Methods

Randomised controlled trial

Phase: II

Accrual dates: July 1998 to May 2000

Participants

No. randomised: 77

Stage/treatment line: Metastatic, first‐line

Countries/sites: Not specified, study authors from a South Korean centre

Setting: Hospital

Characteristics (Group A/B): Metastatic colorectal adenocarcinoma; age ≤ 75 years (median 58/57 years); male (50/79%); PS ECOG ≤ 2 (PS ECOG 0: 11/3%)

Interventions

Group A: Oral doxifluridine (5‐dFUR) 333 mg/m² tds + leucovorin 15 mg bd, D1‐7 and D15‐21 q28d (n randomised = 38)

Group B: IV bolus 5‐FU 400 mg/m²/d plus leucovorin 20 mg/m²/d D1‐5, q28d (n randomised = 39)

“In the presence of objective response or stable disease, each group of patients was treated for a maximum of 12 cycles. In the case of a complete response, 2 additional cycles were given. The treatment was continued until there was progression, unacceptable toxicity, or a patient’s refusal” (patients and methods, paragraph 2, page 99)

Outcomes

ORR (WHO criteria, 1981)

PFS (treated as TTP in this review, based on the definition provided), OS

Grade ≥ 3 AEs (WHO toxicity criteria, version not specified)

Median follow‐up: 17.0 m (PFS/OS)

Study Details

Journal article

Funding sources and declarations of interest

Funding sources: None declared

Declarations of interest: None declared

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not specified

Allocation concealment (selection bias)

Unclear risk

Not specified

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

Low risk

Not specified, blinding unlikely

(i) ORR/PFS (treated as TTP): Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: This study was not used for the meta‐analysis for these outcomes

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

Not specified

(i) ORR/PFS (treated as TTP): High

Outcome assessment at risk of bias if there was lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: This study was not used for the meta‐analysis for these outcomes

Schedule of assessment and follow‐up

Unclear risk

(i) Response (influences ORR/PFS): Low

Quote: "All measurable lesions were assessed every three cycles..." (patients and methods, paragraph 3, page 99)

Quote: "Each cycle was repeated every four weeks" (patients and methods, paragraph 2, page 99)

Therefore, responses were evaluated at the same frequency in both treatment arms

(ii) Survival (influences PFS/OS): Unclear

Follow‐up duration and assessment frequency for survival events were not specified

(iii) Grade ≥ 3 AEs: Low

Quote: "Side effects ... were evaluated at the beginning of each cycle" (patients and methods, paragraph 4, page 99)

Therefore, grade ≥ 3 AEs were evaluated at the same frequency in both treatment arms

Incomplete outcome data (attrition bias)
All outcomes

High risk

(i) ORR/PFS (treated as TTP): High

11/38 (29%) 5‐dFUR/LV and 6/39 (15%) 5‐FU/LV patients were not evaluable.

Quote: "... 38 were randomly assigned to group A and 39 to group B" (results, paragraph 1, page 99)

Quote: "... the evaluable patients were 27 patients in group A and 33 patients in group B, respectively" (results, paragraph 3, page 99)

(ii) OS: Low

Although not defined in the Methods, censoring was noted in the KM curves (Fig. 1 and 2, page 100). No evidence suggested bias related to censoring

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Quote: "The effects of the treatments were analysed using both the intent‐to‐treat principle and per‐protocol analysis that included only evaluable patients" (patients and methods, paragraph 5, page 99)

Safety analysis:

Not specified

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

Low risk

(i) ECOG PS: Low (Table 1, page 99)

(ii) Median age: Low (Table 1, page 99)

(iii) Number of metastatic organs: Low (Table 1, page 99)

Other bias

Unclear risk

Subsequent therapies: Unclear ‐ not specified

Methods

Randomised controlled trial

Phase: III

Design: Factorial (2 × 2), following protocol amendment in October 2005

Accrual dates: July 2004 to August 2010

Participants

No. randomised: 1608

Stage/treatment type: Stage II or III rectal cancer, neoadjuvant

Countries/sites: USA, Canada (multiple sites)

Setting: Hospital

Characteristics (group 1/2/3/4/5/6): Unresected stage II or III rectal adenocarcinoma; age > 18 years (patients ≤ 59 years: 59.2/52.7/56.1/61.4/57.1/61.2%); male (68.0/67.8/67.0/68.1/67.8/67.6%); PS 0/1

Interventions

Grp 1 (5‐FU (2 Arm), pre‐amendment): 5‐FU 225 mg/m²/d (n randomised = 147)

Grp 2 (CAPE (2 Arm), pre‐amendment): capecitabine 825 mg/m² oral BD (n randomised = 146)

Grp 3 (5‐FU (4 Arm), post‐amendment): 5‐FU 225 mg/m²/d 5 days/wk (n randomised = 330)

Grp 4 (5‐FU + OX (4 Arm), post‐amendment): 5‐FU 225 mg/m²/d 5 days/wk, oxaliplatin 50 mg/m² IV weekly (n randomised = 329)

Grp 5 (CAPE (4 Arm), post‐amendment): capecitabine 825 mg/m² oral BD 5 days/wk (n randomised = 326)

Grp 6 (CAPE + OX (4 Arm), post‐amendment): capecitabine 825 mg/m² oral BD 5 days/wk, oxaliplatin 50 mg/m² IV weekly (n randomised = 330)

All participants received neoadjuvant radiotherapy: 180 cGy per day, 5 doses per week for 25 fractions. Minimal boost: 540 cGy (3 days in 180 cGy fractions) for T3 non‐fixed and distal cancers; 1080 cGy (3 days in 360 cGy fractions) for T4 fixed and/or distal cancers

All chemotherapy given for the duration of radiotherapy

Outcomes

Locoregional control at 3 years

OS

DFS

Time to local‐regional recurrence

Grade ≥ 3 AEs (NCI CTCAE, version 4.0)

No details on median follow‐up

Study Details

Journal article and abstract

Funding sources and declarations of interest

Funding sources: US National Cancer Institute at the National Institutes of Health, US Department of Health and Human Services, Public Health Service grants

Declarations of interest: None declared

Notes

Following the October 2005 protocol amendment, oxaliplatin was added to form a 2 × 2 factorial design. Daily dose of fluoropyrimidine chemotherapy was unchanged. However, capecitabine and 5‐FU treatment were given 5 days a week (reduced from 7), coinciding with days of planned radiation therapy

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "...randomly assigned to treatment groups using the NSABP biased‐coin minimization algorithm" (methods, paragraph 3, page 2)

Allocation concealment (selection bias)

Unclear risk

Unclear ‐ not specified

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Not specified, blinding unlikely

(i) DFS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias if there was lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

Not specified

(i) DFS: High

Outcome assessment at risk of bias if there was lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias if there was lack of blinding

Schedule of assessment and follow‐up

Unclear risk

(i) Locoregional recurrence (influences DFS): Low

Quote: "Following surgery, MRI or CT scans were required every 12 months for two years, and proctoscopy or sigmoidoscopy annually for five years" (methods, paragraph 2, page 2)

(ii) Survival (influences DFS/OS): Unclear

It was unclear whether any follow‐up (e.g. clinical reviews) other than that described above was performed to detect survival events, and whether they were the same in both oral and intravenous arms

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (attrition bias)
All outcomes

Low risk

(i) DFS/OS: Low

19/801 participants from the analysis population on the 5‐FU arm had no follow‐up, whereas 9/794 participants on the capecitabine arm had no follow‐up (correspondence with Dr. Carmen Allegra, received 22 July 2016)

(ii) Grade ≥ 3 AEs: Low

From the analysis population, 21/801 (3%) and 7/794 (1%) participants in the 5‐FU and CAPE arms, respectively, were missing safety outcome data (Table 2, page 6)

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

From the analysis population, 5/806 (0.6%) and 8/802 (1%) participants were excluded from the 5‐FU and CAPE arms, respectively, because they were ineligible (Figure 1, page 4)

Safety analysis: Unclear ‐ not specified

Selective reporting (reporting bias)

Unclear risk

No protocol available

Similarity of arms at baseline

Unclear risk

(i) PS: Unclear ‐ information not specified

(ii) Median/mean age: Unclear ‐ information not specified

(iii) TNM stage: Unclear ‐ information not specified

Other bias

Unclear risk

Subsequent therapies: Unclear

Quote: "...we do not have complete information concerning the type and use of adjuvant therapy in the study patients" (discussion, paragraph 5, page 7)

Risk of bias considerations in a factorial study: Unclear

Quote: "... no evidence of oxaliplatin‐treatment‐by‐fluoropyrimidine‐treatment interaction (P = .46)" for 3‐year locoregional recurrence (results, paragraph 2, page 4)

No tests for interaction were reported for the other outcomes

Methods

Randomised controlled trial

Phase: Not specified

Accrual dates: Not specified

Participants

No. randomised: 60

Stage/treatment line: Inoperable/advanced/recurrent colorectal cancer, no prior 5‐FU or Ftorafur and at least 4 weeks elapsed from previous chemotherapy (only those with no prior chemotherapy were analysed)

Countries/sites: Authors from Denmark

Setting: Hospital

Characteristics (Arm A/B): Inoperable/advanced/recurrent colorectal cancer; age (median 55/59 years); male (43/37%); PS (WHO) ≤ 3

Interventions

Arm I: Oral Ftorafur 1 gm/m²/d D1‐21, q35d (n randomised = 30)

Arm II: IV bolus 5‐FU 500 mg/m²/d D1‐5, q35d (n randomised = 30)

Treatment continued until intractable toxicity or PD

Outcomes

ORR (WHO criteria, 1979)

OS

Median follow‐up: Not specified

Study Details

Journal article

Funding sources and declarations of interest

Funding sources: None declared

Declarations of interest: None declared

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not specified

Allocation concealment (selection bias)

Unclear risk

Not specified

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

Low risk

Not specified, blinding unlikely

(i) ORR: Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: This study was not used for the meta‐analysis for this outcome

(iii) Grade ≥ 3 AEs: Not outcomes for this study  

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

Not specified.

(i) ORR: High

Outcome assessment at risk of bias if there was lack of blinding

(ii) OS: This study was not used for the meta‐analysis for this outcome

(iii) Grade ≥ 3 AEs: Not outcomes for this study

Schedule of assessment and follow‐up

Unclear risk

(i) Response (influences ORR): Unclear ‐ not specified

(ii) Survival (influences OS): This study was not used for the meta‐analysis for this outcome

(iii) Grade ≥ 3 AEs: Not outcomes for this study

Incomplete outcome data (attrition bias)
All outcomes

High risk

(i) ORR: High

20% of patients in the 5‐FU arm were not evaluable (Table 1, page 434)

(ii) OS: This study was not used for the meta‐analysis for this outcome

(iii) Grade ≥ 3 AEs: Not outcomes for this study

Incomplete outcome data (ITT analysis)

High risk

Efficacy analysis: High

The efficacy analysis population excluded those who refused treatment, had protocol violations, or were lost to follow‐up (10/60) (Table 1, page 434)

Safety analysis:

The safety analysis population received at least 1 treatment cycle

Quote: "They received at least one treatment cycle with 5‐FU or Ftorafur" (material and methods, paragraph 4, page 434)

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

Unclear risk

i) PS: Unclear ‐ only median and range reported (Table 1, page 434)

ii) Median age: Low (Table 1, page 434)

iii) No. of involved organs: Unclear ‐ not specified

Other bias

Unclear risk

Subsequent therapies: Unclear ‐ not provided

Methods

Randomised controlled trial

Phase: II, non‐comparative

Accrual dates: April 1993 to September 1994

Participants

No. randomised: 130

Stage/treatment line: Metastatic, first‐line (no previous adjuvant chemotherapy)

Countries/sites: Italy, 13 institutions

Setting: Hospital

Characteristics (Arm A/B): Metastatic colorectal adenocarcinoma; age < 80 years (median 61/61 years); male (52/59%); PS ECOG ≤ 2

Interventions

Arm A: Oral doxifluridine (5‐dFUR) 750 mg/m² bd plus oral levo‐leucovorin 25 mg/dose D1‐4, q12d (n randomised = 67)

Arm B: IV 5‐dFUR 3000 mg/m² plus l‐leucovorin 25 mg D1‐5, q21d (n randomised = 63)

"It was initially planned to deliver five cycles to the patients in arm A and three cycles to those in arm B. In the case of a complete response (CR), partial response (PR), or stable disease (SD), the patients were to receive an additional 4 and 2 cycles, respectively. In the case of a subsequent CR or PR following the documentation of SD or PR at the first evaluation, further 4 cycles for arm A and 2 cycles for arm B were administered" (patients and methods, paragraph 4, page 2088)

Outcomes

ORR (WHO criteria, 1981)

Grade ≥ 3 AEs (NCI CTC, 1981)

Time to treatment failure (TTF, treated as PFS in this review, based on the definition provided)

OS

Median follow‐up: 10 m (TTF/OS)

Study Details

Journal article

Funding sources and declarations of interest

Funding sources: None declared

Declarations of interest: None declared

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "...randomly allocated to receive oral or i.v. 5‐dFUR, balanced in blocks of varying sizes" (patients and methods, paragraph 2, page 2089)

Allocation concealment (selection bias)

Low risk

Quote: "... the patients were registered at a central randomization office ..." (patients and methods, paragraph 2, page 2089)

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Not specified, blinding unlikely

(i) ORR/TTF(treated as PFS): Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias if there was lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

Not specified.

(i) ORR/TTF(treated as PFS): High

Outcome assessment at risk of bias if there was lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias if there was lack of blinding

Schedule of assessment and follow‐up

High risk

(i) Response (influences ORR/TTF (treated as PFS)): Unclear

Quote: "It was initially planned to deliver five cycles to the patients in arm A and three cycles to those in arm B. In the case of a complete response (CR), partial response (PR), or stable disease (SD), the patients were to receive an additional 4 and 2 cycles, respectively. In the case of a subsequent CR or PR following the documentation of SD or PR at the first evaluation, further 4 cycles for arm A and 2 cycles for arm B were administered" (patients and methods, paragraph 4, page 2089)

Quote: "Oral 5‐dFUR ... was administered ... for 4 days repeated every 12 days (arm A); intravenous 5‐dFUR was administered ... for 5 consecutive days every 21 days (arm B)" (patients and methods, paragraph 3, page 2089)

Therefore, the schedule of assessment for both treatment arms up until the second evaluation was similar

However, no information was provided on the response evaluation schedule following the second evaluation

(ii) Survival (influences TTF(treated as PFS)/OS): Unclear ‐ not specified

(iii) Grade ≥ 3 AEs: High

Quote: "Side effects were ... evaluated at the beginning of each cycle" (patients and methods, paragraph 8, page 2089)

"Oral 5‐dFUR ... was administered ... for 4 days repeated every 12 days (arm A); intravenous 5‐dFUR was administered ... for 5 consecutive days every 21 days (arm B)" (patients and methods, paragraph 3, page 2089)

Therefore, safety evaluations occurred more frequently in arm A

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

(i) ORR: Low

The sum of participants who achieved CR, PR, SD, and “Treatment failure” appears to be the same as the number randomised (Table 2, page 2091)

(ii) TTF (treated as PFS)/OS: Low

Although censoring was not defined in the Methods, censoring was noted in the KM curves (Figure 1 and Figure 2, page 2091). No evidence of bias related to censoring

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Quote "The activity of the treatments was analyzed using both the intent‐to‐treat principle (including the entire group of patients) and standard analysis (which excludes inadequately treated cases)" (statistical analysis, paragraph 1, page 2089)

Safety analysis:

Analyses included those who received treatment

Quote: "As three of the patients randomized to arm B were censored because no treatment was administered, the safety analysis was based on the results derived from 127 subjects" (results, paragraph 7, page 2090)

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

Unclear risk

(i) PS: Unclear ‐ reported as ECOG PS 0‐1 vs 2 (Table 1, page 2090)

(ii) Median age: Low (Table 1, page 2090)

(iii) No. of involved organs: Unclear ‐ not specified

Other bias

Unclear risk

Subsequent therapies: Unclear ‐ not provided

Methods

Randomised controlled trial

Phase: III

Accrual dates: May 1996 to July 1997

Participants

No. randomised: 380

Stage/treatment line: Metastatic, first‐line

Countries/sites: Multi‐nation, 47 sites. Europe (n = 291), Canada (n = 55), Australia (n = 24), New Zealand (n = 5), and Israel (n = 5)

Setting: Hospital

Characteristics (Arm I/II): Metastatic colorectal adenocarcinoma; age > 18 years (median 61/62 years); male (67/64%); PS ECOG ≤ 2 (ECOG 0: 39/33%)

Interventions

Arm I: Oral UFT 300 mg/m²/d plus leucovorin (LV) 90 mg/d D1‐28, q35d (n randomised = 190)

Arm II: IV bolus 5‐FU 425 mg/m²/d plus LV 20 mg/m²/d D1‐5, q35d (n randomised = 190)

Outcomes

TTP

OS

ORR (WHO criteria ‐ modified)

Grade ≥ 3 AEs (NCI CTC, version not specified)

Median follow‐up ‐ Not specified

Study Details

Journal article

Funding sources and declarations of interest

Funding sources: Taiho Pharmaceutical Company, Bristol‐Myers Squibb

Declarations of interest: None declared

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not specified

Allocation concealment (selection bias)

Unclear risk

Not specified

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Not specified, blinding unlikely

(i) ORR/TTP: Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias if there was lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

(i) ORR/TTP: Unclear

Quote: "Efficacy was evaluated locally with data subsequently centrally reviewed" (patients and methods, paragraph 5, page 3619)

However, the role of the central review in the reported response data was not described

(ii) OS: Low

Not specified. Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Not specified. Outcome assessment at risk of bias if there was lack of blinding   

Schedule of assessment and follow‐up

Unclear risk

(i) Response (influences ORR/TTP): Low

Quote: "Tumor reassessment ... was repeated after every two cycles, with an additional computed tomography scan at week 15" (patients and methods, paragraph 5, page 3619)

Quote: "On both treatment arms, treatment cycles were to be repeated every 35 days" (patients and methods, paragraph 3, page 3618)

Therefore, responses were evaluated at the same frequency in both treatment arms

(ii) Survival (influences OS): Unclear

The schedule of follow‐up after progression was not specified

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (attrition bias)
All outcomes

Low risk

(i) ORR: Low

1% (2/190) of patients in both arms were not assessed (Table 2, page 3619)

(ii) TTP/OS: Low

Although not defined in the Methods, censoring was noted from the KM curves for both outcomes (Fig 1 and 2, pages 3621 and 3622). No evidence of bias related to censoring

(iii) Grade ≥ 3 AEs: Low

The greatest percentage of outcome data missing for an AE in any arm was 11%; there were similar percentages missing from each arm (Tables 4, 5 and 6, page 3623)

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Quote: "All efficacy analyses have been presented by treatment arm as randomized ..." (patients and methods, paragraph 7, page 3619)

Safety analysis:

Quote: "All 373 patients who received at least one dose of study medication were evaluated for safety and were analyzed according to the treatment arm as treated" (results, paragraph 18, page 3622)

Selective reporting (reporting bias)

Unclear risk

No protocol was available.

Similarity of arms at baseline

Unclear risk

(i) PS: Low (Table 1, page 3619)

(ii) Median age: Low (Table 1, page 3619)

(iii) No. of involved organs: Unclear ‐ not clearly specified.

Quote: "The median number of disease sites was two in both treatment arms" (results, paragraph 4, page 3619)

Other bias

Low risk

Subsequent therapies: Low

Similar percentages of participants and types of chemotherapy were used in the second‐line setting after progression, in each arm

Quote: "Secondary chemotherapy was administered to 41% (78 of 190) of patients receiving UFT/LV, and 39% (75 of 190) of patients receiving 5‐FU/LV" (results, paragraph 16, page 3622)

Quote: "The most frequently administered secondary chemotherapy was fluoropyrimidines only, in 49% of the 78 UFT/LV patients and in 47% of the 75 5‐FU/LV patients who took secondary chemotherapy, followed by irinotecan only (28% in each arm). In patients receiving secondary chemotherapy, oxaliplatin alone or in combination with irinotecan was given to 13% (10 of 78) of UFT/LV treated patients and 16% (12 of 75) of 5‐FU/LV treated patients" (results, paragraph 16, page 3622)

Methods

Randomised controlled trial

Phase: III

Design:

Part One ‐ 2‐arm, 1:1 randomisation to XELOX vs FOLFOX4

Part Two ‐ 2 × 2 factorial (protocol amendment to include randomisation to bevacizumab (BEV) or placebo); 1:1:1:1 randomisation to XELOX + placebo, XELOX + BEV, FOLFOX‐4 + placebo, FOLFOX‐4 + BEV

Accrual dates: Part One ‐ July 2003 to May 2004; Part Two ‐ February 2004 to February 2005

Participants

No. randomised: 2035

Stage/treatment line: Metastatic, first‐line

Countries/sites: Multi‐nation; Europe (n = 1048), Canada (n = 343), Oceania (n = 188), US (n = 178), Central/Eastern Asia (n = 163), South America (n = 65), and South Africa (n = 49)

Setting: Hospital

Characteristics Part One (Arm I/II): Metastatic colorectal adenocarcinoma; age ≥ 18 years (median 61/62 years); male (61/64%); PS ECOG ≤ 1 (PS ECOG 0: 50/51%)

Characteristics Part Two (Arm I/II/III/IV): Metastatic colorectal adenocarcinoma; age ≥ 18 years (median 61/61/60/60 years); male (59/61/53/59%); PS ECOG ≤ 1 (PS ECOG 0: 59/59/60/57%)

Interventions

Part One:

Arm I (XELOX): oxaliplatin 130 mg/m² D1 plus capecitabine 1000 mg/m² bd for 14 d, q21d (n randomised = 317)

Arm II (FOLFOX4): oxaliplatin 85 mg/m² D1 plus leucovorin 200 mg/m²/d, IV bolus 5‐FU 400 mg/m²/d and 5‐FU 600 mg/m²/d 22‐hour infusion D1‐2, q14d (n randomised = 317)

Part Two:

Arm I: XELOX + placebo (n randomised = 350)

Arm II: XELOX + BEV 7.5 mg/kg D1, q21d (n randomised = 350)

Arm III: FOLFOX‐4 + placebo (n randomised = 351)

Arm IV: FOLFOX‐4 + BEV 5 mg/kg D1, q14d (n randomised = 350)

Treatment continued until PD or for 48 weeks, whichever came first (study treatment phase). Participants who completed the 48‐week treatment phase without PD were eligible to continue treatment until PD in a post‐study treatment phase

Outcomes

PFS

OS

ORR (RECIST, version 1.0)

TTF

Grade ≥ 3 AEs (NCI CTC, version 3)

Median follow‐up: PFS 17.7 m (cut‐off date 31 January 2006), OS cut‐off date 31 July 2008

Study Details

Journal articles

Funding sources and declarations of interest

Declarations of interest: Roche, Sanofi‐Aventis

Funding sources: Roche

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not specified

Allocation concealment (selection bias)

Low risk

Quote: "Patients were assigned to treatment using an interactive voice response system" (patients and methods, paragraph 4, page 2007)

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Quote "... open‐label" (patients and methods, paragraph 1, page 2007)

(i) ORR/PFS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding    

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

(i) ORR/PFS: Low

Quote: "Tumor responses were assessed by investigators and also by an independent response review committee" (patients and methods, paragraph 9, page 2007)

Similar ORs were obtained for the response rates, which were "Investigator assessed" and "IRC assessed" (Table 2, page 2010)

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Schedule of assessment and follow‐up

Unclear risk

(i) Response (influences ORR/PFS): Low

Quote: "Tumor assessments (computed tomography scan, magnetic resonance imaging) were ... repeated after every two XELOX cycles and every three FOLFOX‐4 cycles (i.e., every sixth week in both arms and at the end of treatment)" (patients and methods, paragraph 9, page 2007)

(ii) Survival (influences PFS/OS): Low

Quote: "After completion of study treatment, patients were followed every 3 months until PD and/or death" (patients and methods, paragraph 9, page 2007)

(iii) Grade ≥ 3 AEs: Unclear ‐ no schedule was provided

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

(i) ORR: Unclear ‐ not specified

(ii) PFS/OS: Low

Quote: "Patients who were not reported as having died at the time of the analysis were censored using the date they were last known to be alive" (Cassidy et al, British Journal of Cancer, 2011: patients and methods, paragraph 9, page 59). No evidence of bias related to censoring

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Quote: "The intent‐to‐treat (ITT) patient population included all patients who underwent randomization and signed the informed consent form" (patients and methods, paragraph 11, page 2007)

Safety analysis:

Quote: "All patients receiving at least one dose of study drug were included in the safety analysis" (patients and methods, paragraph 11, page 2007)

Selective reporting (reporting bias)

Unclear risk

No protocol was available.

Similarity of arms at baseline

Low risk

(i) PS: Low (Table 1, 2009)

(ii) Median age: Low (Table 1, 2009)

(iii) No. of involved organs: Low (Table 1, 2009)

Other bias

Low risk

Subsequent therapies: Low

Quote: "There were no major imbalances between the treatment groups with respect to the use of second‐line therapy ..." (results, paragraph 9, page 2009)

Risk of bias considerations in a factorial study: Low

For efficacy analysis ‐ Quote: "Both a clinically relevant and statistically significant (P = .7025) treatment interaction was ruled out" (results, paragraph 4, page 2008)

For safety analysis ‐ Quote: "The addition of bevacizumab did not alter the similarities and differences in safety profile between XELOX and FOLFOX‐4" (results, paragraph 14, page 2010)

Methods

Randomised controlled trial

Phase: III

Accrual dates: May 2004 to April 2007

Participants

No. randomised: 322

Stage/treatment line: Metastatic, first‐line

Countries/sites: Italy, 23 Southern Italy Cooperative Oncology group (SICOG) centres

Setting: Hospital

Characteristics (Arm I/II): Metastatic colorectal adenocarcinoma; age ≥ 18 years (median 65/64 years); male (54/66%); PS ECOG ≤ 2 (PS ECOG 0: 60/61%)

Interventions

Arm I (OXAFAFU): IV oxaliplatin 85 mg/m², 6S‐leucovorin 250 mg/m² D1, IV bolus fluorouracil 850 mg/m² D2, q14d (n randomised = 164)

Arm II (OXXEL): IV oxaliplatin 100 mg/m² D1 plus capecitabine 1000 mg/m² bd D1‐D11, q14d (n randomised = 158)

Treatment continued until PD, unacceptable toxicity, or participant refusal, or a maximum of 12 cycles

Outcomes

ORR (WHO criteria, 1981)

PFS

OS

Grade ≥ 3 AEs (WHO criteria, 1981)

Median follow‐up: 24 months (PFS/OS)

Study Details

Journal article and abstracts

Funding sources and declarations of interest

Funding sources: SICOG

Declarations of interest: No conflicts of interest

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not specified

Allocation concealment (selection bias)

Unclear risk

Not specified

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Not specified, blinding unlikely

(i) ORR/PFS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias if there was lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

Not specified

(i) ORR/PFS: High

Outcome assessment at risk of bias if there was lack of blinding

(ii)OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias if there was lack of blinding     

Schedule of assessment and follow‐up

Low risk

(i) Response (influences ORR/PFS): Low

Quote: "In both arms, cycles were repeated every 2 weeks" (methods, paragraph 5, page 219)

Quote: "CT or MRI scan was repeated after every 4 cycles" (methods, paragraph 4, page 219)

Therefore, responses were evaluated at the same frequency in both treatment arms

Quote: "Response was ... reassessed 8 weeks after the date of their first documentation; only confirmed responses were computed in the activity analysis" (methods, paragraph 4, page 219)

(ii) Survival (influences PFS/OS): Low

Quote: "After discontinuation of first‐line treatment, patients were followed every 2 months to assess the disease status
and survival" (methods, paragraph 6, page 219)

(iii) Grade ≥ 3 AEs: Low

Quote: "During treatment, WBC count with differential was performed weekly. Biochemistry, symptoms, body weight, and nonhematological toxicity were checked before each cycle" (methods, paragraph 2, page 218‐9)

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

(i) ORR: Low

11% of patients in the OXXEL arm and 10% of patients in the OXAFAFU arm were not assessed

(Comella et al, ASCO Gastrointestinal Cancers Symposium, 2008 ‐ slides associated with abstract 344)

(ii) PFS/OS: Low

It is likely that censoring has occurred (Figures 1 and 2, pages 222 and 223). No evidence of bias related to censoring

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Quote: "... 322 eligible patients ... were randomized to the OXXEL (158 patients) or OXAFAFU (164 patients) arm"

This was the same as the number of participants at risk at t = 0 in Figure 1 (PFS curve) and Figure 2 (OS curve) (pages 222 and 223), as well as the total number of participants described in the ITT response data (Comella et al, ASCO Gastrointestinal Cancers Symposium, 2008 ‐ slides associated with abstract 344)

Safety analysis:

Not specified

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

Low risk

(i) PS: Low (Table 1, page 220)

(ii) Median age: Low (Table 1, page 220)

(iii) No. of involved organs: Low (Table 1, page 220)

Other bias

Low risk

Subsequent therapies: Low

Post‐study treatment was similar in both arms (Comella et al, ASCO Gastrointestinal Cancers Symposium, 2008 ‐ slides associated with abstract 344)

Methods

Randomised controlled trial

Phase: III

Accrual dates: December 2004 to June 2007

Participants

No. randomised: 3451

Stage/treatment type: High‐risk stage II or stage III colon cancer, adjuvant

Countries/sites: 330 centres in 34 countries (including USA, Europe, Asia, and Australia)

Setting: Hospital

Characteristics (Arm A/B/C) for ITT population: Adjuvant colon cancer; age ≥ 18 years (median 58/58/58 years); male (57/51/55%); PS ECOG 0‐1 (PS ECOG 0: 86/85/85%)

Interventions

Arm A (FOLFOX4): D1 oxaliplatin 85 mg/m², LV 200 mg/m², IV bolus fluorouracil 400 mg/m², followed by IV fluorouracil 600mg/m² 22‐hour continuous infusion on D1 and 2, q14d from W1‐24; W25‐48 observation only (n randomised = 1151)

Arm B (Bevacizumab (Bev)‐FOLFOX4): FOLFOX4 + Bev 5 mg/kg D1 q14d from W1‐24, then Bev alone 7.5 mg/kg D1 q21d from W25‐48 (n randomised = 1155)

Arm C (Bev‐XELOX): capecitabine 1000 mg/m² oral bd D1‐14, oxaliplatin 130 mg/m² D1 + Bev 7.5 mg/kg D1 q21d from W1‐24, then Bev alone 7.5 mg/kg D1 q21d from W25‐48 (n randomised = 1145)

Total of 12 courses

Outcomes

DFS

OS

Grade ≥ 3 AEs (NCI CTCAE, version 3.0)

Median follow‐up: For patients with stage III disease who did not have DFS events at the data cut‐off date ‐ Arm A 48.5 m, Arm B 48.3 m, Arm C 48.3 m

Data cut‐off dates: DFS ‐ 30 June 2010, OS ‐ 30 June 2012

Study Details

Journal article and abstract

Funding sources and declarations of interest

Funding sources: Genentech, Roche, Chugai

Declarations of interest: Honoraria from Roche‐Genentech, Merck‐Serono, Sanofi‐Aventis, Amgen

Notes

All efficacy results were only reported for stage III participants in all arms

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "A block design randomisation procedure (block size of six) was used" (methods, paragraph 3, page 1226)

Allocation concealment (selection bias)

Low risk

Quote: "Randomisation was done after surgery using a centralised interactive computerised system" (methods, paragraph 3, page 1226)

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Quote: "The study had an open‐label design" (methods, paragraph 3, page 1226)

(i) DFS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

(i) DFS: High

Outcome assessment at risk of bias from lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Schedule of assessment and follow‐up

Unclear risk

(i) Disease recurrence (influences DFS): Low

Quote: "Recurrences or new occurrences were based on investigator tumour assessments, and pre‐scheduled every 6 months after randomisation until year 4, then annually thereafter" (methods, paragraph 7, page 1227)

(ii) Survival (influences DFS/OS): Low

Quote: "Survival status was assessed every 6 months in the first 4 years after randomisation, then annually thereafter" (methods, paragraph 8, page 1227)

(iii) Grade ≥ 3 AEs: Unclear

Quote: "Adverse events were monitored until at least 28 days after the last dose of study treatment or end of observation
phase" (methods, paragraph 9, page 1227)

However, the frequency/schedule of monitoring in both arms was unclear

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

(i) DFS/OS: Low

Quote: "Event‐free patients at the clinical cutoff date were censored at the last date at which they were known to be disease‐free" (methods, paragraph 7, page 1227)

Quote: "Patients who were still alive at the clinical cutoff date were censored at the date at which they were last confirmed to be alive" (methods, paragraph 8, page 1227)

No evidence of bias related to censoring

(ii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Quote: "Patients who were event‐free at a given time point were censored at that time point" (methods, paragraph 11, page 1228)

ITT population included all participants randomised to their allocated treatments (Figure 1, page 1227)

Safety analysis:

Quote: "The safety population comprised all patients who received at least one dose of study treatment" (methods, paragraph 12, page 1228)

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

Low risk

(i) PS: Low (Table 1, page 1227)

(ii) Median age: Low (Table 1, page 1227)

(iii) TNM stage: Low (stage II vs stage III, and stage III N1 vs N2) (Table 1, page 1227)

Other bias

Low risk

Subsequent therapies: Low

Participants in the Bev‐FOLFOX4 and Bev‐XELOX groups received similar subsequent drug therapy after a recurrence or a new occurrence of colorectal cancer in the stage III ITT population (supplementary appendix, Table 1, page 6)

Methods

Randomised controlled trial

Phase: III

Accrual dates: January 1999 to September 2004

Participants

No. randomised: 155

Stage/treatment type: T3 or T4 rectal adenocarcinoma, with or without nodal metastasis, or any T stage tumours with nodal metastasis; neoadjuvant

Countries/sites: Spain, 3 sites

Setting: Hospital

Characteristics (Arm I/II): Locally advanced rectal adenocarcinoma; age ≤ 80 years (median 65/63 years); male (74/66%); PS WHO 0‐2 (PS ECOG 0: 63/64%)

Interventions

Arm I (FU+LV): LV 20 mg/m² followed by IV bolus FU 350 mg/m² for 5 consecutive days during first and fifth weeks of radiotherapy (n randomised = 77)

Arm II (UFT + LV): Single course of oral LV 12.5 mg bd and oral UFT 300 mg/m²/d on D 8‐36 of the radiotherapy course (n randomised = 78)

Radiotherapy consisted of a total dose of 45 Gy given in 25 fractions of 1.8 Gy, 5 fractions per week

Outcomes

DFS

OS

Grade ≥ 3 AEs (ECOG CTC)

Median follow‐up: 22 m, insufficient for DFS outcome

Study Details

Journal article

Funding sources and declarations of interest

Funding sources: None declared

Declarations of interest: No conflicts of interest

Notes

The scientific committee decided to stop the study because of slow accrual after 155 participants (63% of planned accrual) from the 3 participating hospitals had been randomised

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomly assigned in blocks of 10 ... " (methods and materials, paragraph 3, page 103)

Allocation concealment (selection bias)

Low risk

Quote: "Eligible patients were centrally randomized ..." (methods and materials, paragraph 3, page 103)

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Quote: "...open‐label clinical trial ..." (methods and materials, paragraph 1, page 103)

(i) DFS: This study was not used for the meta‐analysis for this outcome

(ii) OS: This study was not used for the meta‐analysis for this outcome

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

(i) DFS: This study was not used for the meta‐analysis for this outcome

(ii) OS: This study was not used for the meta‐analysis for this outcome

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Schedule of assessment and follow‐up

Low risk

(i) Disease recurrence (influences DFS) and (ii) Survival (influences DFS/OS)

Note: DFS and OS were not included in the meta‐analysis owing to < 3 years of median follow‐up

Quote: "Patients were evaluated every 2 months for the first 6 months, every 3 months for the next 6 months, at 6‐month intervals for the next 4 years, and then yearly" (methods and materials, paragraph 10, page 103)

(iii) Grade ≥ 3 AEs: Low

Quote: "During therapy, patients were monitored weekly for acute toxicity" (methods and materials, paragraph 9, page 103)

Quote: "Follow‐up was planned every 3 months following completion of therapy....The same schedule was applied for both arms." (correspondence with Dr. de la Torre, received 13 August 2012)

Incomplete outcome data (attrition bias)
All outcomes

Low risk

(i) Survival (DFS and OS): Low

Censoring was noted in the KM curves (Fig. 1, page 106). No evidence of bias related to censoring

This study was not used for the meta‐analysis of DFS and OS outcomes

(ii) Grade ≥ 3 AEs: Low

No missing data from participants in the safety analysis population (correspondence with Dr. de la Torre, received 13 August 2012)

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

"One patient randomized to the FU+LV arm and 2 patients randomized to the UFT+LV arm were excluded from all
analyses of acute adverse events and outcome" (results, paragraph 3, page 104)

Safety analysis: Analyses were also performed in the same population as described above

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

Low risk

(i) PS: Low (Table 1, page 104)

(ii) Median age: Low (Table 1, page 104)

(iii) TNM stage: Low (Table 1, page 104)

Other bias

Unclear risk

Subsequent therapies: Unclear ‐ not specified

Methods

Randomised controlled trial

Phase: III

Accrual dates: April 2002 to August 2004

Participants

No. randomised: 348

Stage/treatment line: Metastatic, first‐line

Countries/sites: Spain, 29 sites

Setting: Hospital

Characteristics (Arm I/II): Metastatic colorectal cancer; age ≥ 18 years (median 64/65 years); male (63/58%); KPS ≥ 70% (KPS > 70%: 89/90%)

Interventions

Arm I (XELOX): capecitabine 1000 mg/m² bd D1‐14 plus oxaliplatin 130 mg/m² D1, q21d for 12C (n randomised = 174)

Arm II (FUOX): Infusional FU 2250 mg/m² D1, 8, 15, 22, 29, 36 plus oxaliplatin 85 mg/m² D1, 15 and 29 q42d for 6C (n randomised = 174)

or until PD, intolerable AEs, or participant refusal

Outcomes

TTP

Grade ≥ 3 AEs (NCI CTC, version 2.0); HFS assessed using 3‐grade scale previously described (Blum 1999)

ORR (RECIST, version 1.0)

OS

Median follow‐up: 17.5 m (TTP/OS; cut‐off date 15 June 2006)

Study Details

Journal article

Funding sources and declarations of interest

Funding sources: Treatment of Digestive Tumors (TTD), Madrid, Spain, Roche, Sanofi‐Aventis

Declarations of interest: Sanofi‐Aventis, Roche

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomly assigned ... using a centrally generated computer randomization code" (patients and methods, paragraph 4, page 4225)

Allocation concealment (selection bias)

Low risk

Quote as above

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Quote: "...open‐label, phase III trial..." (patients and methods, paragraph 1, page 4225)

(i) ORR/TTP: Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

(i) ORR/TTP: High

Quote: "The response was assessed only by the investigators" (patients and methods, paragraph 8, page 4225)

Outcome assessment at risk of bias from lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Schedule of assessment and follow‐up

High risk

(i) Response (influences ORR/TTP): Low

Quote: " Imaging studies ... were repeated every 12 weeks during treatment" (patients and methods, paragraph 7, page 4225)

(ii) Survival (influences OS): Unclear ‐ not specified

(iii) Grade ≥ 3 AEs: High

Quote: "Patients were evaluated for adverse events before oxaliplatin administration" (patients and methods, paragraph 5, page 4225)

Quote: "XELOX consisted of oral capecitabine ... ... plus oxaliplatin ... on day 1 every 3 weeks. FUOX consisted of FU ... ... plus oxaliplatin ... on days 1, 15, and 29 every 6 weeks" (patients and methods, paragraph 4, page 4225)

Therefore, participants were evaluated for AEs more frequently in the FUOX arm than in the XELOX arm

Incomplete outcome data (attrition bias)
All outcomes

Low risk

(i) ORR: Low

13% of patients in the XELOX arm and 9% of patients in the FUOX arm were not assessable (Table 2, page 4227)

(ii) TTP/OS: Low

Although not defined in Methods, censoring was noted in the KM curves (Fig 1 & 2, page 4227). No evidence of bias related to censoring

(iii) Grade ≥ 3 AEs: Low

Quote: “Safety was evaluated in all patients who received treatment..." (results, paragraph 5, page 4227)

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Quote: "...348 patients (intent‐to‐treat population) were ... randomly assigned to treatment: 174 to XELOX and 174 to FUOX. Six patients (three in each treatment arm) did not initiate study treatment, leaving 342 patients who constituted the per‐protocol population" (results, paragraph 1, page 4225)

Quote: "The primary statistical analysis of efficacy was ... between groups in the per‐protocol population" (patients and methods, paragraph 9, page 4225)

Safety analysis:

Quote: “Safety was evaluated in all patients who received treatment (XELOX, n = 171; FUOX, n = 171) ..." (results, paragraph 5, page 4227)

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

Unclear risk

(i) PS: Unclear ‐ presented as KPS ≤ 70% vs > 70% (Table 1, page 4226)

(ii) Median age: Low (Table 1, page 4226)

(iii) No. of involved organs: Unclear ‐ not specified

Other bias

Low risk

Subsequent therapies: Low

Quote: "A total of 199 patients (58.2%) received second‐line chemotherapy: 99 patients (57.9%) in the XELOX arm and 100 patients (58.5%) in the FUOX group" (results, paragraph 4, page 4226)

Other

Quote: "... significantly more patients in the XELOX arm (26%) than in the FUOX arm (16%) had received previous adjuvant chemotherapy (P = .032), which consisted of fluoropyrimidine therapy with or without LV" (results, paragraph 1, page 4225)

Methods

Randomised controlled trial

Phase: III

Accrual dates: June 1995 to August 1997

Participants

No. randomised: 816

Stage/treatment line: Metastatic, first‐line

Countries/sites: Multi‐nation, 85 sites ‐ USA and Puerto Rico (n = 466), Canada (n = 100), Europe (n = 250)

Setting: Hospital

Characteristics (Arm I/II): Metastatic colorectal cancer; age > 18 years (median 64/64 years); male (61/60%); PS ECOG 0‐2 (PS ECOG 0: 45/43%)

Interventions

Arm I (UFT/LV): UFT 300 mg/m²/d and LV 75 mg/d (US) or 90 mg/d (non‐USA countries) D1‐28, q35d (n randomised = 409)

Arm II (5‐FU/LV): 5‐FU 425 mg/m²/d plus LV 20 mg/m²/d D1‐5, q28d (n randomised = 407)

Outcomes

OS

TTP

ORR (WHO criteria, modified)

Grade ≥ 3 AEs (CTC, version not specified)

Median follow‐up: Not specified.

Study Details

Journal article

Funding sources and declarations of interest

Funding sources: Taiho Pharmaceutical Company, Bristol‐Myers Squibb

Declarations of interest: None declared

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not specified

Allocation concealment (selection bias)

Low risk

Quote: "Patients were centrally randomized ..." (patients and methods, paragraph 2, page 3607)

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Not specified, blinding unlikely

(i) ORR/TTP: Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias if there was lack of blinding   

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

Not specified

(i) ORR/TTP: High

Outcome assessment at risk of bias if there was lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias if there was lack of blinding  

Schedule of assessment and follow‐up

High risk

(i) Response (influences ORR/TTP): High

Quote: "Tumor reassessment, including tumor measurements and a computed tomography scan of the
abdomen and pelvis, was repeated after every two courses ..." (patients and methods, paragraph 7, page 3607)

Quote: "In the UFT/LV treatment arm ...cycles repeated every 35 days...In the 5‐FU/LV treatment arm ... cycles repeated every 28 days" (patients and methods, paragraph 3, page 3607)

Therefore, responses were evaluated more frequently in the 5‐FU/LV arm

(ii) Survival (influences OS): Unclear ‐ not specified

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (attrition bias)
All outcomes

Low risk

(i) ORR: Low

1 patient in the 5‐FU/LV arm (< 1%) and no patients in the UFT/LV arm were not assessable (Table 2, page 3608)

(ii) TTP/OS: Low

Although not defined in the Methods, censoring was noted in the KM curves (Figure 1, page 3610). No evidence of bias related to censoring

(iii) Grade ≥ 3 AEs: Low

Other than data for LFTs, which were not of interest for the review, relevant AEs have < 7% of safety outcome data missing (Table 4, 5, and 6, pages 3611 and 3612)

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Quote: "All efficacy analyses are presented by treatment arm as randomized" (patients and methods, paragraph 8, page 3608)

Safety analysis:

Quote: "All 802 patients who received at least one dose of study medication were evaluated for safety and were analyzed based on the treatment arm as treated" (results, paragraph 18, page 3610)

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

Unclear risk

(i) PS: Low (Table 1, page 3608)

(ii) Median age: Low (Table 1, page 3608)

(iii) No. of involved organs: Unclear ‐ not specified

Other bias

Low risk

Subsequent therapies: Low

Quote: "Secondary chemotherapy was administered to 52% of patients assigned to UFT/LV and 50% of patients assigned to 5‐FU/LV. Information about the type of drugs included in subsequent chemotherapy was not collected" (results, paragraph 17, page 3610)

Methods

Randomised controlled trial

Phase: II, non‐comparative

Accrual dates: February 2007 to June 2008

Participants

No. randomised: 302

Stage/treatment line: Metastatic, first‐line

Countries/sites: Multi‐nation; Argentina, Australia, Austria, Belgium, Brazil, France, Germany, Greece, Hong Kong, Israel, Italy, Mexico, Poland, Thailand

Setting: Hospital

Characteristics (Arm I/II): Metastatic colorectal cancer; age ≥18 years (median 60.0/61.5 years); male (63/63%); KPS ≥ 60 (PS ECOG 0: 79/79%)

Interventions

Arm I (UFOX + cetuximab): D1 cetuximab (loading dose 400 mg/m² then 250 mg/m² weekly, thereafter) followed by oxaliplatin 85 mg/m² D1 and 15, UFT (tegafur 250 mg/m²/d, uracil 560 mg/m²/d) and folinic acid 90 mg/d D1‐21, q28d (n randomised = 152)

Arm II (FOLFOX4 + cetuximab): D1 cetuximab (as per Arm I) followed by oxaliplatin 85 mg/m² D1 and 15, folinic acid 200 mg/m², IV bolus 5‐FU 400 mg/m² and 5‐FU 600 mg/m² 22‐hour infusion D1, 2, 15, and 16, q28d (n randomised = 150)

Treatment continued until disease progression, withdrawal of consent, or unacceptable toxicity

Outcomes

PFS

OS

ORR (RECIST, version 1.0)

Grade ≥ 3 AEs (NCI CTC, version 3.0)

Median follow‐up: Clinical cut‐off for PFS ‐ 30 June 2009; clinical cut‐off for OS ‐ 31 August 2011

Study Details

Journal article and abstract/poster

Funding sources and declarations of interest

Funding sources: Merck KGaA

Declarations of interest: Merck‐Serono, Roche, Amgen

Notes

Of note, this study was designed before demonstration of KRAS mutation status was a predictive biomarker for cetuximab response. Enrollment was therefore independent of KRAS mutation status. Additionally, recruitment was curtailed after demonstration of KRAS mutation status as a predictive biomarker for cetuximab response

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "... patients were randomly assigned ... using a centralized stratified permuted block randomization procedure" (patients and methods, paragraph 4, page 15)

Allocation concealment (selection bias)

Low risk

Quote as above

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Quote: "...open‐label phase II study" (patients and methods, paragraph 4, page 15)

(i) ORR/PFS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

(i) ORR/PFS: High

The study was not blinded, and independent review was not performed (correspondence with Dr. Peter Eggleton, received 22 July 2012)

Outcome assessment at risk of bias from lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Schedule of assessment and follow‐up

Low risk

(i) Response (influences ORR/PFS): Low

Quote: "Investigators assessed response to treatment every 8 weeks based on radiological imaging (CT or MRI scans)..." (patients and methods, paragraph 6, page 16)

Quote: "After permanent treatment cessation, patients were followed every 3 months to collect data on progression..." (patients and methods, paragraph 6, page 16)

Quote: "This particular regimen of UFT and oxaliplatin was chosen to allow a 4‐week dosing cycle, which ensured that all assessments were carried out at the same time in each treatment arm" (patients and methods, paragraph 5, page 15)
(ii) Survival (influences PFS/OS): Low

Survival assessment was performed 6 weeks after final tumour assessment (correspondence with Dr. Peter Eggleton, received 2 August 2012)

Subsequently, quote: "After permanent treatment cessation, patients were followed every 3 months to collect data on ... survival ..." (patients and methods, paragraph 6, page 16)

(iii) Grade ≥ 3 AEs: Low

Assessments for adverse events followed identical schedules (correspondence with Dr. Peter Eggleton, received 2 August 2012)

Incomplete outcome data (attrition bias)
All outcomes

Low risk

(i) ORR: Low

Similar proportions of participants were not evaluable in both arms (Table 3, page 20)

(ii) PFS/OS: Low

Although not defined in the Methods, censoring was noted in the KM curves for PFS/OS (Figure 2, page 21). No evidence of bias related to censoring

(iii) Grade ≥ 3 AEs: Low

Data related to grade ≥ 3 adverse events were collected until the clinical cut‐off date (30 June 2009). No missing outcome data before that time (correspondence with Dr. Peter Eggleton, received 24 July 2016)

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Quote: "The primary efficacy analysis of PFS ... was carried out on the intention‐to‐treat (ITT) population, comprising all randomized patients" (patients and methods, paragraph 9, page 16)

Safety analysis:

Quote: "Safety analyses were performed on the safety population, which comprised all randomized patients who received any dose of any study treatment" (patients and methods, paragraph 10, page 16)

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

High risk

(i) PS: Low (Table 1, page 18)

(ii) Median age: Low (Table 1, page 18)

(iii) No. organs involved: Low (Table 1, page 18)

(iv) KRAS mut: High

Information on KRAS mut status was available for 93/150 (62%) of the ITT population in the FOLFOX4 + cetuximab arm and 87/152 (57%) of the ITT population in the UFOX + cetuximab arm (Figure 1, page 17)

A greater proportion of participants with known KRAS mutant status in the UFOX + cetuximab arm 47/87 (54%) were KRAS mutant than in the FOLFOX4 + cetuximab arm 37/93 (40%) – 14% difference (Table 1, page 18)

Other bias

Low risk

Subsequent therapies: Low

A similar proportion of participants received different types of subsequent second‐line therapy after disease progression, in each arm (supplementary table 1)

Methods

Randomised controlled trial

Phase: III

Accrual dates: May 2003 to August 2004

Participants

No. randomised: 306

Stage/treatment line: Metastatic, first‐line

Countries/sites: France, 33 sites

Setting: Hospital

Characteristics (Arm I/II): Metastatic colorectal cancer; age ≥ 18 years (median 66/64 years); male (64/60%); PS ECOG ≤ 2 (PS ECOG 0‐1 92/93%)

Interventions

Arm I (XELOX): oxaliplatin 130 mg/m² D1 plus oral capecitabine 1000 mg/m² bd D1‐14, q21d (n randomised = 156)

Arm II (FOLFOX): 6 D1 oxaliplatin 100 mg/m², leucovorin 400 mg/m², IV bolus 5‐FU 400 mg/m², and 5‐FU 2400‐3000 mg/m² 46‐hour infusion, q14d (n randomised = 150)

Treatment was continued for 24 weeks or until disease progression, whichever came first

Outcomes

ORR (RECIST, version 1.0)

PFS

OS

Grade ≥ 3 AEs (NCI‐CTC, version 3)

Median follow‐up: 18.8 months for ITT population, all outcomes

Study Details

Journal article and abstract

Funding sources and declarations of interest

Funding sources: Roche

Declarations of interest: Roche

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were assigned in a 1:1 ratio to a treatment group by centralised, adaptive randomisation (minimisation method) ..." (materials and methods, paragraph 3, page 683)

Allocation concealment (selection bias)

Low risk

Quote as above

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Quote: "...open‐label study" (materials and methods, paragraph 1, page 683)

(i) ORR/PFS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding   

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

(i) ORR/PFS: Low

Quote: "Tumour responses were validated in a centralised, blinded review of CT scans by an independent response committee (IRC)" (materials and methods, paragraph 7, page 684)

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Schedule of assessment and follow‐up

High risk

(i) Response (influences ORR/PFS): High

Quote: "Tumour assessments (CT scan and MRI) were ... repeated at cycles 3 and 6 in the XELOX group and cycles 4
and 8 in the FOLFOX‐6 group ..." (materials and methods, paragraph 7, page 684)

Quote: "XELOX ...every 3 weeks. FOLFOX‐6 ...every 2 weeks" (materials and methods, paragraph 4, page 683)

Therefore, the first and second response assessments were performed later in the XELOX arm (weeks 9 and 18) compared with the FOLFOX‐6 arm (weeks 8 and 16)

(ii) Survival (influences PFS/OS): Low

Quote: "After completion of study treatment, patients were reassessed every 3 months until 18 months after the end of treatment for the last randomised patient" (materials and methods, paragraph 7, page 684)

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

(i) ORR: Low

Quote: "...a small imbalance between the two treatment groups with respect to the percentage of patients not assessable for response (12.2% in XELOX vs. 8.7% in FOLFOX‐6)..." (discussion, paragraph 2, pages 687 and 688)

(ii) PFS/OS: Low

Although not defined in the Methods, censoring was noted in the KM curves (Figures 2 and 3, pages 687 and 688). No evidence of bias related to censoring.

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Quote: "The intent‐to‐treat (ITT) population included all patients who underwent randomisation" (materials and methods, paragraph 10, page 684)

Safety analysis:

Quote: "All patients receiving at least one dose of study treatment were included in the safety population" (materials and methods, paragraph 10, page 684)

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

Unclear risk

(i) PS: Unclear

Reported as ECOG 0‐1 vs 2 (Table 2, page 686)

(ii) Median age: Low (Table 2, page 686)

(iii) No. of involved organs: Low (Table 2, page 686)

Other bias

Unclear risk

Subsequent therapies: Unclear

Quote: "Although the protocol did not include monitoring of second‐line therapies following study drug discontinuation, the possibility that second‐line therapies may have influenced the OS results cannot be ruled out" (discussion, paragraph 1, page 687)

Methods

Randomised controlled trial

Phase: II, non‐comparative

Accrual dates: March 2006 to January 2008

Participants

No. randomised: 145

Stage/treatment line: Metastatic, first‐line

Countries/sites: 15 centres in France, La Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) study

Setting: Hospital

Characteristics (Arm I/II): Metastatic colorectal cancer; age 18 to 75 years (median 61/61 years); male (64/48%); PS ECOG 0‐2 (PS ECOG 0: 54/60%)

Interventions

Arm I (XELIRI + bevacizumab (BEV)): irinotecan 200 mg/m² D1 and capecitabine 1000 mg/m² (800 mg/m² if ≥ 65 years) bd D1‐14 plus BEV 7.5 mg/kg D1, q21d for a maximum of 8 cycles (n randomised = 72)

Arm II (FOLFIRI + BEV): Irinotecan 180 mg/m², leucovorin 400 mg/m², and IV bolus fluorouracil 400 mg/m² followed by 2400 mg/m² 46‐hour infusion plus 5 mg/kg BEV D1, q14d for a maximum of 12 cycles (n randomised = 73)

For participants whose disease was controlled after 6 months of BEV and chemotherapy, BEV (7.5 mg/kg every 3 weeks) was continued as a single‐agent maintenance therapy in both arms until progressive disease

Outcomes

PFS ‐ 6 months, PFS

Grade ≥ 3 AEs (NCI CTCAE, version 3.0)

ORR (RECIST, version 1.0)

OS

Median follow‐up: 36 months for both Arm I/II; final analysis 15 March 2010

Study Details

Journal article, abstract, oral poster presentation, and journal article for translational sub‐study

Funding sources and declarations of interest

Funding sources: Roche, Pfizer, and Chugai

Declarations of interest: Roche, Chugai, Pfizer, Amgen, Boeringer, Merck Serono

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was performed using the minimisation method (using a 10% random factor) (correspondence with Dr. Jean‐Pierre Pignon, received 1 August 2012)

Allocation concealment (selection bias)

Low risk

Central randomisation by fax was used (correspondence with Dr. Jean‐Pierre Pignon, received 1 August 2012)

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Quote: "... open‐label, non‐comparative phase II study" (patients and methods, paragraph 1, page 1237)

(i) ORR/PFS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding     

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

(i) ORR/PFS: High

Outcome assessment at risk of bias from lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Schedule of assessment and follow‐up

High risk

(i) Response (influences ORR/PFS): Low

Quote: "Tumour assessments using abdominal and/or thoracic computed tomography (CT) or magnetic resonance imaging (MRI) were performed at baseline and every 8 weeks until progression" (patients and methods, paragraph 5, page 1238)

(ii) Survival (influences PFS/OS): Low

Quote: "After disease progression, patients were followed up at least every 2 months until death" (patients and methods, paragraph 4, page 1238)

(iii) Grade ≥ 3 AEs: High

Quote: "During treatment, physical examination, ECOG performance status, BP, and blood and biochemistry analyses were repeated every cycle" (patients and methods, paragraph 4, page 1237)

Quote: "treatment with either ... XELIRI ... every 3 weeks ... or FOLFIRI ... every 2 weeks" (patients and methods, paragraph 3, page 1237)

Quote: "During bevacizumab maintenance, clinical examination, BP, blood/urine analysis and ECOG performance status were performed every 3 weeks" (patients and methods, paragraph 4, page 1237 and 1238)

Therefore, safety evaluation was performed more frequently in the FOLFIRI + BEV group during combination treatment

Safety assessment was 3‐weekly during treatment with BEV alone for both arms

Incomplete outcome data (attrition bias)
All outcomes

Low risk

(i) ORR: Low

Outcome data were available for all randomised participants, including those who had 'early stopping' (correspondence with Dr. Jean‐Pierre Pignon, received 1 August 2012)

(ii) PFS/OS: Low

As above

(iii) Grade ≥ 3 AEs: Low

Quote: "All 145 patients were evaluable for safety..." (results, paragraph 5, page 1239)

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Analysis was according to treatment as randomised (Fig. 1, page 1239)

Safety analysis:

Analysis was according to treatment as randomised (Fig. 1, page 1239)

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

Low risk

(i) PS: Low (Table 1, page 1239)

(ii) Median age: Low (Table 1, page 1239)

(iii) No. of involved organs: Low (Table 1, page 1239)

Other bias

Low risk

Similar proportions of participants in the XELIRI + BEV and FOLFIRI + BEV groups received different types of subsequent drug therapy following progression on first‐line treatment (supplementary material, supplementary Tables 1 and 2, pages 4‐7)

Methods

Randomised controlled trial

Phase: III

Accrual dates: April 1999 to September 2000 (closed)

Participants

No. randomised: 125 of planned 950

Stage/treatment line: Metastatic, first‐line

Countries/sites: USA, 24 study sites and one Expanded Participation Project (EPP) site

Setting: Hospital

Characteristics (Arm A/B): Metastatic colorectal cancer; age ≥ 18 years (median 64/65 years); male (64/62%); PS ECOG 0‐2 (PS ECOG 0: 45/43%)

Interventions

Arm A: Continuous 5‐FU infusion 300 mg/m²/d D1‐28, q35d (n randomised = 64)

Arm B: Oral eniluracil 11.5 mg/m² and oral 5‐FU 1.15 mg/m² bd D1‐28, q35d (n randomised = 61)

Outcomes

ORR (ECOG Solid Tumour Response Criteria)

PFS

OS

Grade ≥ 3 AEs (CTC, version 2.0)

Median follow‐up: 1.3 years, all outcomes

Study Details

Technical report and study protocol

Funding sources and declarations of interest

Funding sources: National Cancer Institute, DHHS

Declarations of interest: None declared

Notes

This study was closed early, after accrual of 125 of a planned 950 participants, following results of the Van Cutsem 2001a and Schilsky 2002a studies

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was performed with permuted blocks within strata algorithm, with override protection for treatment imbalances that could occur within the main institutions of the cooperative group due to the stratified algorithm (correspondence with Dr. Paul Catalano, received 10 July 2012)

Allocation concealment (selection bias)

Low risk

Permuted blocks of undisclosed size were generated within strata. Additionally, accruals occurred over time across many treating centres, making it very unlikely that one could decode the randomisation algorithm and predict the next assignment in the sequence (correspondence with Dr. Paul Catalano, received 10 July 2012)

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

No blinding occurred in the trial (correspondence with Dr. Paul Catalano, received 10 July 2012)

(i) ORR/PFS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

No blinding

(i) ORR/PFS: High

Outcome assessment at risk of bias from lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding  

Schedule of assessment and follow‐up

Low risk

(i) Response (influences ORR/PFS): Low

Response assessments were performed every 10 weeks. For those with measurable disease, if a CR/PR was achieved, this was confirmed after 4 weeks (E5296 study protocol, page 14)

(ii) Survival (influences OS): Low

Post‐treatment follow‐up was the same for both arms: every 3 months if < 2 years from study entry, every 6 months if 2 to 5 years from study entry, and every 12 months if > 5 years from study entry (E5296 study protocol, page 20)

(iii) Grade ≥ 3 AEs: Low

Complete blood count (CBC) was examined weekly and other AE assessments were performed before each treatment cycle (E5296 protocol, page 14). One cycle was every 35 days for both arms (E5296 study protocol, page 6)

Incomplete outcome data (attrition bias)
All outcomes

Low risk

(i) ORR: Low

The sum of those with unevaluable and unknown responses was 5/62 (8%) in the IV 5‐FU arm and 3/61 (5%) in the oral 5‐FU + eniluracil arm (Table 11, page 22)

(ii) PFS/OS: Low

Survival outcomes were known for all participants who were eligible, were ineligible, and had withdrawn (correspondence with Dr. Paul Catalano, received 10 July 2012)
(iii) Grade ≥ 3 AEs: Low

Quote: "Toxicity data was submitted for 63 patients randomized to arm A and 59 patients randomized to arm B" (results, paragraph 6, page 9)

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Presented results were analysed according to allocated treatment (section 7.1, page 8 and Table 1, page 12). This excluded patients who were found to be ineligible (after randomisation) and who withdrew from the study before treatment (2/125, 1.6%) (results, paragraph 1, page 8 and Table 1, page 12)

Safety analysis:

Analysis was performed for those who had toxicity data submitted (results, paragraph 6, page 9, and Table 8, pages 20 and 21)

Selective reporting (reporting bias)

Low risk

The same outcomes were reported in the study protocol and in the technical report

Similarity of arms at baseline

Unclear risk

(i) PS: Low (Table 3, page 13)

(ii) Median age: Low (Table 3, page 13)

(iii) No. of involved organs: Unclear ‐ not specified

Other bias

Unclear risk

Subsequent therapies: Unclear ‐ not specified

Methods

Randomised controlled trial

Phase: III

Design: For Period 1 (the only period of interest for this review), 3 × 2 factorial design with randomisation to FOLFIRI vs mIFL vs CapeIRI (open‐label), and randomisation to celecoxib vs placebo (double‐blind)

Accrual dates: Period 1 February 2003 to March 2004

Participants

No. randomised: 430

Stage/treatment line: Metastatic, first‐line

Countries/sites: For Periods 1 and 2, participants were enrolled in USA, Canada, Australia, and New Zealand, at 99 sites

Setting: Hospital

Characteristics (Arm A/B/C): Metastatic colorectal cancer; age ≥ 18 years (median 61/62/62 years); male (63.9/58.9/54.5%); PS ECOG 0‐1 (PS ECOG 0: 52.1/49.6/48.3%)

Interventions

Arm A (FOLFIRI + *celecoxib/placebo): irinotecan 180 mg/m², LV 400 mg/m², IV bolus FU 400 mg/m², followed by 5FU 2400 mg/m² 46‐hour infusion, q14d (n randomised = 144)

Arm B (mIFL + celecoxib/placebo): irinotecan 125 mg/m², LV 20 mg/m², IV bolus FU 500 mg/m² D1 and 8, q21d (n randomised = 141)

Arm C (CapeIRI + celecoxib/placebo): irinotecan 250 mg/m² D1 and oral capecitabine 1000 mg/m² bd D1‐14, q21d (n randomised = 145)

*Oral celecoxib 400 mg bd or placebo tablets; permanently discontinued on 19 January 2005.

Treatment continued until PD, unacceptable toxicity from chemotherapy, or withdrawal of consent

Outcomes

PFS

OS

ORR (RECIST, version 1.0)

Grade ≥ 3 AEs (NCI CTC, version 2.0)

Median follow‐up: 34 months (cut‐off date Nov 17 2006)

Study Details

Journal article

Funding sources and declarations of interest

Funding sources: Pfizer

Declarations of interest: Pfizer, Sanofi‐Aventis, Genentech, AstraZeneca, Bristol‐Myers Squibb, Amgen, Imclone Systems Inc, Roche, Boerhinger Ingelheim

Notes

Study was terminated after enrolment of 547 of a planned 900 participants. Accrual to this trial had slowed after report of cardiovascular concerns with celecoxib, despite celecoxib/placebo administration for all participants was permanently discontinued in January 2005

16 participants (11.1%) in Arm I chose to have bevacizumab after the study amendment (bevacizumab 5 mg/kg IV on D1, repeated every 2 weeks), and 7 participants (5.0%) in Arm II chose to have bevacizumab after the study amendment (bevacizumab 7.5 mg/kg IV on D1, repeated every 3 weeks)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not specified

Allocation concealment (selection bias)

Unclear risk

Not specified

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Quote: "...randomly assigning patients to one of three open‐label chemotherapy arms ..." (patients and methods, paragraph 2, page 4780)

(i) ORR/PFS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

(i) ORR/PFS: High

Outcome assessment at risk of bias from lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding  

Schedule of assessment and follow‐up

High risk

(i) Response (influences ORR/PFS): Low

Quote: "During chemotherapy, a follow‐up CT/MRI of the abdomen/pelvis and chest x‐ray or chest CT/MRI were to be performed every 6 weeks. Assessments were performed every 6 weeks until PD or on chemotherapy discontinuation" (patients and methods, paragraph 10, page 4781)

(ii) Survival (influences PFS/OS): Low

Quote: "After PD, the patient was observed every 3 months for survival" (patients and methods, paragraph 10, page 4781)

(iii) Grade ≥ 3 AEs: High

Participants were reviewed for safety assessments every week during the first cycle, and then every cycle (communication with Dr. Justin Binko, received 26 July 2012)

Quote: "...FOLFIRI ... repeated every 2 weeks ... mIFL ... repeated every 3 weeks. CapeIRI ... repeated every 3 weeks" (patients and methods, paragraph 5, page 4780)

Therefore, following cycle 1, participants in the FOLFIRI arm underwent more frequent safety evaluations than those in the mIFL and CapeIRI arms

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

(i) ORR: Unclear ‐ not specified

(ii) PFS/OS: Low

PFS‐

Quote: "For patients without documented PD, data were censored on the date of the last tumor assessment with nonprogression status or, for patients who started a second‐line therapy, at the date of the start of new therapy" (patients and methods, paragraph 11, page 4781). No evidence of bias related to censoring

OS‐

Quote: "...in the absence of confirmation of death, data were censored at the last date the patient was known to be alive" (patients and methods, paragraph 12, page 4781). No evidence of bias related to censoring

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Quote: "Efficacy analyses included all patients randomly assigned on an intent‐to‐treat basis" (patients and methods, paragraph 14, page 4781)

Safety analysis:

Quote: "Safety analyses included all treated patients ..." (patients and methods, paragraph 14, page 4781)

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

Unclear risk

(i) PS: Low (Table 2, page 4783)

(ii) Median age: Low (Table 2, page 4783)

(iii) No. of involved organs: Unclear ‐ not specified

A similar median number of measurable target metastatic lesions for all 3 treatment arms was reported in a published author reply, quote: "The median number of measurable target metastatic lesions was 3.2 for FOLFIRI, 3.1 for mIFL, and 3.1 for CapeIRI" (Fuchs et al, Journal of Clinical Oncology 2008, paragraph 2)

Other bias

Low risk

Subsequent therapies: Low

Quote: "The rates of utilization of poststudy salvage chemotherapy did not differ significantly between the three first‐line chemotherapy arms in period 1 (77% for FOLFIRI, 75% for mIFL, and 77% for CapeIRI)" (results, paragraph 4, page 4783)

Other bias:

Some participants in the FOLFIRI and mIFL arms from period 1 received BEV, although this was only a small percentage in each arm

Quote: "After activation of this study amendment, patients randomly assigned to FOLFIRI or mIFL during period 1 had the option of adding bevacizumab to their current regimen. Among patients enrolled during period 1, 16 patients on the FOLFIRI arm added bevacizumab to their regimen, and seven patients on the mIFL arm added bevacizumab to their regimen" (patients and methods, paragraph 6, page 4780)

Risk of bias considerations in a factorial study: Unclear ‐ tests for interaction not specified

Methods

Randomised controlled trial

Phase: Not specified

Accrual dates: December 2002 to November 2003

Participants

No. randomised: 150

Stage/treatment line: Metastatic, first‐line

Countries/sites: USA, 33 sites

Setting: Hospital

Characteristics (Arm I/II/III): Metastatic colorectal cancer; age ≥ 18 years (median 62/62/62.5 years); male (57/62/65%); PS ECOG 0‐1 (PS ECOG 0: 61/58/52%)

Interventions

Arm I (mFOLFOX6): oxaliplatin 85 mg/m², LV 350 mg, IV bolus FU 400 mg/m² and 2400 mg/m² 46‐hour infusion, q14d (n randomised = 50)

Arm II (bFOL): oxaliplatin 85 mg/m² D1 and 15, LV 20 mg/m², IV bolus FU 500 mg/m² D1, 8, and 15, q28d (n randomised = 50)

Arm III (CapeOx): oxaliplatin 130 mg/m² D1 and capecitabine 1000 mg/m² bd D1‐15, q21d (n randomised = 50)

Treatment continued until PD, unacceptable toxicity, extended toxicity‐related dose delay or withdrawal of consent

Outcomes

ORR (RECIST, version 1.0)

TTP (treated as PFS in this review, based on the definition provided)

Grade ≥ 3 AEs (NCI CTC, version 2.0)

OS

Median follow‐up: All outcomes ‐ 16.9, 15.1, 15.0 months, for Arms 1 through 3, respectively

Study Details

Journal article

Funding sources and declarations of interest

Funding sources: Sanofi‐Aventis

Declarations of interest: Sanofi‐Aventis, Genentech BioOncology, Bristol Myers‐Squibb, Taiho, Samyang Confirma Biotech, Amgen

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not specified

Allocation concealment (selection bias)

Unclear risk

Not specified

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Quote: "TREE‐1 and TREE‐2 were two sequentially conducted, randomized, open‐label cohorts in this study" (patients and methods, paragraph 1, page 3524)

(i) ORR/TTP (treated as PFS): Low

Outcome assessment unlikely to be influenced by lack of blinding

This study was not used for the meta‐analysis of the TTP (treated as PFS) outcome

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

(i) ORR/TTP (treated as PFS): High

Outcome assessment at risk of bias from lack of blinding

This study was not used for the meta‐analysis of the TTP (treated as PFS) outcome

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding   

Schedule of assessment and follow‐up

High risk

(i) Response (influences ORR/TTP (treated as PFS)): Low

Quote: "Tumor assessments were repeated every 12 weeks in TREE‐1 ..." (patients and methods, paragraph 5, page 3524)

This study was not used for the meta‐analysis of the TTP (treated as PFS) outcome

(ii) Survival (influences TTP (treated as PFS)/OS): High

Quote: "After treatment discontinuation, patients in TREE‐2 were followed for survival at 3‐month intervals for at least 2 years and every 6 months thereafter until lost to follow‐up or consent withdrawal; these data were collected for patients in TREE‐1 who consented retrospectively" (patients and methods, paragraph 5, page 3524)

No information was provided regarding the relative numbers of participants in each arm of TREE‐1 who consented retrospectively

This study was not used for meta‐analysis of the TTP (treated as PFS) outcome

(iii) Grade ≥ 3 AEs: High

Quote: "Clinical assessments and toxicities were recorded on day 1 of each cycle and at the end of treatment" (patients and methods, paragraph 5, page 3524)

Quote: "In TREE‐1, patients received mFOLFOX6 ... every 2 weeks ..., bFOL ... every 4 weeks ... , or CapeOx ... every 3 weeks ..." (patients and methods, paragraph 1, page 3524)

Therefore, participants underwent safety evaluations more frequently in the mFOLFOX arm

Incomplete outcome data (attrition bias)
All outcomes

High risk

(i) ORR: High

23% of participants were missing reported confirmed response data in the CapeOx arm (Table 4, page 3527)

(ii) TTP (treated as PFS): Low

Quote: "TTP was censored at the last date the patient was known to be progression free for patients who did not have objective tumor progression and who were either still on study at the time of the analysis or who were removed from follow‐up before documentation of objective tumor progression. For patients who received second‐line treatment prior to progression or death, TTP was censored at the time of starting the new therapy" (Table 4, page 3527)

No evidence of bias related to censoring

This study was not used for the meta‐analysis of TTP (treated as PFS) outcome

OS: Unclear ‐ Not specified

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Quote: "All analyses are for the as‐treated population, which includes all randomly assigned patients receiving at least one treatment" (patients and methods, paragraph 6, page 3524)

Quote: "In TREE‐1, 147 of 150 patients were treated (one was ineligible for prior chemotherapy and two did not start treatment)" (results, paragraph 2, page 3524)

Therefore, 2% of randomised participants were excluded from the efficacy analysis population

Safety analysis:

Same as for efficacy

Selective reporting (reporting bias)

Unclear risk

No protocol was available.

Similarity of arms at baseline

Unclear risk

(i) PS: Low (Table 1, page 3525)

(ii) Median age: Low (Table 1, page 3525)

(iii) No. of involved organs: Unclear ‐ not specified

Other bias

Unclear risk

Subsequent therapies: Unclear ‐ not specified for the different arms within TREE‐1

Methods

Randomised controlled trial

Phase: Not specified

Accrual dates: November 2003 to April 2004

Participants

No. randomised: 223

Stage/treatment line: Metastatic, first‐line

Countries/sites: USA, 57 sites

Setting: Hospital

Characteristics (Arm I/II/III): Metastatic colorectal cancer; age ≥ 18 years (median 64/57/62 years); male (61/49/58%); PS ECOG 0‐1 (PS ECOG 0: 61/54/65%)

Interventions

Arm I (mFOLFOX6 + bevacizumab (BEV)): oxaliplatin 85 mg/m², LV 350 mg, IV bolus 5FU 400 mg/m², and 5‐FU 2400 mg/m² 46‐hour infusion, q14d + BEV 5 mg/kg D1, q14d (n randomised = 75)

Arm II (bFOL + BEV): oxaliplatin 85 mg/m² D1 and 15, LV 20 mg/m², IV bolus FU 500 mg/m² D1, 8, and 15, q28d + BEV 5 mg/kg D1, q14d (n randomised = 74)

Arm III (CapeOx + BEV): oxaliplatin 130 mg/m² D1 and capecitabine 850 mg/m² bd D1‐15, q21 plus BEV 7.5 mg/kg D1, q21d (n randomised = 74)

Treatment continued until PD, unacceptable toxicity, extended toxicity‐related dose delay, or withdrawal of consent

Outcomes

ORR (RECIST, version 1.0)

TTP (treated as PFS in this review, based on the definition provided)

Grade ≥ 3 AEs (NCI CTC, version 2.0)

OS

Median follow‐up: All outcomes, 17.9, 17.6 and 18.5 months in Arm I‐III, respectively.

Study Details

Journal article

Funding sources and declarations of interest

Funding sources: Sanofi‐Aventis

Declarations of interest: Sanofi‐Aventis, Genentech BioOncology, Bristol Myers‐Squibb, Taiho, Samyang Confirma Biotech, Amgen

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not specified

Allocation concealment (selection bias)

Unclear risk

Not specified

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Quote: "TREE‐1 and TREE‐2 were two sequentially conducted, randomized, open‐label cohorts in this study" (patients and methods, paragraph 1, page 3524)

(i) ORR/TTP (treated as PFS): Low

Outcome assessment unlikely to be influenced by lack of blinding

This study was not used for the meta‐analysis of the TTP (treated as PFS) outcome

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

(i) ORR/TTP (treated as PFS): High

Outcome assessment at risk of bias from lack of blinding

This study was not used for meta‐analysis of the TTP (treated as PFS) outcome

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Schedule of assessment and follow‐up

High risk

(i) Response (influences ORR/TTP (treated as PFS)): Low

Quote: "Tumor assessments were repeated ... every 6 weeks in TREE‐2" (patients and methods, paragraph 5, page 3524)

This study was not used for meta‐analysis of the TTP (treated as PFS) outcome

(ii) Survival (influences TTP (treated as PFS)/OS): Low

Quote: "After treatment discontinuation, patients in TREE‐2 were followed for survival at 3‐month intervals for at least 2 years and every 6 months thereafter until lost to follow‐up or consent withdrawal ..." (patients and methods, paragraph 5, page 3524)

This study was not used for the meta‐analysis of the TTP (treated as PFS) outcome.

(iii) Grade ≥ 3 AEs: High

Quote: "Clinical assessments and toxicities were recorded on day 1 of each cycle and at the end of treatment" (patients and methods, paragraph 5, page 3524)

Quote: "In TREE‐1, patients received mFOLFOX6 ... every 2 weeks ..., bFOL ... every 4 weeks ... , or CapeOx ... every 3 weeks ... In TREE‐2, patients received one of the same three chemotherapy regimens as in TREE‐1 but with the addition of bevacizumab ..." (patients and methods, paragraph 1, page 3524)

Therefore, participants underwent safety evaluations more frequently in the mFOLFOX arm

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

(i) ORR: Low

Confirmed tumour response data were reported for ≥ 85% of participants in all arms (Table 4, page 3527)

(ii) TTP (treated as PFS): Low

Quote: "TTP was censored at the last date the patient was known to be progression free for patients who did not have objective tumor progression and who were either still on study at the time of the analysis or who were removed from follow‐up before documentation of objective tumor progression. For patients who received second‐line treatment prior to progression or death, TTP was censored at the time of starting the new therapy" (Table 4, page 3527)

There was no evidence of bias related to censoring

This study was not used for meta‐analysis of the TTP (treated as PFS) outcome

OS: Unclear ‐ not specified

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (ITT analysis)

High risk

Efficacy analysis: High

Quote: "All analyses are for the as‐treated population, which includes all randomly assigned patients receiving at least one treatment" (patients and methods, paragraph 6, page 3524). 4/75 (5.3%) , 4/74 (5.4%) and 2/74 (3%) patients were excluded from the mFOLFOX6 + BEV, bFOL + BEV and CapeOx + BEV arms, respectively (from results, paragraph 1, page 3524 and Table 2, page 3525)

Safety analysis:

Same as for efficacy

Selective reporting (reporting bias)

Unclear risk

No protocol was available.

Similarity of arms at baseline

High risk

(i) PS: Low (Table 1, page 3525)

(ii) Median age: High

5‐year difference between bFOL + BEV and CapeOx + BEV arms (Table 1, page 3525)

(iii) No. of involved organs: Unclear ‐ not specified

Other bias

Unclear risk

Subsequent therapies: Unclear ‐ not specified for the different arms within TREE‐2

Methods

Randomised controlled trial

Phase: III

Accrual dates: September 1996 to February 1998

Participants

No. randomised: 605

Stage/treatment line: Metastatic, first‐line

Countries/sites: Multi‐nation, 61 sites ‐ USA (n = 48), Canada (n = 9), Brazil (n = 2), and Mexico (n = 2)

Setting: Hospital

Characteristics (Arm I/II/): Metastatic colorectal cancer; age ≥ 18 years (median 64/63 years); male (59.9/65.0%); KPS ≥ 70% (median 90/90%)

Interventions

Arm I: capecitabine 1250 mg/m² bd D1‐14, q21d (n randomised = 302)

Arm II: IV bolus 5‐FU 425 mg/m² plus LV 20 mg/m² D1‐5, q28d (n randomised = 303)

Treatment continued until PD, unacceptable toxicity, or scheduled assessment at 30 weeks. Participants with a tumour response or SD were allowed to enter a continuation phase up to a total of 48 weeks. Treatment continuation beyond 48 weeks (post‐continuation phase) for participants without PD was provided at the discretion of the investigator

Outcomes

ORR (WHO criteria, 1979)

TTP (treated as PFS in this review, based on the definition provided)

OS

Grade ≥ 3 AEs (NCI CTC, revised December 1994)

No details on median follow‐up

Study Details

Journal articles

Funding sources and declarations of interest

Funding sources: F. Hoffman‐La Roche

Declarations of interest: None declared

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "... patients were randomly assigned to treatment with capecitabine or 5‐FU/LV according to a computer‐generated randomization code" (patients and methods, paragraph 3, page 2283)

Allocation concealment (selection bias)

Low risk

Quote: "The patients were randomized centrally by country in blocks of four patients" (patients and methods, paragraph 3, page 2283)

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Quote: "... open‐label, randomized, parallel‐group study ..." (patients and methods, paragraph 3, page 2283)

(i) ORR/TTP (treated as PFS): Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

(i) ORR/TTP (treated as PFS): Low

Quote: "Investigator assessments of tumor response were reviewed, solely on the basis of imaging, by an independent review committee (IRC) composed of radiologists who were blinded to the treatment received, the clinical condition of the patient, and the investigator’s evaluation" (patients and methods, paragraph 8, page 2284)

The absolute ORR was higher for capecitabine than for 5‐FU/LV for both of these assessments (Table 2, page 2285)

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Schedule of assessment and follow‐up

Low risk

(i) Response (influences ORR/TTP (treated as PFS)): Low

Quote: "Assessments of tumor dimensions and involved sites were performed before the start of treatment and were scheduled after weeks 6, 12, 18, 24, and 30 of therapy. Further assessments were performed after weeks 39 and 48 for patients who received prolonged therapy (up to 48 weeks). Follow‐up assessments for disease progression and survival monitoring were performed every 3 months after the end of treatment" (patients and methods, paragraph 8, page 2284)

(ii) Survival (influences TTP (treated as PFS)/OS): Low

Quote: "Follow‐up assessments for ... survival monitoring were performed every 3 months after the end of treatment" (patients and methods, paragraph 8, page 2284)

(iii) Grade ≥ 3 AEs: Low

Quote: "Safety evaluations were conducted at least monthly until 4 weeks after the end of therapy..." (patients and methods, paragraph 9, page 2284)

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

(i) ORR: Low

For Investigator assessed responses, missing post‐baseline data for 7.3% of participants in the capecitabine arm and for 12.5% in the 5‐FU/LV arm (Table 2, page 2285)

(ii) TTP (treated as PFS)/OS: Unclear ‐ not specified

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Quote: "The analyses of efficacy were based on all randomized patients" (patients and methods, paragraph 12, page 2284)

Safety analysis:

Quote: "The analyses of toxicity were based on the safety population, which included all patients who received at least one dose of study treatment" (patients and methods, paragraph 13, page 2284)

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

Unclear risk

(i) PS: Unclear

KPS was reported as a mean/median (Table 1, page 2285)

(ii) Median age: Low (Table 1, page 2285)

(iii) No. of organs: Unclear‐ not specified

Other bias

Unclear risk

Subsequent therapies: Unclear ‐ not specified

Methods

Randomised controlled trial

Phase: III

Accrual dates: March 2002 to December 2007

Participants

No. randomised: 401

Stage/treatment type: Rectal adenocarcinoma; adjuvant‐ R0 resection, neoadjuvant‐ cT3‐4 N0 or cT_any N+

Countries/sites: Germany, 35 sites

Setting: Hospital

Characteristics (Arm I/II): Rectal adenocarcinoma; age ≥ 18 years (median 65/64 years); male (65/67%); PS WHO 0‐1 (PS WHO 0: 61/49%)

Interventions

Adjuvant cohort:

Arm I: Two cycles of capecitabine 2500 mg/m² D1‐14, q21d, followed by chemoradiotherapy 50.4 Gy plus capecitabine 1650 mg/m² D1‐38, then 3 cycles of capecitabine (n randomised and with post‐randomisation data = 116)

Arm II: Two cycles IV bolus fluorouracil 500 mg/m² D1‐5, repeated D29‐33, followed by chemoradiotherapy 50.4 Gy plus infusional fluorouracil 225 mg/m² daily, then 2 cycles of bolus fluorouracil (n randomised and with post‐randomisation data = 115)

Neoadjuvant cohort:

Arm I: Chemoradiotherapy (50.4 Gy plus capecitabine 1650 mg/m² daily), followed by radical surgery and 5 cycles of capecitabine 2500 mg/m² per day for 14 days (n randomised and with post‐randomisation data = 81)

Arm II: Chemoradiotherapy (50.4 Gy plus infusional fluorouracil 1000 mg/m² D1‐5 and 29‐33), followed by radical surgery and four cycles of bolus fluorouracil 500 mg/m² for 5 days (n randomised and with post‐randomisation data = 80)

Surgery: TME for tumours of the lower two‐thirds of the rectum and PME for the upper third, assuming a 5 cm distal margin without coning, were mandatory for the adjuvant cohort and recommended for the neoadjuvant cohort. For low‐lying tumours, the decision between low anterior resection and abdominoperineal excision was left to the surgeon’s discretion

Outcomes

OS (5 years)

DFS

Grade ≥ 3 AEs (NCI‐CTC, version 2.0)

Median follow‐up: 52 months for all outcomes

Study Details

Journal article

Funding sources and declarations of interest

Funding sources: Roche Pharma AG

Declarations of interest: Roche Pharma AG, Chugai Pharma, Amgen, Merck KGaA, Ariad, Bristol‐Myers Squibb, Novartis, Merck Sharp & Dohme

Notes

Study protocol was amended in March 2005, to include patients with locally advanced rectal cancer receiving preoperative chemoradiotherapy (neoadjuvant cohort). Recruitment to the adjuvant cohort was continued

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomly allocated ... using permuted blocks with stratification by centre and clinical or pathological tumour stage (T3–4 N0 vs T1–2 N_positive vs T3–4 N_positive)" (methods, paragraph 5, page 580)

Allocation concealment (selection bias)

Low risk

Quote: "Local investigators were masked to next assignment in the sequence" (methods, paragraph 5, pages 580 and 581)

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Quote: "... open‐label, non‐inferiority, phase 3 trial ..." (methods, paragraph 1, page 580)

(i) DFS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

(i) DFS: High

Quote: "The study was open‐label; patients, treating physicians, and data managers and analysts were not masked to group assignment" (methods, paragraph 5, page 581)

Outcome assessment at risk of bias from lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Schedule of assessment and follow‐up

High risk

(i) Disease recurrence (influences DFS): Low

Quote: "Follow‐up, done for 5 years after the start of therapy..." (methods, paragraph 12, page 582)

(ii) Survival (influences DFS/OS): Low

Quote: "Follow‐up, done for 5 years after the start of therapy..." (methods, paragraph 12, page 582)

(iii) Grade ≥ 3 AEs: High

Quote: "Vital signs, haematology, and biochemistry were monitored weekly during chemoradiotherapy and before each chemotherapy cycle" (methods, paragraph 10, page 581)

Quote: "Capecitabine was given twice daily ... on days 1–14, and repeated on day 22" (methods, paragraph 8, page 581)

Quote: "Fluorouracil bolus was administered on five consecutive days (days 1–5) and repeated on day 29" (methods, paragraph 9, page 581)

Therefore, these safety evaluations occurred more frequently in the capecitabine arm

Incomplete outcome data (attrition bias)
All outcomes

Low risk

(i) DFS: Low

Quote: "DFS was analysed using censored failure times ..." (methods, paragraph 15, page 583). No evidence of bias related to censoring

(ii) OS: Low

OS was also analysed with censoring using the last date of contact or death (correspondence with Dr. Ralf‐Dieter Hofheinz, received 1 August 2012). No evidence of bias related to censoring

(iii) Grade ≥ 3 AEs: Low

Data were available for all participants in the analysis population (correspondence with Dr. Ralf‐Dieter Hofheinz, received 1 August 2012)

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Participants were analysed according to the treatment arm allocated (Figure 3, page 582)

However, quote: "All analyses were based on all patients with post‐randomisation data" (methods, paragraph 13, page 582). Therefore, 9/401 (2.2%) participants were excluded from the analyses (Figure 3, page 582)

Safety analysis:

Same as for efficacy

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

Low risk

(i) PS: Low (Table 1, page 583)

(ii) Median age: Low (Table 1, page 583)

(iii) TNM stage: Low (Table 1, page 583)

Other bias

Unclear risk

Subsequent therapies: Unclear ‐ similarity of therapy following recurrence or new occurrence of disease not specified

Methods

Randomised controlled trial

Phase: II

Accrual dates: November 2007 to February 2010

Participants

No. randomised: 60

Stage/treatment line: Unresectable primary or metastases (all enrolled patients had metastases); first‐ or second‐line (if second‐line, first‐line therapy with FOLFOX was mandated), patients who had previous adjuvant chemotherapy had > 6 months elapsed since treatment

Countries/sites: Japan, from 12 institutes of theTohoku Clinical Oncology Research and Education Society (T‐CORE)

Setting: Hospital

Characteristics (Arm I/II): Metastatic colorectal cancer; age 20 to 75 years (median 62.0/62.5 years); male (56.7/60.0%); PS ECOG 0‐1

Interventions

Arm I (Sequential IRIS‐bevacizumab (BEV)): D1 irinotecan 150 mg/m² plus BEV 7.5 mg/kg, followed by S‐1 40‐60 mg* oral bd D3‐16, q21d (n randomised = 30)

*S‐1 doses: 80 mg/d if BSA < 1.25 m²; 100 mg/d if BSA 1.25 to 1.5 m²; 120 mg/d if BSA > 1.5 m²

Arm II (mFOLFIRI‐BEV): D1 irinotecan 150 mg/m², LV 200 mg/m², IV bolus 5‐FU 400 mg/m², followed by 5‐FU 2400 mg/m² 46‐hour continuous infusion, plus BEV 5 mg/kg D1, q14d (n randomised = 30)

Outcomes

PFS

ORR (RECIST, version 1.0)

Grade ≥ 3 AEs (AE assessments occurred up to 12 weeks) (CTCAE, version 3.0)

Median follow‐up: 324 days (range, 41 to 843 days)

Study Details

Journal article and abstract/poster

Funding sources and declarations of interest

Funding sources: Tohoku Clinical Oncology Research and Education

Declarations of interest: Chugai Pharmaceutical Co., Ltd., and Novartis Pharma, Inc.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Dynamic allocation was performed (UMIN‐CTR UMIN000000770)

Allocation concealment (selection bias)

Low risk

Central allocation was used (UMIN‐CTR UMIN000000770)

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Unblinded (UMIN‐CTR UMIN000000770)

(i) ORR/PFS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: This study was not used for the meta‐analysis for this outcome

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

(i) ORR/PFS: Low

Quote: "Effectiveness was judged comprehensively using blinded tests on the treatment methods by 3 or more physicians not including primary physicians" (patients and methods, paragraph 7, page 103)

(ii) OS: This study was not used for the meta‐analysis for this outcome

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias from lack of blinding

Schedule of assessment and follow‐up

High risk

(i) Response (influences ORR): Low

Imaging was performed at the same time‐points in both arms. Physician assessments for PFS were performed using the same schedule in both arms (correspondence with Dr. Shunsuke Kato, received 15 October 2013)

(ii) Survival (influences PFS): Low

Physician assessments for PFS were performed using the same schedule in both arms (correspondence with Dr. Shunsuke Kato, received 15 October 2013)

(iii) Grade ≥ 3 AEs: High

Quote: "With regard to safety data, the patients’ health status was observed and blood samples were tested during weekly medical examinations by the attending physician until 4 weeks after commencing treatment and repeated after the fifth week at the start of each new course of treatment" (patients and methods, paragraph 7, page 103)

Treatment cycles were every 3 weeks for the sequential IRIS‐BEV group and every 2 weeks for the mFOLFIRI‐BEV group (patients and methods, paragraph 3, page 103)

Therefore, safety evaluations were performed more frequently in the mFOLFIRI‐BEV arm

Incomplete outcome data (attrition bias)
All outcomes

Low risk

(i) ORR: Low

The reason for 'NE' (non‐evaluable) disease (Table 3, page 105) in 16.7% of the sequential IRIS‐BEV group and 13.3% of the mFOLFIRI‐BEV group was non‐measurable disease in all cases. No missing outcome data (correspondence with Dr. Shunsuke Kato, received 15 October 2013)

(ii) PFS: Low

Participants lost to follow‐up without progression were censored on the last day if it was confirmed that no progression or death occurred (correspondence with Dr. Shunsuke Kato, received 15 October 2013). No evidence of bias related to censoring

(iii) Grade ≥ 3 AEs: Low

The maximum percentage of participants missing data for the grade ≥ 3 AEs of interest was 16.7% (Table 2, page 105). Similar number of participants were missing data in both arms (correspondence with Dr. Shunsuke Kato, received 15 October 2013)

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Analysis for efficacy outcomes kept participants in the intervention groups to which they were randomised, regardless of the intervention received (correspondence with Dr. Shunsuke Kato, received 15 October 2013)

Safety analysis:

Safety analysis population comprised those with available grade ≥ 3 AE data (correspondence with Dr. Shunsuke Kato, received 15 October 2013)

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

Unclear risk

(i) PS: Low (Table 1, page 104)

(ii) Median age: Low (Table 1, page 104)

(iii) No. of involved organs: Unclear ‐ not specified

(Similar number of patients with "Number of metastases ‐ 1/2/3" in both arms) (Table 1, page 104)

Other bias

Unclear risk

Subsequent therapies: Unclear ‐ not specified

Methods

Randomised controlled trial

Phase: Not specified

Accrual dates: October 1997 to February 1999

Participants

No. randomised: 166

Stage/treatment type: Stage II/III resected rectal adenocarcinoma, adjuvant

Countries/sites: South Korea, single site (Yonsei University College of Medicine)

Setting: Hospital

Characteristics (Arm I/II): Resected rectal adenocarcinoma; age < 70 years (median 52.3/59.5 years); male (61/64%); PS ECOG ≤ 2

Interventions

Arm I: IV bolus 5‐FU 450 mg/m²/daily and leucovorin 20 mg/m²/d D1‐5, q28d for 12 cycles with *radiotherapy (n randomised = 74)

Arm II: Oral doxifluridine 700 mg/m²/d with oral leucovorin 20 mg/m²/d D1‐21, q28d for 12 cycles with radiotherapy (n randomised = 92)

*Radiotherapy commenced with C3 at a dose of 5400 cGy at 180 Gy/d, 5 days per week for 6 consecutive weeks

Outcomes

Grade ≥ 3 AEs (WHO criteria, version not specified)

Median follow‐up: more than 15 months, range, 6 to 26 months. Less than 3 year follow‐up

Study Details

Journal article (in Korean)

Funding sources and declarations of interest

Funding sources: None declared

Declarations of interest: None declared

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomization lists were stratified by a medical statistician, using randomly permuted blocks of varying sizes" (materials and methods, paragraph 1, page 675)

Allocation concealment (selection bias)

Unclear risk

Not specified

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

(i) DFS: This study was not used for the meta‐analysis for this outcome

(ii) OS: This study was not used for the meta‐analysis for this outcome

(iii) Grade ≥ 3 AEs: High

Not specified, blinding unlikely. Outcome assessment at risk of bias if there was lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

(i) DFS: This study was not used for the meta‐analysis for this outcome

(ii) OS: This study was not used for the meta‐analysis for this outcome

(iii) Grade ≥ 3 AEs: High

Not specified. Outcome assessment at risk of bias if there was lack of blinding

Schedule of assessment and follow‐up

Unclear risk

(i) Disease recurrence (influences DFS): Unclear ‐ not specified

(ii) Survival (influences DFS/OS): This study was not used for the meta‐analysis for this outcome

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

(i) DFS: This study was not used for the meta‐analysis for this outcome

(ii) OS: This study was not used for the meta‐analysis for this outcome

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (ITT analysis)

Unclear risk

Efficacy analysis: Unclear

Not specified. Note that the number of participants reported in the IV vs oral arm differed substantially‐ 74 vs 92 participants, respectively (Table 1, page 676)

Safety analysis:

Not specified

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

High risk

(i) PS: Unclear ‐ not specified

(ii) Mean age: High

7.2 year difference in mean age between arms (Table 1, page 676)

(iii) TNM stage: Low (stage II vs III)

Quote: "There was no difference of TNM stage distribution between two groups of patients (P = .454); stage II was 25 in the IV arm and 41 in the oral arm; and stage III was 49 in the IV arm and 51 in the oral arm (results, paragraph 1, page 675)

Other bias

Unclear risk

Subsequent therapies: Unclear ‐ similarity of therapy following recurrence or new occurrence of disease not specified

Methods

Randomised controlled trial

Phase: III

Design: Factorial, 2 × 2

Accrual dates: May 2003 to April 2004 (closed 12 January 2005)

Participants

No. randomised: 85

Stage/treatment line: Metastatic, first‐line

Countries/sites: European Organisation for Research and Treatment of Cancer (EORTC) study

Setting: Hospital

Characteristics (Arm I/II/III/IV): Metastatic colorectal cancer; age ≥ 18 years (median 66.0/60.5/63.0/65.0 yrs); male (79/64/52/57%); PS WHO 0‐2 (PS WHO 0: 53/64/61/57%)

Interventions

Arm I (FOLFIRI + celecoxib): irinotecan 180 mg/m² D1, 15, 22, FA 200 mg/m² D1, 2, 15, 16, 29, 30, IV bolus 5‐FU 400 mg/m² followed by 22‐hour continuous infusion 600 mg/m² D1, 2, 15, 16, 29, 30 + celecoxib 800 mg daily (n randomised = 19)

Arm II: FOLFIRI plus placebo (n randomised = 22)

Arm III (CAPIRI plus celecoxib): irinotecan 250 mg/m² D1 and 22 and capecitabine 1000 mg/m² bd D1‐15 and 22‐36 + celecoxib 800 mg daily (n randomised = 23)

Arm IV: CAPIRI plus placebo (n randomised = 21)

Treatment continued up to a planned total of 6 cycles or until PD, unacceptable toxicity, or withdrawal of consent. Participants with a response or SD were allowed to continue treatment beyond 6 cycles at the discretion of the investigator

Outcomes

PFS

Grade ≥ 3 AEs (NCI CTC, version 2)

ORR (RECIST, version 1.0)

OS

Median follow‐up: 14.6 months for all outcomes

Study Details

Journal article

Funding sources and declarations of interest

Funding sources: Roche, Pharmacia (currently Pfizer), Aventis (currently Sanofi‐Aventis)

Declarations of interest: None declared

Notes

"...after the enrolment of only 85 patients, recruitment was suspended as a consequence of seven deaths not due to disease progression. One more patient subsequently died following the suspension of recruitment. Six deaths occurred in patients receiving CAPIRI and two in those receiving FOLFIRI ... Five deaths in the CAPIRI arm and both of those in the FOLFIRI arm were deemed to be treatment related. Underlying risk factors could not be identified as a likely explanation for these fatal toxic effects. On the basis of the outcome of this review, the trial was officially closed on 12 January 2005" (results, paragraph 1, page 922)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomly assigned to receive centrally using a minimization technique" (patients and methods, paragraph 4, page 922)

Allocation concealment (selection bias)

Low risk

Quote as above

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Not specified, blinding unlikely

(i) ORR/PFS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias if there was lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

Not specified.

(i) ORR/PFS: High

Outcome assessment at risk of bias if there was lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias if there was lack of blinding

Schedule of assessment and follow‐up

Unclear risk

(i) Response (influences ORR/PFS): Low

Quote: "Evaluation of disease status was carried out every 6 weeks during treatment and every 8 weeks subsequently until the documentation of disease progression" (patients and methods, paragraph 3, page 921)

(ii) Survival (influences PFS/OS): Unclear ‐ not specified

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

(i) ORR: Low

Response was not assessable or early death occurred in 8/44(18%) participants in the CAPIRI arm and in 4/41(10%) participants in the FOLFIRI arm (Table 3, page 924)

(ii) PFS/OS: Low

Quote: "Patients with no evidence of PD at the time of their last visit were censored at that time" (patients and methods, paragraph 3, page 922)

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Quote: "... assessed in the intention‐to‐treat (ITT) population" (patients and methods, paragraph 3, page 922)

Quote: "...enrollment of ... 85 patients ..." (results, paragraph 1, page 922). This is the same number of participants presented in all of the efficacy analyses. (Table 3 and 4, page 924, and Figure 1, page 925)

Safety analysis:

Analyses included those who received study drug, quote: "Three patients (4%) did not receive study drugs and are therefore not included in the safety analysis" (results, paragraph 3, page 922)

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

Low risk

(i) PS: Low (Table 2, 923)

(ii) Median age: Low (Table 2, 923)

(iii) No. of involved organs: Low (Table 2, 923)

Other bias

Unclear risk

Subsequent therapies: Unclear ‐ not specified

Risk of bias considerations in a factorial study: Unclear

Quote: "...in view of the fact that response rates were lower in both celecoxib arms compared with the corresponding placebo arms for both regimens, it is possible that celecoxib may actually reduce the response to chemotherapy..." (discussion, paragraph 5, page 925)

Quote: "Celecoxib did not appear to modulate the toxicity of the chemotherapy; thus it is very unlikely that the toxicity observed with CAPIRI was due to celecoxib" (discussion, paragraph 5, page 925)

No tests for interaction were reported

Methods

Randomised controlled trial

Phase: III

Accrual dates: February 1997 to March 1999

Participants

No. randomised: 1608

Stage/treatment type: Stage II/III adenocarcinoma of the colon, adjuvant

Countries/sites: National Surgical Adjuvant Breast and Bowel Project (NSABP) study

Setting: Hospital

Characteristics (Arm I/II): resected Stage II/III colon cancer (age < 60 years: 41.7/41.2%); male (51.6/53.5%); PS ECOG ≤2

Interventions

Arm I (FU/LV): LV 500 mg/m² and IV bolus FU 500 mg/m² weekly W1 to 6, q56d for 3 cycles (n randomised = 803)

Arm II (UFT/LV): UFT 300 mg/m²/d and LV 90 mg/d D1‐28, q35d for 5 cycles (n randomised = 805)

Outcomes

OS

DFS

Grade ≥ 3 AEs (NCI toxicity criteria, 1958)

Median follow‐up: 62.3 months among surviving patients

Study Details

Journal article

Funding sources and declarations of interest

Funding sources: NSABP Foundation

Declarations of interest: Taiho

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not specified

Allocation concealment (selection bias)

Unclear risk

Not specified

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Not specified, blinding unlikely.

(i) DFS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias if there was lack of blinding    

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

Not specified

(i) DFS: High

Outcome assessment at risk of bias if there was lack of blinding

(ii) OS: Low

Outcome assessment unlikely to be influenced by lack of blinding

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias if there was lack of blinding  

Schedule of assessment and follow‐up

High risk

(i) Disease recurrence (influences DFS): Low

Quote: "Starting 6 months after the completion of protocol chemotherapy and continuing through 5 years after random assignment, patients were to be re‐evaluated semiannually. Five years after random assignment, a status of disease report was required on a yearly basis" (patients and methods, paragraph 4, page 2060)

(ii) Survival (influences DFS/OS): Low

Quote as above
(iii) Grade ≥ 3 AEs: High

Quote: "Before the administration of each cycle of chemotherapy, patients had a physical examination, CBCs, and chemistry profiles including hepatic and renal function studies. During active chemotherapy, patients in both groups underwent weekly CBCs" (patients and methods, paragraph 3, page 2060)

Quote: "Patients randomly assigned to the FU+LV group received three 8‐week cycles of intravenous chemotherapy" (patients and methods, paragraph 2, page 2060)

Quote: "Patients randomly assigned to the UFT+LV group received five 5‐week cycles ..." (patients and methods, paragraph 2, page 2060)

Therefore, participants in the UFT+LV arm had more frequent safety evaluations than those in the FU+LV arm

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

(i)(ii) DFS/OS: Unclear

Quote: "Our primary analyses include all patients who were eligible and had follow‐up information (intent to treat)" (patients and methods, paragraph 8, page 2060)

However, no indication whether this follow‐up information was complete for all outcomes

(iii) Grade ≥ 3 AEs: Unclear ‐ not specified

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low ‐ Analyses were performed on what was described as an ’intent to treat’ population but included only those who were eligible and had follow‐up information.

Quote: "Fifty patients (3.1%) were deemed ineligible
(27 were assigned to the FU+LV arm, and 23 were assigned to the UFT+LV arm)." (results, paragraph 1, page 2060)

Safety analysis: Analyses performed on those who were eligible and had follow‐up

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

Unclear risk

(i) PS: Unclear ‐ not specified

(ii) Median age: Unclear ‐ not specified

Baseline age was dichotomised into < 60 years vs ≥ 60 years (Table 1, page 2061)

(iii) TNM stage: Low (stage II vs stage III and stage III N1 vs N2)

N1 vs N2: Low (Table 1, page 2061)

Other bias

Unclear risk

Subsequent therapies: Unclear ‐ similarity of therapy following recurrence or new occurrence of disease not specified

Methods

Randomised controlled trial

Phase: II

Accrual dates: December 2001 to March 2005

Participants

No. randomised: 118

Stage/treatment line: Metastatic, first‐line

Countries/sites: Gruppo Oncologico Aree Metropolitane (GOAM) study

Setting: Hospital

Characteristics (Arm A/B): Metastatic colorectal adenocarcinoma; age > 18 years (median 64/67 years); male (50/53.2%); KPS ≥ 70% (Median 90/90%)

Interventions

Arm A (pviFOX): oxaliplatin 130 mg/m² D1 and protracted venous infusion 5‐FU 250 mg/m²/d D1‐21, q21d (n randomised = 56)

Arm B (XELOX): oxaliplatin 130 mg/m² D1 and oral capecitabine 1000 mg/m² bd D1‐14, q21d (n randomised = 62)

Treatment continued for 6 cycles or until PD, at the investigators' discretion

Outcomes

ORR (RECIST, version 1.0)

TTP

Grade ≥ 3 AEs (CTC criteria, version 2.0)

No details on median follow‐up

Study Details

Journal article

Funding sources and declarations of interest

Funding sources: None declared

Declarations of interest: No conflicts of interest

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not specified

Allocation concealment (selection bias)

Unclear risk

Not specified

Blinding of participants and personnel (performance bias)
DFS/PFS/TTP/ORR

High risk

Not specified, blinding unlikely

(i) ORR/TTP: Low

Outcome unlikely to be influenced by lack of blinding

(ii) OS: This study was not used for the meta‐analysis for this outcome

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias if there was lack of blinding

Blinding of outcome assessment (detection bias)
DFS/PFS/TTP/ORR

High risk

Not specified

(i) ORR/TTP: High

Outcome assessment at risk of bias if there was lack of blinding

(ii) OS: This study was not used for the meta‐analysis for this outcome

(iii) Grade ≥ 3 AEs: High

Outcome assessment at risk of bias if there was lack of blinding

Schedule of assessment and follow‐up

Low risk

(i) Response (influences ORR/TTP): Low

Quote: "Every three cycles, re‐evaluation was scheduled with the recording of the symptoms, weight, KPS, physical examination and chest‐abdominal‐pelvic CT...." (patients and methods, paragraph 5, page 3163)

Quote: "In both arms, the treatment was repeated every 21 days ..." (patients and methods, paragraph 3, page 3162)

(ii) Survival (influences OS): Not applicable

This was not an outcome of interest for this study

(iii) Grade ≥ 3 AEs: Low

Quote: " ... the recording of the symptoms, side‐effects and physical examination was carried out prior to each cycle, blood count and blood‐chemistry tests for liver and kidney function before and 10 days after each cycle. ..." (patients and methods, paragraph 5, page 3163)

Quote: "In both arms, the treatment was repeated every 21 days ..." (patients and methods, paragraph 3, page 3162)

Incomplete outcome data (attrition bias)
All outcomes

Low risk

(i) ORR/TTP: Low

Response was not evaluable in 3/56 (5.4%) participants in the pviFOX arm and in 5/62 (8.1%) participants in the XELOX arm (Table 5, page 3166)

(ii) OS: N/A

Not applicable, as this was not an outcome of interest for this study

(iii) Grade ≥ 3 AEs: Low

Analyses were performed in those with evaluable data ‐ 54/56 in the pviFOX arm and 61/62 in the XELOX arm (Table 4, page 3165)

Although the reasons for participants not having evaluable data were unclear, only a low percentage had non‐evaluable data.

Incomplete outcome data (ITT analysis)

Low risk

Efficacy analysis: Low

Quote: "Efficacy analyses were based on an intent‐to‐treat analysis" (patients and methods, paragraph 7, page 3164)

Quote: "One hundred and twenty‐two patients were enrolled between December 2001 and March 2005. Four patients resulted [sic] ineligible and were excluded from the randomisation" (results, paragraph 1, page 3164)

These 118 randomised participants were included in the efficacy analyses (Table 5 and Fig. 1, page 3166)

Safety analysis:

Analyses were performed in those with evaluable data ‐ 54/56 in the pviFOX arm and 61/62 in the XELOX arm (Table 4, page 3165)

Selective reporting (reporting bias)

Unclear risk

No protocol was available

Similarity of arms at baseline

High risk

(i) PS: Unclear

Reported as median KPS only (Table 1, page 3163)

(ii) Median age: Low (Table 1, page 3163)

(iii) No. of involved organs: High

A 16.5% difference between arms with respect to the number of participants with 1 vs more than 1 metastatic site (30/56 (53.6%) in the pviFOX arm and 23/62 (37.1%) in the XELOX arm) (Table 1, page 3163)

Other bias

Unclear risk

Subsequent therapies:

Quote: "...60 have received a second‐line chemotherapy, 25 and 35 in arms A and B, respectively" (results, paragraph 7, page 3165)

Similar proportions in each arm received second‐line therapy, but OS was not an outcome in this study

Methods

Randomised controlled trial

Phase: Not specified

Accrual dates: June 2010 to September 2012

Participants

No. randomised: 70

Stage/treatment line: Locally advanced or metastatic; first‐line chemotherapy for locally advanced or metastatic CRC (if recurrence occurred after neoadjuvant therapy or adjuvant chemotherapy an interval of at least 6 months from completing therapy was mandated)

Countries/sites: Single‐centre study in China (The No. 3 People's Hospital of Zhengzhou, Zhengzhou Tumour Hospital)

Setting: Hospital

Characteristics (Arm I/II): Locally advanced or metastatic; age 18 to 75 years; PS ECOG 0‐1 (unclear)

Interventions

Arm I (SOX): L‐OHP 130 mg/m² D1 IV infusion, S‐1 oral for 14 days. S‐1 dose calculated according to BSA: 80 mg/d for BSA < 1.25 m²; 100 mg/d for BSA ≥ 1.25 m² but < 1.5 m²; 120 mg/d for BSA ≥ 1.5 m² but < 1.8 m²; 140 mg/d for BSA > 1.8 m². Schedule repeated every 3 weeks (n randomised = 35)

Arm II (FOLFOX4): L‐OHP 85 mg/m² IV D1, leucovorin (CF) 200 mg/m² IV D1‐2, 5‐FU 400 mg/m² IV bolus D1‐2, infusional 5‐FU 1200 mg/m² IV continuous over 44 hours (n randomised = 35)
Schedule repeated every 2 weeks

Outcomes

Grade ≥ 3 AEs (NCI‐CTC, version 3.0)

ORR (reported only after 2 cycles of chemotherapy) (RECIST, version not specified)

No details on median follow‐up

Study Details