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Fluoropirimidinas por vía oral versus intravenosa para el cáncer colorrectal

Appendices

Appendix 1. Search strategy for CENTRAL, the Cochrane Library

Cochrane Library Issue 5, 20 May 2016 (292 hits in CENTRAL)

1. MeSH descriptor Colorectal Neoplasms explode all trees

2. ((cancer* or carcinoma* or neoplasm* or adenoma* or adenocarcinom* or tumour* or tumor* or polyp* or malignan*) near3 (colorectal* or colon* or rect*))

3. (#1 OR #2)

4. MeSH descriptor Fluorouracil explode all trees

5. MeSH descriptor Antimetabolites, Antineoplastic explode all trees

6. CapeIri or CapeOx or fluoropyrimidine* or $fluorouracil or 5 FU or 5‐FU or 5FU or $uracil or Capecitabine or Xeloda or Tegafur or S1 or S‐1 or Orzel or 776C85 or UFT or Xelox or Xeliri or Capox or Capiri

7. (#4 OR #5 OR #6)

8. (oral* and (intravenous* or infusion*))

9. (#3 AND #7 AND #8)

Appendix 2. Search strategy for MEDLINE (OVID)

MEDLINE (OVID) 1950 to 14 June 2016 (322 hits)

1. exp Colorectal Neoplasms/

2. ((cancer* or carcinoma* or neoplasm* or adenoma* or adenocarcinom* or tumour* or tumor* or polyp* or malignan*) adj3 (colorectal* or colon* or rect*)).mp.

3. 1 or 2

4. exp Fluorouracil/

5. exp Antimetabolites/

6. (CapeIri or CapeOx or fluoropyrimidine* or $fluorouracil or 5 FU or 5‐FU or 5FU or $uracil or Capecitabine or Xeloda or Tegafur or S1 or S‐1 or Orzel or 776C85 or UFT or Xelox or Xeliri or Capox or Capiri).mp.

7. 4 or 5 or 6

8. (oral* and (intravenous* or infusion*)).mp.

9. 3 and 7 and 8

10. randomized controlled trial.pt.

11. controlled clinical trial.pt.

12. randomized.ab.

13. placebo.ab.

14. clinical trials as topic.sh.

15. randomly.ab.

16. trial.ti.

17. 10 or 11 or 12 or 13 or 14 or 15 or 16

18. exp animals/ not humans.sh.

19. 17 not 18

20. 9 and 19

Appendix 3. Search strategy for Embase (OVID)

Embase (OVID) 1974 to 14 June 2016 (498 hits):

1. exp large intestine tumor/

2. ((cancer* or carcinoma* or neoplasm* or adenoma* or adenocarcinom* or tumour* or tumor* or polyp* or malignan*) adj3 (colorectal* or colon* or rect*)).mp.

3. 1 or 2

4. exp fluorouracil/

5. exp antimetabolite/

6. (CapeIri or CapeOx or fluoropyrimidine* or $fluorouracil or 5 FU or 5‐FU or 5FU or $uracil or Capecitabine or Xeloda or Tegafur or S1 or S‐1 or Orzel or 776C85 or UFT or Xelox or Xeliri or Capox or Capiri).mp.

7. 4 or 5 or 6

8. (oral* and (intravenous* or infusion*)).mp.

9. 3 and 7 and 8

10. CROSSOVER PROCEDURE.sh.

11. DOUBLE‐BLIND PROCEDURE.sh.

12. SINGLE‐BLIND PROCEDURE.sh.

13. (crossover* or cross over*).ti,ab.

14. placebo*.ti,ab.

15. (doubl* adj blind*).ti,ab.

16. allocat*.ti,ab.

17. trial.ti.

18. RANDOMIZED CONTROLLED TRIAL.sh.

19. random*.ti,ab.

20. 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19

21. (exp animal/ or exp invertebrate/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans or man or men or wom?n).ti.)

22. 20 not 21

23. 9 and 22

Appendix 4. Search strategy for Web of Science (Web of Knowledge)

This search was performed on 16 June 2016, with the search dates including 1900 to 2016 (9.6.2016).

Set

Results

Search Terms

# 20

904

#17 AND #9

# 19

165,735

#18 AND #17

# 18

3,118,135

TOPIC: (human) ORTOPIC: (humans)

# 17

1,641,761

#16 OR #15 OR #14 OR #13 OR #12 OR #11 OR #10

# 16

1,223,762

TOPIC: (trial)

# 15

278,002

TOPIC: (randomly)

# 14

495,021

TOPIC: (clinical trial)

# 13

204,807

TOPIC: (placebo)

# 12

650,738

TOPIC: (randomized)

# 11

209,393

TOPIC: (controlled clinical trial)

# 10

317,506

TOPIC: (randomized controlled trial) ORTOPIC: (randomised controlled trial)

# 9

1,131

#8 AND #7 AND #6

# 8

318,494

#2 OR #1

# 7

38,132

TOPIC: (oral*) ANDTOPIC: (intravenous* or infusion*)

# 6

286,602

#5 OR #4 OR #3

# 5

286,550

TOPIC: (fluoropyrimidine* or fluorouracil or 5 FU or 5‐FU or 5FU or uracil or capecitabine or xeloda or tegafur or S1 or S‐1 or orzel or 776C85 or UFT or Xelox or Xeliri or Capox or Capiri or Capeox or Capeiri)

# 4

40,442

TOPIC: (fluorouracil)

# 3

76

TOPIC: (antimetabolites, antineoplastic)

# 2

318,494

TOPIC: (cancer* or carcinoma* or neoplasm* or adenoma* or adenocarcinom* or tumour* or tumor* or polyp* or malignan*) ANDTOPIC: (colorectal* or colon* or rectal or rectum)

# 1

8,638

TOPIC: (colorectal neoplasms)

Appendix 5. Efficacy outcomes in studies not suitable for inclusion in meta‐analysis ‐ Patients treated with curative intent for colorectal cancer

Study

Chemotherapy arm

3‐year DFS rate, %; P value

3‐year OS (curative intent studies) rate, %; P value

HR for OS (curative intent studies) (95% CI)

De la Torre 2008

UFT/LV + RT

65.6

74

1.39 (0.66‐2.93)

FU/LV + RT

64.7; P = 0.67

87; P = 0.37

UFT: tegafur/uracil

LV: leucovorin

RT: radiotherapy

Appendix 6. Other information for studies that reported similar adverse event outcomes to "Neutropenia/Granulocytopenia" and "Hand foot syndrome"

Setting

Study

Outcome in our review

Adverse event reported

Chemotherapy arm

Grade ≥ 3 AE (%)

Patients treated with curative intent for CRC

with neoadjuvant and/or adjuvant chemotherapy

Hofheinz 2012

Neutropenia/

Granulocytopenia

Lowered leukocytes

Capecitabine

1.5

Fluorouracil

8.2

Kim 2001a

Neutropenia/

Granulocytopenia

Leukopenia

Doxifluridine + RT

0

5‐FU + RT

6.8

Patients treated with palliative intent for

inoperable advanced or metastatic CRC

with chemotherapy

Bajetta 1996

Neutropenia/

Granulocytopenia

Leukopenia

Oral 5‐dFUR

1.5

IV 5‐dFUR

15

Silvestris 2010

Neutropenia/

Granulocytopenia

Leuko/neutropenia

XELIRI

17.2

FOLFIRI

16.1

Kohne 2008

Neutropenia/

Granulocytopenia

White blood cells

CAPIRI‐Celecoxib/Placebo

14

FOLFIRI‐Celecoxib/Placebo

15.4

Carmichael 2002

HFS

Skin/appendages (including HFS)

UFT/LV

1

5‐FU/LV

1

Porschen 2007

HFS

HFS

CAPOX

Only Grade 2/3 HFS included

FUFOX

AE: adverse event

CRC: colorectal cancer

RT: radiotherapy

5‐FU: 5‐fluorouracil

5‐dFUR: doxifluridine

IV: intravenous

HFS: hand foot syndrome

UFT: tegafur/uracil

LV: leucovorin

Appendix 7. Efficacy outcomes in studies not suitable for inclusion in meta‐analysis ‐ Patients treated with palliative intent for inoperable advanced or metastatic colorectal cancer

Outcome

Study

Line

Chemotherapy arm

Median (95% CI) for PFS, OS, TTP; % for ORR

PFS

Hochster TREE‐1 2008a

First

CapeOx

5.9 m (5.1 to 7.4)

mFOLFOX6

8.7 m (6.5 to 9.8)

bFOL

6.9 m (4.2 to 8.0)

Hochster TREE‐2 2008a

First

CapeOx + BEV

10.3 m (8.6 to 12.5)

mFOLFOX6 + BEV

9.9 m (7.9 to 11.7)

bFOL + BEV

8.3 m (6.6 to 9.9)

OS

Andersen 1987

First

Ftorafur

209 d

5‐FU

211 d

Yu 2005

First, Second

Capecitabine + Irinotecan

17.9 m

5‐FU + Irinotecan

14.2 m

TTP

Silvestris 2010

First

XELIRI

8.7 m

FOLFIRI

6.5 m

Yu 2005

First, Second

Capecitabine + Irinotecan

12.5 m

5‐FU + Irinotecan

8.4 m

ORR

Mei 2014

First

SOX

51.4

FOLFOX4

45.7

Seymour 2011

First

Capecitabine

14

OxCap

32

FU

11

OxFU

38

Silvestris 2010

First

XELIRI

48.4

FOLFIRI

32.2

aOutcome reported as TTP, but treated as PFS in this review based on the definition provided.

CI: confidence interval

PFS: progression‐free survival

OS: overall survival

TTP: time to tumour progression

ORR: objective response rate

BEV: bevacizumab

5‐FU / FU: 5‐fluorouracil

Appendix 8. Adverse event outcomes in studies not suitable for inclusion in meta‐analysis ‐ Patients treated with palliative intent for inoperable advanced or metastatic colorectal cancer

Study

Line of

chemotherapy

Grade ≥3 AE

Chemotherapy arm

Measure of grade ≥ 3 AE

Silvestris 2010

First

Diarrhoea

XELIRI

12.50%

FOLFIRI

3.20%

HFS

XELIRI

Grade 3: n = 1

FOLFIRI

Leuko/neutropenia

XELIRI

17.2%

FOLFIRI

16.1%

Yu 2005

First, Second

Diarrhoea

Capecitabine + Irinotecan

7.40%

5‐FU + Irinotecan

18.80%

HFS

Capecitabine + Irinotecan

0%

5‐FU + Irinotecan

0%

Neutropenia

Capecitabine + Irinotecan

0%

5‐FU + Irinotecan

0%

Nausea/Vomiting

Capecitabine + Irinotecan

0%

5‐FU + Irinotecan

6.25%

Stomatitis

Capecitabine + Irinotecan

0%

5‐FU + Irinotecan

0%

AE: adverse event

HFS: hand foot syndrome

5‐FU: 5‐fluorouracil

Appendix 9. Summary of subgroup analyses for efficacy outcomes ‐ Patients treated with curative intent for colorectal cancer

Efficacy outcome

Hazard ratio (fixed, 95% CI) (No. studies/n) for subgroups, test for subgroup differences

Treatment type

Infusional vs bolus IV fluoropyrimidines

Oral fluoropyrimidine backbone

Chemotherapy

Chemo‐radiotherapy

Infusional

Bolus

Capecitabine

UFT/Ftorafur

Doxifluridine

DFS

0.94 (0.87 to 1.02)

0.91 (0.78 to 1.05)

0.96 (0.85 to 1.08)

0.94 (0.86 to 1.04)

0.91 (0.83 to 0.99)

1.01 (0.88 to 1.15)

－

5/6944

2/1959

3/3881

3/4630

5/6260

2/2643

Chi² = 0.21, P = 0.64; I2 = 0%

Chi² = 0.06, P = 0.81; I2 = 0%

Chi² = 1.70, P = 0.19; I2 = 41.1%

OS

0.93 (0.84 to 1.03)

0.86 (0.70 to 1.06)

0.94 (0.80 to 1.09)

0.93 (0.83 to 1.05)

0.88 (0.79 to 0.98)

1.03 (0.86 to 1.22)

－

5/6943

2/1959

3/3880

3/4630

5/6259

2/2643

Chi² = 0.43, P = 0.51; I2 = 0%

Chi² = 0.00, P = 0.96; I2 = 0%

Chi² = 2.20, P = 0.14; I2 = 54.5%

CI: confidence interval

IV: intravenous

UFT: tegafur/uracil

DFS: disease‐free survival

OS: overall survival

Appendix 10. Summary of subgroup analyses for grade ≥ 3 adverse event outcomes ‐ Patients treated with curative intent for colorectal cancer

Grade ≥3 AE

Odds ratio (fixed, 95% CI) (No. studies/n) for subgroups, test for subgroup differences

Treatment type

Infusional vs bolus IV fluoropyrimidine

Oral fluoropyrimidine backbone

Chemotherapy

Chemo‐radiotherapy

Infusional

Bolus

Capecitabine

UFT/Ftorafur

Doxifluridine

Diarrhoea

1.08 (0.95 to 1.23)

1.28 (0.98 to 1.66)

1.27 (1.06 to 1.53)

0.98 (0.84 to 1.14)

1.15 (0.99 to 1.33)

1.00 (0.83 to 1.21)

32.14 (1.89 to 545.41)

5/7274

4/2277

3/4255

5/4904

5/6616

3/2769

1/166

Chi² = 1.24, P = 0.27; I2 = 19.3%

Chi² = 4.52, P = 0.03; I2 = 77.9%

Chi² = 6.73, P = 0.03. I2 = 70.3%

Vomiting

1.03 (0.80 to 1.32)

1.42 (0.54 to 3.75)

1.56 (1.07 to 2.26)

0.78 (0.57 to 1.08)

1.34 (0.99 to 1.81)

0.67 (0.44 to 1.01)

－

5/7274

3/2111

3/4255

4/4738

5/6616

3/2769

Chi² = 0.39, P = 0.53; I2 = 0%

Chi² = 7.48, P = 0.006; I2 = 86.6%

Chi² = 7.25, P = 0.007; I2 = 86.2%

Nausea

1.13 (0.90 to 1.42)

3.19 (1.22 to 8.36)

1.59 (1.10 to 2.31)

1.00 (0.76 to 1.33)

1.40 (1.04 to 1.88)

1.00 (0.71 to 1.40)

－

5/7274

2/1959

3/4255

3/4586

5/6616

2/2617

Chi² = 4.24, P = 0.04; I2 = 76.4%

Chi² = 3.79, P = 0.05; I2 = 73.6%

Chi² = 2.10, P = 0.15; I2 = 52.3%

AE: adverse event

CI: confidence interval

IV: intravenous

UFT: tegafur/uracil

Appendix 11. Summary of subgroup analyses for efficacy outcomes ‐ Patients treated with palliative intent for inoperable advanced or metastatic colorectal cancer

Efficacy outcome

Hazard ratio (fixed, 95% CI) (No. studies/n) for subgroups, test for subgroup differences

Single agent vs combination therapy

Infusional vs bolus IV fluoropyrimidine

Oral fluoropyrimidine backbone

Oxaliplatin‐based vs irinotecan‐based

Single agent

Combination therapy

Infusional

Bolus

Capecitabine

UFT/Ftorafur

Eniluracil + oral 5‐FU

Doxifluridine

S‐1

Oxaliplatin‐based

Irinotecan‐based

PFS

1.12 (1.04 to 1.21)

1.05 (1.00 to 1.10)

1.05 (1.00 to 1.10)

1.10 (1.03 to 1.19)

1.03 (0.98 to 1.08)

1.36 (1.07 to 1.73)

1.22 (1.10 to 1.36)

1.18 (0.79 to 1.74)

1.02 (0.89 to 1.16)

1.06 (0.99 to 1.13)

1.04 (0.97 to 1.11)

6/2955

16/6513

17/6560

7/3367

13/6703

2/374

3/1618

1/130

4/1102

8/4677

8/1836

Chi² = 2.16, P = 0.14; I2 = 53.8%

Chi² = 1.33, P = 0.25; I2 = 24.7%

Chi² = 13.46, P = 0.009; I2 = 70.3%

Chi² = 0.13, P = 0.72; I2 = 0%

OS

1.02 (0.99 to 1.07)

1.00 (0.95 to 1.06)

1.01 (0.96 to 1.06)

1.02 (0.98 to 1.06)

0.99 (0.95 to 1.04)

1.02 (0.97 to 1.06)

1.20 (1.07 to 1.36)

0.99 (0.65 to 1.50)

0.95 (0.81 to 1.11)

1.00 (0.94 to 1.07)

1.01 (0.92 to 1.10)

10/4465

18/7155

19/7022

13/5057

16/7405

5/1807

3/1618

2/207

3/1042

11/5379

7/1776

Chi² = 0.40, P = 0.53; I2 = 0%

Chi² = 0.10, P = 0.75;I2 = 0%

Chi² = 9.30, P = 0.05; I2 = 57.0%

Chi² = 0.01, P = 0.90; I2 = 0%

TTP

1.08 (1.01 to 1.14)

1.05 (0.84 to 1.32)

1.05 (0.84 to 1.32)

1.08 (1.01 to 1.14)

1.05 (0.84 to 1.32)

1.08 (1.02 to 1.15)

－

0.88 (0.56 to 1.36)

－

－

4/1510

2/460

2/460

4/1510

2/460

3/1433

1/77

Chi² = 0.03, P = 0.86; I2 = 0%

Chi² = 0.03, P = 0.86; I2 = 0%

Chi² = 0.89, P = 0.64; I2 = 0%

ORR

1.11 (0.94 to 1.31)

0.93 (0.85 to 1.03)

0.92 (0.83 to 1.02)

1.12 (0.96 to 1.29)

1.01 (0.91 to 1.12)

0.92 (0.72 to 1.18)

0.84 (0.62 to 1.13)

0.52 (0.28 to 0.99)

1.08 (0.81 to 1.45)

0.92 (0.83 to 1.03)

0.97 (0.79 to 1.19)

11/4208

21/6907

21/6342

14/4773

17/6690

6/1772

3/1522

2/190

4/941

12/5201

9/1706

Chi² = 3.14, P = 0.08: I2 = 68.2%

Chi² = 4.69, P = 0.03; I2 = 78.7%

Chi² = 5.81, P = 0.21; I2 = 31.2%

Chi² = 0.15, P = 0.70; I2 = 0%

CI: confidence interval

IV: intravenous

UFT: tegafur/uracil

5‐FU: 5‐fluorouracil

PFS: progression‐free survival

OS: overall survival

TTP: time to tumour progression

ORR: objective response rate

Appendix 12. Summary of subgroup analyses for grade ≥ 3 adverse event outcomes ‐ Patients treated with palliative intent for inoperable advanced or metastatic colorectal cancer

Grade ≥3 AE

Odds ratio (fixed, 95% CI), (No. studies/n) for subgroups, Test for subgroup differences

Single‐agent vs combination therapy

Infusional vs bolus IV fluoropyrimidine

Oral fluoropyrimidine backbone

Oxaliplatin‐based vs irinotecan‐based

Single agent

Combination therapy

Infusional

Bolus

Capecitabine

UFT/Ftorafur

Eniluracil + oral 5‐FU

Doxifluridine

S‐1

Oxaliplatin‐based

Irinotecan‐based

Diarrhoea

1.22 (1.04 to 1.44)

2.03 (1.77 to 2.32)

2.00 (1.74 to 2.30)

1.31 (1.12 to 1.53)

1.76 (1.54 to 2.00)

1.60 (1.24 to 2.06)

1.04 (0.79 to 1.38)

1.51 (0.64 to 3.56)

3.55 (2.19 to 5.76)

1.73 (1.48 to 2.02)

3.05 (2.33 to 3.99)

10/4566

21/7431

21/7065

12/4932

17/7382

5/1784

3/1617

1/127

4/1087

12/5420

8/1792

Chi² = 21.70, P < 0.00001; I2 = 95.4%

Chi² = 15.57, P < 0.0001; I2 = 93.6%

Chi² = 21.15, P = 0.0003; I2 = 81.1%

Chi² = 12.72, P = 0.0004; I2 = 92.1%

Hand foot syndrome

1.11 (0.48 to 2.56)

4.76(3.32 to 6.82)

3.53 (2.53 to 4.94)

18.68 (4.15 to 84.10)

5.86 (4.01 to 8.58)

0.49 (0.04 to 5.50)

0.04 (0.00 to 0.75)

－

0.66 (0.11 to 4.00)

4.52 (3.03 to 6.75)

5.93 (2.52 to 13.97)

2/343

17/6138

18/6094

3/387

13/5418

2/372

1/122

2/569

10/4608

6/1311

Chi² =9.86 , P = 0.002, I2 = 89.9%

Chi² = 4.48, P = 0.03, I2 = 77.7 %

Chi² = 19.58, P = 0.0002 , I2 = 84.7%

Chi² = 0.32, P = 0.57, I2 = 0%

Neutropenia/ granulocytopenia

0.05 (0.04 to 0.07)

0.24 (0.21 to 0.28)

0.23 (0.20 to 0.26)

0.09 (0.07 to 0.11)

0.21 (0.18 to 0.24)

0.03 (0.02 to 0.05)

0.06 (0.04 to 0.09)

－

0.38 (0.29 to 0.50)

0.15 (0.13 to 0.18)

0.59 (0.47 to 0.73)

9/4447

21/7347

21/6981

11/4813

16/7228

5/1784

3/1625

5/1157

13/5418

7/1710

Chi² = 102.73, P < 0.00001; I2 = 99.0%

Chi² = 56.29, P < 0.00001; I2 = 98.2%

Chi² = 112.47, P < 0.00001; I2 = 97.3%

Chi² = 91.66, P < 0.00001; I2 = 98.9%

Febrile neutropenia

0.05 (0.02 to 0.11)

0.49 (0.36 to 0.66)

0.50 (0.35 to 0.71)

0.13 (0.08 to 0.21)

0.42 (0.30 to 0.58)

0.03 (0.01 to 0.11)

0.08 (0.03 to 0.21)

－

1.82 (0.67 to 4.92)

0.26 (0.16 to 0.40)

1.20 (0.75 to 1.93)

5/3254

14/6153

13/5624

7/3783

11/5419

3/1476

2/1485

3/1027

8/4492

6/1661

Chi² = 27.62, P < 0.00001; I2 = 96.4%

Chi² = 20.33, P < 0.00001; I2 = 95.1%

Chi² = 33.08, P < 0.00001; I2 = 90.9%

Chi² = 21.90, P < 0.00001; I2 = 95.4%

Vomiting

1.11 (0.83 to 1.47)

1.22 (1.00 to 1.50)

1.21 (0.97 to 1.49)

1.15 (0.89 to 1.49)

1.25 (1.02 to 1.52)

1.35 (0.97 to 1.87)

0.68 (0.36 to 1.31)

－

0.32 (0.10 to 1.07)

1.12 (0.90 to 1.40)

1.85 (1.13 to 3.01)

7/3312

17/6216

18/6172

8/3356

13/6029

5/1784

2/1086

3/629

10/4959

6/1038

Chi² = 0.32, P = 0.57; I2 = 0

Chi² = 0.07, P = 0.79; I2 = 0%

Chi² = 8.08, P = 0.04; I2 = 62.9%

Chi² = 3.35, P = 0.07; I2 = 70.2%

Nausea

1.08 (0.81 to 1.44)

1.20 (0.99 to 1.45)

1.18 (0.96 to 1.45)

1.13 (0.87 to 1.46)

1.31 (1.07 to 1.61)

1.35 (0.96 to 1.89)

0.51 (0.28 to 0.91)

－

0.56 (0.28 to 1.10)

1.16 (0.93 to 1.44)

1.29 (0.85 to 1.94)

6/2719

20/7077

21/7033

7/2763

13/5769

5/1784

2/1086

5/1157

11/5066

8/1792

Chi² = 0.35, P = 0.55; I2 = 0%

Chi² = 0.08, P = 0.78; I2 = 0%

Chi² = 14.23, P = 0.003; I2 = 78.9%

Chi² = 0.20, P = 0.65; I2 = 0%

Stomatitis

0.13 (0.09 to 0.19)

0.73 (0.49 to 1.07)

0.65 (0.44 to 0.96)

0.14 (0.09 to 0.20)

0.26 (0.18 to 0.37)

0.15 (0.09 to 0.25)

0.09 (0.00 to 1.65)

0.09 (0.01 to 0.70)

4.45 (1.38 to 14.31)

0.59 (0.38 to 0.92)

2.56 (0.80 to 8.24)

8/3071

14/5647

14/5668

7/3050

10/5598

5/1784

1/122

1/127

4/1087

9/4731

4/697

Chi² = 39.19, P < 0.00001; I2 = 97.4%

Chi² = 32.07, P < 0.00001; I2 = 96.9%

Chi² = 28.83, P < 0.00001; I2 = 86.1%

Chi² = 5.27, P = 0.02; I2 =81.0%

Mucositis

0.08 (0.05 to 0.13)

1.17 (0.62 to 2.21)

1.17 (0.62 to 2.21)

0.08 (0.05 to 0.13)

0.63 (0.24 to 1.64)

0.10 (0.05 to 0.18)

0.10 (0.05 to 0.19)

－

7.16 (1.29 to 39.88)

0.75 (0.32 to 1.77)

2.12 (0.77 to 5.89)

4/2670

8/2292

8/2292

4/2670

3/940

4/1547

2/1495

3/980

3/1142

5/1150

Chi² = 43.07, P < 0.00001; I2 = 97.7%

Chi² = 43.07, P < 0.00001; I2 = 97.7%

Chi² = 31.60, P < 0.00001; I2 = 90.5%

Chi² = 2.33, P = 0.13; I2 = 57.1%

Hyperbilirubinemia

1.83 (0.96 to 3.48)

1.34 (0.62 to 2.90)

1.34 (0.62 to 2.90)

1.83 (0.96 to 3.48)

1.51 (0.87 to 2.61)

0.99 (0.20 to 5.00)

Not estimable

－

4.42 (0.74 to 26.40)

1.26 (0.57 to 2.81)

3.10 (0.12 to 79.23)

3/1311

6/1388

7/1510

2/1189

4/1646

2/372

1/122

2/559

4/1257

2/131

Chi² = 0.37, P = 0.54, I2 = 0%

Chi² = 0.37, P = 0.54, I2 = 0%

Chi² = 1.62, P = 0.45, I2 = 0%

Chi² = 0.28, P = 0.60, I2 =

Any

1.09 (0.84 to 1.42)

0.78 (0.68 to 0.89)

0.77 (0.68 to 0.88)

1.24 (0.93 to 1.65)

0.85 (0.75 to 0.96)

0.69 (0.44 to 1.10)

0.54 (0.26 to 1.11)

－

1.26 (0.58 to 2.74)

0.65 (0.55 to 0.75)

1.16 (0.88 to 1.51)

3/936

12/4500

13/4663

3/773

10/4835

2/372

1/122

1/107

6/3385

5/896

Chi² = 8.71, P = 0.003; I2 = 88.5%

Chi² = 13.55, P = 0.0002; I2 = 92.6%

Chi² = 3.14, P = 0.37; I2 = 4.4%

Chi² = 13.55, P = 0.0002; I2 = 92.6%

AE: adverse event

CI: confidence interval

IV: intravenous

UFT: tegafur/uracil

5‐FU: 5‐fluorouracil

Appendix 13. DFS: Other information for studies where the outcome was suitable for meta‐analysis

Treatment setting

Study

 

Chemotherapy arm

 

 

Survival rate, % (95% CI)

 

3‐year

5‐year

Neoadjuvant

Rectal

Allegra 2015

Capecitabine ± oxaliplatin

66.7

5‐FU ± oxaliplatin

66.4

Neoadjuvant/Adjuvant

Rectal

Hofheinz 2012

 

All (Adjuvant/Neoadjuvant)

Capecitabine

75 (68 to 81), P = 0.07

68 (60 to 74)

Fluorouracil

67 (59 to 73)

54 (45 to 62)

Adjuvant

Capecitabine

78 (69 to 85)

Fluorouracil

69 (59 to 77)

Neoadjuvant

Capecitabine

71 (60 to 80)

Fluorouracil

63 (51 to 73)

 

Adjuvant

Colon

De Gramont 2012

(Stage III)

BEV‐XELOX

75 (72 to 78)

BEV‐FOLFOX4

73 (71 to 76)

Lembersky 2006

 

UFT/LV

74.5

67.0

FU/LV

74.5

68.2

Shimada 2014

 

UFT/LV

77.8

73.6

5‐FU/LV

79.3

74.3

Twelves 2012

 

Capecitabine

64.2

60.8

5‐FU/FA

60.6, P = 0.12

56.7

Colorectal

Pectasides 2015

CAPOX

79.5 (75.9 to 83.1)

mFOLFOX6

79.8 (76.5 to 83.4), P = 0.784

DFS: disease‐free survival

CI: confidence interval

5‐FU / FU: 5‐fluorouracil

BEV: bevacizumab

UFT: tegafur/uracil

LV: leucovorin

FA: folinic acid

Appendix 14. OS (curative intent studies): Other information for studies for which the outcome was suitable for meta‐analysis

Treatment setting

Study

Chemotherapy arm 

Survival rate, % (95% CI)

Neoadjuvant

Rectal

Allegra 2015

Capecitabine ± oxaliplatin

5 years: 80.8

5‐FU ± oxaliplatin

5 years: 79.9

Neoadjuvant/Adjuvant

Rectal

Hofheinz 2012

All (Adjuvant/Neoadjuvant)

Capecitabine

3 years: 87 (81 to 91)

Fluorouracil

3 years: 83 (77 to 88)

Capecitabine

5 years: 76 (67 to 82)

Fluorouracil

5 years: 67 (58 to 74)

Capecitabine

7 years: 71 (60 to 79)

Fluorouracil

7 years: 58 (47 to 67)

Adjuvant

Colon

De Gramont 2012

(Stage III)

BEV‐XELOX

5 years: 82 (80 to 85)

BEV‐FOLFOX4

5 years: 81 (78 to 83)

Lembersky 2006

 

UFT/LV

5 years: 88.4

FU/LV

5 years: 87.0

UFT/LV

5 years: 69.6

FU/LV

5 years: 71.5

UFT/LV

5 years: 78.5

FU/LV

5 years: 78.7

Shimada 2014

UFT + LV

3 years: 93.9

5‐FU + l‐LV

3 years: 94.5

UFT + LV

5 years: 87.5

5‐FU + l‐LV

5 years: 88.4

Twelves 2012

Capecitabine

3 years: 81.3

5‐FU/FA

3 years: 77.6, P = 0.05

Capecitabine

5 years: 71.4

5‐FU/FA

5 years: 68.4

Colorectal

Pectasides 2015

CAPOX

3 years: 86.9 (83.4 to 89.9)

mFOLFOX6

3 years: 87.2 (84.1 to 91.1), P = 0.844

OS: overall survival

CI: confidence interval

5‐FU/ FU: 5‐fluorouracil

BEV: bevacizumab

UFT: tegafur/uracil

LV: leucovorin

FA: folinic acid

Appendix 15. PFS: Other information for studies for which the outcome was suitable for meta‐analysis

Study

Line of chemotherapy

Chemotherapy Arm

Median (95% CI)

Survival rate, % (95% CI)

Bajetta 1996

 

First

 

Oral 5‐dFUR

4 m (1 to 23)

IV 5‐dFUR

7 m (1 to 24)

 

Cassidy 2011a

First

 

XELOX/XELOX‐placebo/XELOX‐BEV (ITT)

8.0 m

FOLFOX‐4/FOLFOX‐4‐placebo/FOLFOX‐4‐BEV (ITT)

8.5 m

XELOX/XELOX‐placebo/XELOX‐BEV(EPP)

7.9 m

FOLFOX‐4/FOLFOX‐4‐placebo/FOLFOX‐4‐BEV (EPP)

8.5 m

 

XELOX‐BEV (ITT)

9.3 m

FOLFOX‐4‐BEV (ITT)

9.4 m

XELOX (ITT)

7.3 m

FOLFOX‐4 (ITT)

7.7 m

Comella 2009

 

First

 

OXXEL

6.6 m (6.0 to 7.0)

OXAFAFU

6.5 m (5.4 to 7.6)

 

Douillard 2014

 

First

 

UFOX + Cetuximab

6.6 m (5.6 to 7.2)

FOLFOX4 + Cetuximab

8.2 m (7.5 to 9.2),

P (log rank) = 0.0048

 

Ducreux 2011

First

XELOX (ITT)

8.8 m

FOLFOX‐6 (ITT)

9.3 m

XELOX (per protocol)

8.9 m

FOLFOX‐6 (per protocol)

9.3 m

Ducreux 2013

 

First

 

XELIRI + BEV

9 m (8 to 10)

6 m: 82 (71 to 90)

FOLFIRI + BEV

9 m (8 to 10)

6 m: 85 (75 to 92)

XELIRI+ BEV

12 m: 25 (16 to 36)

FOLFIRI + BEV

12 m: 18 (11 to 28)

ECOG E5296 2012

 

First

 

Eniluracil/5‐FU

0.4 y (0.2 to 0.5)

5‐FU

0.6 y (0.4 to 0.6), P = 0.021, stratified log‐rank

 

Fuchs 2007

 

First

 

CapeIRI + Celecoxib/Placebo

5.8 m

mIFL + Celecoxib/Placebo

5.9 m, P = 0.46 (comparison of CapeIRI + Celecoxib/Placebo to mIFL + Celecoxib/Placebo)

FOLFIRI + Celecoxib/Placebo

7.6 m, P = 0.015 (comparison of CapeIRI + Celecoxib/Placebo to FOLFIRI + Celecoxib/Placebo)

 

Hoff 2001

 

First

 

Capecitabine

4.3 m (4.1 to 5.1)

5‐FU/LV

4.7 m (4.3 to 5.5)

 

Kato 2012

First or second

Sequential IRIS‐BEV

345 d (312 to 594)

mFOLFIRI‐BEV

324 d (247 to 475), P = 0.71

Kohne 2008

 

First

 

CAPIRI‐Celecoxib/Placebo

5.9 m (4.4 to 8.9)

1 y: 22.6 (11.4 to 36.2)

FOLFIRI‐Celecoxib/Placebo

9.6 m (6.9 to 10.9)

1 y: 29.3 (16.4 to 43.4)

Pectasides 2012

 

First

 

XELIRI + BEV

10.2 m (9.0 to 11.5)

FOLFIRI + BEV

10.8 m (9.7 to 11.8), P = 0.74

 

Porschen 2007

 

First

 

CAPOX

7.1 m

FUFOX

8.0 m

 

Rothenberg 2008

 

Second

 

XELOX (ITT)

4.7 m

FOLFOX‐4 (ITT)

4.8 m

XELOX (per protocol)

5.1 m

FOLFOX‐4 (per protocol)

5.5 m

 

Schilsky 2002a

 

First

 

EU/5‐FU

20 wks (19.1 to 20.9)

5‐FU/LV

22.7 wks (18.3 to 24.6), P = 0.0106, log‐rank

 

Seymour 2011

 

First

 

Capecitabine

5.2 m (2.8 to 6.7)

OxCap

5.8 m (3.3 to 7.4)

FU

3.5 m (2.8 to 6.2)

OxFU

5.8 m (3.2 to 7.6)

 

Shigeta 2016

First

TEGAFIRI +/‐ BEV

9.9 m (6.5 to 14.7)

FOLFIRI +/‐ BEV

10.6 (7.7 to 16.5)

Souglakos 2012

 

First

 

CAPIRI + BEV

8.9 m (7.3 to 10.2)

FOLFIRI + BEV

10.0 m (8.9 to 11.1)

 

Van Cutsem 2001b

 

First

 

Capecitabine

5.2 m

5‐FU/LV

4.7 m

 

Yamada 2013

First

SOX + BEV

10.2 m (9.4 to 11.1)

mFOLFOX + BEV

10.2 m (9.5 to 11.3)

Yamazaki 2015

First

SOL

9.6 m

mFOLFOX6

6.9 m

Yasui 2015

Second

IRIS

5.8 m

FOLFIRI

5.1 m

PFS: progression‐free survival

CI: confidence interval

5‐dFUR: doxifluridine

IV: intravenous

BEV: bevacizumab

ITT: intention‐to‐treat

EPP: Expanded Participation Project

5‐FU: 5‐fluorouracil

LV: leucovorin

Appendix 16. TTP: Other information for studies where the outcome was suitable for meta‐analysis

Study

Line of chemotherapy

Chemotherapy arm

Median (95% CI)

P value

Ahn 2003

 

First

 

5‐dFUR + LV

5.4 m (1 to 18.4)

5‐FU/LV

4.7 m (1 to 25.4)

 

Carmichael 2002

 

First

 

UFT/LV

3.4 m (2.6 to 3.8)

5‐FU/LV 

3.3 m (2.5 to 3.7)

 P = 0.591, stratified log‐rank

Diaz‐Rubio 2007

 

First

 

XELOX

8.9 m (7.8 to 9.9)

FUOX

9.5 m (8.1 to 10.8)

 

Douillard 2002

 

First

 

UFT/LV

3.5 m (3.0 to 4.4)

5‐FU/LV

3.8 m(3.6 to 5.0)

 

Martoni 2006

 

First

 

XELOX

9 m (8 to 10)

pviFOX

7 m (5 to 9)

 

Nogue 2005

 

First

 

FT/LV

5.9 m (5.3 to 6.5)

5‐FU/LV

6.2 m (5.4 to 6.9)

 

TTP: time to progression

CI: confidence interval

5‐dFUR: doxifluridine

LV: leucovorin

5‐FU: 5‐fluorouracil

UFT: tegafur/uracil

Appendix 17. OS (palliative intent studies): Other information for studies where the outcome was suitable for meta‐analysis

Study

Line of chemotherapy

Chemotherapy arm

Median (95% CI)

P value

Survival rate, % (95% CI)

Ahn 2003

 

First

 

5‐dFUR + LV

14.9 m (1 to 26.8)

5‐FU/LV

19.5 m (1.9 to 25.4)

 

 

Bajetta 1996

 

First

 

Oral 5‐dFUR

10.6 m

IV 5‐dFUR

11 m

 

 

Carmichael 2002

 

First

 

UFT/LV

12.2 m

5‐FU/LV 

10.3 m

 P = 0.226, stratified log‐rank

 

Cassidy 2011a

 

First

 

XELOX/XELOX‐placebo/XELOX‐BEV

19.8 m

FOLFOX‐4/FOLFOX‐4‐placebo/FOLFOX‐4‐BEV

19.5 m

XELOX/XELOX‐placebo

19.0 m

FOLFOX‐4/FOLFOX‐4‐placebo

18.9 m

XELOX‐BEV

21.6 m

FOLFOX‐4‐BEV

21.0 m

XELOX

18.8 m

FOLFOX‐4

17.7 m

 

 

Comella 2009

 

First

 

OXXEL

16.0 m (11.2 to 20.2)

OXAFAFU

17.1 m (13.8 to 20.4)

 

 

Diaz‐Rubio 2007

 

First

 

XELOX

18.1 m (15.5 to 20.4)

FUOX

20.8 m (16.6 to 25.0)

 

 

Douillard 2002

 

First

 

UFT/LV

12.4 m (11.2 to 13.6)

5‐FU/LV

13.4 m (11.6 to 15.4)

P = 0.630, stratified log‐rank

Douillard 2014

First

UFOX + Cetuximab

16.8 m (13.9 to 18.5)

FOLFOX4 + Cetuximab

18.4 m (15.3 to 20.9)

Ducreux 2011

First

XELOX (ITT)

19.9 m

FOLFOX‐6 (ITT)

20.5 m

XELOX (per protocol)

20.1 m

FOLFOX‐6 (per protocol)

18.9 m

Ducreux 2013

 

First

 

XELIRI + BEV

23 m (21 to 27)

1 y: 87 (78 to 93)

FOLFIRI + BEV

23 m (21 to 32)

 

1 y: 85 (75 to 91)

XELIRI + BEV

2 y: 49 (37 to 60)

FOLFIRI + BEV

2 y: 48 (37 to 59)

ECOG E5296 2012

 

First

 

Eniluracil/5‐FU

1.0 yr (0.6 to 1.3)

5‐FU

1.5 y (0.9 to 1.8)

P = 0.17, stratified log‐rank

 

Fuchs 2007

 

First

 

CapeIRI + Celecoxib/Placebo

18.9 m

mIFL + Celecoxib/Placebo

17.6 m

FOLFIRI + Celecoxib/Placebo

23.1 m

 

 

Douillard 2014

First

 

UFOX + Cetuximab

16.8 m (13.9 to 18.5)

P = 0.86, log‐rank

FOLFOX4 + Cetuximab

18.4 m (15.3 to 20.9)

 

 

Hochster TREE‐1 2008

 

First

 

CapeOx

17.2 m (12.5 to 22.3)

bFOL

17.9 m (11.5 to 24.6)

mFOLFOX6

19.2 m (14.2 to 24.9)

 

 

Hochster TREE‐2 2008

 

First

 

CapeOx + BEV

24.6 m (21.3 to 31.6)

bFOL + BEV

20.4 m (18.4 to 25.3)

mFOLFOX6 + BEV

26.1 m (18.0 to NE)

 

 

Hoff 2001

 

First

 

Capecitabine

12.5 m (10.5 to 14.2)

5‐FU/LV

13.3 m (12.0‐14.6)

 

 

Kohne 2008

 

First

 

FOLFIRI‐Celecoxib/Placebo

19.9 m (18.9, NR)

1 y: 84.9 (69.4 to 92.9)

CAPIRI‐Celecoxib/Placebo

14.75 m (10.7 to 18.3)

 

1 y: 53.5 (36.0 to 68.2)

Nogue 2005

 

First

 

FT/LV

12.4 m (10.3 to 14.5)

5‐FU/LV

12.2 m (8.9 to 15.7)

 

 

Pectasides 2012

 

First

 

XELIRI + BEV

20.0 m (15.4 to 24.6)

P = 0.099

FOLFIRI + BEV

25.3 m (22.1 to 28.6)

 

 

Porschen 2007

 

First

 

CAPOX

16.8 m

FUFOX

18.8 m

 

 

Rothenberg 2008

 

Second

 

XELOX (ITT)

11.9 m

FOLFOX‐4 (ITT)

12.5 m

XELOX (EPP)

12.9 m

FOLFOX‐4 (EPP)

13.2 m

 

 

Schilsky 2002a

 

First

 

EU/5‐FU

13.3 m (12.0 to 15.1)

5‐FU/LV

14.5 m (12.8 to 16.2)

 P = 0.3135, log rank

 

Seymour 2011

 

First

 

Capecitabine

11.0 m (5.4 to 18.0)

OxCap

12.4 m (5.8 to 18.0)

FU

10.1 m (5.1 to 17.3)

OxFU

10.7 m (5.7 to 17.2)

 

 

Shigeta 2016

First

TEGAFIRI +/‐ BEV

26.7 m (20.4 to 31.0)

FOLFIRI +/‐ BEV

27.7 m (20.0 to 35.0)

Souglakos 2012

 

First

 

CAPIRI + BEV

27.5 m (22.6 to 32.3)

FOLFIRI + BEV

25.7 m (23.0 to 28.4)

 

 

Van Cutsem 2001a

 

First

 

Eniluracil/5‐FU

47.4 wks

5‐FU/LV

63.7 wks

 

 

Van Cutsem 2001b

 

First

 

Capecitabine

13.2 m

P = 0.33, log‐rank

5‐FU/LV

12.1 m

 

 

Yamada 2013

First

SOX + BEV

29.6 m (25.8 to NE)

mFOLFOX + BEV

30.9 m (28.6 to 33.1)

Yamazaki 2015

First

SOL

29.9 m

mFOLFOX6

25.9 m

Yasui 2015

Second

IRIS

17.8 m

FOLFIRI

17.4 m

OS: overall survival

CI: confidence interval

5‐dFUR: doxifluridine

5‐FU: 5‐fluorouracil

LV: leucovorin

IV: intravenous

UFT: tegafur/uracil

BEV: bevacizumab

ITT: intention‐to‐treat

NE: not estimable

NR: not reached

EPP: Expanded Participation Project

EU: eniluracil

Appendix 18. Key historical studies used to estimate the activity of the active control for disease‐free survival

Grage 1981

Taal 2001

Cafiero 2003

Quasar 2007

NCCTG, ECOG‐NCCTG/INT, SWOG‐INT0035, Siena, NCIC‐CTG, FFCD, and GIVIO studies in Gill 2004

Bosset 2006

Bujko 2006

Gerard 2006

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

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Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.1 1 In this graph, the risk of bias for each domain was calculated using the worst assessment documented for that domain in the contributing studies.
Figures and Tables -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.1

1 In this graph, the risk of bias for each domain was calculated using the worst assessment documented for that domain in the contributing studies.

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.1 1 In this summary, the risk of bias for each domain was scored using the worst assessment documented for that domain in the study.
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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.1

1 In this summary, the risk of bias for each domain was scored using the worst assessment documented for that domain in the study.

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Forest plot of disease‐free survival.
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Figure 4

Forest plot of disease‐free survival.

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Forest plot of comparison: 4 Progression‐free survival with, outcome: 4.4 Progression‐free survival with subgroup analysis ‐ oral fluoropyrimidine backbone.
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Figure 5

Forest plot of comparison: 4 Progression‐free survival with, outcome: 4.4 Progression‐free survival with subgroup analysis ‐ oral fluoropyrimidine backbone.

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Funnel plot of progression‐free survival.
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Figure 6

Funnel plot of progression‐free survival.

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Comparison 1 Disease‐free survival, Outcome 1 Disease‐free survival.
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Analysis 1.1

Comparison 1 Disease‐free survival, Outcome 1 Disease‐free survival.

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Comparison 1 Disease‐free survival, Outcome 2 Disease‐free survival with subgroup analysis ‐ Chemotherapy vs chemo‐radiotherapy.
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Analysis 1.2

Comparison 1 Disease‐free survival, Outcome 2 Disease‐free survival with subgroup analysis ‐ Chemotherapy vs chemo‐radiotherapy.

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Comparison 1 Disease‐free survival, Outcome 3 Disease‐free survival with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.
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Analysis 1.3

Comparison 1 Disease‐free survival, Outcome 3 Disease‐free survival with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.

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Comparison 1 Disease‐free survival, Outcome 4 Disease‐free survival with subgroup analysis ‐ Oral fluoropyrimidine backbone.
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Analysis 1.4

Comparison 1 Disease‐free survival, Outcome 4 Disease‐free survival with subgroup analysis ‐ Oral fluoropyrimidine backbone.

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Comparison 2 Overall survival (curative intent studies), Outcome 1 Overall survival (curative intent studies).
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Analysis 2.1

Comparison 2 Overall survival (curative intent studies), Outcome 1 Overall survival (curative intent studies).

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Comparison 2 Overall survival (curative intent studies), Outcome 2 Overall survival (curative intent studies) with subgroup analysis ‐ Chemotherapy vs chemo‐radiotherapy.
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Analysis 2.2

Comparison 2 Overall survival (curative intent studies), Outcome 2 Overall survival (curative intent studies) with subgroup analysis ‐ Chemotherapy vs chemo‐radiotherapy.

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Comparison 2 Overall survival (curative intent studies), Outcome 3 Overall survival (curative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.
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Analysis 2.3

Comparison 2 Overall survival (curative intent studies), Outcome 3 Overall survival (curative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.

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Comparison 2 Overall survival (curative intent studies), Outcome 4 Overall survival (curative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone.
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Analysis 2.4

Comparison 2 Overall survival (curative intent studies), Outcome 4 Overall survival (curative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone.

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Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 1 Grade ≥ 3 diarrhoea (curative intent studies).
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Analysis 3.1

Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 1 Grade ≥ 3 diarrhoea (curative intent studies).

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Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 2 Grade ≥ 3 diarrhoea (curative intent studies) with subgroup analysis ‐ Chemotherapy vs chemo‐radiotherapy.
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Analysis 3.2

Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 2 Grade ≥ 3 diarrhoea (curative intent studies) with subgroup analysis ‐ Chemotherapy vs chemo‐radiotherapy.

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Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 3 Grade ≥ 3 diarrhoea (curative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.
Figures and Tables -
Analysis 3.3

Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 3 Grade ≥ 3 diarrhoea (curative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.

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Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 4 Grade ≥ 3 diarrhoea (curative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone.
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Analysis 3.4

Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 4 Grade ≥ 3 diarrhoea (curative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone.

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Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 5 Grade ≥ 3 hand foot syndrome (curative intent studies).
Figures and Tables -
Analysis 3.5

Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 5 Grade ≥ 3 hand foot syndrome (curative intent studies).

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Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 6 Grade ≥ 3 neutropenia/granulocytopenia (curative intent studies).
Figures and Tables -
Analysis 3.6

Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 6 Grade ≥ 3 neutropenia/granulocytopenia (curative intent studies).

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Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 7 Grade ≥ 3 febrile neutropenia (curative intent studies).
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Analysis 3.7

Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 7 Grade ≥ 3 febrile neutropenia (curative intent studies).

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Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 8 Grade ≥ 3 vomiting (curative intent studies).
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Analysis 3.8

Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 8 Grade ≥ 3 vomiting (curative intent studies).

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Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 9 Grade ≥ 3 nausea (curative intent studies).
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Analysis 3.9

Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 9 Grade ≥ 3 nausea (curative intent studies).

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Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 10 Grade ≥ 3 stomatitis (curative intent studies).
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Analysis 3.10

Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 10 Grade ≥ 3 stomatitis (curative intent studies).

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Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 11 Grade ≥ 3 mucositis (curative intent studies).
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Analysis 3.11

Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 11 Grade ≥ 3 mucositis (curative intent studies).

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Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 12 Grade ≥ 3 hyperbilirubinaemia (curative intent studies).
Figures and Tables -
Analysis 3.12

Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 12 Grade ≥ 3 hyperbilirubinaemia (curative intent studies).

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Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 13 Any grade ≥ 3 adverse events (curative intent studies).
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Analysis 3.13

Comparison 3 Grade ≥ 3 adverse events (curative intent studies), Outcome 13 Any grade ≥ 3 adverse events (curative intent studies).

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Comparison 4 Progression‐free survival, Outcome 1 Progression‐free survival.
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Analysis 4.1

Comparison 4 Progression‐free survival, Outcome 1 Progression‐free survival.

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Comparison 4 Progression‐free survival, Outcome 2 Progression‐free survival with subgroup analysis ‐ Single‐agent vs combination therapy.
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Analysis 4.2

Comparison 4 Progression‐free survival, Outcome 2 Progression‐free survival with subgroup analysis ‐ Single‐agent vs combination therapy.

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Comparison 4 Progression‐free survival, Outcome 3 Progression‐free survival with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.
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Analysis 4.3

Comparison 4 Progression‐free survival, Outcome 3 Progression‐free survival with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.

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Comparison 4 Progression‐free survival, Outcome 4 Progression‐free survival with subgroup analysis ‐ Oral fluoropyrimidine backbone.
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Analysis 4.4

Comparison 4 Progression‐free survival, Outcome 4 Progression‐free survival with subgroup analysis ‐ Oral fluoropyrimidine backbone.

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Comparison 4 Progression‐free survival, Outcome 5 Progression‐free survival for combination therapy with subgroup analysis ‐ Oxaliplatin‐based vs irinotecan‐based.
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Analysis 4.5

Comparison 4 Progression‐free survival, Outcome 5 Progression‐free survival for combination therapy with subgroup analysis ‐ Oxaliplatin‐based vs irinotecan‐based.

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Comparison 4 Progression‐free survival, Outcome 6 Progression‐free survival for combination therapy with subgroup analysis ‐ with Bev vs no Bev.
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Analysis 4.6

Comparison 4 Progression‐free survival, Outcome 6 Progression‐free survival for combination therapy with subgroup analysis ‐ with Bev vs no Bev.

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Comparison 5 Overall survival (palliative intent studies), Outcome 1 Overall survival (palliative intent studies).
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Analysis 5.1

Comparison 5 Overall survival (palliative intent studies), Outcome 1 Overall survival (palliative intent studies).

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Comparison 5 Overall survival (palliative intent studies), Outcome 2 Overall survival (palliative intent studies) with subgroup analysis ‐ Single‐agent vs combination therapy.
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Analysis 5.2

Comparison 5 Overall survival (palliative intent studies), Outcome 2 Overall survival (palliative intent studies) with subgroup analysis ‐ Single‐agent vs combination therapy.

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Comparison 5 Overall survival (palliative intent studies), Outcome 3 Overall survival (palliative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.
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Analysis 5.3

Comparison 5 Overall survival (palliative intent studies), Outcome 3 Overall survival (palliative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.

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Comparison 5 Overall survival (palliative intent studies), Outcome 4 Overall survival (palliative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone.
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Analysis 5.4

Comparison 5 Overall survival (palliative intent studies), Outcome 4 Overall survival (palliative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone.

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Comparison 5 Overall survival (palliative intent studies), Outcome 5 Overall survival (palliative intent studies) for combination therapy with subgroup analysis ‐ Oxaliplatin‐based vs irinotecan‐based.
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Analysis 5.5

Comparison 5 Overall survival (palliative intent studies), Outcome 5 Overall survival (palliative intent studies) for combination therapy with subgroup analysis ‐ Oxaliplatin‐based vs irinotecan‐based.

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Comparison 6 Time to progression, Outcome 1 Time to progression.
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Analysis 6.1

Comparison 6 Time to progression, Outcome 1 Time to progression.

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Comparison 7 Objective response rate, Outcome 1 ORR.
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Analysis 7.1

Comparison 7 Objective response rate, Outcome 1 ORR.

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 1 Grade ≥ 3 diarrhoea (palliative intent studies).
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Analysis 8.1

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 1 Grade ≥ 3 diarrhoea (palliative intent studies).

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 2 Grade ≥ 3 diarrhoea (palliative intent studies) with subgroup analysis ‐ Single‐agent vs combination therapy.
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Analysis 8.2

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 2 Grade ≥ 3 diarrhoea (palliative intent studies) with subgroup analysis ‐ Single‐agent vs combination therapy.

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 3 Grade ≥ 3 diarrhea (palliative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.
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Analysis 8.3

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 3 Grade ≥ 3 diarrhea (palliative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 4 Grade ≥ 3 diarrhoea (palliative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone.
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Analysis 8.4

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 4 Grade ≥ 3 diarrhoea (palliative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone.

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 5 Grade ≥ 3 diarrhoea (palliative intent studies) with subgroup analysis for combination therapy ‐ Oxaliplatin‐based vs irinotecan‐based.
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Analysis 8.5

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 5 Grade ≥ 3 diarrhoea (palliative intent studies) with subgroup analysis for combination therapy ‐ Oxaliplatin‐based vs irinotecan‐based.

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 6 Grade ≥ 3 hand foot syndrome (palliative intent studies).
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Analysis 8.6

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 6 Grade ≥ 3 hand foot syndrome (palliative intent studies).

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 7 Grade ≥ 3 hand foot syndrome (palliative intent studies) with subgroup analysis ‐ Single‐agent vs combination therapy.
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Analysis 8.7

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 7 Grade ≥ 3 hand foot syndrome (palliative intent studies) with subgroup analysis ‐ Single‐agent vs combination therapy.

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 8 Grade ≥ 3 hand foot syndrome (palliative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.
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Analysis 8.8

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 8 Grade ≥ 3 hand foot syndrome (palliative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine.

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 9 Grade ≥ 3 hand foot syndrome (palliative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone.
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Analysis 8.9

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 9 Grade ≥ 3 hand foot syndrome (palliative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone.

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 10 Grade ≥ 3 hand foot syndrome (palliative intent studies) with subgroup analysis for combination therapy ‐ Oxaliplatin‐based vs irinotecan‐based.
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Analysis 8.10

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 10 Grade ≥ 3 hand foot syndrome (palliative intent studies) with subgroup analysis for combination therapy ‐ Oxaliplatin‐based vs irinotecan‐based.

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 11 Grade ≥ 3 neutropenia/granulocytopenia (palliative intent studies).
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Analysis 8.11

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 11 Grade ≥ 3 neutropenia/granulocytopenia (palliative intent studies).

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 12 Grade ≥ 3 febrile neutropenia (palliative intent studies).
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Analysis 8.12

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 12 Grade ≥ 3 febrile neutropenia (palliative intent studies).

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 13 Grade ≥ 3 vomiting (palliative intent studies).
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Analysis 8.13

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 13 Grade ≥ 3 vomiting (palliative intent studies).

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 14 Grade ≥ 3 nausea (palliative intent studies).
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Analysis 8.14

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 14 Grade ≥ 3 nausea (palliative intent studies).

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 15 Grade ≥ 3 stomatitis (palliative intent studies).
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Analysis 8.15

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 15 Grade ≥ 3 stomatitis (palliative intent studies).

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 16 Grade ≥ 3 mucositis (palliative intent studies).
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Analysis 8.16

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 16 Grade ≥ 3 mucositis (palliative intent studies).

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 17 Grade ≥ 3 hyperbilirubinaemia (palliative intent studies).
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Analysis 8.17

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 17 Grade ≥ 3 hyperbilirubinaemia (palliative intent studies).

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Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 18 Any grade ≥ 3 adverse events (palliative intent studies).
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Analysis 8.18

Comparison 8 Grade ≥ 3 adverse events (palliative intent studies), Outcome 18 Any grade ≥ 3 adverse events (palliative intent studies).

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Summary of findings for the main comparison. Oral compared with intravenous fluoropyrimidines for colorectal cancer ‐ Patients treated with curative intent

Oral compared with intravenous fluoropyrimidines for colorectal cancer ‐ Patients treated with curative intent

Patient or population: Patients treated with curative intent for colorectal cancer with neoadjuvant and/or adjuvant chemotherapy

Setting: Hospital

Intervention: Oral fluoropyrimidines

Comparison: Intravenous fluoropyrimidines

Outcomes

Illustrative comparative risks (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Quality of the evidence
(GRADE)

Assumed risk*

Corresponding risk**

Intravenous fluoropyrimidines

Oral fluoropyrimidines

Disease‐free survival

313 per 1000a

291 per 1000

(272 to 313)

HR 0.93
(0.87 to 1.00)

8903
(7 RCTs)

⊕⊕⊕⊝
MODERATEb

Overall survival

222 per 1000c

204 per 1000

(186 to 222)

HR 0.92

(0.84 to 1.00)

8902

(7 RCTs)

⊕⊕⊕⊕
HIGH

Grade ≥ 3 diarrhoea

137 per 1000d

153 per 1000

(135 to 171)

OR 1.12
(0.99 to 1.25)

9551
(9 RCTs)

⊕⊝⊝⊝
VERY LOWb,e,f

Grade ≥ 3 hand foot syndrome

8 per 1000d

37 per 1000

(24 to 57)

OR 4.59g
(2.97 to 7.10)

5731
(5 RCTs)

⊕⊕⊝⊝
LOWb,e

Grade ≥ 3 neutropenia/granulocytopenia

181 per 1000d

25 per 1000

(20 to 29)

OR 0.14

(0.11 to 0.16)

8087

(7 RCTs)

⊕⊕⊕⊝
MODERATEe

*The basis for the assumed risk is provided in footnotes. **The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Pooled estimates from fixed‐effects meta‐analysis are reported in the table
CI: Confidence interval; HR: Hazard ratio; RCTs: randomised controlled trials; OR: Odds ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate

aThe assumed risk for disease‐free survival was based on the 3‐year disease‐free survival rate in the control group from studies in the meta‐analysis (68.7%)

bDowngraded by one level owing to a high risk of bias in included studies.

cThe assumed risk for overall survival was based on the 5‐year overall survival rate in the control group from studies in the meta‐analysis (77.8%)

dThe assumed risk for each grade ≥ 3 AE was the mean risk in the control group from studies in the meta‐analysis

eDowngraded by one level owing to inconsistency of results that was supported by non‐overlapping CIs, high I2 values, and statistically significant heterogeneity of effect estimates

fDowngraded by one level owing to imprecision

gRandom‐effects estimate, OR 2.36 (95% CI 0.52 to 10.74). Pooled effect estimate was sensitive to the meta‐analysis model used

Figures and Tables -
Summary of findings for the main comparison. Oral compared with intravenous fluoropyrimidines for colorectal cancer ‐ Patients treated with curative intent
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Summary of findings 2. Oral compared with intravenous fluoropyrimidines for colorectal cancer ‐ Patients treated with palliative intent

Oral compared with intravenous fluoropyrimidines for colorectal cancer ‐ Patients treated with palliative intent

Patient or population: Patients treated with palliative intent for inoperable advanced or metastatic colorectal cancer with chemotherapy

Setting: Hospital

Intervention: Oral fluoropyrimidines

Comparison: Intravenous fluoropyrimidines

Outcomes

Illustrative comparative risks (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Quality of the evidence
(GRADE)

Assumed risk*

Corresponding risk**

Intravenous fluoropyrimidines

Oral fluoropyrimidines

Progression‐free survival

398 per 1000a

422 per 1000

(406 to 442)

HR 1.06
(1.02 to 1.11)

9927
(23 RCTs)

⊕⊕⊕⊝
MODERATEb

Overall survival

336 per 1000c

343 per 1000

(333 to 353)

HR 1.02

(0.99 to 1.05)

12,079

(29 RCTs)

⊕⊕⊕⊕
HIGH

Grade ≥ 3 diarrhoea

120 per 1000d

199 per 1000

(180 to 221)

OR 1.66
(1.50 to 1.84)

11,997
(30 RCTs)

⊕⊕⊝⊝
LOWb,e

Grade ≥ 3 hand foot syndrome

13 per 1000d

51 per 1000

(37 to 71)

OR 3.92
(2.84 to 5.43)

6481
(18 RCTs)

⊕⊕⊕⊝
MODERATEb

Grade ≥ 3 neutropenia/granulocytopenia

331 per 1000d

56 per 1000

(50 to 60)

OR 0.17

(0.15 to 0.18)

11,794

(29 RCTs)

⊕⊕⊝⊝
LOWb,e

*The basis for the assumed risk is provided in footnotes. **The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Pooled estimates from fixed‐effects meta‐analysis are reported in the table
CI: Confidence interval; HR: Hazard ratio; RCTs: randomised controlled trials; OR: Odds ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate

aThe assumed risk for progression‐free survival was based on the 6‐month progression‐free survival rate in the control group from studies in the meta‐analysis (60.2%)

bDowngraded by one level owing to a high risk of bias in included studies

cThe assumed risk for overall survival was based on the 12‐month overall survival rate in the control group from studies in the meta‐analysis (66.4%)

dThe assumed risk for each grade ≥ 3 AE was the mean risk in the control group from the studies in the meta‐analysis

eDowngraded by one level owing to inconsistency of results that was supported by non‐overlapping CIs, high I2 values, and statistically significant heterogeneity of effect estimates

Figures and Tables -
Summary of findings 2. Oral compared with intravenous fluoropyrimidines for colorectal cancer ‐ Patients treated with palliative intent
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Table 1. Included studies ‐ Patients treated with curative intent for colorectal cancer

Treatment setting

Study ID

Phase

Treatment type

Treatment arm/s (oral), n randomised

Treatment arm/s (IV), n randomised

IV arm: bolus vs Infusional

Neoadjuvant

Rectal

Allegra 2015

III

Fluoropyrimidine combined with RT

Capecitabine (Grp 2), n = 146

Capecitabine (Grp 5), n = 326

Capecitabine + oxaliplatin (Grp 6), n = 330

5‐FU (Grp 1), n = 147

5‐FU (Grp 3), n = 330

5‐FU + oxaliplatin (Grp 4), n = 329

Infusional

De la Torre 2008

III

Fluoropyrimidine combined with RT

UFT (Tegafur/Uracil) + LV with RT, n = 78

5‐FU + LV with RT, n = 77

Bolus

Neoadjuvant/

Adjuvant

Rectal

Hofheinz 2012

III

Fluoropyrimidine combined with RT

Capecitabine with RT, n = 197

∙ Adjuvant cohort: n = 116

∙ Neoadjuvant cohort: n = 81

5‐FU with RT, n = 195

∙ Adjuvant cohort: n = 115

∙ Neoadjuvant cohort: n = 80

Bolus and infusional

Adjuvant

Rectal

Kim 2001a

ND

Fluoropyrimidine combined with RT (after completion of 2C of fluoropyrimidine alone)

5‐dFUR + LV, n = 92

5‐FU + LV, n = 74

Bolus

Colon

De Gramont 2012

III

Combination chemotherapy ‐ Oxaliplatin + Bevacizumab (BEV)

BEV‐XELOX, n = 952

BEV‐FOLFOX4, n = 960

Infusional

Lembersky 2006

III

Fluoropyrimidine alone

UFT + LV, n = 805

5‐FU + LV, n = 803

Bolus

Shimada 2014

III

Fluoropyrimidine alone

UFT + LV, n = 551

5‐FU + LV, n = 550

Bolus

Twelves 2012

III

Fluoropyrimidine alone

Capecitabine, n = 1004

5‐FU + LV, n = 983

Bolus

Colorectal

Pectasides 2015

III

Combination chemotherapy ‐ fluoropyrimidine + oxaliplatin

CAPOX (capecitabine + oxaliplatin), n = 197

mFOLFOX6, n = 211

Infusional

IV: intravenous

RT: radiotherapy

5‐FU: 5‐fluorouracil

UFT: tegafur/uracil

LV: leucovorin

ND: no data available

5‐dFUR: doxifluridine

BEV: bevacizumab
Figures and Tables -
Table 1. Included studies ‐ Patients treated with curative intent for colorectal cancer
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Table 2. Included studies ‐ Patients treated with palliative intent for inoperable advanced or metastatic colorectal cancer (single‐agent fluoropyrimidines)

Oral fluoropyrimidine backbone

Study ID

Phase

Treatment line

Treatment arm/s (Oral), n randomised

Treatment arm/s (IV), n randomised

IV arm: Bolus vs Infusional

Capecitabine

Hoff 2001

III

First

Capecitabine, n = 302

5‐FU + LV, n = 303

Bolus

Van Cutsem 2001b

III

First

Capecitabine, n = 301

5‐FU + LV, n = 301

Bolus

Doxifluridine (5‐dFUR)

Ahn 2003

II

First

5‐dFUR + LV, n = 38

5‐FU + LV, n = 39

Bolus

Bajetta 1996

II

First

5‐dFUR + LV, n = 67

5‐dFUR + LV, n = 63 

Bolus

Eniluracil + oral 5‐FU

ECOG E5296 2012

III

First

Eniluracil/Oral 5‐FU, n = 61

5‐FU, n = 64

Infusional

Schilsky 2002a

III

First

Eniluracil/Oral 5‐FU, n = 488

5‐FU + LV, n = 493

Bolus

Van Cutsem 2001a

III

First

Eniluracil/Oral 5‐FU, n = 268

5‐FU + LV, n = 263

Bolus

Ftorafur/tegafur (FT)

Andersen 1987

ND

First

Ftorafur, n = 30

5‐FU, n = 30

Bolus

Nogue 2005

Unclear; described as Phase IV in abstracts

First

FT + LV, n = 114

5‐FU + LV, n = 123

Bolus

Ftorafur + uracil (UFT)

Carmichael 2002

III

First

UFT + LV, n = 190

5FU + LV, n = 190

Bolus

Douillard 2002

III

First

UFT + LV, n = 409

5‐FU + LV, n = 407

Bolus

IV: intravenous

5‐FU: 5‐fluorouracil

LV: leucovorin

5‐dFUR: doxifluridine

ND: no data available

FT: tegafur

UFT: tegafur + uracil
Figures and Tables -
Table 2. Included studies ‐ Patients treated with palliative intent for inoperable advanced or metastatic colorectal cancer (single‐agent fluoropyrimidines)
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Table 3. Included studies ‐ Patients treated with palliative intent for inoperable advanced or metastatic colorectal cancer (combination chemotherapy)

Chemotherapy

Study ID

Phase

Study design ‐ other details

Treatment line

Treatment arm/s (Oral), n randomised

Treatment arm/s (IV), n randomised

IV arm: Bolus vs Infusional

Oxaliplatin

Combination with capecitabine

Cassidy 2011a

III

2 × 2 factorial ‐ following protocol amendment

First

XELOX alone, n = 317

FOLFOX‐4 alone, n = 317

Infusional

XELOX + Placebo, n = 350

FOLFOX‐4 + Placebo, n = 351

Infusional

XELOX + BEV, n = 350

FOLFOX‐4 + BEV, n = 350

Infusional

Comella 2009

III

First

OXXEL (Capecitabine + oxaliplatin), n = 158

OXAFAFU (5‐FU/LV + Oxaliplatin), n = 164

Bolus

Diaz‐Rubio 2007

III

First

XELOX, n = 174

FUOX (5‐FU + Oxaliplatin), n = 174

Infusional

Ducreux 2011

III

First

XELOX, n = 156

FOLFOX‐6, n = 150

Infusional

Hochster TREE‐1 2008

ND

First

CapeOx, n = 50

mFOLFOX6, n = 50

Infusional

bFOL, n = 50

Bolus

Hochster TREE‐2 2008

ND

First

CapeOx + BEV, n = 74

mFOLFOX6 + BEV, n = 75

Infusional

bFOL + BEV, n = 74

Bolus

Martoni 2006

II

First

XELOX, n = 62

pviFOX, n = 56

Infusional

Porschen 2007

III

First

CAPOX, n = 242

FUFOX, n = 234

Infusional

Rothenberg 2008

III

Second

XELOX, n = 313

FOLFOX‐4, n = 314

Infusional

Seymour 2011

ND

2 × 2 factorial, cross‐over (only from no oxaliplatin to oxaliplatin)

First

Capecitabine or OxCap, n = 229

∙ Capecitabine, n = 115

∙ OxCap, n = 114

5‐FU or OxFU, n = 230

∙ 5‐FU, n = 115

∙ OxFU, n = 115

Infusional

Combination with Ftorafur/uracil (UFT)

Douillard 2014

II

First

UFOX + Cetuximab, n = 152

FOLFOX4 + Cetuximab, n = 150

Infusional

Combination with S‐1

Mei 2014

ND

First

SOX, n = 35

FOLFOX4, n = 35

Infusional

Yamada 2013

III

First

SOX‐BEV, n = 256

mFOLFOX6‐BEV, n = 256

Infusional

Yamazaki 2015

II

First

SOL (S‐1 + oxaliplatin + oral LV), n = 56

mFOLFOX6, n = 51

Infusional

Irinotecan

Combination with capecitabine

Ducreux 2013

II

First

XELIRI + BEV, n = 72

FOLFIRI + BEV, n = 73

Infusional

Fuchs 2007

III

3 × 2 factorial (Period 1)

First

CapeIRI + Celecoxib/Placebo, n = 145

FOLFIRI + Celecoxib/Placebo, n = 144

Infusional

mIFL + Celecoxib/Placebo, n = 141

Bolus

Kohne 2008

III

2 × 2 factorial

First

CAPIRI + Celecoxib/Placebo, n = 44

FOLFIRI + Celecoxib/Placebo, n = 41

Infusional

Pectasides 2012

III

First

XELIRI + BEV, n = 143

FOLFIRI + BEV, n = 142

Infusional

Silvestris 2010

II

First

XELIRI, n = ND

FOLFIRI, n = ND

Infusional

Souglakos 2012

II

First

CAPIRI + BEV, n = 168

FOLFIRI + BEV, n = 168

Infusional

Yu 2005

ND

First and second

Capecitabine + Irinotecan, n = 27

5‐FU + Irinotecan, n = 16

Infusional

Combination with Ftorafur/uracil (UFT)

Shigeta 2016

II

First

TEGAFIRI (UFT, leucovorin, irinotecan) ± BEV, n = 35

FOLFIRI ± BEV, n = 36

Infusional

Combination with S‐1

Kato 2012

II

First and second

Sequential IRIS‐BEV, n = 30

mFOLFIRI‐BEV, n = 30

Infusional

Yasui 2015

II/III

Second

IRIS (Irinotecan + S‐1), n = 213

FOLFIRI, n = 213

Infusional

IV: intravenous

BEV: bevacizumab

ND: no data available

UFT: tegafur/uracil
Figures and Tables -
Table 3. Included studies ‐ Patients treated with palliative intent for inoperable advanced or metastatic colorectal cancer (combination chemotherapy)
Navigate to table in Review
Table 4. Grade ≥ 3 adverse events ‐ Reported relationships to treatment in different studies

Setting

Related

Related and unrelated

Not specified

Patients treated with curative intent for CRC

with neoadjuvant and/or adjuvant chemotherapy

Twelves 2012

De Gramont 2012

Allegra 2015

De la Torre 2008

Hofheinz 2012

Kim 2001a

Lembersky 2006

Pectasides 2015

Shimada 2014

Patients treated with palliative intent for

inoperable advanced or metastatic CRC

with chemotherapy

 

Ahn 2003

ECOG E5296 2012

Fuchs 2007

Hoff 2001

Nogue 2005

Schilsky 2002a

Seymour 2011

Souglakos 2012

Van Cutsem 2001a

Van Cutsem 2001b

Yamazaki 2015

Cassidy 2011a

Douillard 2014

Hochster TREE‐1 2008

Hochster TREE‐2 2008

Kato 2012

Rothenberg 2008

Shigeta 2016

Yamada 2013

Yasui 2015

 

Bajetta 1996

Carmichael 2002

Comella 2009

De la Torre 2008

Diaz‐Rubio 2007

Douillard 2002

Ducreux 2011

Ducreux 2013

Kohne 2008

Martoni 2006

Pectasides 2012

Porschen 2007

Silvestris 2010

Yu 2005

CRC: colorectal cancer
Figures and Tables -
Table 4. Grade ≥ 3 adverse events ‐ Reported relationships to treatment in different studies
Navigate to table in Review
Table 5. Included studies that contributed to pooled effect estimates for each outcome ‐ Patients treated with curative intent for colorectal cancer

Study ID

Outcome

Efficacy

Grade ≥ 3 AE

DFS

OS

Diarrhoea

HFS

Neutropenia/

granulocytopenia

Febrile neutropenia

Vomiting

Nausea

Stomatitis

Mucositis

Hyperbilirubinemia

Any

Allegra 2015

X

X

X

X

X

X

X

X

X

X

X

De Gramont 2012

X

X

X

X

X

X

X

X

De la Torre 2008

Oa

Oa

X

Ob

X

X

X

Xc

Xc

Hofheinz 2012

X

X

X

X

X

X

X

X

X

X

Kim 2001a

X

X

Lembersky 2006

X

X

X

X

X

X

X

X

Pectasides 2015

X

X

X

X

X

X

X

X

X

Shimada 2014

X

X

X

X

X

X

X

X

X

Twelves 2012

X

X

X

Ob

X

Xd

Xd

X

Oe

X

X: Study contributed to the pooled effect estimate for the outcome

O: Study reported the outcome but did not contribute to the pooled effect estimate for the outcome

aInsufficient follow‐up time ‐ median 22 months in each arm (< 3 years)

bAssessed grade ≥ 3 HFS using criteria not considered to be sufficiently similar to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (versions 2.0 to 4.0)

cReported combined data for grade ≥ 3 stomatitis and mucositis

dReported combined data for grade ≥ 3 vomiting and nausea

eAssessed grade 3 ≥ hyperbilirubinaemia using criteria not considered to be sufficiently similar to NCI CTCAE (versions 2.0 to 4.0 and 1981) and World Health Organisation (WHO) (1981 version)

AE: adverse event

DFS: disease‐free survival

OS: overall survival

HFS: hand foot syndrome
Figures and Tables -
Table 5. Included studies that contributed to pooled effect estimates for each outcome ‐ Patients treated with curative intent for colorectal cancer
Navigate to table in Review
Table 6. Included studies that contributed to pooled effect estimates for each outcome ‐ Patients treated with palliative intent for inoperable advanced or metastatic colorectal cancer

Study ID

Outcome

Efficacy

Grade ≥ 3 AE

PFS

TTP

OS

ORR

Diarrhoea

HFS

Neutropenia/

granulocytopenia

Febrile neutropenia

Vomiting

Nausea

Stomatitis

Mucositis

Hyperbilirubinemia

Any

Ahn 2003

X

X

X

Oa

Oa

Oa

Oa

Andersen 1987

Ob

X

Bajetta 1996

X

X

X

X

X

Carmichael 2002

X

X

X

X

X

X

Xc

Xc

Xd

Xd

Oe

Cassidy 2011a

X

X

X

X

X

X

X

Xc

Xc

X

X

Comella 2009

X

X

X

X

X

X

X

Diaz‐Rubio 2007

X

X

X

X

X

X

X

X

X

X

X

Douillard 2002

X

X

X

X

Of

X

X

Xc

Xc

Xd

Xd

Oe

Douillard 2014

X

X

X

X

X

X

X

X

X

X

X

X

X

Ducreux 2011

X

X

X

X

X

X

X

X

X

X

Ducreux 2013

X

X

X

X

X

X

X

X

X

X

X

ECOG E5296 2012

X

X

X

X

X

X

X

X

X

X

X

Fuchs 2007

X

X

X

X

X

X

X

X

X

Hochster TREE‐1 2008

Ob

X

X

X

X

X

Xc

Xc

X

Hochster TREE‐2 2008

Ob

X

X

X

X

X

Xc

Xc

X

Hoff 2001

X

X

X

X

Og

X

X

X

X

X

Kato 2012

X

X

X

X

X

X

X

X

X

Kohne 2008

X

X

X

X

X

X

X

X

X

Martoni 2006

X

X

X

X

X

X

X

Mei 2014

Oh

X

X

Xc

Xc

Nogue 2005

X

X

X

X

X

Xc

Xc

X

Pectasides 2012

X

X

X

X

X

X

X

X

X

X

X

Porschen 2007

X

X

X

X

X

X

X

X

Rothenberg 2008

X

X

X

X

X

X

X

X

X

X

Oi

X

Schilsky 2002a

X

X

X

X

Og

X

X

X

X

X

Seymour 2011

X

X

Oj

X

X

X

X

X

X

X

Shigeta 2016

X

X

X

X

X

X

X

X

Xd

Xd

X

X

Silvestris 2010

Ob

Oa

Oa

Oa

Souglakos 2012

X

X

X

X

X

X

X

X

X

X

Van Cutsem 2001a

X

X

X

X

X

X

X

Van Cutsem 2001b

X

X

X

X

Og

X

X

X

X

Yamada 2013

X

X

X

X

X

X

X

X

X

Xd

Xd

X

Yamazaki 2015

X

X

X

X

X

X

X

X

X

Yasui 2015

X

X

X

X

X

X

X

Xd

Xd

Yu 2005

Ob

Ob

X

Oa

Oa

Oa

Oa

Oa

X: Study contributed to the pooled effect estimate for the outcome

O: Study reported the outcome but did not contribute to the pooled effect estimate for the outcome

aUnclear number of participants assessed for outcomes in both arms

bHazard ratios could not be estimated either directly or indirectly from the provided information

cReported combined data for grade ≥3 vomiting and nausea

dReported combined data for grade ≥3 stomatitis and mucositis

eAssessed grade ≥ 3 hyperbilirubinaemia using Common Toxicity Criteria (CTC), version not specified

fAssessed grade ≥ 3 HFS using CTC, version not specified

gAssessed grade ≥ 3 HFS using criteria not considered to be sufficiently similar to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (versions 2.0 to 4.0)

hORR reported after 2 cycles of chemotherapy

iAssessed grade ≥3 hyperbilirubinaemia using criteria not considered to be sufficiently similar to NCI CTCAE (versions 2.0 to 4.0 and 1981) and World Health Organisation (WHO) (1981 version)

jORR reported 12 to 14 weeks after start of treatment

AE: adverse event

PFS: progression‐free survival

TTP: time to progression

OS: overall survival

ORR: objective response rate

HFS: hand foot syndrome
Figures and Tables -
Table 6. Included studies that contributed to pooled effect estimates for each outcome ‐ Patients treated with palliative intent for inoperable advanced or metastatic colorectal cancer
Navigate to table in Review
Table 7. Risk of bias for studies contributing to the quantitative synthesis for disease‐free survival

Risk of bias assessment

Low

Unclear

High

No studies

No studies

Allegra 2015

De Gramont 2012

Hofheinz 2012

Lembersky 2006

Pectasides 2015

Shimada 2014

Twelves 2012

Figures and Tables -
Table 7. Risk of bias for studies contributing to the quantitative synthesis for disease‐free survival
Navigate to table in Review
Table 8. Risk for bias for studies contributing to the quantitative synthesis for progression‐free survival

Risk of bias assessment

Low

Unclear

High

Souglakos 2012

Cassidy 2011a

Bajetta 1996

Yamazaki 2015

Hoff 2001

Comella 2009

Rothenberg 2008

Douillard 2014

Van Cutsem 2001b

Ducreux 2011

Ducreux 2013

ECOG E5296 2012

Fuchs 2007

Kato 2012

Kohne 2008

Pectasides 2012

Porschen 2007

Schilsky 2002a

Seymour 2011

Shigeta 2016

Van Cutsem 2001a

Yamada 2013

Yasui 2015

Figures and Tables -
Table 8. Risk for bias for studies contributing to the quantitative synthesis for progression‐free survival
Navigate to table in Review
Table 9. Sensitivity analyses

Sensitivity analyses for PFS outcome

Original analysis: (effect estimatea, fixed
(95% CI)) 

Sensitivity analysis: (effect estimatea, fixed
(95% CI))

Excluding studies with 'High' risk of bias

1.06 (1.02 to 1.11)

1.01 (95% CI 0.96 to 1.07)

Excluding Seymour 2011 study (frail and elderly study population)

1.06 (1.02 to 1.11)

1.07 (1.03 to 1.11)

Excluding second‐line studies in patients treated with palliative intent for inoperable or metastatic colorectal cancerb

1.06 (1.02 to 1.11)

1.07 (1.03 to 1.12)

aEffect estimates presented as inverse‐variance hazard ratios for time‐to‐event outcomes, and Mantel‐Haenszel odds ratios for adverse events

bAnalysis excluding Kato 2012, Rothenberg 2008, Yasui 2015, and Yu 2005. Kato 2012 and Yu 2005 included patients receiving first‐ or second‐line treatment

PFS: progression‐free survival

CI: confidence interval
Figures and Tables -
Table 9. Sensitivity analyses
Navigate to table in Review
Comparison 1. Disease‐free survival

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Disease‐free survival Show forest plot

7

8903

Hazard Ratio (Fixed, 95% CI)

0.93 [0.87, 1.00]

2 Disease‐free survival with subgroup analysis ‐ Chemotherapy vs chemo‐radiotherapy Show forest plot

7

8903

Hazard Ratio (Fixed, 95% CI)

0.93 [0.87, 1.00]

2.1 Chemotherapy

5

6944

Hazard Ratio (Fixed, 95% CI)

0.94 [0.87, 1.02]

2.2 Chemo‐radiotherapy

2

1959

Hazard Ratio (Fixed, 95% CI)

0.91 [0.78, 1.05]

3 Disease‐free survival with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine Show forest plot

6

8511

Hazard Ratio (Fixed, 95% CI)

0.95 [0.88, 1.02]

3.1 Infusional intravenous fluoropyrimidine

3

3881

Hazard Ratio (Fixed, 95% CI)

0.96 [0.85, 1.08]

3.2 Bolus intravenous fluoropyrimidine

3

4630

Hazard Ratio (Fixed, 95% CI)

0.94 [0.86, 1.04]

4 Disease‐free survival with subgroup analysis ‐ Oral fluoropyrimidine backbone Show forest plot

7

8903

Hazard Ratio (Fixed, 95% CI)

0.93 [0.87, 1.00]

4.1 Capecitabine

5

6260

Hazard Ratio (Fixed, 95% CI)

0.91 [0.83, 0.99]

4.2 UFT/Ftorafur

2

2643

Hazard Ratio (Fixed, 95% CI)

1.01 [0.88, 1.15]
Figures and Tables -
Comparison 1. Disease‐free survival
Navigate to table in Review
Comparison 2. Overall survival (curative intent studies)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival (curative intent studies) Show forest plot

7

8902

Hazard Ratio (Fixed, 95% CI)

0.92 [0.84, 1.00]

2 Overall survival (curative intent studies) with subgroup analysis ‐ Chemotherapy vs chemo‐radiotherapy Show forest plot

7

8902

Hazard Ratio (Fixed, 95% CI)

0.92 [0.84, 1.00]

2.1 Chemotherapy

5

6943

Hazard Ratio (Fixed, 95% CI)

0.93 [0.84, 1.03]

2.2 Chemotherapy with radiotherapy

2

1959

Hazard Ratio (Fixed, 95% CI)

0.86 [0.70, 1.06]

3 Overall survival (curative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine Show forest plot

6

8510

Hazard Ratio (Fixed, 95% CI)

0.93 [0.85, 1.02]

3.1 Infusional intravenous fluoropyrimidine

3

3880

Hazard Ratio (Fixed, 95% CI)

0.94 [0.80, 1.09]

3.2 Bolus intravenous fluoropyrimidine

3

4630

Hazard Ratio (Fixed, 95% CI)

0.93 [0.83, 1.05]

4 Overall survival (curative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone Show forest plot

7

8902

Hazard Ratio (Fixed, 95% CI)

0.92 [0.84, 1.00]

4.1 Capecitabine

5

6259

Hazard Ratio (Fixed, 95% CI)

0.88 [0.79, 0.98]

4.2 UFT/Ftorafur

2

2643

Hazard Ratio (Fixed, 95% CI)

1.03 [0.86, 1.22]
Figures and Tables -
Comparison 2. Overall survival (curative intent studies)
Navigate to table in Review
Comparison 3. Grade ≥ 3 adverse events (curative intent studies)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Grade ≥ 3 diarrhoea (curative intent studies) Show forest plot

9

9551

Odds Ratio (M‐H, Fixed, 95% CI)

1.12 [0.99, 1.25]

2 Grade ≥ 3 diarrhoea (curative intent studies) with subgroup analysis ‐ Chemotherapy vs chemo‐radiotherapy Show forest plot

9

9551

Odds Ratio (M‐H, Fixed, 95% CI)

1.12 [0.99, 1.25]

2.1 Chemotherapy

5

7274

Odds Ratio (M‐H, Fixed, 95% CI)

1.08 [0.95, 1.23]

2.2 Chemo‐radiotherapy

4

2277

Odds Ratio (M‐H, Fixed, 95% CI)

1.28 [0.98, 1.66]

3 Grade ≥ 3 diarrhoea (curative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine Show forest plot

8

9159

Odds Ratio (M‐H, Fixed, 95% CI)

1.09 [0.97, 1.23]

3.1 Infusional intravenous fluoropyrimidine

3

4255

Odds Ratio (M‐H, Fixed, 95% CI)

1.27 [1.06, 1.53]

3.2 Bolus intravenous fluoropyrimidine

5

4904

Odds Ratio (M‐H, Fixed, 95% CI)

0.98 [0.84, 1.14]

4 Grade ≥ 3 diarrhoea (curative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone Show forest plot

9

9551

Odds Ratio (M‐H, Fixed, 95% CI)

1.12 [0.99, 1.25]

4.1 Capecitabine

5

6616

Odds Ratio (M‐H, Fixed, 95% CI)

1.15 [0.99, 1.33]

4.2 UFT/Ftorafur

3

2769

Odds Ratio (M‐H, Fixed, 95% CI)

1.00 [0.83, 1.21]

4.3 Doxifluridine

1

166

Odds Ratio (M‐H, Fixed, 95% CI)

32.14 [1.89, 545.41]

5 Grade ≥ 3 hand foot syndrome (curative intent studies) Show forest plot

5

5731

Odds Ratio (M‐H, Fixed, 95% CI)

4.59 [2.97, 7.10]

6 Grade ≥ 3 neutropenia/granulocytopenia (curative intent studies) Show forest plot

7

8707

Odds Ratio (M‐H, Fixed, 95% CI)

0.14 [0.11, 0.16]

7 Grade ≥ 3 febrile neutropenia (curative intent studies) Show forest plot

4

2925

Odds Ratio (M‐H, Fixed, 95% CI)

0.59 [0.18, 1.90]

8 Grade ≥ 3 vomiting (curative intent studies) Show forest plot

8

9385

Odds Ratio (M‐H, Fixed, 95% CI)

1.05 [0.83, 1.34]

9 Grade ≥ 3 nausea (curative intent studies) Show forest plot

7

9233

Odds Ratio (M‐H, Fixed, 95% CI)

1.21 [0.97, 1.51]

10 Grade ≥ 3 stomatitis (curative intent studies) Show forest plot

5

4212

Odds Ratio (M‐H, Fixed, 95% CI)

0.21 [0.14, 0.30]

11 Grade ≥ 3 mucositis (curative intent studies) Show forest plot

4

2233

Odds Ratio (M‐H, Fixed, 95% CI)

0.64 [0.25, 1.62]

12 Grade ≥ 3 hyperbilirubinaemia (curative intent studies) Show forest plot

3

2757

Odds Ratio (M‐H, Fixed, 95% CI)

1.67 [0.52, 5.38]

13 Any grade ≥ 3 adverse events (curative intent studies) Show forest plot

5

7741

Odds Ratio (M‐H, Fixed, 95% CI)

0.82 [0.74, 0.90]
Figures and Tables -
Comparison 3. Grade ≥ 3 adverse events (curative intent studies)
Navigate to table in Review
Comparison 4. Progression‐free survival

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Progression‐free survival Show forest plot

23

9927

Hazard Ratio (Fixed, 95% CI)

1.06 [1.02, 1.11]

2 Progression‐free survival with subgroup analysis ‐ Single‐agent vs combination therapy Show forest plot

22

9468

Hazard Ratio (Fixed, 95% CI)

1.07 [1.03, 1.11]

2.1 Single agent

6

2955

Hazard Ratio (Fixed, 95% CI)

1.12 [1.04, 1.21]

2.2 Combination therapy

16

6513

Hazard Ratio (Fixed, 95% CI)

1.05 [1.00, 1.10]

3 Progression‐free survival with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine Show forest plot

23

9927

Hazard Ratio (Fixed, 95% CI)

1.06 [1.02, 1.11]

3.1 Infusional intravenous fluoropyrimidine

17

6560

Hazard Ratio (Fixed, 95% CI)

1.05 [1.00, 1.10]

3.2 Bolus intravenous fluoropyrimidine

7

3367

Hazard Ratio (Fixed, 95% CI)

1.10 [1.03, 1.19]

4 Progression‐free survival with subgroup analysis ‐ Oral fluoropyrimidine backbone Show forest plot

23

9927

Hazard Ratio (Fixed, 95% CI)

1.06 [1.02, 1.11]

4.1 Capecitabine

13

6703

Hazard Ratio (Fixed, 95% CI)

1.03 [0.98, 1.08]

4.2 UFT/Ftorafur

2

374

Hazard Ratio (Fixed, 95% CI)

1.36 [1.07, 1.73]

4.3 Eniluracil + oral 5‐FU

3

1618

Hazard Ratio (Fixed, 95% CI)

1.22 [1.10, 1.36]

4.4 Doxifluridine

1

130

Hazard Ratio (Fixed, 95% CI)

1.18 [0.79, 1.74]

4.5 S‐1

4

1102

Hazard Ratio (Fixed, 95% CI)

1.02 [0.89, 1.16]

5 Progression‐free survival for combination therapy with subgroup analysis ‐ Oxaliplatin‐based vs irinotecan‐based Show forest plot

16

6513

Hazard Ratio (Fixed, 95% CI)

1.05 [1.00, 1.10]

5.1 Oxaliplatin‐based

8

4677

Hazard Ratio (Fixed, 95% CI)

1.06 [0.99, 1.13]

5.2 Irinotecan‐based

8

1836

Hazard Ratio (Fixed, 95% CI)

1.04 [0.97, 1.11]

6 Progression‐free survival for combination therapy with subgroup analysis ‐ with Bev vs no Bev Show forest plot

14

6139

Hazard Ratio (Fixed, 95% CI)

1.03 [0.98, 1.08]

6.1 With Bevacizumab

6

2033

Hazard Ratio (Fixed, 95% CI)

1.00 [0.94, 1.07]

6.2 No Bevacizumab

9

4106

Hazard Ratio (Fixed, 95% CI)

1.06 [0.99, 1.13]
Figures and Tables -
Comparison 4. Progression‐free survival
Navigate to table in Review
Comparison 5. Overall survival (palliative intent studies)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival (palliative intent studies) Show forest plot

29

12079

Hazard Ratio (Fixed, 95% CI)

1.02 [0.99, 1.05]

2 Overall survival (palliative intent studies) with subgroup analysis ‐ Single‐agent vs combination therapy Show forest plot

28

11620

Hazard Ratio (Fixed, 95% CI)

1.02 [0.99, 1.05]

2.1 Single agent

10

4465

Hazard Ratio (Fixed, 95% CI)

1.02 [0.99, 1.07]

2.2 Combination therapy

18

7155

Hazard Ratio (Fixed, 95% CI)

1.00 [0.95, 1.06]

3 Overall survival (palliative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine Show forest plot

29

12079

Hazard Ratio (Fixed, 95% CI)

1.02 [0.99, 1.05]

3.1 Infusional intravenous fluoropyrimidine

19

7022

Hazard Ratio (Fixed, 95% CI)

1.01 [0.96, 1.06]

3.2 Bolus intravenous fluoropyrimidine

13

5057

Hazard Ratio (Fixed, 95% CI)

1.02 [0.98, 1.06]

4 Overall survival (palliative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone Show forest plot

29

12079

Hazard Ratio (Fixed, 95% CI)

1.02 [0.99, 1.05]

4.1 Capecitabine

16

7405

Hazard Ratio (Fixed, 95% CI)

0.99 [0.95, 1.04]

4.2 UFT/Ftorafur

5

1807

Hazard Ratio (Fixed, 95% CI)

1.02 [0.97, 1.06]

4.3 Eniluracil + oral 5‐FU

3

1618

Hazard Ratio (Fixed, 95% CI)

1.20 [1.07, 1.36]

4.4 Doxifluridine

2

207

Hazard Ratio (Fixed, 95% CI)

0.99 [0.65, 1.50]

4.5 S‐1

3

1042

Hazard Ratio (Fixed, 95% CI)

0.95 [0.81, 1.11]

5 Overall survival (palliative intent studies) for combination therapy with subgroup analysis ‐ Oxaliplatin‐based vs irinotecan‐based Show forest plot

18

7155

Hazard Ratio (Fixed, 95% CI)

1.00 [0.95, 1.06]

5.1 Oxaliplatin‐based

11

5379

Hazard Ratio (Fixed, 95% CI)

1.00 [0.94, 1.07]

5.2 Irinotecan‐based

7

1776

Hazard Ratio (Fixed, 95% CI)

1.01 [0.92, 1.10]
Figures and Tables -
Comparison 5. Overall survival (palliative intent studies)
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Comparison 6. Time to progression

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Time to progression Show forest plot

6

1970

Hazard Ratio (Fixed, 95% CI)

1.07 [1.01, 1.14]
Figures and Tables -
Comparison 6. Time to progression
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Comparison 7. Objective response rate

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 ORR Show forest plot

32

11115

Odds Ratio (M‐H, Fixed, 95% CI)

0.98 [0.90, 1.06]
Figures and Tables -
Comparison 7. Objective response rate
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Comparison 8. Grade ≥ 3 adverse events (palliative intent studies)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Grade ≥ 3 diarrhoea (palliative intent studies) Show forest plot

30

11997

Odds Ratio (M‐H, Fixed, 95% CI)

1.66 [1.50, 1.84]

2 Grade ≥ 3 diarrhoea (palliative intent studies) with subgroup analysis ‐ Single‐agent vs combination therapy Show forest plot

30

11997

Odds Ratio (M‐H, Fixed, 95% CI)

1.66 [1.50, 1.84]

2.1 Single agent

10

4566

Odds Ratio (M‐H, Fixed, 95% CI)

1.22 [1.04, 1.44]

2.2 Combination therapy

21

7431

Odds Ratio (M‐H, Fixed, 95% CI)

2.03 [1.77, 2.32]

3 Grade ≥ 3 diarrhea (palliative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine Show forest plot

30

11997

Odds Ratio (M‐H, Fixed, 95% CI)

1.66 [1.50, 1.84]

3.1 Infusional intravenous fluoropyrimidine

21

7065

Odds Ratio (M‐H, Fixed, 95% CI)

2.00 [1.74, 2.30]

3.2 Bolus intravenous fluoropyrimidine

12

4932

Odds Ratio (M‐H, Fixed, 95% CI)

1.31 [1.12, 1.53]

4 Grade ≥ 3 diarrhoea (palliative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone Show forest plot

30

11997

Odds Ratio (M‐H, Fixed, 95% CI)

1.66 [1.50, 1.84]

4.1 Capecitabine

17

7382

Odds Ratio (M‐H, Fixed, 95% CI)

1.76 [1.54, 2.00]

4.2 UFT/Ftorafur

5

1784

Odds Ratio (M‐H, Fixed, 95% CI)

1.60 [1.24, 2.06]

4.3 Eniluracil + oral 5‐FU

3

1617

Odds Ratio (M‐H, Fixed, 95% CI)

1.04 [0.79, 1.38]

4.4 Doxifluridine

1

127

Odds Ratio (M‐H, Fixed, 95% CI)

1.51 [0.64, 3.56]

4.5 S‐1

4

1087

Odds Ratio (M‐H, Fixed, 95% CI)

3.55 [2.19, 5.76]

5 Grade ≥ 3 diarrhoea (palliative intent studies) with subgroup analysis for combination therapy ‐ Oxaliplatin‐based vs irinotecan‐based Show forest plot

20

7212

Odds Ratio (M‐H, Fixed, 95% CI)

2.00 [1.75, 2.29]

5.1 Oxaliplatin‐based

12

5420

Odds Ratio (M‐H, Fixed, 95% CI)

1.73 [1.48, 2.02]

5.2 Irinotecan‐based

8

1792

Odds Ratio (M‐H, Fixed, 95% CI)

3.05 [2.33, 3.99]

6 Grade ≥ 3 hand foot syndrome (palliative intent studies) Show forest plot

18

6481

Odds Ratio (M‐H, Fixed, 95% CI)

3.92 [2.84, 5.43]

7 Grade ≥ 3 hand foot syndrome (palliative intent studies) with subgroup analysis ‐ Single‐agent vs combination therapy Show forest plot

18

6481

Odds Ratio (M‐H, Fixed, 95% CI)

3.89 [2.82, 5.37]

7.1 Single agent

2

343

Odds Ratio (M‐H, Fixed, 95% CI)

1.11 [0.48, 2.56]

7.2 Combination therapy

17

6138

Odds Ratio (M‐H, Fixed, 95% CI)

4.76 [3.32, 6.82]

8 Grade ≥ 3 hand foot syndrome (palliative intent studies) with subgroup analysis ‐ Infusional vs bolus intravenous fluoropyrimidine Show forest plot

18

6481

Odds Ratio (M‐H, Fixed, 95% CI)

3.92 [2.84, 5.43]

8.1 Infusional intravenous fluoropyrimidine

18

6094

Odds Ratio (M‐H, Fixed, 95% CI)

3.53 [2.53, 4.94]

8.2 Bolus intravenous fluoropyrimidine

3

387

Odds Ratio (M‐H, Fixed, 95% CI)

18.68 [4.15, 84.10]

9 Grade ≥ 3 hand foot syndrome (palliative intent studies) with subgroup analysis ‐ Oral fluoropyrimidine backbone Show forest plot

18

6481

Odds Ratio (M‐H, Fixed, 95% CI)

3.92 [2.84, 5.43]

9.1 Capecitabine

13

5418

Odds Ratio (M‐H, Fixed, 95% CI)

5.86 [4.01, 8.58]

9.2 UFT/Ftorafur

2

372

Odds Ratio (M‐H, Fixed, 95% CI)

0.49 [0.04, 5.50]

9.3 Eniluracil + oral 5‐FU

1

122

Odds Ratio (M‐H, Fixed, 95% CI)

0.04 [0.00, 0.75]

9.4 S‐1

2

569

Odds Ratio (M‐H, Fixed, 95% CI)

0.66 [0.11, 4.00]

10 Grade ≥ 3 hand foot syndrome (palliative intent studies) with subgroup analysis for combination therapy ‐ Oxaliplatin‐based vs irinotecan‐based Show forest plot

16

5919

Odds Ratio (M‐H, Fixed, 95% CI)

4.76 [3.31, 6.83]

10.1 Oxaliplatin‐based

10

4608

Odds Ratio (M‐H, Fixed, 95% CI)

4.52 [3.03, 6.75]

10.2 Irinotecan‐based

6

1311

Odds Ratio (M‐H, Fixed, 95% CI)

5.93 [2.52, 13.97]

11 Grade ≥ 3 neutropenia/granulocytopenia (palliative intent studies) Show forest plot

29

11794

Odds Ratio (M‐H, Fixed, 95% CI)

0.17 [0.15, 0.18]

12 Grade ≥ 3 febrile neutropenia (palliative intent studies) Show forest plot

19

9407

Odds Ratio (M‐H, Fixed, 95% CI)

0.27 [0.21, 0.36]

13 Grade ≥ 3 vomiting (palliative intent studies) Show forest plot

23

9528

Odds Ratio (M‐H, Fixed, 95% CI)

1.18 [1.00, 1.40]

14 Grade ≥ 3 nausea (palliative intent studies) Show forest plot

25

9796

Odds Ratio (M‐H, Fixed, 95% CI)

1.16 [0.99, 1.36]

15 Grade ≥ 3 stomatitis (palliative intent studies) Show forest plot

21

8718

Odds Ratio (M‐H, Fixed, 95% CI)

0.26 [0.20, 0.33]

16 Grade ≥ 3 mucositis (palliative intent studies) Show forest plot

12

4962

Odds Ratio (M‐H, Fixed, 95% CI)

0.17 [0.12, 0.24]

17 Grade ≥ 3 hyperbilirubinaemia (palliative intent studies) Show forest plot

9

2699

Odds Ratio (M‐H, Fixed, 95% CI)

1.62 [0.99, 2.64]

18 Any grade ≥ 3 adverse events (palliative intent studies) Show forest plot

14

5436

Odds Ratio (M‐H, Fixed, 95% CI)

0.83 [0.74, 0.94]
Figures and Tables -
Comparison 8. Grade ≥ 3 adverse events (palliative intent studies)
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