Supplemental Content

Price Adjusters:

Price adjuster developed by Brown et al. using the Prospective Payment System Hospital Price (PPS) index and

Geographic Adjustment Factor (GAF) was applied to Medicare part A claims (inpatient, hospice and home health); whereas for part B claims (outpatient, physician and device and medical equipment) Medicare Economic Index

(MEI) and Geographic Practice Cost Index (GPCI) were used. These county level price adjusters were obtained by special request from the National Cancer Institute Table 1. Distribution of characteristics by chemotherapy status in patients with stage III colon cancer before propensity score matching Column N (%) P-value Characteristics 5 - Fluorouracil FOLFOX No Chemotherapy Total N=10,252 N=1,860 N=3,070 N=5,322 Age (years) <0.01 65-69 354 (19.03) 1,087 (35.41) 437 (8.21) 70-74 444 (23.87) 954 (31.07) 651 (12.23) 75-79 509 (27.37) 697 (22.70) 980 (18.41) 80+ 553 (29.73) 332 (10.81) 3,254 (61.14) Race/ethnicity <0.01 Caucasians 1,530 (82.26) 2,597 (84.59) 4,376 (82.22) African Americans 149 (8.01) 230 (7.49) 502 (9.43) Others 181 (9.73) 243 (7.92) 444 (8.34) Gender <0.01 Male 826 (44.41) 1,469 (47.85) 2,066 (38.82) Female 1,034 (55.59) 1,601 (52.15) 3,256 (61.18) Marital status <0.01 Married 1,027 (55.22) 1,914 (62.35) 2,016 (37.88) Unmarried 774 (41.61) 1,042 (33.94) 3,121 (58.64) Unknown 59 (3.17) 114 (3.71) 185 (3.48) Comorbidity Scores <0.01 0 841 (45.22) 1,656 (53.94) 2,003 (37.64) 1 551 (29.62) 881 (28.70) 1,483 (27.87) 2 265 (14.25) 328 (10.68) 884 (16.61) ≥3 203 (10.91) 205 (6.68) 952 (17.89) SES (poverty) 0.07 1st (Low SES) 457 (24.57) 737 (24.01) 1,343 (25.23) 2nd 457 (24.57) 722 (23.52) 1,339 (25.16) 3rd 467 (25.11) 755 (24.59) 1,330 (24.99) 4th (High SES) 479 (25.75) 856 (27.88) 1,310 (24.61) Tumor grade 0.09 Well differentiated 90 (4.84) 146 (4.76) 283 (5.32) Moderately differentiated 1,165 (62.63) 1,907 (62.12) 3,223 (60.56) Poorly differentiated 521 (28.01) 879 (28.63) 1,521 (28.58) Undifferentiated 50 (2.69) 62 (2.02) 163 (3.06) Unknown/Missing 34 (1.83) 76 (2.48) 132 (2.48) Year of Diagnosis <0.01 2004 659 (35.43) 285 (9.28) 778 (14.62) 2005 357 (19.19) 452 (14.72) 867 (16.29) 2006 278 (14.95) 559 (18.21) 947 (17.79) 2007 247 (13.28) 594 (19.35) 929 (17.46) 2008 176 (9.46) 597 (19.45) 927 (17.42) 2009 143 (7.69) 583 (18.99) 874 (16.42) SEER Areas <0.01 Mid-West 280 (15.05) 413 (13.45) 706 (13.27) North East 484 (26.02) 655 (21.34) 1,244 (23.37) South 423 (22.74) 806 (26.25) 1,237 (23.24) West 673 (36.18) 1,196 (38.96) 2,135 (40.12) FOLFOX: 5-Fluorouracil + Oxaliplatin; SES: Socio-Economic Status; SEER: Survival Epidemiology and End Results Propensity Score Matching Approach:

In order to perform a propensity score matching for treatment groups i.e. no chemotherapy, 5-fluorouracil and

FOLFOX, a multinomial logistic regression analysis was performed. Covariates included age, race, gender, marital status, tumor grade, comorbidity score, socioeconomic status, year of diagnosis and state of residence. Result for this regression is provided in table 2 of this supplemental material. The propensity score obtained from this regression was then used to conduct a 1:1:1 nearest neighbor matching using the SAS macro built by Rassen et. al. [12]. The macro matches the two treatment groups simultaneously with the referent group, where none of the pairs of patients exceed the caliper value (0.05 for the study). The SAS macro is provided below and necessary files are available at http://www.drugepi.org/dope-downloads/#Pharmacoepidemiology Toolbox. Characteristics of the matched sample are provided in the manuscript (table 2).

%INCLUDE "/path/to/toolbox/sas/java_utils.sas"; %INCLUDE "/path/to/toolbox/sas/matching.sas"; /* remember, no spaces in the path! */ %toolbox_Start(%QUOTE(/path/to/toolbox/java/pharmacoepi.jar)); /* Estimate 3-group propensity score with polytomous */ /* logistic regression */ PROC LOGISTIC DATA=input_cohort_3way ORDER=data DESCENDING; CLASS expcat; MODEL expcat(ref="1") = covariate1 covariate2 ... / LINK=glogit; OUTPUT OUT=input_3way_cohort_long(KEEP=id expcat _level_ prob) PRED=prob; RUN; /* The output from above will contain one row per patient per */ /* level. Transform to one row per patient with one variable per level */ PROC TRANSPOSE DATA=input_3way_cohort_long OUT=input_3way_cohort PREFIX=prob; BY id expcat; RUN; /* Run 1:1:1 nearest neighbor match */ %match_NearestNeighborMatch ( input_3way_cohort, output_3way_cohort, %QUOTE(c:\temp\), var_patient_id = id, var_exposure = expcat, var_ps = prob1 prob2, exp_groups = 1 2 3, caliper=0.05, ratio=3, ); Table 2. Multinomial logistic regression for chemotherapy types to obtain propensity score for conducting the 1:1:1 match using the macro (n=10,252) 5 - Fluorouracil vs. No FOLFOX vs. No Chemotherapy Chemotherapy Odds ratio (95% CI) Odds ratio (95% CI) Age (years) 65-69 1.00 1.00 70-74 0.91 (0.75 - 1.10) 0.62 (0.53 - 0.73) 75-79 0.70 (0.58 - 0.84) 0.29 (0.25 - 0.34) 80+ 0.24 (0.20 - 0.29) 0.04 (0.04 - 0.05) Race/ethnicity Caucasians 1.00 1.00 African Americans 0.77 (0.62 - 0.96) 0.64 (0.53 - 0.79) Others 1.30 (1.05 - 1.61) 0.86 (0.70 - 1.06) Gender Male 1.00 1.00 Female 1.10 (0.97 - 1.24) 1.12 (1.00 - 1.25) Marital status Married 1.00 1.00 Unmarried 0.60 (0.53 - 0.68) 0.49 (0.44 - 0.55) Unknown 0.77 (0.51 - 0.98) 0.78 (0.58 - 1.03) Tumor grade Well differentiated 1.00 1.00 Moderately differentiated 1.25 (0.96 - 1.63) 1.28 (1.00 - 1.64) Poorly differentiated 1.23 (0.94 - 1.63) 1.38 (1.07 - 1.79) Undifferentiated 1.21 (0.79 - 1.86) 0.77 (0.51 - 1.17) Unknown/Missing 0.84 (0.52 - 1.36) 1.09 (0.72 - 1.65) Comorbidity Scores 0 1.00 1.00 1 0.95 (0.83 - 1.09) 0.81 (0.71 - 0.92) 2 0.77 (0.65 - 0.91) 0.48 (0.41 - 0.56) ≥3 0.59 (0.49 - 0.71) 0.26 (0.22 - 0.31) SES (poverty) 1st (Low SES) 1.00 1.00 2nd 1.00 (0.84 - 1.18) 0.94 (0.81 - 1.10) 3rd 1.02 (0.86 - 1.21) 1.05 (0.89 - 1.24) 4th (High SES) 1.02 (0.85 - 1.22) 1.21 (1.02 - 1.44) Year of Diagnosis 2004 1.00 1.00 2005 0.50 (0.42 - 0.59) 1.56 (1.28 - 1.91) 2006 0.39 (0.33 - 0.47) 2.08 (1.70 - 2.53) 2007 0.36 (0.30 - 0.43) 2.32 (1.90 - 2.83) 2008 0.26 (0.21 - 0.31) 2.37 (1.94 - 2.89) 2009 0.23 (0.18 - 0.28) 2.51 (2.05 - 3.06) SEER Areas California 1.00 1.00 Connecticut 1.46 (1.13 - 1.87) 1.14 (0.89 - 1.47) Georgia 0.96 (0.74 - 1.25) 1.19 (0.96 - 1.47) Hawaii 0.86 (0.48 - 1.54) 1.53 (0.92 - 2.53) Iowa 1.44 (1.14 - 1.81) 0.96 (0.76 - 1.21) Kentucky 1.17 (0.94 - 1.46) 0.89 (0.72 - 1.09) Louisiana 1.28 (1.00 - 1.63) 1.46 (1.17 - 1.82) Michigan 1.35 (1.04 - 1.74) 1.52 (1.20 - 1.93) New Jersey 1.38 (1.15 - 1.65) 1.17 (0.98 - 1.39) New Mexico 0.72 (0.46 - 1.12) 1.06 (0.73 - 1.53) Utah 1.31 (0.86 - 2.01) 1.44 (0.97 - 2.14) Washington 0.89 (0.67 - 1.20) 1.05 (0.81 - 1.35) FOLFOX: 5-Fluorouracil + Oxaliplatin; SES: Socio-Economic Status; SEER: Survival Epidemiology and End Results

Table 3. Total Health Care Costs Per Month in Different Disease Phases by Chemotherapy Type Total Health Care Costs Per Month Chemotherapy Regimens Mean US Dollars, $ (Standard Error) Initial Phase* (12 Months After Diagnosis) N=3,033 No Chemotherapy 6,386 (506.18) 5 - Fluorouracil 6,553 (191.18) FOLFOX 9,771 (268.08) Continuing Phase* (Between Initial and Terminal Phase) N=2,658 No Chemotherapy 1,029 (69.59) 5 - Fluorouracil 2,012 (250.03) FOLFOX 1,874 (101.34) Terminal Phase* (12 Months Before Death) N=1,459 No Chemotherapy 13,222 (730.00) 5 - Fluorouracil 8,586 (320.04) FOLFOX 10,115 (347.19) SE – Standard Error; FOLFOX: 5-Fluorouracil + Oxaliplatin *Costs incurred in the last year of life will be assigned to the terminal Phase. If patients lived for less than or equal to a year then all costs were assigned to the terminal phase. Similarly, costs incurred in the first year following diagnosis were assigned to Initial Phase and if the patient lived more than a year but less than or equal to two years than the costs remaining after a year of terminal phase were assigned to the initial phase. If the patient lived more than two years then the time between the initial phase and terminal phase was assigned as continuing phase

Table 4. Scenario Analysis for Effectiveness and Cost Effectiveness for Chemotherapy Treatment Groups

Total Health Care Cost Effectiveness ICER ($)* ($) Best Case Worst Case Best Case Worst Case Median Life Years Median QALY Mean (SE) Per QALY gained Per QALY gained (SE) (SE) No Chemotherapy 2.82 (0.16) 1.78 (0.12) 85,422 (2,171.36) - - 5 - Fluorouracil 4.97 (0.27) 2.85 (0.18) 125,338 (2,694.24) 18,565 37,304 FOLFOX 5.30 (0.30) 3.08 (0.20) 168,628 (4,107.53) 127,324 188,218 ICER: Incremental Cost-Effectiveness Ratio; QALY: Quality Adjusted Life Year; SE: Standard Error; FOLFOX: 5- Fluorouracil + Oxaliplatin *ICER calculated by arranging in ascending order of total health care cost. Table 5. Effectiveness and Cost Effectiveness for Chemotherapy Treatment Groups Using Inverse Probability Treatment Weight Approach

Effectiveness Total Health Care Cost ($) ICER ($)* Median Life Years Per Life Year Median QALY (SE) Mean (SE) (SE) Gained No Chemotherapy 3.10 (0.07) 2.23 (0.07) 84,060 (971.95) - Other Chemotherapy 4.60 (0.26) 3.33 (0.28) 113,797 (2,616.64) 19,824 5 - Fluorouracil 4.70 (0.16) 3.38 (0.17) 117,592 (2,031.23) 37,950 FOLFOX 5.24 (0.15) 3.84 (0.16) 196,250 (6,575.52) 145,663 QALY – Quality Adjusted Life Year; ICER – Incremental Cost Effectiveness Ratio; SE – Standard Error; FOLFOX: 5-Fluorouracil + Oxaliplatin *ICER calculated by arranging in ascending order of total health care cost. Figure 1: Comparison of Cost effectiveness planes for chemotherapy regimens

Cost Effectiveness Plane - FOLFOX vs. 5-Fluorouracil Cost Effectiveness Plane - 5-Fluorouracil vs. No Chemotherapy 70000 60000

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