Methods

Multicentre, randomised, two‑stage, open‐label, noncomparative, parallel‐group phase II study conducted between June 2006 and April 2010.

Participants

135 adult females with a histologic or cytologic diagnosis of advanced breast cancer previously treated with anthracycline and taxanes..

Median age 52 and 51.5 years in platinum and control arms, respectively.
Age range 29 to 77 years.
100% advanced breast cancer.
30% 1st‐line, 70% 2nd‐line.
100% previously treated with anthracycline and taxanes.

Interventions

Pemetrexed and carboplatin vs vinorelbine and gemcitabine.

ARM A: Pemetrexed 600 mg/m² (intravenously for 10 min on day 1) and carboplatin (given over approximately 30 min beginning after the end of the pemetrexed infusion for target area under the curve (AUC) 5.0) on day 1, after pretreatment with folic acid, vitamin B12 and dexamethasone.

ARM B: Vinorelbine 30 mg/m² (given over approximately 6 to 10 min) and gemcitabine 1,200 mg/m² (given over approximately 30 min) were administered on day 1 and day 8.

Outcomes

Response.
Time to progressive disease (TTPD; Kaplan‐Meier curve) defined as "the time from the date of study enrolment to the first documented date of progressive disease or death from study disease".
Time to treatment failure (TTTF; presented as medians in months; not extractable for hazard ratio calculation) defined as the time from date of study enrolment to the first documented date of death from any cause, progressive disease, or study treatment discontinuation due to adverse event.

Grades 3 and 4 adverse events (only reported when event occurred in ≥ 10% of participants in each treatment group).

QoL (EORTC questionnaires, QLQ‑C30 global health status, and QLQ‑BR23 body image).

Notes

Data for TTTF was not extractable because only event numbers and median TTFs were reported (i.e. pemetrexed and carboplatin: events/total = 60/69, median TTTF = 4.8 months; vinorelbine and gemcitabine: events/total= 58/66, median TTTF = 5.1 months).

Data for some adverse event types such as anaemia were not extractable because event data were only reported for event types which occurred in ≥ 10% of participants in each treatment group.
Estimated min follow‐up = 0.3 months (based on first censoring tick on TTP curve).
Estimated max follow‐up = 22 months (based on last censoring tick on TTP curve).

QoL: Pemetrexed/carboplatin participants had significantly greater deterioration in global health status scores (follow‐up minus baseline scores) than vinorelbine/gemcitabine participants. There was no significance difference in body image scores between groups.

Median TTPD was 5.1 (95% CI: 4.1 to 8.0) months for pemetrexed/carboplatin arm and 5.6 months (95% CI: 4.2 to 7.5) months for vinorelbine/gemcitabine arm.

This study was sponsored by Eli Lilly and Company, Indianapolis, IN, USA.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Participants were "randomised either to Arm A …or to Arm B..."; no additional details were provided on how random assignment was achieved in the trial report.

Allocation concealment (selection bias)

Unclear risk

Method of concealment was not described.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label trial.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Open‐label study but not clear if outcome assessors were blinded to intervention. For tumour response rates, radiological assessments performed before treatment at every other cycle. No further details provided.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Low risk

All 69 and 66 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analyses (intent‐to‐treat analyses).

Incomplete outcome data (attrition bias) (binary outcomes)

High risk

12 of 69 and 10 of 66 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response (16.3% of all randomised participants). 4 of 69 and 0 of 66 participants randomised to intervention and control groups, respectively, were not included in the safety population for evaluating toxicities (3.0% of all randomised participants).

Selective reporting (reporting bias)

Unclear risk

Quality of life was not included in ClinicalTrials.gov record (https://clinicaltrials.gov/ct2/show/NCT00325234) but was included in the trial report. All other outcomes in the trial report were listed in the ClinicalTrials.gov record and vice versa.

Other bias

Low risk

None identified.

Methods

RCT multicentre phase III trial.
Randomisation method not reported.

Accrual October 1995 to April 1999.
Baseline comparability: no significant imbalance apparent or reported.

Participants

186 women with histologically confirmed metastatic breast cancer (1 ineligible ‐185 entered trial) in the treatment‐comparison Berruti 2002 A (186 participants also for Berruti 2002 B).
Median age 58.
Age range 28 to 75.
100% metastatic breast cancer.
100% first‐line.
All participants anthracycline‐naive.

Interventions

EPI vs EPI + CDDP.

ARM A: Epirubicin 60 mg/m² on days 1 and 2 every 21 days.

ARM B: EPI + CDDP: Epiubicin 60 mg/m² IV on days 1 and 2 + platinum 30 mg/² IV on day 1 and 2 every 21 days.

Outcomes

Overall survival measured from the date of randomisation until death (insufficient OS data reported to calculate hazard ratio for pooling).
Time to progression (Kaplan‐Meier curve), defined as "the time elapsed from randomisation until disease progression or death" (this would usually be called progression‐free survival because death from any cause is treated as an event).
Response.
Toxicity.

Notes

The trial was part of a factorial 2 x 2 design (4 arms n = 371) to answer two questions. IT IS INCLUDED IN THIS REVIEW AS TWO TRIALS: Berruti (a) and Berrutti (b). Intention‐to‐treat analyses used for overall survival and time to progression.
Toxic deaths n = 6, due to either hematologic toxicity, pulmonary thromboembolism, congestive heart failure, arrhythmia, hepatorenal syndrome, or sudden death.
Estimated min follow‐up = 4.5 months (based on the median number of cycles received).
Estimated max follow‐up = 64 months (based on last event on the curve).
Last follow‐up reported as March 2001.
Median TTP: 10.8 to 12.2 months LND arms; 9.9 to 8.6 months non‐LND arms.
Median survival: 28.8 CDDP arms; 29.5 non‐CDDP arms; 29.8 LND arms 27.3 non‐LND arms (insufficient OS data reported to calculate hazard ratio for pooling).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported in detail.

Allocation concealment (selection bias)

Unclear risk

Not reported ‐ stated as "randomized" only.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information in trial publication.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

No information in trial publication. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Standard criteria used for classifying tumour response; physical examination or radiography took place. No further details provided.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Unclear risk

92 of 93 and 93 of 93 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analysis (modified intent‐to‐treat).

Incomplete outcome data (attrition bias) (binary outcomes)

Low risk

8 of 93 and 5 of 93 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response (7.5% of all randomised participants). 3 of 93 and 1 of 93 participants randomised to intervention and control groups, respectively, were not included in the safety population for evaluating toxicities (2.2% of all randomised participants).

Selective reporting (reporting bias)

Unclear risk

No trial registration or published protocol prespecifying all study outcomes. Study began recruitment before July 1, 2005 so expectation of registration or published protocol was low.

Other bias

Low risk

None identified.

Methods

RCT mulitcentre phase III trial.
Randomisation method not reported.

Accrual October 1995 to April 1999.
Baseline comparability: no significant imbalance apparent or reported.

Participants

186 women with histologically confirmed metastatic breast cancer.
Median age 58.
Age range 35 to 74.
100% metastatic breast cancer.
100% first‐line.
All participants anthracycline‐naive.

Interventions

EPI + LND vs EPI + CDDP + LND.

ARM A: EPI + LND: Epiubicin 60 mg/m² IV on days 1 and 2 every 21 days and Lonidamine 450 mg po every day.

ARM B: EPI + CDDP + LND: Epiubicin 60 mg/m² IV on days 1 and 2 + cisplatin 30 mg/m² IV on days 1 and 2 every 21 days + lonidamine 450 mg po every day. LND was pursued until progression. Remaining chemotherapy was delivered up to a maximum of 6 weeks.

Outcomes

Overall survival measured from the date of randomisation until death.
Time to progression (Kaplan‐Meier curve), defined as "the time elapsed from randomisation until disease progression or death" (this would usually be called progression‐free survival because death from any cause is treated as an event).
Response.
Toxicity.

Notes

Toxic deaths n = 5, due to either hematologic, toxicity, pulmonary thromboembolism, congestive heart failure, arrhythmia, hepatorenal syndrome or sudden death.
Estimated min follow‐up = 4.5 months (based on the median number of cycles received).
Estimated max follow‐up = 64 months (based on last event on the curve).
Last follow‐up reported as March 2001.
Median TTP: 10.8 to 12.2 months LND arms; 9.9 to 8.6 months non‐LND arms.
Median survival: 28.8 CDDP arms; 29.5 non‐CDDP arms; 29.8 LND arms; 27.3 non‐LND arms (insufficient OS data reported to calculate hazard ratio for pooling).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported in detail.

Allocation concealment (selection bias)

Unclear risk

Not reported ‐ stated as "randomized" only.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information in trial publication.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

No information in trial publication. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Standard criteria used for classifying tumour response; physical examination or radiography took place. No further details provided.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Low risk

All 93 and 93 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analyses (intent‐to‐treat analyses).

Incomplete outcome data (attrition bias) (binary outcomes)

Low risk

8 of 93 and 5 of 93 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response (8.6% of all randomised participants). 3 of 93 and 2 of 93 participants randomised to intervention and control groups, respectively, were not included in the safety population for evaluating toxicities (2.7% of all randomised participants).

Selective reporting (reporting bias)

Unclear risk

No trial registration or published protocol prespecifying all study outcomes. Study began recruitment before July 1, 2005 so expectation of trial registration or published protocol was low.

Other bias

Low risk

None identified.

Methods

Randomised phase III trial.

Participants

126 mTNBC participants between age group of 38 to 72 years and who had already received anthracyclines and taxanes and had relapsed and could not afford ixabepilone and/or avastin.

Interventions

'No platinum' arm: endoxan 50 mg per day at 10 am and methotrexate 2.5 mg twice a day at 9 am and 5 pm.
Platinum arm: Same as above but with 'cisplatinum'.

Outcomes

Response.
Overall survival (insufficient OS data reported to calculate hazard ratio for pooling).

Time to progression (insufficient TTP data reported to calculate hazard ratio for pooling).

Toxicity (no results reported).

Notes

Abstract only.

Median follow‐up not stated.

Median TTP: Platinum arm 13 months vs 'no platinum' arm 7 months (insufficient TTP data reported to calculate hazard ratio for pooling).

Median OS: Platinum arm 16 months vs 'no platinum' arm 12 months (insufficient OS data reported to calculate hazard ratio for pooling).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Stratified on more than one factor. Quote: "Patients were randomised to either... stratified by number of sites of metastasis and with or without visceral metastasis with or without bisphosphonates."

Allocation concealment (selection bias)

Unclear risk

Method of concealment was not described in the abstract.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information provided in the abstract.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

No information provided in the abstract. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

No information provided in the abstract.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Low risk

All 60 and 66 participants randomised to intervention and control groups, respectively, appear to have been analysed in time‐to‐event analyses (intent‐to‐treat analyses), but only median times were reported (hence no extractable time‐to‐event data).

Incomplete outcome data (attrition bias) (binary outcomes)

Unclear risk

All randomised participants appear to have been assessed/assessable for tumour response. This was not entirely clear though, as it was not explicitly stated and they may have simply used randomised participant denominators.

Selective reporting (reporting bias)

High risk

The abstract mentions that toxicity was recorded but no results were reported. In addition, there was no trial registration or published protocol containing prespecified outcomes. The date when participant recruitment began was not reported, but given that this was first published in September 2009, it seemed likely that recruitment began after July 1, 2005. As of April 2015, there has been no further results published other than those in the conference abstract.

Other bias

Low risk

None identified.

Methods

Multicentre randomised phase II study.

Participants were randomised to control or platinum arms, with control participants additionally receiving platinum upon progression.

Participants

112 women with stage IV triple‐negative metastatic breast cancer measurable by RECIST criteria and negative for ER, PR, and HER2 (0 or 1 on immunohistochemistry and/or normal gene copy number by fluorescence in situ hybridisation), of which 102 were treated and included in time‐to‐event analyses.

Median age 52 and 49 years in platinum and control arms, respectively.
Age range 28 to 33 years.
100% metastatic breast cancer.
Of the 102 participants analysed: 55 (54%) were treated in the second‐ or third‐line setting, but not with previous EGFR inhibitor or platinum for metastatic disease; 84 (98%) had received an anthracycline; 65 (76%) had also received a taxane.

Interventions

Ce vs Ce + C.

ARM 1: Cetuximab (400 mg/m² load then 250 mg/m² per week intravenously (IV)) alone, with carboplatin (area under the curve of 2, once per week IV) added after progression.

ARM 2: Cetuximab (400 mg/m² load then 250 mg/m² per week intravenously and with carboplatin
(area under the curve of 2, once per week IV).

Outcomes

Response.
Overall survival (Kaplan‐Meier curve).
Time to progression, defined as "treatment initiation to documented progression" (Kaplan‐Meier curve; y‐axis label typo "Progression‐free survival").

Toxicity (data not extractable because results for Arm 2 were combined with Arm 1 participants after progression).

Notes

Estimated min follow‐up = 0.25 months (based on first censoring tick on TTP curve).
Estimated max follow‐up = 38.3 months (based on last censoring tick on TTP curve).

Median OS was 7.5 months (95% CI, 5.0 to 11.6) for arm one and 10.4 months (95% CI, 7.7 to 13.1) for arm 2.

Study supported by Bristol‐Myers Squibb, University of North Carolina Breast Cancer Specialized Program of Research, Avon Partners‐for‐Progress awards and by National Institutes of Health.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quotes: "Patients were randomly assigned…" and "Constrained block randomizations (block size 21 plus 21) kept the imbalance between the arms to four at most".

Allocation concealment (selection bias)

Unclear risk

Method of concealment was not described.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Quote: "Single Blind (Outcomes Assessor)" at https://clinicaltrials.gov/show/NCT00232505 implying that participants and personnel were aware of treatment allocation.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

Single Blind (Outcomes Assessor). Assessment of overall survival was unlikely to be influenced by no or incomplete blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Low risk

Cyclical evaluations including biochemical tests, CT or MRI imaging every 8 weeks, in addition to an independent evaluation of OTRR by "investigators blinded to treatment arms and not involved in the study".

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Unclear risk

102 of 112 randomised participants were analysed in time‐to‐event analyses (modified ITT). The 10 excluded participants were excluded after enrolment but before treatment, but no information was provided on the randomised groups of these excluded participants.

Incomplete outcome data (attrition bias) (binary outcomes)

Unclear risk

10 of 112 randomised participants were excluded from all analyses, with no information provided on the randomised groups of these excluded participants. In addition to these 10 excluded participants: 6 of 71 and 0 of 31 participants in the (known) intervention and control groups, respectively, were not assessed/assessable for tumour response (14.3% of all randomised participants); 6 of 71 and 0 of 31 participants in the (known) intervention and control groups, respectively, were excluded from the safety population for evaluating toxicities (14.3% of all randomised participants) (toxicity data were not extractable because results for Arm 2 were combined with Arm 1 participants after progression).

Selective reporting (reporting bias)

Low risk

Toxicity was not listed under 'outcomes' in ClinicalTrials.gov record (https://clinicaltrials.gov/show/NCT00232505), but it was mentioned in the 'secondary objectives' section of the record. All other outcomes in the trial report were listed in the ClinicalTrials.gov record and vice versa.

Other bias

Unclear risk

26 participants in the control arm were additionally given carboplatin after progression. This may have attenuated any differences between treatment arms in overall survival.

Methods

National, multicentre, RCT, Accrual May 1985 to April 1988. Randomisation ‐ telephone call to central office. Treatment allocation by randomly permuted blocks of two.
Baseline comparability: no significant imbalance apparent or reported.

Participants

140 women with histologically confirmed metastatic breast cancer.
Median age 57.
Age range 32 to 75.
100% metastatic breast cancer.
100% first‐line.
Unclear whether the prior adjuvant therapy received by 22% of participants included anthracyclines.

Interventions

CMF vs PE.

ARM A: Cyclophosphamide 100 mg/m², orally days 1 to 14; Methotrexate 40 mg/m² IV days 1 and 8; Fluorouracil 600 mg/m² IV days 1 and 8 repeated every 4 weeks;

ARM B: Cisplatin 100 mg/m² IV day 1 (with hydration and mannitol forced diuresis); etoposide 100 mg/m² IV days 1, 3 and 5 repeated every 3 weeks.

Outcomes

Overall survival (curve).
Time to progression (calculated from beginning of chemotherapy; insufficient TTP data reported to calculate hazard ratio for pooling).
Response (calculated from beginning of chemotherapy).
Toxicity.

Notes

Min follow‐up: 12 months (reported).
Max follow‐up: 48 months (reported).
Median TTP: 8 m CMF, 7.7 m PE (P = 0.84) (insufficient TTP data reported to calculate hazard ratio for pooling).
Median survival: 18.7 m CMF, 19 months PE (P = 0.86).
Treatment suspended in 5 participants due to toxicity.

Study supported by Associozione Italiens per la Ricerca sul Cancro and in part by Progetto Finalizzato Oncologia of Consiglio Nazionale delle Ricerche.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported in sufficient detail.

Allocation concealment (selection bias)

Low risk

Central randomisation.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information in trial publication.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

No information in trial publication. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Low risk

Tumour response rate evaluated every 3 cycles and every 3 months after suspension of treatment and were assessed "by an extramural review committee for response to treatment" (p. 666).

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Low risk

70 of 70 and 70 of 70 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analyses (intent‐to‐treat analyses).

Incomplete outcome data (attrition bias) (binary outcomes)

Low risk

5 of 70 and 5 of 70 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response (7.1% of all randomised participants). 0 of 70 and 2 of 70 participants randomised to intervention and control groups, respectively, were not included in the safety population for evaluating toxicities (1.4% of all randomised participants).

Selective reporting (reporting bias)

Unclear risk

No trial registration or published protocol prespecifying all study outcomes. Study began recruitment before July 1, 2005 so expectation of trial registration or published protocol was low.

Other bias

Low risk

None identified.

Methods

National multicentre RCT. Randomisation and treatment allocation methods not reported.
Baseline comparability: no significant imbalance apparent or reported.

Participants

186 (183 eligible) women with metastatic breast cancer.
Median age 57.
Age range 32 to 75.
100% metastatic breast cancer.
100% first‐line.
Unclear whether the prior adjuvant therapy received by about 45% of participants included anthracyclines.

Interventions

CMF vs MPEPIV or MPEMI.

ARM A: CMF: Cyclophosphamide 600 mg/m² days 1 to 8; methotrexate 40 mg/m² days 1 to 8; Fluorouracil 600 mg/m² days 1 to 9; every 4 weeks.

ARM B: MPEPIV: Methotrexate 100 mg/m² days 1 to 8, + leucovorin rescue; cisplatin (P) 70 mg/m², day 1; epirubicin 70 mg/m² day 1 + vincristine 1.4 mg/m² days 1 to 8; every 3 weeks. MPEMI: Methotrexate 100 mg/m² days 1 to 8 + rescue; cisplatin 70 mg/m² day 2; etoposide (E) 100 mg/m² days 1 to 2; mitomycin (MI) 6 mg/m² day 1; every 3 weeks.

Outcomes

Time to progression (insufficient TTP data reported to calculate hazard ratio for pooling).
Survival (insufficient OS data reported to calculate hazard ratio for pooling).
Response.
Toxicity (no extractable data).

Notes

Conference abstract (1996).

Median TTP: 10.7 CMF, 9.5 MPEPIV or MPEMI (insufficient TTP data reported to calculate hazard ratio for pooling).
Median survival: 28.7 months CMF, 31.2 MPEPIV or MPEMI (insufficient OS data reported to calculate hazard ratio for pooling).
Follow‐up could not be estimated.
Toxicity data was not extractable. The study reported that the platinum regimen "... was substantially more toxic than CMF, but tolerable, with no toxic deaths: the toxicities platelet, haemoglobin, vomiting, diarrhoea and mucositis were significantly more frequent in... " the platinum arm.

Study "Supported by CNR Flnalyzed Project ACRO and by AIRC."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported in sufficient detail. Stated as "randomised" only.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information provided in the abstract.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

No information in abstract. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

No details provided in the abstract.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Unclear risk

91 of 93 and 92 of 93 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analysis (modified intent‐to‐treat), but only median times were reported (hence, no extractable time‐to‐event data).

Incomplete outcome data (attrition bias) (binary outcomes)

Unclear risk

5 of 93 and 9 of 93 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response (9.1% of all randomised participants). It is not clear how many participants were included in the safety population, but toxicity data were not extractable anyway.

Selective reporting (reporting bias)

Unclear risk

No trial registration or published protocol prespecifying all study outcomes. Study began recruitment before July 1, 2005 so expectation of trial registration or published protocol was low.

Other bias

Low risk

None identified.

Methods

National, multicentre, RCT, accrual July 1988 to June 1991. Randomisation was by telephone to a central office in blocks of two.

Treatment allocation not reported.
Baseline comparability: no significant imbalance apparent or reported.

Participants

109 (105 eligible) women with histologically confirmed metastatic breast cancer.
Median age 53/57.
Age range 26 to 72.
100% metastatic breast cancer.
100% first‐line.
Unclear whether the prior adjuvant therapy received by 58% of participants included anthracyclines.

Interventions

CMF vs PE + CMF + AL.

ARM A: Cyclophosphamide 100 mg/m² po days 1 to 14 + methotrexate 40 mg/m² IV bolus days 1 and 8 + 5‐FU 6000 mg/m² IV bolus days 1 and 8, 4 weekly cycles.

ARM B: Cisplatin 100 mg/m2 i.v. infusion for 30 minutes on day 1; etoposide 100 mg/m2 i.v. infusion for 15 minutes on days 1, 3, and 5, 3 week intervals. Cyclophosphamide 100 mg/m² po days 1 to 14 + methotrexate 40 mg/m² IV bolus days 1 and 8 + 5‐FU 6000 mg/m² IV bolus days 1 and 8, 4 weekly cycles. Doxorubicin 60 mg/m2 i.v. bolus on day 2; leucovorin 500 mg/m2 i.v. infusion for 2 hours on days 1 and 8; 5‐FU 600 mg/m2 i.v. bolus 1 hour after the beginning of leucovorin infusion on days 1 and 8; allopurinol, 900 mg 24 hours after each 5‐FU dose, 3 week intervals.

Outcomes

Overall survival (Kaplan‐Meier curve).
Time to progression, calculated from the date of randomisation to the date of the last progression occurring during the administration of the whole program (insufficient TTP data reported to calculate hazard ratio for pooling).
Response.
Toxicity.

Notes

The trial included 2 complex protocol treatments, rotational crossing and sequential intensification. The rotational crossing protocol was not included because of the difficulty in separating the cisplatin‐related outcomes. Intent‐to‐treat for survival, TTP and toxicity on all eligible participants.
Estimated min follow‐up: 6 months (calculated from planned months of treatment per patient).
Estimated max follow‐up: 132 months (calculated from date of randomisation to date of submission for publication).
Reported med follow‐up: 78 months.
Median TTP: 6.55 months CMF, 15 months PE + CMF + AL (P = 0.0004) (insufficient TTP data reported to calculate hazard ratio for pooling).
Median survival: 27.5 months CMF, 27.2 months PE + CMF + AL.
No toxic deaths reported.

Study "Supported by Assoc. Ital. Ricerca sul Cancro (AIRC) and by PF ACRO of the Consiglio Nazionale Delle Ricerche (CNR)."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported in sufficient detail.

Allocation concealment (selection bias)

Low risk

Central randomisation.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information in trial publication.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

No information in trial publication. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Low risk

Tumour response rate evaluated every 2 cycles and every 3 months after suspension of treatment and were assessed "by an extramural treatment response review committee".

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Unclear risk

105 of 109 randomised participants were analysed in time‐to‐event analyses (modified ITT). The randomised groups of the 4 excluded participants were not clear. Potential bias reported as participants with progression on CMF were immediately withdrawn.

Incomplete outcome data (attrition bias) (binary outcomes)

Low risk

4 of 109 randomised participants were excluded from all analyses, with no information provided on the randomised groups of these excluded participants (7.3% of all randomised participants). In addition to these 10 excluded participants: 3 of 50 and 1 of 55 participants in the (known) intervention and control groups, respectively, were not assessed/assessable for tumour response; no participants in the (known) intervention and control groups, respectively, were excluded from the safety population for evaluating toxicities (3.7% of all randomised participants).

Selective reporting (reporting bias)

Unclear risk

No trial registration or published protocol prespecifying all study outcomes. Study began recruitment before July 1, 2005 so expectation of trial registration or published protocol was low.

Other bias

Low risk

None identified.

Methods

Randomised unblinded phase II study. Randomisation was 1:2 ratio of standard to experimental arm.
Baseline comparability: no significant imbalance apparent or reported.

Participants

221 (193 eligible) women with histologically confirmed metastatic breast cancer.
Age range < 40 to 70+.
100% metastatic breast cancer.
100% first‐line.
Unclear whether the prior adjuvant therapy received by some participants included anthracyclines.

Interventions

CAF vs C + CAF

ARM A: CAF: cyclophosphamide 600 mg/m² IV day 1, doxorubicin 45 mg/m² IV day 1, fluorouracil 500 mg/m² IV days 1 and 8, every 4 weeks. Following a total doxorubicin dose of 540 mg/m² (including any adjuvant doxorubicin), methotrexate was substituted at 40 mg/m² IV days 1 and 8 (30 mg/m² for participants 60 or older).

ARM B: C: Carboplatin 400 mg/m² IV bolus escalated by 50 mg/m² depending on day 1 nadir counts. Repeated every 28 days for up to 4 cycles followed by standard CAF.

Outcomes

Overall survival (Kaplan‐Meier, data from trialist).
Response.
Toxicity.

Notes

Participants randomised to the phase II arm (n = 178) were randomised to CAF alone or to one of 5 phase II agents including carboplatin followed by CAF. Carboplatin data (from the published paper) only is included in the review (n = 49).
2 participants did not receive any protocol treatment, 23 were ineligible (unexplained).
Only eligible participants were included in the published analysis.
Min follow‐up: 16 months (provided by trialist).
Max follow‐up: 136 months (provided by trialist).
Median survival: 19.6 months CAF, 14.9 months C + CAF.
3 toxic deaths on CAF arm attributed to treatment‐induced sepsis.

For time‐to‐event analyses, intent‐to‐treat data and numbers of participants randomised and included as eligible were provided by the trialist (ITT).

Study "Supported in part by National Institutes of Health grants."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported. Stated as "randomised" only.

Allocation concealment (selection bias)

Unclear risk

Not reported ‐ stated as "randomised" only.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information in trial publication.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

No information in trial publication. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Blood tests and scans completed; no further details provided.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Low risk

All 52 and 169 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analyses (intent‐to‐treat analyses).

Incomplete outcome data (attrition bias) (binary outcomes)

Unclear risk

3 of 52 and 25 of 169 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response (12.7% of all randomised participants). 3 of 52 and 25 of 169 participants randomised to intervention and control groups, respectively, were not included in the safety population for evaluating toxicities (12.7% of all randomised participants).

Selective reporting (reporting bias)

Unclear risk

No trial registration or published protocol prespecifying all study outcomes. Study began recruitment before July 1, 2005 so expectation of trial registration or published protocol was low.

Other bias

Low risk

None identified.

Methods

Single centre, prospective cross‐over RCT. Randomisation by dynamic allocation. Accrual not detailed.
Baseline comparability: no significant imbalance apparent or reported.

Participants

88 (86 eligible) postmenopausal women with histologically confirmed metastatic breast cancer.
Median age 58.
100% metastatic breast cancer.
92% first‐line.
All participants anthracycline‐naive.

Interventions

CFP vs CFP + CAP

ARM A: CFP: Cyclophosphamide 150 mg/m² per day; 5‐Fluorouracil 300 mg/m² per day IV infusion on days 1 through 5 every 5 weeks; prednisone 30 mg/d po days 1 through 14, 20 mg/d days 15 through 21; then 10 mg daily.
ARM B: CAP: Cyclophosphamide 400 mg/m² and adriamycin 40 mg/m² on single day IV. Cis‐dichlordiammine platinum (CDDP) 40 mg/m² in 500 mL 5% dextrose/0.5 normal saline 1 hour IV infusion for 4 cycles then cross over to CFP as above.

Outcomes

Overall survival (Kaplan‐Meier curve from time of first treatment).
Time to progression (Kaplan‐Meier curve suggests breast cancer deaths and disease progression are defined events).
Response.
Toxicity.

Notes

Abstract.
Estimated min follow‐up: 4 months (based on number of intervention cycles).
Estimated max follow‐up: 55 months OS, 44 months TTP (based on last event on curves).
Median TTP: 9.3 months CFP, 6 months CFP + CAP.
Median survival: 18.2 months CFP, 11.4 months CFP + CAP (follow‐up for survival was continued for participants with disease progression for whom the trial was terminated).
Trialists reported bias may have been introduced by the time to progression of 7 participants who refused further treatment and were censored at time off the study.
No toxic deaths reported.
Trial terminated before projected accrual due to the therapeutic trend in favour of CFP.

86 of 88 randomised participants were analysed in time‐to‐event analyses (modified ITT).

Study supported in part by National Cancer Institute, National Institutes of Health.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported in sufficient detail.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information in trial publication.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

No information in trial publication. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Standard criteria used for classifying tumour response; no further details provided.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Unclear risk

86 of 88 randomised participants were analysed in time‐to‐event analyses (modified ITT). No information was provided on the randomised groups of the 2 excluded participants.

Incomplete outcome data (attrition bias) (binary outcomes)

Low risk

2 of 88 randomised participants were excluded from all analyses, with no information provided on the randomised groups of these excluded participants. Apart from the 2 excluded participants (2.3% of all randomised participants), there were no missing data for tumour response; 1 of 45 and 2 of 41 participants in the (known) intervention and control groups, respectively, were excluded from the safety population for evaluating toxicities (5.7% of all randomised participants).

Selective reporting (reporting bias)

Unclear risk

No trial registration or published protocol prespecifying all study outcomes. Study began recruitment before July 1, 2005 so expectation of trial registration or published protocol was low.

Other bias

Low risk

None identified.

Methods

Multicentre prospective randomised controlled trial.

Participant characteristics at baseline: no differences reported.

Participants

137 women with progressing metastatic breast cancer with at least one measurable target lesion and at least one previous chemotherapy agent.

Interventions

OXA + FU vs VIN + FU

Arm A: OXA + FU: Oxaliplatin 130 mg/m² 2 hours IV on day 1 plus 5‐fluorouracil 750 mg/m² daily by continuous IV infusion days 1 to 5 q 3 weeks.

Arm B: VIN + FU: Vinorelbine 25 mg/m² IV bolus plus 5‐fluorouracil 750 mg/m² daily by continuous IV infusion days 1 to 5 q 3 weeks.

Outcomes

Overall survival (insufficient OS data reported to calculate hazard ratio for pooling).

Progression‐free survival (insufficient PFS data reported to calculate hazard ratio for pooling).

Response rate.

Toxicity (grade‐specific data not reported).

Notes

Abstract.

Follow‐up could not be estimated.

Efficacy was evaluated by radiological assessment every 6 weeks; responses were confirmed at least 4 weeks later.

Median PFS: 19.1 weeks OXA + FU, 22.9 weeks VIN + FU (P = 0.26) (insufficient PFS data reported to calculate hazard ratio for pooling).
Median survival: 61.7 weeks OXA + FU, 71 weeks VIN + FU (P = 0.26) (insufficient OS data reported to calculate hazard ratio for pooling).

The study was prematurely discontinued due to accrual difficulty related to competitive drugs introduced (Capecitabine) in the same clinical setting.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported. Stated as "randomised" only.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information provided in the 2 abstracts.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

No information provided in the 2 abstracts. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Quote: "Efficacy was evaluated by radiological assessment every 6 wks; responses are confirmed at least 4 wks later" (abstract from 2004). No further details provided.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Low risk

All 68 and 69 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analyses (intent‐to‐treat analyses), but only median times were reported (hence no extractable time‐to‐event data)

Incomplete outcome data (attrition bias) (binary outcomes)

Unclear risk

All randomised participants appear to have been assessed/assessable for tumour response and included in the safety population for evaluating toxicities (only toxic death data extractable as grade‐specific data not reported for other conditions). This was not entirely clear though, as it was not explicitly stated and the authors may have simply used randomised participant denominators.

Selective reporting (reporting bias)

Unclear risk

No trial registration or published protocol prespecifying all study outcomes. Study began recruitment before July 1, 2005 so expectation of trial registration or published protocol was low.

Other bias

Low risk

None identified.

Methods

Phase II RCT. Allocation assigned to intervention in a 2:1 randomisation. Accrual February 1994 to January 1997.
Baseline comparability: no significant imbalance apparent or reported.

Participants

59 women with cytologically or histologically confirmed metastatic/advanced inoperable breast cancer.
Median age 47/48.
Age range 28 to 73.
61% metastatic breast cancer.
39% locally advanced.
83% first‐line.
All participants anthracycline‐naive.

Interventions

ECycloF vs EcisF.

ARM A: ECycloF: 5‐Fluorouracil 200 mg/m² continuous IV every 24 hours + epirubicin 60 mg/m² by IV bolus every 3 weeks for 6 courses + Cyclophosphamide 600 mg/m² by IV bolus every 3 weeks for 6 courses.

ARM B: ECisF: 5‐Fluorouracil 200 mg/m² IV every 24 hours + epirubicin 60 mg/m² by IV bolus every 3 weeks for 6 courses + cisplatin 60 mg/m² IV every 3 weeks for 6 courses.

Outcomes

Overall survival, measured from start of treatment (insufficient OS data reported to calculate hazard ratio for pooling).
Progression‐free survival, endpoints not defined (Kaplan‐Meier curve, measured from start of treatment).

Time to progression, endpoints not defined (medians only).
Response.
Toxicity.

Notes

Metastatic and locoregional results reported separately for response.
Combined metastatic and locoregional toxicity data as published, were included in the review on the assumption that stage of disease might not influence toxicity.
2 not assessable for toxicity due to death (cause unexplained) following 1 treatment.
4 participants crossed from cisplatin to carboplatin, as per protocol, due to tinnitis (n = 2) and poor renal function (n = 2); unclear if participants had metastatic breast cancer or locally advanced.
Min follow‐up: 4 months (reported).
Max follow‐up: 32 months (reported), 23 months PFS (based on last event on curve).
Median TTP: 7 months.
Median survival: 10 m ECisF, 13 m ECycloF (insufficient OS data reported to calculate hazard ratio for pooling).

All 59 randomised metastatic participants were analysed in time‐to‐event PFS analysis (ITT).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported. Stated as "randomised" only.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information in trial publication.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

No information in trial publication. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Standard criteria used for classifying tumour response; no further details provided.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Low risk

All 21 and 38 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analyses (intent‐to‐treat analyses).

Incomplete outcome data (attrition bias) (binary outcomes)

Unclear risk

The study reported "Patients who received at least two cycles of chemotherapy were assessable for response... ", but they did report how many metastatic participants completed at least 2 cycles. The study calculated response rates using the numbers of randomised participants as denominators, which may or may not mean that all metastatic participants completed at least 2 cycles. Combined metastatic and locoregional toxicity data were included in this review on the assumption that stage of disease might not influence toxicity. All 96 metastatic and locoregional participants randomised to intervention and control groups, respectively, were included in the safety population for evaluating toxicities.

Selective reporting (reporting bias)

Unclear risk

No trial registration or published protocol prespecifying all study outcomes. Study began recruitment before July 1, 2005 so expectation of trial registration or published protocol was low.

Other bias

Unclear risk

None identified.

Methods

A prospective, open‐label, randomised phase II clinical trial carried out in the Cancer Hospital, Chinese Academy of Medical Sciences.

Participants

53 metastatic triple‐negative breast cancer (mTNBC) participants aged ≥18 years with histologically confirmed ER‐, PR‐, and HER2‐ primary breast cancer.

Median age 48 and 49 years in platinum and control arms, respectively.
Age range 27 to 71 years.
100% mTNBC.

100% 1st‐line.
No prior treatment of advanced disease.

All the participants had received anthracyclines while 66.7% of participants in the TP arm and 57.7% of participants in the TX arm received paclitaxel in the adjuvant/neoadjuvant setting..

Interventions

TP vs TX.

TP ARM: Docetaxel 75 mg/m² plus cisplatin 75 mg/m² IV infusion day 1.

TX ARM: Docetaxel 75 mg/m² IV infusion day 1 plus capecitabine 1000 mg/m² bid, 2 weeks on, 1 week off.

Outcomes

Response.
Overall survival (Kaplan‐Meier curve).
Progression‐free survival, defined as "the time from the start of the treatment until disease progression or death" (Kaplan‐Meier curve).

Common adverse events.

Notes

Estimated min follow‐up = 6 months (based on first event on OS curve).
Estimated max follow‐up = 42 months (based on last event on OS curve).

Median PFS time: Docetaxel + cisplatin arm 10.9 months, docetaxel + capecitabine arm 4.8 months, P < 0.001.

Median survival time: Docetaxel + cisplatin arm 32.8 months, docetaxel + capecitabine arm 21.5 months, P = 0.027.

All 53 randomised participants were analysed in time‐to‐event analyses (ITT).

Funding grant: AVON China breast cancer research grant and the National Natural Science Foundation of China.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "patients were randomized…"; no additional details were provided on how random assignment was achieved in the trial report.

Allocation concealment (selection bias)

Unclear risk

Method of concealment was not described.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label trial.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Not clear if outcome assessors were blinded to allocated intervention. Tumour response rates evaluated by CT or MRI every two cycles; no further details provided.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Low risk

All 27 and 26 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analyses (intent‐to‐treat analyses).

Incomplete outcome data (attrition bias) (binary outcomes)

Low risk

All randomised participants were assessed/assessable for tumour response. All randomised participants appear to have been included in the safety population for evaluating toxicities.

Selective reporting (reporting bias)

High risk

No trial registration or published protocol containing prespecified outcomes could be found. The date when participant recruitment began was not reported, but given that this was first published in December 2012 and that there were only 53 participants, it seems highly likely that recruitment began after July 1, 2005. Consequently, there was a high expectation of trial registration.

Other bias

Low risk

Baseline characteristics similar across groups except for histological grade, where the docetaxel‐platinum arm had a greater number of grade III tumours than the docetaxel‐capecitabine arm.

Methods

Prospective RCT. Central randomisation and stratification.
Baseline comparability: no significant imbalance apparent or reported.

Participants

327 eligible women (5 excluded) with histologically confirmed metastatic breast cancer.
100% metastatic breast cancer.
100% first‐line.
54% anthracycline‐naive.

Interventions

PE vs PCb.

ARM A: PE: 6 cycles epirubicin 80 mg/m² followed by paclitaxel 175 mg/m².

ARM B: PCb: 6 cycles of paclitaxel 175 mg/m² in a 3‐hour infusion immediately followed by carboplatin 6 AUC.
All cycles given every 3 weeks.

Outcomes

Overall survival (Kaplan‐Meier curve).
Time to treatment failure (Kaplan‐Meier curve) calculated from the randomisation date to the date progression of the disease was documented (participants who discontinued their treatment for any reason or probably died from disease‐related causes were considered at that time, as treatment failures).
Response.
Toxicity.
Quality of life (EORTC QLQ‐C30).

Notes

Estimated min follow‐up: 3 months.
Estimated max follow‐up: 36 months TTF, 36 months OS (based on last event on curves).
Median TTF: not reported.
Median survival: not reported.
QoL: PCb was associated with an improvement both in the emotional functioning scale and in sleep disturbance symptoms compared with PE. No other QoL differences were found.
No toxic deaths reported.

327 of 332 randomised participants were analysed in time‐to‐event analyses (modified ITT)

Note that 'Fountzilas 2004' was labelled 'Fountzilas 2002' in the original version of this review and its TTF estimate was incorrectly included in PFS/TTP meta‐analyses. This has been corrected in the 2016 review update.

Study "Supported by a Hellenic Cooperative Oncology Group research grant (HE R‐11b/99). Dr George Fountzilas received research support from Bristol–Myers Squibb, Aventis and AstraZeneca."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomized centrally at the HeCOG Data Office in Athens and stratified according to the history of previous adjuvant chemotherapy and risk category in a modified version of that used by Cavalli et al."

Allocation concealment (selection bias)

Low risk

Central randomisation.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information in trial publication.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

No information in trial publication. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Low risk

Images for tumour response were reviewed by an "independent radiological response review committee", 83% were reviewed by this committee (p. 1518).

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Unclear risk

327 of 332 randomised participants were analysed in time‐to‐event analyses (modified ITT). No information was provided on the randomised groups of the 5 excluded participants.

Incomplete outcome data (attrition bias) (binary outcomes)

Low risk

5 of 332 randomised participants were excluded from all analyses, with no information provided on the randomised groups of these excluded participants. In addition to these 5 excluded participants: 14 of 164 and 10 of 163 participants in the (known) intervention and control groups, respectively, were not assessed/assessable for tumour response (8.7% of all randomised participants); 4 of 164 and 1 of 163 participants in the (known) intervention and control groups, respectively, were excluded from the safety population for evaluating toxicities (3.0% of all randomised participants).

Selective reporting (reporting bias)

Unclear risk

No trial registration or published protocol prespecifying all study outcomes. Study began recruitment before July 1, 2005 so expectation of trial registration or published protocol was low.

Other bias

Unclear risk

None identified.

Methods

Prospective RCT. Central stratified block randomisation.

Baseline comparability ‐ all characteristics equal with the exception of performance status and the incidence of osseous metastases at study entry.

Participants

Total of 437 women with histologically confirmed metastatic breast cancer 'entered' the study (this included participants in both treatment‐comparisons Fountzilas 2009 A and Fountzilas 2009 B). 21 were found 'ineligible' leaving 416 'eligible' participants, of which 272 were in Fountzilas 2009 A.
100% metastatic breast cancer.
100% first‐line.

Interventions

Pw vs PCb.

ARM A: Pw: Paclitaxel 80 mg/m² for 12 weeks.

ARM B: PCb: Paclitaxel 175 mg/m² + carboplatin 6 AUC for 6 (3 week) cycles.

Outcomes

Overall survival.
Time to progression (insufficient TTP data reported to calculate hazard ratio for pooling).
Response.
Toxicity.
Quality of life (EUROQOL questionnaire).

Notes

The effective number of intervention participants allocated to Fountzilas 2009 A for calculating treatment effects was halved because Fountzilas 2009 A and Fountzilas 2009 B shared a common intervention group.

Minimum reported follow‐up 0.01 months.

Maximum reported follow‐up 56.9 months.

No toxic deaths reported.

Median TTP: 11.5 months PCb (0.01 to 54.6), 11.4 months Pw (0.92 to 56.9) (insufficient TTP data reported to calculate hazard ratio for pooling).

Changes in QoL (EQ‐5D index and EQ VAS Score) across time did not differ significantly between groups.

21 participants in Arms A, B and C were excluded after they 'entered' the study as they were found to be ineligible.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported in sufficient detail.

Allocation concealment (selection bias)

Low risk

Centralised.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information in trial publication.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

No information in trial publication. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Response assessed by blood and biochemistry tests, CT scans during and after treatment but "central evaluation of imaging material pertinent to tumor response was not performed in this study" and it was unclear whether or not the study was open‐label.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Unclear risk

21 randomised participants were excluded from time‐to‐event analyses across all three treatment arms before the commencement of treatment (modified intent‐to‐treat). No information was provided on the randomised groups of the 21 excluded participants.

Incomplete outcome data (attrition bias) (binary outcomes)

Unclear risk

21 randomised participants were excluded from all analyses, with no information provided on the randomised groups of these excluded participants. In addition to these 21 excluded participants: 17 of 136 and 16 of 136 participants in the (known) intervention and control groups, respectively, were not assessed/assessable for tumour response (11.8% of all randomised participants); 5 of 136 and 3 of 136 in the (known) intervention and control groups, respectively, were excluded from the safety population for evaluating toxicities (2.5% of all randomised participants).

Selective reporting (reporting bias)

Unclear risk

No trial registration or published protocol prespecifying all study outcomes. Study began recruitment before July 1, 2005 so expectation of trial registration or published protocol was low.

Other bias

Low risk

None identified.

Methods

Prospective RCT. Central stratified block randomisation.

Baseline comparability ‐ all characteristics equal with the exception of performance status and the incidence of osseous metastases at study entry.

Participants

Total of 437 women with histologically confirmed metastatic breast cancer 'entered' the study (this included participants in both treatment‐comparisons Fountzilas 2009 A and Fountzilas 2009 B). 21 were found 'ineligible' leaving 416 'eligible' participants, of which 280 were in Fountzilas 2009 B.
100% metastatic breast cancer.
100% first‐line.

Interventions

PCb vs GDoc

ARM B: PCb: Paclitaxel 175 mg/m² + carboplatin 6 AUC for 6 (3 week) cycles.

ARM C: GDoc: Gemcitabine 1000 mg/m² + docetaxel 75 mg/m² for 6 (3 week) cycles.

Outcomes

Overall survival.
Time to progression (insufficient TTP data reported to calculate hazard ratio for pooling).
Response.
Toxicity.
Quality of life (EUROQOL questionnaire).

Notes

The effective number of intervention participants allocated to Fountzilas 2009 B for calculating treatment effects was halved because Fountzilas 2009 A and Fountzilas 2009 B shared a common intervention group.

Minimum reported follow‐up 0.01 months.

Maximum reported follow‐up 56.9 months.

No toxic deaths reported.

Median TTP: 11.5 months PCb (0.01 to 54.6), 10.4 months GDoc (0.01 to 51.4) (insufficient TTP data reported to calculate hazard ratio for pooling).

Changes in QoL (EQ‐5D index and EQ VAS Score) across time did not differ significantly between groups.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported in sufficient detail.

Allocation concealment (selection bias)

Low risk

Centralised.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information in trial publication.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

No information in trial publication. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Response assessed by blood and biochemistry tests, CT scans during and after treatment but "central evaluation of imaging material pertinent to tumor response was not performed in this study" and it was unclear whether or not the study was open‐label.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Unclear risk

21 randomised participants were excluded from time‐to‐event analyses across all three treatment arms (modified intent‐to‐treat). No information was provided on the randomised groups of the 21 excluded participants.

Incomplete outcome data (attrition bias) (binary outcomes)

High risk

21 randomised participants were excluded from all analyses, with no information provided on the randomised groups of these excluded participants. In addition to these 21 excluded participants: 17 of 136 and 30 of 144 participants in the (known) intervention and control groups, respectively, were not assessed/assessable for tumour response (18.4% of all randomised participants); 5 of 136 and 10 of 144 in the (known) intervention and control groups, respectively, were excluded from the safety population for evaluating toxicities (6.1% of all randomised participants).

Selective reporting (reporting bias)

Unclear risk

No trial registration or published protocol prespecifying all study outcomes. Study began recruitment before July 1, 2005 so expectation of trial registration or published protocol was low.

Other bias

Low risk

None identified.

Methods

Prospective, open‐label, multicentre, randomised, phase 3 trial at 12 institutions or hospitals
in China.

Participants

240 Chinese participants (236 analysed) with breast cancer aged 18 to 70 years who had metastatic triple‐negative breast cancer (mTNBC) histologically confirmed at the primary tumour, with clinical, imaging, histological or cytological evidence of metastatic (stage IV) disease.

Median age 47 and 48 years in platinum and control arms, respectively.
Age interquartile range 42 to 57 and 43 to 55 years in platinum and control arms, respectively.
100% mTNBC.

100% 1st‐line.

152 (64%) of the 236 participants had received anthracyclines.

195 (83%) of the 236 participants had received taxanes.

Interventions

Cisplatin + gemcitabine vs paclitaxel + gemcitabine.

Platinum ARM: Cisplatin plus gemcitabine (cisplatin 75 mg/m² on day 1; gemcitabine 1250 mg/m² on days 1 and 8) intravenously every 3 weeks for a maximum of eight cycles, or until disease progression or intolerable toxic effects developed.

Control ARM: Paclitaxel plus gemcitabine (paclitaxel 175 mg/m² on day 1; gemcitabine 1250 mg/m² on days 1 and 8) intravenously every 3 weeks for a maximum of eight cycles, or until disease progression or intolerable toxic effects developed.

Outcomes

Response.
Overall survival.
Progression‐free survival, defined as "the time from the date of randomisation to progression or death from any cause".

Adverse events.

Notes

4 participants were randomised but not analysed for OS or PFS (i.e. modified ITT).

An additional 9 participants were not assessable for response.
Estimated min follow‐up = 3 months (based on first censoring tick on OS curve).
Estimated max follow‐up = 35 months (based on last censoring tick on OS curve).

Median progression‐free survival was 7.73 months (95% CI 6.16 to 9.30) in the cisplatin plus gemcitabine group and 6.47 months (5.76 to 7.18) in the paclitaxel plus gemcitabine group.

Median survival time was 22.3 months in the cisplatin plus gemcitabine group and 18.6 months in the paclitaxel plus gemcitabine group; not reported in the text of the study paper but estimated from Kaplan‐Meier curve.

118 of 120 randomised metastatic participants were analysed in time‐to‐event PFS analyses (modified ITT).

The study was funded by Shanghai Natural Science Foundation and gemcitabine was provided by Eli Lilly.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Randomisation was done centrally via a block randomisation of size eight, with no stratification factors, via an interactive web‐response system."

Allocation concealment (selection bias)

Low risk

Central allocation. Quote: "Randomisation was done centrally…" and "After checking the inclusion criteria, the study coordinator sent the allocated treatment back to the investigator by fax."

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label trial.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

The extent and/or the effectiveness of intended blinding was not clear. Quote: "Tumour response was assessed by a team of local investigators … and when needed, with independent central assessment, every two cycles until disease progression." Assessment of toxicity appeared to be unblinded. Quote: "Adverse events were recorded at each treatment visit, at each follow‐up visit, and at the end‐of‐study visit."

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Unclear risk

118 of 120 and 118 of 120 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analysis (modified intent‐to‐treat analysis).

Incomplete outcome data (attrition bias) (binary outcomes)

Low risk

8 of 120 and 5 of 120 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response (5.4% of all randomised participants). 2 of 120 and 2 of 120 participants randomised to intervention and control groups, respectively, were not included in the safety population for evaluating toxicities (1.7% of all randomised participants).

Selective reporting (reporting bias)

Low risk

Overall survival was not listed under 'outcomes' in ClinicalTrials.gov record (https://clinicaltrials.gov/ct2/show/NCT01287624) but it was mentioned in the 'purpose' section of the record. All other outcomes in the trial report were listed in the ClinicalTrials.gov record and vice versa.

Other bias

Unclear risk

Baseline characteristics were generally similar across groups except for ECOG performance status, number of metastatic organ sites and menopausal status.

Methods

Prospective randomised non‐blinded multicentre phase III study. No stratification for prognostic factors or centres. Central randomisation.
Baseline comparability: no significant imbalance apparent or reported.

Participants

201 women with histologically confirmed locally advanced or metastatic breast cancer previously treated with anthracyclines (193 eligible).
Median age 47/49.
Age range 18 to 70.
96% metastatic breast cancer.
20% first‐line.
60% 2nd line.
20% 3rd line.
All participants had previously received anthracycline therapy.

Interventions

T vs VP‐16 + P.

ARM A: Paclitaxel 175 mg/m² IV, day 1 q3 weeks.
ARM B: Cisplatin 70 mg/m² IV, day 1 q3 weeks + oral etoposide (VP‐16) 50 mg bid, po, days 1 to 7 q3 weeks.

Outcomes

Overall survival (Kaplan‐Meier curve).
Time to progression (Kaplan‐Meier curve) defined as "the duration between the first day of study treatment and date of progression".
Response.
Toxicity.

Notes

Conference powerpoint slide presentation.
193 eligible:
‐ 3 died before treatment.
‐ 5 withdrew consent.
‐ 1 had an accident and did not commence treatment.
Participants crossed over after 2 cycles if disease progressed or there was no evidence of response: 47 crossed to Arm A; 37 crossed to Arm B.
185 assessable for response.
Estimated min follow‐up: 4.5 months (based on the median number of cycles received).
Estimated max follow‐up: 45 months TTP, 48 months OS (based on last events on curves).
Median TTP: 6 months Arm B, 3.9 months Arm A.
Median survival: 13 months Arm B, 10 months Arm A.
4 toxic deaths (Arm B, n = 2; Arm A, n = 3).

193 of 202 randomised metastatic participants were analysed in time‐to‐event PFS analyses (modified ITT).

"Bristol Myers Squibb (Turkey) supplied limited number of paclitaxel for this trial".

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported other than "No stratification was carried out for prognostic factors or centers."

Allocation concealment (selection bias)

Low risk

Central randomisation.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

"nonblinded study"

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

Non‐blinded study. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Low risk

Quote: "Responses were reviewed by two independent experts to confirm the response status blindly for treatment received" (p. 2).

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Unclear risk

96 of 100 and 97 of 101 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analysis (modified intent‐to‐treat analysis).

Incomplete outcome data (attrition bias) (binary outcomes)

Low risk

9 of 100 and 7 of 101 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response (8.0% of all randomised participants). 7 of 100 and 4 of 101 participants randomised to intervention and control groups, respectively, were not included in the safety population for evaluating toxicities (4.0% of all randomised participants).

Selective reporting (reporting bias)

Unclear risk

No trial registration or published protocol prespecifying all study outcomes. Study began recruitment before July 1, 2005 so expectation of trial registration or published protocol was low.

Other bias

Low risk

None identified.

Methods

Prospective phase III RCT. Randomisation, treatment, allocation methods, and accrual not detailed.
Baseline comparability: no significant imbalance apparent or reported.

Participants

128 women with metastatic breast cancer.
Age range 30 to 70.
100% metastatic breast cancer.
100% first‐line.
All participants anthracycline‐naive.

Interventions

CMFVP vs CAP.

ARM A: CMFVP: Cyclophosphamide 200 mg/m² IV days 1, 2, 3, 4, 5 + methotrexate 20 mg/m² IV days 2, 4 + 5‐fluorouracil 500 mg/m² IV days 1, 3, 5 + vincristine 1 mg/m² po days 1 and 5 + prednisolone 40 mg po days 1, 2, 3, 4, 5.
3 to 4 week cycles.
ARM B: CAP: cis‐platinum 30 mg/m² IV days 1, 3, 5; + adriamycin 40 mg/m² IV day 1 + cyclophosphamide 200 mg/m² IV days 1, 3, 5.

Outcomes

Overall survival (insufficient OS data reported to calculate hazard ratio for pooling).
Response.
Toxicity.

Notes

Trial analysis not intent‐to‐treat:
‐ 123 evaluable following > 2 cycles.
‐ 5 not evaluable, unexplained..
Min follow‐up: 6 months (reported).
Max follow‐up: 33 months (reported).
Preliminary data reported survival in favour of CAP (33%) vs CMFVP (53%), P < 0.05 (insufficient OS data reported to calculate hazard ratio for pooling).
No toxic deaths reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported. Stated as "randomised" only.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information in trial publication.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

No information in trial publication. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Standard criteria used to assess tumour response but no further details provided.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

High risk

61 of 65 and 62 of 63 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analysis. Excluded participants included those who did not complete more than 2 cycles of chemotherapy (per‐protocol analysis), but only median times were reported (hence no extractable time‐to‐event data).

Incomplete outcome data (attrition bias) (binary outcomes)

Low risk

4 of 65 and 1 of 63 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response or included in the safety population for evaluating toxicities (3.9% of all randomised participants).

Selective reporting (reporting bias)

Unclear risk

No trial registration or published protocol prespecifying all study outcomes. Study began recruitment before July 1, 2005 so expectation of trial registration or published protocol was low.

Other bias

Low risk

None identified.

Methods

Prospective RCT. Stratification prior to randomisation. Randomisation and allocation methods not detailed.
Accrual June 1984 to 1986.
Imbalance in prominent metastatic site (prevalence of visceral metastases 21 vs 31) was created by unevaluable participants being taken off the trial after the first cycle.

Participants

142 women with metastatic or locoregional advanced inoperable breast cancer.
Median age 53.
Age range 29 to 70.
58% metastatic breast cancer.
42% locally advanced non‐resectable breast cancer.
100% first‐line.
All participants anthracycline‐naive.

Interventions

CAP vs FAC.

ARM A: FAC (n = 68): 5‐Fluorouracil 500 mg/m² days 1 and 8; adriamycin 50 mg/m² 500 mg/m² day 1; cyclophosphamide 500 mg/m² day 1.
ARM B: CAP (n = 58): Cyclophosphamide 200 mg/m² IV days 1,3 and 5; adriamycin 40 mg/m² IV day 1; platinum 30 mg/m² IV day 1,3 and 5.

Outcomes

Overall survival (Kaplan‐Meier curve).
Response.
Toxicity.

Notes

126 evaluable for > 2 cycles.
16 withdrawn after 1 cycle:
‐ 1 early death due to progression.
‐ 5 further treatment refusals.
‐ 10 lost to follow‐up.

Proportion of total numbers with either metastatic or locoregionally advanced disease was not reported. However, 53 reported with predominant metastatic site of soft tissue: 73 were reported with predominant site as viscera or bones; hence, an assumption made that at least 58% (73/126) were likely to have metastatic breast cancer.
Min follow‐up: 1 month (reported).
Max follow‐up: 30 months (reported).
Median survival: 13 months CAP, 9 months FAC.
No toxic deaths reported.

126 of 142 participants that had > 2 cycles were analysed in time‐to‐event OS analysis (per‐protocol analysis).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not detailed.

Allocation concealment (selection bias)

Unclear risk

Not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information in trial publication.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

No information in trial publication. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Standard criteria used to assess tumour response but no further details provided.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

High risk

58 of 68 and 68 of 74 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analysis. Excluded participants included those who did not complete more than 2 cycles of chemotherapy (per‐protocol analysis).

Incomplete outcome data (attrition bias) (binary outcomes)

Unclear risk

10 of 69 and 6 of 74 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response or included in the safety population for evaluating toxicities (11.3% of all randomised participants).

Selective reporting (reporting bias)

Unclear risk

No trial registration or published protocol prespecifying all study outcomes. Study began recruitment before July 1, 2005 so expectation of trial registration or published protocol was low.

Other bias

Low risk

None identified.

Methods

Phase III RCT. Central randomisation registered, stratified by ECOG performance status. Accrual from July 1987 to November 1990. Baseline comparability: no significant imbalance apparent or reported.

Participants

155 women with histologically proven locally advanced or metastatic breast cancer.
Median age 52/55.
Age range 27 to 69.
91% metastatic breast cancer.
100% first‐line.
All participants anthracycline‐naive.

Interventions

EPI vs EPI + CIS.

ARM A: Epirubicin 70 mg/m² days 1 and 8 every 4 weeks.

ARM B: Epirubicin 60 mg/m² days 1 and 8 + cisplatin 100 mg/m² day 1 every 4 weeks.

Outcomes

Overall survival (Kaplan‐Meier curve).
Time to progression (Kaplan‐Meier curve, "calculated as the time from the drug administration to progression for both responders and nonresponders").
Response.
Toxicity.

Notes

Oopherectomy performed in premenopausal participants, n = 45 (32%).
Trial claimed 'intent‐to‐treat' analysis for all randomised participants and outcomes, although:
‐ 10 were declared ineligible (EPI, n = 7; EPI + CIS, n = 3).
‐ 6 refused treatment after 1 cycle (EPI + CIS arm) and were excluded.
Hence, given 139 of 155 randomised participants were analysed in time‐to‐event analyses and 6 participants who started but did not complete treatment were excluded, this represented per‐protocol analyses for time‐to‐event data.
Epirubicin was continued until disease progression or to cumulative dose of 1000 mg/m2. Cisplatin was discontinued after 6 cycles. Doses of epirubicin were adjusted according to WBC and platelet counts on the day of treatment. Cisplatin was adjusted according to nephrotoxicity.
Reported min follow‐up: 0.1 months.
Reported max follow‐up: 77.7 months TTP and OS.
Median TTP: 8.4 months EPI, 15.3 months EPI + CIS.
Median survival: 15.1 months, EPI; 21.5, months EPI + CIS.
5 deaths were attributed to treatment: nephrotic syndrome: n = 1, leukaemia: n = 2, congestive cardiac failure: n = 1, and thrombocytopenia: n = 1.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported in sufficient detail.

Allocation concealment (selection bias)

Low risk

Central randomisation.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information in trial publication.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

No information in trial publication. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

"evaluation of response ... was done according to WHO criteria" (p. 460) but no further details provided.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

High risk

65 of 74 and 74 of 81 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analysis. Excluded participants included those who did not complete more than 2 cycles of chemotherapy (per‐protocol analysis).

Incomplete outcome data (attrition bias) (binary outcomes)

Unclear risk

9 of 74 and 7 of 81 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response or included in the safety population for evaluating toxicities (10.3% of all randomised participants).

Selective reporting (reporting bias)

Unclear risk

No trial registration or published protocol prespecifying all study outcomes. Study began recruitment before July 1, 2005 so expectation of trial registration or published protocol was low.

Other bias

Low risk

None identified.

Methods

Randomised, multicentre, phase III trial. Accrual between November 1998 and May 2002.

Baseline characteristics reported as well balanced between study arms.

Participants

196 women with histologically proven HER2 positive metastatic breast cancer.
Median age 55/56.
Age range 33 to 83.
100% metastatic breast cancer.
100% first‐line for metastatic breast cancer.

100% HER2 positive.

Interventions

TPa vs TPC.

ARM A: TPa: Trastuzumab 4 mg/kg + paclitaxel 175mg/m².

ARM B: TPC: Trastuzumab 4 mg/kg + paclitaxel 175mg/m² + carboplatin 6 AUC.

Outcomes

Overall survival.

Progression‐free survival, defined as the interval between the date of first dose and the date of progression or death as a result of any cause.

Response.

Toxicity.

Notes

Minimum reported follow‐up: < 1 month.

Maximum reported follow‐up: 56.8 months.

No deaths due to toxicity.

Randomisation procedure not stated ‐ just reported as "randomised".

Stratified by IHC score (2+ or 3+).
Participants with prior adjuvant or neo‐adjuvant chemotherapy: TPa, 46%; TPC, 46%. Participants were eligible provided a taxane had not been used and that cumulative doxorubicin exposure was < 360 mg/m².

Reported hazard ratios and confidence intervals were inconsistent with the Kaplan Meier curves. For example, the text stated that the difference in OS "was not statistically significant", yet the reported 95% confidence interval was 0.88 to 0.92 (not only was the confidence interval highly statistically significant, it was far too narrow, given the cohort size). Consequently, we extracted OS and TTP data from the Kaplan‐Meier curves rather than relying on the reported hazard ratios.

Study "Supported by grants from Bristol‐Myers Squibb Co, Princeton, NJ, and Genentech Inc, South San Francisco, CA."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported in detail.

Allocation concealment (selection bias)

Unclear risk

Not stated.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No information in trial publication.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

No information in trial publication. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Quote: "Tumor assessments were performed by physical examination before every cycle, with imaging studies evaluating indicator lesions repeated every other cycle" (p. 2787). No further details provided on whether central assessment took place.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Low risk

All 98 and 98 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analyses (intent‐to‐treat analyses).

Incomplete outcome data (attrition bias) (binary outcomes)

Low risk

6 of 98 and 4 of 98 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response (5.1% of all randomised participants). One randomised participant(control group) was excluded from the safety population for evaluating toxicities (0.5% of all randomised participants).

Selective reporting (reporting bias)

Unclear risk

No trial registration or published protocol prespecifying all study outcomes. Study began recruitment before July 1, 2005 so expectation of trial registration or published protocol was low.

Other bias

Low risk

None identified.

Methods

Randomised multicentre phase II trial. Accrual between 2003 and 2006.

Groups comparable at baseline in all regards except menopausal status.

Participants

Overall, a total of 141 participants (91 in Arm A + Arm B) with histologically confirmed metastatic breast cancer.

Median age: ˜ 60.

100% metastatic breast cancer.

First line: ˜ 36%.

Anthracycline‐naive: ˜ 43%.

Interventions

GemVin vs GemCis.

ARM A: GemVin: Gemcitabine 1000 mg/m² + vinorelbine 25 mg/m².

ARM B: GemCis: Gemcitabine 1000 mg/m²+ cisplatin 30 mg/m².

Treatment for a maximum of six (3 week) cycles.

Outcomes

Overall survival (Kaplan‐Meier).

Time to progression, defined as "time from the start of therapy to first evidence of progressive disease or last follow‐up" (but TTP was also interchangeably referred to as PFS at various points in the paper) (Kaplan‐Meier).

Response rate.

Toxcity.

Quality of life.

Notes

No reported deaths due to toxicity.

Estimated min follow‐up: 1 month.

Estimated max follow‐up: 47 months.

Median PFS: 5.7 months, 95% CI: 3.9 to 8.2 (GemVin); 6.9 months, 95% CI: 5.8 to 8.8 (GemCis).

Median OS: 17.5 months, 95% CI: 12.2 to 30.0 (GemVin); 13.0 months, 95% CI: 11.0 to 19.2 (GemCis).

Randomisation procedure not stated ‐ just reported as "randomised".

All randomised participants were analysed in time‐to‐event analyses (ITT).

"This study was supported by Lilly GmbH Germany."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported. Stated as "randomised" only.

Allocation concealment (selection bias)

Unclear risk

Not stated.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Registered as 'open‐label' trial (https://www.clinicaltrials.gov/ct2/show/NCT00480597).

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

Open‐label study. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Blood and biochemistry tests, and imaging took place during therapy. No details were provided on whether there was a central (independent) evaluation team for assessing tumour response rates.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Low risk

All 45 and 46 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analyses (intent‐to‐treat analyses).

Incomplete outcome data (attrition bias) (binary outcomes)

High risk

10 of 45 and 9 of 46 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response (20.3% of all randomised participants). 0 of 45 and 4 of 46 participants randomised to intervention and control groups, respectively, were not included in the safety population for evaluating toxicities (5.8% of all randomised participants).

Selective reporting (reporting bias)

Low risk

All outcomes in the trial report were listed in the ClinicalTrials.gov record and vice versa (https://www.clinicaltrials.gov/ct2/show/NCT00480597).

Other bias

Low risk

None identified.

Methods

Randomised multicentre phase II trial. Accrual between 2003 and 2006.

Groups comparable at baseline in all regards except menopausal status.

Participants

Overall 141 participants (95 in Arm B + Arm C) with histologically confirmed metastatic breast cancer.

Median age: ˜ 60 years.

100% metastatic breast cancer.

First‐line: ˜ 36%.

Anthracycline‐naive: ˜ 43%.

Interventions

GemCis vs GemCap.

ARM B: GemCis: Gemcitabine 1000 mg/m² + cisplatin 30 mg/m².

ARM C: GemCap: Gemcitabine 1000 mg/m² + capecitabine 1.300 mg/m².

Treatment for a maximum of six (3 week) cycles.

Outcomes

Overall survival (Kaplan‐Meier).

Time to progression, defined as "time from the start of therapy to first evidence of progressive disease or last follow‐up" (but TTP was also interchangeably referred to as PFS at various points in the paper) (Kaplan‐Meier).

Response rate.

Toxcity.

Notes

No reported deaths due to toxicity.

Estimated min follow‐up: 1 month.

Estimated max follow‐up: 47 months.

Median PFS: 6.9 months, 95% CI: 5.8 to 8.8 (GemCis); and 8.3 months, 95% CI: 4.3 to 9.6 (GemCap).

Median OS: 13.0 months, 95% CI: 11.0 to 19.2 (GemCis); and 19.4 months, 95% CI: 16.6 to 22.0 (GemCap).

All randomised participants were analysed in time‐to‐event analyses (ITT).

"This study was supported by Lilly GmbH Germany."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported. Stated as "randomised" only.

Allocation concealment (selection bias)

Unclear risk

Not stated.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Registered as "open label" trial (https://www.clinicaltrials.gov/ct2/show/NCT00480597).

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

Open‐label study. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Blood and biochemistry tests, and imaging took place during therapy. No details were provided on whether there was a central (independent) evaluation team for assessing tumour response rates.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Low risk

All 45 and 50 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analyses (intent‐to‐treat analyses).

Incomplete outcome data (attrition bias) (binary outcomes)

High risk

10 of 45 and 9 of 50 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response (18.1% of all randomised participants). 0 of 45 and 1 of 50 participants randomised to intervention and control groups, respectively, were not included in the safety population for evaluating toxicities (1.4% of all randomised participants).

Selective reporting (reporting bias)

Low risk

All outcomes in the trial report were listed in the ClinicalTrials.gov record and vice versa (https://www.clinicaltrials.gov/ct2/show/NCT00480597).

Other bias

Low risk

None identified.

Methods

Randomised phase III trial.

Participants

341 metastatic and 35 recurrent locally advanced triple‐negative or BRCA1/2 breast cancer. 43 BRCA + participants (29 known (i.e. 16 TNBC, 12 ER‐positive, HER2‐negative, 1 ER unknown, HER2‐negative) & 14 research test).

Interventions

C vs D.

C: Carboplatin (AUC 6 every 3 weeks for six cycles).

D: Docetaxel (100 mg/m² every 3 weeks for six cycles).

Outcomes

Response.
Overall survival (insufficient OS data reported to calculate hazard ratio for pooling).

Progession‐free survival (insufficient PFS data reported to calculate hazard ratio for pooling).

Toxicity (no results reported).

Notes

Abstracts only.

Median follow‐up: 11 months.

Median PFS: Carboplatin 3.1 (95% CI 2.5 to 4.2) vs docetaxel 4.5 (95% CI 4.1 to 5.2) months; absolute difference ‐0.4 (95%CI ‐1.1 to 0.3), P = 0.29 (insufficient PFS data reported to calculate hazard ratio for pooling).

Median OS: Carboplatin 12.4 (95% CI 10.4 to 15.3) vs docetaxel 12.3 (95% CI 10.5 to 13.6) months; absolute difference ‐0.2 (95% CI ‐1.1 to 0.8), P = 0.31 (insufficient OS data reported to calculate hazard ratio for pooling).

Subgroup analysis restricted to 43 BRCA1/2+ participants showed carboplatin was associated with significantly greater proportions of objective responses (68% vs 33%; P = 0.03).

"Sponsor: Institute of Cancer Research, United Kingdom".

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Quote: "patients were randomized" ; no additional details were provided on how random assignment was achieved in the abstracts or ClinicalTrials.gov record (https://clinicaltrials.gov/ct2/show/NCT00532727).

Allocation concealment (selection bias)

Unclear risk

Method of concealment was not described in the abstracts.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label trial.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

Open‐label trial. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Insufficient information provided in the available abstracts.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Low risk

All 188 and 188 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analyses (intent‐to‐treat analyses), but only median times were reported (hence no extractable time‐to‐event data).

Incomplete outcome data (attrition bias) (binary outcomes)

Unclear risk

All randomised participants were included in response rate denominators, but it was not explicitly stated that all participants were assessed/assessable. No toxicity results reported.

Selective reporting (reporting bias)

High risk

TTP, TTF and toxicity were specified as outcomes in ClinicalTrials.gov record (https://clinicaltrials.gov/ct2/show/NCT00532727), but no results for these outcomes were provided in the abstracts.

Other bias

Unclear risk

Unable to assess from the abstracts.

Methods

Randomised multicentre phase III trial. Accrual between 11 December 2001 and 23 March 2004.

Groups comparable at baseline.

Participants

263 participants with histologically confirmed metastatic breast cancer.

Median age 52/51 years.

100% metastatic breast cancer.

100% first‐line.

Interventions

TH vs TCH

ARM A: TH: Trastuzumab 2 mg/kg + docetaxel 100 mg/m².

ARM B: TCH: Trastuzumab 2 mg/kg + docetaxel 75 mg/m² + carboplatin 6 AUC.

Outcomes

Overall survival (Kaplan‐Meier curves and unadjusted HRs).

Progression‐free survival (Kaplan‐Meier curves and unadjusted HRs) defined as "the interval from the day of random assignment to the date of disease progression, diagnosis of second primary malignancy or death" (the authors used the terms TTP and PFS interchangeably).

Response rate.

Toxicity (frequencies for some conditions were not grade‐specific and therefore could not be used for pooling).

Notes

Estimated min follow‐up: 6 months.

Estimated max follow‐up: 78 months.

Median TTP: 11.1 and 10.4 months for TH and TCH arms, respectively.

Median OS: 37.1 and 37.4 months for TH and TCH arms, respectively.

Reported HRs were for Arm B as the reference group and were thus inverted.

All 263 randomised participants were analysed in time‐to‐event analyses (ITT).

Research Funding: Pfizer, Sanofi‐Aventis, Roche, GlaxoSmithKline.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Quote: "Patients were randomly assigned... Treatment allocation was based on a dynamic minimization procedure, stratified by center and by prior neoadjuvant chemotherapy."

Allocation concealment (selection bias)

Unclear risk

Not stated.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

"Treatment was not blinded" (p.151).

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

Open‐label study. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Imaging for tumour response took place before, during, and after chemotherapy. No details were provided on whether there was a central (independent) evaluation team for assessing tumour response rates.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Low risk

All 132 and 131 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analyses (intent‐to‐treat analyses).

Incomplete outcome data (attrition bias) (binary outcomes)

Low risk

5 of 132 and 1 of 131 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response (2.3% of all randomised participants). One randomised participant(control) was excluded from the safety population for evaluating toxicities (0.3% of all randomised participants).

Selective reporting (reporting bias)

Unclear risk

Most outcomes in the trial report were listed in the ClinicalTrials.gov record and vice versa (https://clinicaltrials.gov/ct2/show/NCT00047255). However, the ClinicalTrials.gov record indicated that pathologic, molecular, genetic and biochemical markers would also be assessed, but these were not reported on in the paper.

Other bias

Low risk

None identified.

Methods

Randomised multicentre phase II trial. Accrual between March 2005 and December 2007.

Groups comparable at baseline except length of disease‐free interval of > 24 months at enrolment.

Participants

Total of 147 women overall (100 in Arm 1 and Arm 3) with histologically or cytologically confirmed metastatic breast cancer.

Median age 48 years.

100% metastatic breast cancer.

97.3% of participants had received neoadjuvant or adjuvant anthracycline based chemotherapy.

Interventions

GemCis vs GemPac.

ARM 1: GemPac: Paclitaxel 150 mg/m² + gemcitabine 2500 mg/m².

ARM 3: GemCis: Gemcitabine 2500 mg/m² + cisplatin 50 mg/m².

Outcomes

Overall survival (Kaplan‐Meier).

Progression‐free survival, endpoints not stated (Kaplan‐Meier).

Response rate.

Time to treatment failure (insufficient TTF data reported to calculate hazard ratio for pooling).

Toxicity.

Notes

Estimated min follow‐up: 2 months.

Estimated max follow‐up: 24 months.

Median OS: GemPac = 15.5 months (10.4 to 26.7), GemCis = 20.1 months (12.4 to 21.6).

Median PFS:GemPac = 4.8 months (4.2 to 7.0) , GemCis = 4.8 months (3.7 to 8.1).

Median TTF: GemPac = 5.8 months (4.2 to 5.8), GemCis = not calculable.

99 of 100 randomised participants analysed in time‐to‐event analyses (modified ITT).

"This study was sponsored by Eli Lilly and Company".

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported in detail other than stratified on one factor only. Quote: "Eligible patients were randomly assigned in a 1:1:1 ratio, stratified by country...".

Allocation concealment (selection bias)

Unclear risk

Not stated.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label trial.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

Open‐label study. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Qutote: "Tumor assessments were performed at baseline (within 4 weeks of enrolment) and at the end of cycles 4 and 8" (p. 205) and during follow‐up. No mention of a central (independent, blinded) adjudication team for assessing tumour response.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Unclear risk

50 of 51 and 49 of 49 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analysis (modified intent‐to‐treat analysis).

Incomplete outcome data (attrition bias) (binary outcomes)

Low risk

3 of 51 and 5 of 49 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response (7.9% of all randomised participants). One randomised participant(intervention) was excluded from the safety population for evaluating toxicities (1.3% of all randomised participants).

Selective reporting (reporting bias)

Low risk

All outcomes in the trial report were listed in the ClinicalTrials.gov record and vice versa (https://clinicaltrials.gov/ct2/show/study/NCT00191854).

Other bias

Low risk

None identified.

Methods

Randomised multicentre phase II trial. Accrual between March 2005 and December 2007.

Groups comparable at baseline except length of disease‐free interval of > 24 months at enrolment.

Participants

Total of 147 women overall (96 in Arm 1 and Arm 2) with histologically or cytologically confirmed metastatic breast cancer.

Median age 48 years.

100% metastatic breast cancer.

97.3% of participants had received neoadjuvant or adjuvant anthracycline‐based chemotherapy.

Interventions

GemCarb vs GemPac.

ARM 1: GemPac: Paclitaxel 150 mg/m² + gemcitabine 2500 mg/m².

ARM 2: GemCarb: Gemcitabine 2500 mg/m² + carboplatin 2.5 AUC.

Outcomes

Overall survival (Kaplan‐Meier).

Progression‐free survival, endpoints not stated (Kaplan‐Meier).

Response rate.

Time to treatment failure (insufficient TTF data reported to calculate hazard ratio for pooling).

Toxicity.

Notes

Estimated min follow‐up: 2 months.

Estimated max follow‐up: 24 months.

Median OS: GemPac = 15.5 months (10.4 to 26.7), GemCarb = 22.8 months (13.3 – not calculable).

Median PFS: GemPac = 4.8 months (4.2 to 7.0), GemCarb = 4.3 months (3.7 to 5.9).

Median TTF: GemPac = 5.8 months (4.2 to 5.8), GemCarb = 4.3 months (3.7 – not calculable).

All 96 randomised participants analysed in time‐to‐event analyses (ITT).

"This study was sponsored by Eli Lilly and Company".

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation not reported in detail other than stratified on one factor only. Quote: "Eligible patients were randomly assigned in a 1:1:1 ratio, stratified by country...".

Allocation concealment (selection bias)

Unclear risk

Not stated.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label trial.

Blinding of outcome assessment (detection bias) (overall survival)

Low risk

Open‐label study. Unlikely that assessment of overall survival would be influenced by lack of blinding.

Blinding of outcome assessment (detection bias) (outcomes other than overall survival and quality of life)

Unclear risk

Quote: "Tumor assessments were performed at baseline (within 4 weeks of enrolment) and at the end of cycles 4 and 8" (p. 205) and during follow‐up. No mention of a central (independent, blinded) adjudication team for assessing tumour response.

Incomplete outcome data (attrition bias) (time‐to‐event outcomes)

Low risk

All 47 and 49 participants randomised to intervention and control groups, respectively, were analysed in time‐to‐event analyses (intent‐to‐treat analyses).

Incomplete outcome data (attrition bias) (binary outcomes)

Low risk

3 of 47 and 5 of 49 participants randomised to intervention and control groups, respectively, were not assessed/assessable for tumour response (7.0% of all randomised participants). No participants were excluded from the safety population for evaluating toxicities.

Selective reporting (reporting bias)

Low risk

All outcomes in the trial report were listed in the ClinicalTrials.gov record and vice versa (https://clinicaltrials.gov/ct2/show/study/NCT00191854).

Other bias

Low risk

None identified.