Appendix A. Search Strategies

** Supplemental Data **

Medline 1 1. exp *Therapeutics/ 2. *colorectal neoplasms/ or *adenomatous polyposis coli/ or *colonic neoplasms/ or *colorectal neoplasms, hereditary nonpolyposis/ 3. limit 2 to (english language and humans and yr="2001 - 2011") 4. 1 and 3 5. Medicare/ 6. SEER Program/ 7. 5 or 6 8. 4 and 7

Medline 2 1. exp *Therapeutics/ 2. *colorectal neoplasms/ or *adenomatous polyposis coli/ or *colonic neoplasms/ or *colorectal neoplasms, hereditary nonpolyposis/ 3. limit 2 to (english language and humans and yr="2001 - 2011") 4. 1 and 3 5. 4 6. limit 5 to "all aged (65 and over)" 7. efficacy.mp. 8. effectiveness.mp. 9. exp treatment outcome/ 10. survival benefit.mp. 11. 7 or 8 or 9 or 10 12. 6 and 11 13. exp Age Factors/ 14. 12 and 13

Medline 3 1. exp *Therapeutics/ 2. *colorectal neoplasms/ or *adenomatous polyposis coli/ or *colonic neoplasms/ or *colorectal neoplasms, hereditary nonpolyposis/ 3. limit 2 to (english language and humans and yr="2001 - 2011") 4. 1 and 3 5. 4 6. limit 5 to "all aged (65 and over)" 7. efficacy.mp. 8. effectiveness.mp. 9. exp treatment outcome/ 10. survival benefit.mp. 11. 7 or 8 or 9 or 10 12. 6 and 11 13. elderly.ti. 14. elderly.ab. 15. 13 or 14 16. 12 and 15

Medline 4 1. exp *Therapeutics/ 2. *colorectal neoplasms/ or *adenomatous polyposis coli/ or *colonic neoplasms/ or *colorectal neoplasms, hereditary nonpolyposis/ 3. limit 2 to (english language and humans and yr="2001 - 2011") 4. 1 and 3 5. 4 6. limit 5 to "all aged (65 and over)" 7. *Treatment outcome/ or efficacy.mp. or effectiveness.mp. or survival benefit.mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier] 8. 6 and 7

Medline 5 1. exp *Therapeutics/ 2. *colorectal neoplasms/ or *adenomatous polyposis coli/ or *colonic neoplasms/ or *colorectal neoplasms, hereditary nonpolyposis/ 3. limit 2 to (english language and humans and yr="2001 - 2011") 4. 1 and 3 5. 4 6. limit 5 to "all aged (65 and over)" 7. exp "health care economics and organizations"/ 8. 6 and 7

EBM 1 1. *colorectal neoplasms/ 2. *colonic neoplasms/ 3. 1 or 2 4. 3 5. limit 4 to "all aged (65 and over)" 6. limit 5 to humans 7. limit 6 to english 8. limit 7 to yr="2001 - 2011" 9. (treatment outcome or surgery or chemotherapy or drug therapy).mp. [mp=ti, ot, ab, tx, kw, ct, sh, hw] 10. 8 and 9 11. (cost or cost analysis or economics).mp. [mp=ti, ot, ab, tx, kw, ct, sh, hw] 12. 10 and 11

EBM 2 1. *colorectal neoplasms/ 2. *colonic neoplasms/ 3. 1 or 2 4. 3 5. limit 4 to "all aged (65 and over)" 6. limit 5 to humans 7. limit 6 to english 8. limit 7 to yr="2001 - 2011" 9. (treatment outcome or surgery or chemotherapy or drug therapy).mp. [mp=ti, ab, tx, kw, ct, ot, sh, hw] 10. 8 and 9 11. elderly.mp. [mp=ti, ot, ab, tx, kw, ct, sh, hw] 12. 10 and 11 Appendix B. Study Characteristics

Author Year Study Type A Chemotherapy Regimen (Reference) g e

R a n g e Bensmaine 45 2001 OS < FOLFOX 1. Bolus/short 5-FU infusion (≤4h) +/- LV: either daily (2-5 6 consecutive days), repeated weekly or every 3-4 weeks; 2. 0 high-dose-intensity intermittent infusional schedule: all 5- , FU IV infusions ≥8h and ≤48h, given at weekly or biweekly intervals +/- LV 3. Continuous infusion: 5-FU IV continuous ≥ infusion (<1000 mg/m2), +/- LV for at least 4 dys. All 6 regimens +/- ox: either biweekly 80-100 mg/m2/cycle or 0 every 3-4 weeks 100-130 mg/m2/cycle) McKibbin 27 2008 OS 2 5-FU/Ox Not specified 4 - 6 5 ,

6 6 - 9 5 Mattioli 46 2005 Trial 7 FOLFOX Ox 45 mg/m2 IV (as 90-min infusion), followed by LV 200 0 mg/m2 IV (as 2-h infusion), bolus 5-FU 400 mg/m2 IV (10- - min infusion) and 22-h infusion 5-FU, 600 mg/m2 IV, given 8 for 2 consecutive days; repeated every 2 weeks 5 Andre 54 2004 Trial 1 FOLFOX or w/out 5-FU/LV: 2-h infusion of 200 mg/m2 LV followed by bolus 9 ox 400 mg/m2 5-FU and then 22-h infusion 600 mg 5-FU - mg/m2 given on 2 consecutive days every 14 days for 12 6 cycles, +/- ox: 2-h infusion 85 mg/m2 on day 1 4 ,

6 5 - 7 5 Goldberg 32 2006 Trial analysis 1 FOLFOX FOLFOX4: ox 85 mg/m2 (day 1) plus hybrid bolus and 8 infusional 5-FU and LV (days 1 and 2) administered - bimonthly 6 9 ,

7 0 - 7 5 Goldberg 32 2006 Trial analysis 1 FOLFOX FOLFOX4: ox 85 mg/m2 (day 1) plus hybrid bolus and 8 infusional 5-FU and LV (days 1 and 2) administered - bimonthly 6 9 ,

≥ 7 0 Goldberg 32 2006 Trial analysis 1 FOLFOX FOLFOX4: ox 85mg/m2 (day 1) plus hybrid bolus and 8 infusional 5-FU and LV (days 1 and 2) administered - bimonthly 6 9 ,

≥ 7 0 Goldberg 32 2006 Trial analysis 1 FOLFOX FOLFOX4: ox 85 mg/m2 (day 1) plus hybrid bolus and 8 infusional 5-FU and LV (days 1 and 2) administered - bimonthly 6 9 ,

≥ 7 0 48 2 Pfeiffer 2005 Trial 3 CapeOx XELOX30: cap 1000 mg/m orally twice daily on days 1-14 3 & ox 130 mg/m2 as 30-min infusion on day 1 - 6 1 ,

6 2 - 7 4 Rosati 47 2010 Trial 7 CapeOx Ox 65 mg/m2 IV on days 1 and 8 and cap 1000 mg/m2 0 orally twice daily days 1-14; repeated every 21 days - 7 8 Schmoll 29 2007 Trial analysis 2 CapeOx XELOX: 2-h IV infusion of ox 130 mg/m2 on day 1 and oral 2 cap 1000 mg/m2 twice daily given 14 days of 3-week cycle - and for total of 8 cycles. 1st dose of cap given on the 6 evening of day 1 and last dose on morning of day 15 of 4 each cycle. ,

6 5 - 8 3 Jensen 22 2006 Trial 2 CapeOx cap 1250 mg/m2 twice daily for 2 weeks every 3 weeks 4 alone then adding ox 130 mg/m2 on day 1 (XELOX) - 6 9 ,

7 0 - 7 4 ,

7 0 - 8 2 Lee 55 2004 ≥ Cap cap 1250 mg/m2 twice daily days 1-14 every 3 weeks Trial 7 0 Jensen 22 2006 Trial 2 Cap cap 1250 mg/m2 twice daily for 2 weeks every 3 weeks 4 - 7 4 ,

7 5 - 8 2 Diaz-Rubio 56 2004 Trial analysis < Cap Not specified 4 0 ,

4 1 - 6 9 ,

≥ 7 0 Zuckerman 26 2009 OS 6 5-FU/LV Not specified 6 - 6 9 ,

7 0 - 7 4 ,

7 5 - 7 9 ,

8 0 - 8 4 ,

≥ 8 5

Zuckerman 26 2009 OS 6 5-FU/LV Not specified 6 - 6 9 ,

7 0 - 7 4 ,

7 5 - 7 9 ,

8 0 - 8 4 ,

≥ 8 5 McKibbin 27 2008 OS 2 5-FU alone Not specified 4 - 6 5 ,

6 6 - 9 5 Schrag 41 2001 OS 6 5-FU/LV or 5-FU, Not specified 5 LV, floxuridine - 6 9 ,

7 0 - 7 4 ,

7 5 - 7 9 ,

8 0 - 8 4 ,

8 5 - 8 9 ,

≥ 9 0 Fata 51 2001 OS < 5-FU/LV or Lev or Not specified 6 both 5 ,

≥ 6 5 Maughan 57 2003 Trial 3 5-FU/LV (2 diff 5-FU/LV: 1. DeGramont: IV LV 200 mg/m2 (max 350mg) 2 regimens) or over 2h, followed by 5-FU 400 mg/m2 bolus over 5 min and - raltitrexed 5-FU infusion 600 mg/m2 over 22h, repeated on day 2; 5 repeat every 2 weeks 2. Lokich: continuous IV infusion 5- 4 FU 300 mg/m2/d given through ambulatory pump; 3. , ralitrexed- 3 mg/m2 given IV over 15 min every 3 weeks

5 5 - 6 4 ,

6 5 - 7 4 ,

7 5 - 8 1 Chau 52 2004 Trial 2 5-FU/LV or PVI 5- 5-FU/LV: 5-FU 425 mg/m2 IV and LV 20 mg/m2 IV bolus 7 FU days 1-5 every 28 days for 6 months; PVI (protracted - venous infusion) 5-FU: 300 mg/m2/d for 12 weeks 6 9 ,

7 0 - 9 5 Mattioli 50 2001 Trial 7 5-FU/LV DeGramont: LV, 100 mg/m2 IV as 2-h infusion followed by 0 bolus 5-FU 400 mg/m2 IV and 22-h infusion 5-FU, 600 - mg/m2 IV, given for 2 consecutive days, every 2 weeks 8 8 Sakamoto 49 2004 Trial analysis < 5-FU (oral): FU, Not specified for oral FUs. If randomly assigned to 5 UFT, HCFU experimental group, given IV mitomycin 6 mg/m2 at 1 week 0 (carmofur) +/- and once monthly for 6 months , mitomycin or FU (IV) 5 0 - 5 4 ,

5 5 - 5 9 ,

6 0 - 6 4 ,

6 5 - 6 9 ,

≥ 7 0 Sargent 31 2001 Trial analysis ≤ 5-FU/LV or Lev 5-FU/LV: 5-FU 370-425 mg/m2 and LV 20-200 mg/m2 daily 7 for 5 days, repeated every 4-5 weeks. 5-FU/Lev: rapid IV 0 injection of 5-FU 450 mg/m2 on 5 consecutive days. , Starting day 28, weekly injections of 450 mg/m2 5-FU. Throughout treatment, lev administered orally 50 mg three > times daily on days 1-3, repeated every 2weeks 7 0 Sargent 31 2001 Trial analysis ≤ 5-FU/Lev 5-FU/Lev: rapid IV injection of 5-FU 450 mg/m2 on 5 7 consecutive days. On day 28, began weekly injections of 0 450 mg/m2 5-FU. Throughout tx, lev administered orally 50 , mg three times daily on days 1-3, repeated every 2 weeks

> 7 0 Sargent 31 2001 Trial analysis ≤ 5-FU/LV 5-FU/LV: 5-FU 370-425 mg/m2 and LV 20-200 mg/m2 daily 7 for 5 days, repeated every 4-5 weeks. 0 ,

> 7 0 Schmoll 29 2007 Trial analysis 2 5-FU/LV 5-FU/LV given as 2 diff regimens: 1) Mayo Clinic: rapid IV 4 infusion of LV 20 mg/m2 followed by an IV bolus FU 425 - mg/m2 on days 1-5 of a 4-wk cycle for a total of 6 cycles. 2) 6 Roswell Park: 2-h IV infusion of LV 500 mg/m2 plus IV 4 bolus injection of FU 500 mg/m2 (initiated during the LV , infusion) on day 1 of weeks 1-6 of an 8-wk cycle, for a total of 4 cycles 6 5 - 8 2 Diaz-Rubio 56 2004 Trial analysis < 5-FU/LV 5-FU/LV Mayo Clinic Regimen 4 0 ,

4 1 - 6 9 ,

≥ 7 0 McKibbin 27 2008 OS 2 Iri/5-FU Not specified 4 - 6 5 ,

6 6 - 9 5 Rosati 53 2006 OS 7 Iri Iri 80 mg/m2/d on days 1 and 8, given as 1-h IV infusion; 0 repeated every 3 weeks - 7 9 Moehler 35 2010 OS 2 Iri/5-FU/LV 1. Weekly regimen: iri 80 mg/m2, LV 500 mg/m2 as 2-h 8 infusion, and 5-FU 2000-2300 mg/m2 as 24-h continuous - infusion or 2. biweekly regimen (FOLFIRI: iri 180 mg/m2, 6 LV 200 mg/m2 and 5-FU bolus 400 mg/m2 on day 1 9 followed by a 46-h continuous infusion of 5-FU 2400 , mg/m2)

7 0 - 8 7 Chau 33 2004 Trial 2 Iri Iri 350 mg/m2 IV over 30 min every 3 weeks for 8 cycles 9 - 6 9 ,

7 0 - 8 0 Rosati 47 2010 Trial 7 Iri/Cap Iri 80 mg/m2 IV days 1 and 8 and cap 1000 mg/m2 orally 0 twice daily days 1-14; every 21 days - 9 0 Raman 30 2007 OS 6 Bev Not specified 5 - 6 9 ,

7 0 - 7 4 ,

7 5 - 9 0 Allegra 34 2009 Trial analysis < Bev +/- 5-FU/Ox mFOLFOX6 +/- bev = LV 400 mg/m2 IV on day 1, FU 400 6 mg/m2 IV bolus on day 1 followed by 2400 mg/m2 IV over 0 46h, and ox 85 mg/m2 IV on day 1. Bev was given on , experimental arm at 5 mg/kg IV on day 1. All therapy given every 2 weeks for 12 doses or for bev, 26 doses ≥ 6 0 McKibbin 27 2008 OS 2 5-FU/Ox or 5- Various regimens, including FOLFOX, IFL, CapeOx, 4 FU/Iri or 5-FU FOLFIRI, Roswell Park, and Cap alone - alone, or anyone 6 of the 3 options 5 with Bev or Cet ,

6 6 - 9 5 Haller28 2011 Trial 2 CapeOx or 5- XELOX, Mayo Clinic 5-FU/LV, or Roswell Park 5-FU/LV 2 FU/LV regimens - 8 3 *5-FU = 5-fluorouracil; LV = leucovorin; Ox = oxaliplatin; Cap = capecitabine; Iri = irinotecan; Bev = Bevacizumab; Cet = Cetuximab; OS = Observational Study