy in this multiple logistic regression model because radiation therapy did not have an independent association with oxaliplatinchemotherapy receipt in univariate analysis and, moreover, more than 96% of patients did not receive radiation therapy; it was considered clinically and statistically insignificant in predicting chemotherapy use. Although radiation was not included in the final model, race and tumor grade were included because of their clinical significance.26-28 We did not include any interaction terms in our final multiple logistic regression model because none of them added power to this model.
Discussion Only around 49% of Medicare beneficiaries with resected stage III colon cancer received chemotherapy after tumor resection. Only 23% of the chemotherapy patients received oxaliplatin-containing chemotherapy between 2003 and 2005. Oxaliplatin chemotherapy use was 7 times higher in 2005 compared with 2003 because the drug was approved for use in stage III colon cancer in 2004. Early use of oxaliplatin chemotherapy for stage III colon cancer may be due to its effectiveness and previous 2002 US FDA approval for use in stage IV metastatic colon cancer.
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SEER uses the urban/rural codes to identify geographic regions based on population size. The “rural” category has a population of ⬍ 2500; thus the number of patients with colon cancer in this region was expected to be lower than in more populated regions, ie, “big metro,” “metro,” or “urban.” Moreover, the number of patients who received oxaliplatin-containing chemotherapy in “rural” regions is less than 11; therefore the results of oxaliplatin-containing chemotherapy use in “rural” regions should be compared carefully with other regions. Our results are consistent with the results from a study by Hao et al,13 which examined the effect of neighborhood rurality in the receipt of adjuvant chemotherapy. Our results indicate that the odds of receiving oxaliplatin-containing chemotherapy are ⬎ 40% less if the patient is from a “less urban”/“rural” region than if the patient is from a “big metro” region. This result however differs from 2 previous studies that suggested more use of chemotherapy in “nonrural” regions than in “rural” regions (not significant at 95% confidence interval).29,30 The studies that showed no significant difference used a “rural” vs. “nonrural” measure, whereas the study by Hao et al used “urban,” “less urban,” and “rural.” Our study used 5 geographic dimensions that made it more sensitive to the variations. We also performed the analysis with 3-dimension classifications of “urban”/“rural” codes, and the results remained the same. However in another scenario in which we converted our classification system to “rural” vs. “nonrural,” the results became insignificant at the 95% confidence level. Therefore we confirmed the justification of Hao et al that the differences in the results of these studies are a result of differences in the measurement of geographic regions. Our age and racial disparity results are consistent with the literature.11,14,15 We examined whether the geographic variations in cancer care explain the underuse of chemotherapy in older age groups. We found that older patients in “rural” regions are less likely to receive oxaliplatin chemotherapy compared with those in “big metro” regions (Table 2). Interestingly, a similar trend was also found in African Americans and patients who are single. The plausible explanations for geographic disparity may include financial constraints, geographic barriers (long-distance travel) to get current more effective therapies, patient awareness and preferences about these new effective therapies, and/or physicians’ knowledge and attitudes.13,31 Medicare covers all the colon cancer–related ex-
Janki M. Panchal et al Table 3 Odds Ratios of Receiving Oxaliplatin Chemotherapy, by Patient Characteristics Variable
% Treated
Unadjusted OR (95% CI)
P Value
Adjusted OR (95% CI)
P Value
66-70
36.08
1.0 (referent)
⬍ .0001a
1.0 (referent)
⬍ .0001a
71-75
31.55
0.70 (0.55-0.88)
.003
0.70 (0.54-0.91)
.008
76-80
23.05
0.49 (0.38-0.63)
⬍ .001
0.48 (0.36-0.63)
⬍ .0001
81 and older
9.33
0.24 (0.17-0.33)
⬍ .001
0.22 (0.16-0.32)
⬍ .0001
White
84.36
1.0 (referent)
.937a
1.0 (referent)
.413a
African American
7.68
1.12 (0.79-1.58)
0.529
1.40 (0.93-2.12)
.111
Other
7.96
1.03 (0.73-1.45)
0.851
0.92 (0.63-1.35)
.677
Male
49.11
1.0 (referent)
.020a
1.0 (referent)
.337a
Female
50.89
0.81 (0.67-0.96)
0.20
0.90 (0.73-1.12)
.337
Single
5.90
1.0 (referent)
⬍ .0001a
1.0 (referent)
.002a
Married
66.39
1.48 (1.02-2.17)
.041
1.72 (1.11-2.65)
.015
Other
27.71
0.90 (0.61-1.34)
.608
1.18 (0.75-1.86)
.473
2003
18.79
1.0 (referent)
⬍ .0001a
1.0 (referent)
⬍ .0001a
2004
34.98
2.79 (2.19-3.55)
⬍ .0001
2.86 (2.22-3.68)
⬍ .0001
2005
46.23
7.28 (5.67-9.35)
⬍ .0001
8.21 (6.29-10.72)
⬍ .0001
Big metro
57.48
1.0 (referent)
.202a
1.0 (referent)
.056a
Metro
28.12
0.89 (0.72-1.09)
.258
0.90 (0.71-1.15)
.398
Age (y)
Race
Sex
Marital Status
Year of Diagnosis
Geographic Location
Urban
5.08
0.78 (0.52-1.17)
.224
0.70 (0.44-1.13)
.147
Less Urban
7.96
0.77 (0.55-1.07)
.123
0.58 (0.38-0.87)
.008
Rural
1.37
0.55 (0.27-1.14)
.109
0.51 (0.23-1.15)
.102
Quintile 1
15.23
1.0 (referent)
.005a
1.0 (referent)
.337a
Quintile 2
18.93
1.27 (0.94-1.73)
.121
1.06 (0.75-1.59)
.739
Quintile 3
16.87
0.99 (0.73-1.36)
.996
0.79 (0.55-1.15)
.217
Quintile 4
22.22
1.33 (0.99-1.79)
.059
1.00 (0.69-1.46)
.994
Quintile 5
26.75
1.59 (1.19-2.12)
.002
1.09 (0.75-1.59)
.629
None
57.48
1.0 (referent)
.011a
1.0 (referent)
.007a
1
27.3
0.82 (0.67-1.02)
.070
0.79 (0.62-1.00)
.054
2
10.43
0.70 (0.52-0.94)
.018
0.71 (0.50-0.99)
.048
3 or more
4.80
0.60 (0.40-0.91)
.015
0.50 (0.32-0.80)
.004
Well differentiated
3.84
1.0 (referent)
.060a
1.23 (0.74-2.05)
.226a
Moderately differentiated
62.00
1.32 (0.84-2.08)
.226
1.52 (0.89-2.58)
.426
Poorly differentiated
31.14
1.66 (1.04-2.65)
.034
1.17 (0.54-2.50)
.124
Unknown
3.02
1.22 (0.62-2.39)
.559
0.82
0.83 (0.22-3.13)
⬍ .0001
Median Household Income
Comorbidity
Tumor Grade
.692
Node Involvement Not examined
0.56 (0.14-2.29)
.417
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Geographic Disparity in Chemotherapy Use Table 3 (Continued) Variable
% Treated
Unadjusted OR (95% CI)
P Value
Adjusted OR (95% CI)
P Value
1-3
58.57
1.0 (referent)
.780
1.0 (referent)
⬍ .0001a
4 or more
40.60
1.82 (1.51-2.21)
⬍ .0001
1.99 (1.59-2.49)
.609
⬍ 45 mm
54.46
1.0 (referent)
.552a
1.0 (referent)
.584a
⬎ 45 mm
45.54
0.95 (0.79-1.14)
0.552
0.94 (0.77-1.16)
0.584
97.67
1.0 (referent)
.381a
—
—
a
Tumor Size
Radiation Therapy None Some radiation
1.23
0.64 (0.30-1.38)
.255
—
Unknown
1.10
0.71 (0.31-1.62)
.418
—
Abbreviation: OR ⫽ odds ratio. a The P value is for the variable in whole.
penses; therefore financial constraints would not be the primary reason for this disparity. We did not have enough data or resources to clearly examine the other reasons behind these geographic variations, yet this study provides a starting point for the follow-up studies that examine why these treatment disparities exist and how we can eliminate them. Several limitations are noted in the study. First, the study involves a cohort from the SEER/Medicare linked database that offered a more generalizable sample population than that included in clinical trials. However several exclusion criteria were applied for sample selection, which resulted in considerable loss of data, especially for patients enrolled in HMOs. Therefore external validity was compromised as a result of losing patients younger than 66 years, patients enrolled in HMOs, and patients who did not undergo surgery. Although studies have confirmed the generalizability of the SEER enrolled population, this population is not a perfect representation of the US population. Moreover, the study was not randomized; thus there may be some unmeasured factors influencing the rate of use of oxaliplatin chemotherapy. Despite these limitations, this study evaluated data for a relatively large cohort of elderly Medicare patients and provided essential information on disparities in chemotherapy use for patients with stage III colon cancer, focusing specifically on oxaliplatin-based chemotherapy. Patterns of use that relate specifically to recommended oxaliplatin plus 5-FU/LV will inform providers and researchers how these newer regimens are being used as standard chemotherapy in real-world settings. Moreover, this article examines the subject of geographic disparity in the use of cancer care, which has not been widely studied in the past, despite the fact that delivery of care varies widely across regions. This article focuses mainly on the most understudied population, ie, older Medicare patients with colon cancer. Unlike clinical trials, such observational studies that use large population-based data allow us to evaluate the rate of use in patients older than 75 years and patients from all races/ethnicities. In conclusion, chemotherapy use varies across geographic regions, especially for new chemotherapy drugs like oxaliplatin, which in combination with 5-FU/LV is considered standard adjuvant chemotherapy for patients with resected stage III colon cancer. Age and race are reported to be strong predictors of chemotherapy use. Further
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research is needed to examine thoroughly the potential reasons behind the geographic disparity and explore the ways to provide highquality cancer care to all patients according to their preferences and needs.
Clinical Practice Points ●
●
This study examined geographic variation and socio-demographic disparities in the use of Oxaliplatin-containing chemotherapy which has not been widely studies in the past. Our results suggest that chemotherapy use varies across geographic regions.
Acknowledgments We acknowledge the efforts of the National Cancer Institute, Center for Medicare and Medicaid Services, Information Management Services Inc, and the Surveillance, Epidemiology, and End Results Program tumor registries in the creation of this database. The interpretation and reporting of these data are the sole responsibilities of the authors. This study was supported in part by a grant from the Agency for Healthcare Research and Quality (R01-HS018956) and in part by a grant from the Cancer Prevention and Research Institute of Texas (RP101207).
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Skillings JR, Levine M, Rayner HL, et al. Levamisole and 5-fluorouracil therapy for resected colon cancer: a new indication. CMAJ 1991; 144:297-301. 2. Moertel CG, Fleming TR, Macdonald JS, et al. Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann Intern Med 1995; 122:321-6. 3. Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990; 322:352-8. 4. André T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004; 350:2343-451. 5. de Gramont A, Boni C, Navarro M, et al. Oxaliplatin/5FU/LV in the adjuvant treatment of stage II and stage III colon cancer: efficacy results with a median follow-up of 4 years. J Clin Oncol 2005; 23(suppl):abstract 3501. 6. Kuebler JP, Wieand HS, O’Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol 2007; 25:2198-204. 7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Available at: http://www.nccn.org/professionals/ physician_gls/f_guidelines.asp. Accessed: October 18, 2012.
Janki M. Panchal et al 8. Smith RE. Trends in recommendations for myelosuppressive chemotherapy for the treatment of solid tumors. J Natl Compr Canc Netw 2006; 4:649-58. 9. National Cancer Institute. Cancer trends progress report 2009/10 Update. Colorectal cancer treatment. Available at: http://progressreport.cancer.gov/doc_detail. asp?pid⫽1&did⫽2009&chid⫽94&coid⫽924&mid⫽. Accessed: March 22, 2011. 10. Du XL, Meyer TE, Franzini L. Meta-analysis of racial disparities in survival in association with socioeconomic status among men and women with colon cancer. Cancer 2007; 109:2161-70. 11. Zuckerman IH, Rapp T, Onukwugha E, et al. Effect of age on survival benefit of adjuvant chemotherapy in elderly patients with stage III colon cancer. J Am Geriatr Soc 2009; 57:1403-10. 12. Center to Reduce Cancer Health Disparities: Economic costs of cancer health disparities: summary of meeting proceedings 2004; US Department of Health and Human Services, National Institutes of Health. Available at: http://crchd.cancer. gov/attachments/NCIeconomiccosts.pdf. Accessed: March 22, 2011. 13. Hao Y, Landrine H, Jemal A, et al. Race, neighbourhood characteristics and disparities in chemotherapy for colorectal cancer. J Epidemiol Community Health 2011; 65:211-7. 14. Davidoff AJ, Rapp T, Onukwugha E, et al. Trends in disparities in receipt of adjuvant therapy for elderly stage III colon cancer patients: the role of the medical oncologist evaluation. Med Care 2009; 47:1229-36. 15. Obeidat NA, Pradel FG, Zuckerman IH, et al. Racial/ethnic and age disparities in chemotherapy selection for colorectal cancer. Am J Manag Care 2010; 16:515-22. 16. Henry KA, Niu X, Boscoe FP. Geographic disparities in colorectal cancer survival. Int J Health Geogr 2009; 8:48. 17. Potosky AL, Harlan LC, Kaplan RS, et al. Age, sex, and racial differences in the use of standard adjuvant therapy for colorectal cancer. J Clin Oncol 2002; 20:1192-202. 18. Centers for Disease Control and Prevention. United States Cancer Statistics: 19992008 cancer incidence and mortality data. Available at: http://www.cdc.gov/uscs. Accessed: October 18, 2012. 19. Cress RD, Sabatino SA, Wu XC, et al. Adjuvant chemotherapy for patients with stage III colon cancer: results from a CDC-NPCR patterns of Care study. Clin Med Oncol 2009; 3:107-19.
20. National Cancer Institute. Surveillance Epidemiology and End Results. Overview of the SEER program. Available at; http://seer.cancer.gov/about/. Accessed: October 18, 2012. 21. National Cancer Institute. Surveillance Epidemiology and End Results. Characteristics of the SEER population compared with the total United States population. Available at: http://seer.cancer.gov/registries/characteristics.html. Accessed: October 18, 2012. 22. Zippin C, Lum D, Hankey BF. Completeness of hospital cancer case reporting from the SEER program of the National Cancer Institute. Cancer 1995; 76:2343-50. 23. Nattinger AB, McAuliffe TL, Schapira MM. Generalizability of the surveillance, epidemiology, and end results registry population: factors relevant to epidemiologic and health care research. J Clin Epidemiol 1997; 50:939-45. 24. Centers for Medicare & Medicaid Services. Medicare enrollment reports. Available at: https://www.cms.gov/MedicareEnrpts/. Accessed: October 15, 2010. 25. USDA Economic Research Service. Rural-urban continuum codes. Available at: http://www.ers.usda.gov/data-products/rural-urban-continuum-codes.aspx. Accessed: October 18, 2012. 26. Dimou A, Syrigos KN, Saif MW. Disparities in colorectal cancer in African-Americans vs whites: before and after diagnosis. World J Gastroenterol 2009; 15:3734-43. 27. Etzioni DA, El-Khoueiry AB, Beart RW, Jr. Rates and predictors of chemotherapy use for stage III colon cancer: a systematic review. Cancer 2008; 113:3279-89. 28. Mack CD, Carpenter W, Meyer AM, et al. Racial disparities in receipt and comparative effectiveness of oxaliplatin for stage III colon cancer in older adults. Cancer 2012; 118:2925-34. 29. Ayanian JZ, Zaslavsky AM, Fuchs CS, et al. Use of adjuvant chemotherapy and radiation therapy for colorectal cancer in a population-based cohort. J Clin Oncol 2003; 21:1293-300. 30. Wu X, Chen VW, Andrews PA, et al. Treatment patterns for stage III colon cancer and factors related to receipt of postoperative chemotherapy in Louisiana. J La State Med Soc 2004; 156:255-61. 31. Muss HB, Cohen HJ, Lichtman SM. Clinical research in the older cancer patient. Hemato/Oncol Clin North Am 2000; 14:283-91.
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