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Referencias

References to studies included in this review

Amadori 2013 {published data only}

Amadori D, Carrasco E, Roesel S, Labianca R, Uziely B, Soldatenkova V, et al. A randomized phase II non‐comparative study of pemetrexed‑carboplatin and gemcitabine‑vinorelbine in anthracycline‐ and taxane‐pretreated advanced breast cancer patients. International Journal of Oncology 2013;42(5):1778‐85. CENTRAL
Amadori D, La Torre I, Carrasco EM, Roesel S, Labianca R, Moreau‐Donnet V, et al. A randomized phase II study of pemetrexed‐carboplatin and gemcitabine‐vinorelbine in patients with anthracycline‐ and taxane‐pretreated advanced breast cancer. Journal of Clinical Oncology 2011;29(15 Suppl):1051‐1051. CENTRAL
NCT00325234. Pemetrexed‐carboplatin and gemcitabine‐vinorelbine in advanced breast cancer. clinicaltrials.gov/ct2/show/results/NCT00325234 (accessed 13 April 2016). CENTRAL

Berruti 2002 A {published data only}

Berruti A, Bitossi R, Gorzegno G, Bottini A, Alquati P, De Matteis A, et al. Time to progression in metastatic breast cancer patients treated with epirubicin is not improved by the addition of either cisplatin or lonidamine: final results of a phase III study with a factorial design. Journal of Clinical Oncology 2002;20(20):4150‐9. CENTRAL

Berruti 2002 B {published data only}

Berruti A, Bitossi R, Gorzegno G, Bottini A, Alquati P, De Matteis A, et al. Time to progression in metastatic breast cancer patients treated with epirubicin is not improved by the addition of either cisplatin or lonidamine: final results of a phase III study with a factorial design. Journal of Clinical Oncology 2002;20(20):4150‐9. CENTRAL

Bhattacharyya 2009 {published data only}

Bhattacharyya GS, Basu S, Agarwal V, Malhotra H, Pareekh PM, Babu KG, et al. 41LBA Single institute phase II study of weekly cisplatinum and metronomic dosing of endoxan and methotrexate in second line metastatic breast cancer triple‐negative. European Journal of Cancer Supplements. 2009; Vol. 7, issue 3:18‐19. CENTRAL

Carey 2012 {published data only}

Carey LA, Rugo HS, Marcom PK, Mayer EL, Esteva FJ, Ma CX, et al. TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple‐negative breast cancer. Journal of Clinical Oncology 2012;30(21):2615‐23. CENTRAL
NCT00232505. Cetuximab with or without carboplatin in treating women with estrogen receptor‐negative, progesterone receptor‐negative metastatic breast cancer. clinicaltrials.gov/show/NCT00232505 (accessed 13 April 2016). CENTRAL

Cocconi 1991 {published data only}

Cocconi G, Bisagni G, Bacchi M, Boni C, Bartolucci R, Ceci G, et al. Cisplatin and etoposide as first‐line chemotherapy for metastatic breast carcinoma: a prospective randomized trial of the Italian Oncology Group for Clinical Research. Journal of Clinical Oncology 1991;9(4):664‐9. CENTRAL

Cocconi 1996 {published data only}

Cocconi G, Bella M, Bartolucci R, Basurto C, Colozza M, Indelli M. Continuous CMF compared to a short chemotherapy using cisplatin‐containing combinations in metastatic breast carcinoma. A prospective randomized study. Annals of Oncology 1996;7(Suppl 5):22. CENTRAL

Cocconi 1999 {published data only}

Cocconi G, Bisagni G, Bella M, Acito L, Anastasi P, Carpi A, et al. Comparison of CMF (cyclophosphamide, methotrexate, and 5‐fluorouracil) with a rotational crossing and a sequential intensification regimen in advanced breast cancer: a prospective randomized study. American Journal of Clinical Oncology 1999;22(6):593‐600. CENTRAL

Costanza 1999 {published data only}

Costanza ME, Weiss RB, Henderson IC, Norton L, Berry DA, Cirrincione C, et al. Safety and efficacy of using a single agent or a phase II agent before instituting standard combination chemotherapy in previously untreated metastatic breast cancer patients: report of a randomized study‐‐Cancer and Leukemia Group B 8642. Journal of Clinical Oncology 1999;17(5):1397‐406. CENTRAL

Creagan 1984 {published data only}

Creagan ET, Green SJ, Ahmann DL, Ingle JN, Edmonson JH, Marschke RF‐J. A phase III clinical trial comparing the combination cyclophosphamide, adriamycin, cisplatin with cyclophosphamide, 5‐ fluorouracil, prednisone in patients with advanced breast cancer. Journal of Clinical Oncology 1984;2(11):1260‐5. CENTRAL

Delaloge 2004 {published data only}

Delaloge S, Tubiana‐Hulin M, Wardley A, Del Mastro L, Santoro A, Zambelli A, et al. A multistep randomized phase II/III trial comparing Oxaliplatin (OXA)+5 fluorouracil (FU) to vinorelbine (VIN) + FU (FUN) after taxane (T)/anthracycline (A) failure in advanced/metastatic breast cancer (MBC) patients (pts): Final results. Journal of Clinical Oncology. 2004; Vol. 22 Supplement:14S. CENTRAL

Eisen 1998 {published data only}

Eisen T, Smith IE, De Boer R, Ellis PA. A randomised phase II trial of infusional 5‐FU and epirubicin with cyclophosphamide versus cisplatin in advanced breast cancer. Breast Cancer Research & Treatment 1997;46(1):94. CENTRAL
Eisen T, Smith IE, Johnston S, Ellis PA, Prendiville J, Seymour MT, et al. Randomized phase II trial of infusional fluorouracil, epirubicin, and cyclophosphamide versus infusional fluorouracil, epirubicin, and cisplatin in patients with advanced breast cancer. Journal of Clinical Oncology 1998;16(4):1350‐7. CENTRAL

Fan 2012 {published data only}

Fan Y, Xu BH, Yuan P, Ma F, Wang JY, Ding XY, et al. Docetaxel–cisplatin might be superior to docetaxel–capecitabine in the first‐line treatment of metastatic triple‐negative breast cancer. Annals of Oncology 2013;24(5):1219‐25. CENTRAL

Fountzilas 2004 {published data only}

Fountzilas G, Kalofonos HP, Bafaloukos D, Papakostas P, Kosmidis P, Gogas H, et al. Paclitaxel and epirubicin versus paclitaxel and carboplatin as first‐line chemotherapy in patients with advanced breast cancer: A phase III study conducted by the Hellenic Cooperative Oncology Group. Annals of Oncology 2002;13(Suppl 5):46‐69. CENTRAL
Fountzilas G, Kalofonos HP, Dafni U, Papadimitriou C, Bafaloukos D, Papakostas P, et al. Paclitaxel and epirubicin versus paclitaxel and carboplatin as first‐line chemotherapy in patients with advanced breast cancer: a phase III study conducted by the Hellenic Cooperative Oncology Group. Annals of Oncology 2004;15(10):1517‐26. CENTRAL

Fountzilas 2009 A {published data only}

Fountzilas G, Dafni U, Dimopoulos MA, Koutras A, Skarlos D, Papakostas P, et al. A randomized phase III study comparing three anthracycline‐free taxane‐based regimens, as first‐line chemotherapy, in metastatic breast cancer. A Hellenic Cooperative Oncology Group Study. Breast Cancer Research and Treatment 2009;11:87‐99. CENTRAL

Fountzilas 2009 B {published data only}

Fountzilas G, Dafni U, Dimopoulos MA, Koutras A, Skarlos D, Papakostas P, et al. A randomized phase III study comparing three anthracycline‐free taxane‐based regimens, as first‐line chemotherapy, in metastatic breast cancer. A Hellenic Cooperative Oncology Group Study. Breast Cancer Research and Treatment 2009;11:87‐99. CENTRAL

Hu 2015 {published data only}

Hu XC, Zhang J, Xu BH, Cai L, Ragaz J, Wang ZH, et al. Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first‐line therapy for metastatic triple‐negative breast cancer (CBCSG006): a randomised, open‐label, multicentre, phase 3 trial. Lancet Oncology 2015;16(4):436‐46. CENTRAL
NCT01287624. Gemcitabine plus cisplatin versus gemcitabine plus paclitaxel in triple negative breast cancer (TNBC). clinicaltrials.gov/ct2/show/NCT01287624 (accessed 13 April 2016). CENTRAL

Icli 2005 {published data only}

Icli F, Akbulut H, Uner A, Bulent Y, Altinbas M, Baltali E, et al. Paclitaxel (T) vs cisplatin + VP‐16 (EP) in metastatic breast cancer patients treated with anthracyclines: A phase III randomized study, Turkish Oncology Group. Annals of Oncology2002; Vol. 13:47. CENTRAL
Icli F, Akbulut H, Uner A, Yalcin B, Baltali E, Altinbas M, et al. Cisplatin plus oral etoposide (EoP) combination is more effective than paclitaxel in patients with advanced breast cancer pretreated with anthracyclines: a randomised phase III trial of Turkish Oncology Group. British Journal of Cancer 2005;92:639‐44. CENTRAL

Kolaric 1985 {published data only}

Kolaric K, Vukas D, Roth A, Potrebica V, Cervek J, Cerar O. Cyclophosphamide, adriamycin and platinum (CAP) combination chemotherapy, a new effective approach in the treatment of disseminated breast cancer. Preliminary report. Tumori 1985;71:159‐65. CENTRAL

Kolaric 1989 {published data only}

Kolaric K, Vukas D, Potrebica V. Combination of cyclophosphamide, adriamycin and platinum (CAP) versus 5‐fluorouracil, adriamycin and cyclophosphamide (FAC) as primary treatment in metastatic breast cancer: results of a prospective randomized study. Tumori 1989;75:132‐6. CENTRAL

Nielsen 2000 {published data only}

Nielsen D, Dombernowsky P, Larsen SK, Hansen OP, Skovsgaard T. Epirubicin or epirubicin and cisplatin as first‐line therapy in advanced breast cancer. A phase III study. Cancer Chemotherapy & Pharmacology 2000;46(6):459‐66. CENTRAL
Ryberg M, Nielsen D, Skovsgaard T, Hansen J, Jensen BV, Dombernowsky P. Epirubicin cardiotoxicity: An analysis of 469 patients with metastatic breast cancer. Journal of Clinical Oncology 1998;16(11):3502‐8. CENTRAL

Robert 2006 {published data only}

Robert N, Leyland‐Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER‐2‐overexpressing metastatic breast cancer. Journal of Clinical Oncology 2006;24(18):2786‐92. CENTRAL

Stemmler 2011 A {published data only}

NCT00480597. Gemcitabine/vinorelbine versus gemcitabine/cisplatin versus gemcitabine/capecitabine in metastatic breast cancer. clinicaltrials.gov/ct2/show/NCT00480597 (accessed 13 April 2016). CENTRAL
Stemmler HJ, DiGioia D, Freier W, Tessen HW, Gitsch G, Jonat W, et al. Randomised phase II trial of gemcitabine plus vinorelbine vs gemcitabine plus cisplatin vs gemcitabine plus capecitabine in patients with pretreated metastatic breast cancer. British Journal of Cancer 2011;104(7):1071‐8. CENTRAL

Stemmler 2011 B {published data only}

NCT00480597. Gemcitabine/vinorelbine versus gemcitabine/cisplatin versus gemcitabine/capecitabine in metastatic breast cancer. clinicaltrials.gov/ct2/show/NCT00480597 (accessed 13 April 2016). CENTRAL
Stemmler HJ, DiGioia D, Freier W, Tessen HW, Gitsch G, Jonat W, et al. Randomised phase II trial of gemcitabine plus vinorelbine vs gemcitabine plus cisplatin vs gemcitabine plus capecitabine in patients with pretreated metastatic breast cancer. British Journal of Cancer 2011;104(7):1071‐8. CENTRAL

Tutt 2014 {published data only}

NCT00532727. Triple negative breast cancer trial (TNT). clinicaltrials.gov/show/NCT00532727 (accessed 13 April 2016). CENTRAL
Tutt A, Ellis P, Kilburn L, Gilett C, Pinder S, Abraham J, et al. The TNT trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). Cancer Research 2015;75(9 Supplement):S3‐01. CENTRAL
Tutt A, Ellis P, Kilburn LS. The TNT trial: A randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced trip‐negative or BRCA1/2 breast cancer. Thirty‐Seventh Annual CTRC‐AACR San Antonio Breast Cancer Symposium; December 9‐13, 2014; San Antonio, TX. 2014; Vol. 75:S3‐1. CENTRAL

Valero 2011 {published data only}

Forbes JF, Pienkowski T, Valero V, Eiermann W, Von Minckwitz G, Martin M, et al. BCIRG 007: Randomized phase III trial of trastuzumab plus docetaxel with or without carboplatin first‐line in HER2 positive metastatic breast cancer (MBC). Journal of Clinical Oncology 2006;24(Supplement):18S. CENTRAL
NCT00047255. Docetaxel and trastuzumab with or without carboplatin in treating women with HER2‐positive breast cancer. clinicaltrials.gov/ct2/show/NCT00047255 (accessed 13 April 2016). CENTRAL
Valero V, Forbes J, Pegram MD, Pienkowski T, Eiermann W, Von Minckwitz G, et al. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first‐line chemotherapy for patients with HER2‐gene‐amplified metastatic breast cancer (BCIRG 007 Study): Two highly active therapeutic regimens. Journal of Clinical Oncology 2011;29(2):149‐56. CENTRAL

Xu 2011 A {published data only}

NCT00191854. Gemcitabine combinations in metastatic breast cancer (MBC), 1st Line. clinicaltrials.gov/ct2/show/results/NCT00191854 (accessed 13 April 2016). CENTRAL
Xu B, Jiang Z, Kim SB, Yu S, Feng J, Malzyner A, et al. Biweekly gemcitabine‐paclitaxel, gemcitabine‐carboplatin, or gemcitabine‐cisplatin as first‐line treatment in metastatic breast cancer after anthracycline failure: a phase II randomized selection trial. Breast Cancer 2011;18(3):203‐12. CENTRAL

Xu 2011 B {published data only}

NCT00191854. Gemcitabine combinations in metastatic breast cancer (MBC), 1st Line. clinicaltrials.gov/ct2/show/results/NCT00191854 (accessed 13 April 2016). CENTRAL
Xu B, Jiang Z, Kim SB, Yu S, Feng J, Malzyner A, et al. Biweekly gemcitabine‐paclitaxel, gemcitabine‐carboplatin, or gemcitabine‐cisplatin as first‐line treatment in metastatic breast cancer after anthracycline failure: a phase II randomized selection trial. Breast Cancer 2011;18(3):203‐12. CENTRAL

References to studies excluded from this review

Cartei 1996 {published data only}

Cartei, MPP. Epirubicin versus platin and etoposide: A cross over study in breast cancer. Tumori. 1996; Vol. 82, issue Supplement:125. CENTRAL

Crump 2008 {published data only}

Crump M, Gluck S, Tu D, Stewart D, Levine M, Kirkbride P, et al. Randomized trial of high‐dose chemotherapy with autologous peripheral‐blood stem‐cell support compared with standard‐dose chemotherapy in women with metastatic breast cancer: NCIC MA.16. Journal of Clinical Oncology 2008;26(1):37‐43. CENTRAL

Hogdall 1993 {published data only}

Hogdall CK, Soletormos G, Nielsen D, Norgaard PB, Dombernowsky P, Clemmensen I. Prognostic value of serum tetranectin in patients with metastatic breast cancer. Acta Oncologica 1993;32:631‐6. CENTRAL

Perez 2001 {published data only}

NCT00025688. A randomized, phase II trial of weekly taxol (paclitaxel) versus weekly taxol plus paraplatin (carboplatin) as first‐line chemotherapy in patients age 65 years or older with metastatic breast cancer. clinicaltrials.gov/ct2/show/study/NCT00025688 (accessed April 12 2016). CENTRAL

Perez 2002 {published data only}

Perez EA. Phase III randomized study of Paclitaxel, Carboplatin, and Trastuzumab (Herceptin) as first‐line chemotherapy in women with overexpressed HER‐2, metastatic breast cancer. www.cancer.gov/clinical trials 2002. CENTRAL

Somlo 2015 {published and unpublished data}

Somlo G, Frankel PH, Luu TH, Ma CX, Arun B, Garcia AA, et al. Efficacy of the PARP inhibitor (PI) ABT‐888 (veliparib [vel]) either with carboplatin (carb) or as a single agent followed by post‐progression therapy in combination with carb in patients (pts) with BRCA1‐or BRCA2‐(BRCA)‐associated metastatic breast cancer (MBC). Journal of Clinical Oncology 2015;33(15 Suppl):520. CENTRAL

Wang 2008 {published data only}

Wang Y, Wu Q, Su F, Zhou L, Ye Z, Yang J, et al. Phase II study of docetaxel plus epirubicin versus docetaxel plus cisplatin as first‐line chemotherapy for metastatic breast cancer. Chinese Journal of Oncology 2008;30(7):541‐4. CENTRAL

References to ongoing studies

BRCA {unpublished data only}

Triple negative trial: a randomised phase III trial of carboplatin compared to docetaxel for patients with metastatic or recurrent locally advanced ER‐, PR‐ and HER2‐breast cancer. clinicaltrials.gov/show/NCT00532727 (accessed 12 April 2016). CENTRAL

NCT00201760 {unpublished data only}

NCT00201760. A randomized phase II study of gemcitabine/ trastuzumab and gemcitabine/ cisplatin/ trastuzumab in patients with metastatic breast cancer. clinicaltrials.gov/show/NCT00201760 (accessed 12 April 2016). CENTRAL

NCT00717951 {unpublished data only}

NCT00717951. A randomised, multi‐center study of docetaxol plus capecitabine or cisplatin in anthracycline‐pretreated patients with advanced breast cancer. clinicaltrials.gov/show/NCT00717951 (accessed April 12 2016). CENTRAL

NCT01506609 {unpublished data only}

NCT01506609. A randomized, phase 2 study of the efficacy and tolerability of veliparib in combination with temozolomide or veliparib in combination with carboplatin and paclitaxel versus placebo plus carboplatin and paclitaxel in subjects with BRCA1 or BRCA2 mutation and metastatic breast cancer. clinicaltrials.gov/show/NCT01506609 (accessed 12 April 2016). CENTRAL

NCT01898117 {unpublished data only}

NCT01898117. Triple‐B study;carboplatin‐cyclophosphamide versus paclitaxel with or without bevacizumab as first‐line treatment in advanced triple negative breast cancer (Triple‐B). clinicaltrials.gov/show/NCT01898117 (accessed 12 April 2016). CENTRAL

NCT02207335 {unpublished data only}

NCT02207335. A multicenter randomized phase III clinical trial of gemcitabine in combination with capecitabine versus gemcitabine plus carboplatin as first‐line treatment in triple‐negative recurrent or metastatic breast cancer. clinicaltrials.gov/ct2/show/NCT02207335 (accessed 12 April 2016). CENTRAL

NCT02207361 {unpublished data only}

NCT02207361. A randomized prospective clinical trial of paclitaxel in combination with carboplatin versus paclitaxel plus epirubicin as first‐line treatment in metastatic breast cancer. clinicaltrials.gov/ct2/show/NCT02207361 (accessed 12 April 2016). CENTRAL

TnAcity {unpublished data only}

Yardley DA, Brufsky A, Conte P, Cortes J, Glück S, Nabholtz J‐MA, et al. TnAcity: A phase 2/3 randomized study of weekly nab‐paclitaxel in combination with either gemcitabine or carboplatin vs gemcitabine/carboplatin as first‐line treatment for triple‐negative metastatic breast cancer. Cancer Research 2013;73(24 Supplement):OT3. CENTRAL

Beslija 2009

Beslija S, Bonneterre J, Burstein HJ, Cocquyt V, Gnant M, Heinemann V, et al. Third consensus on medical treatment of metastatic breast cancer. Annals of Oncology 2009;20(11):1771‐85.

Burzykowski 2008

Burzykowski T, Buyse M, Piccart‐Gebhart MJ, Sledge G, Carmichael J, Lück HJ, et al. Evaluation of tumor response, disease control, progression‐free survival, and time to progression as potential surrogate end points in metastatic breast cancer. Journal of Clinical Oncology 2008;26(12):1987‐92.

Carrick 2004

Carrick S, Ghersi D, Wilcken N, Simes J. Platinum containing regimens for metastatic breast cancer. Cochrane Database of Systematic Reviews 2004, Issue 3. [DOI: 10.1002/14651858.CD003374.pub3]

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Amadori 2013

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.

Berruti 2002 A

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.

Berruti 2002 B

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.

Bhattacharyya 2009

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.

Carey 2012

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.

Cocconi 1991

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.

Cocconi 1996

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.

Cocconi 1999

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.

Costanza 1999

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.

Creagan 1984

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.

Delaloge 2004

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.

Eisen 1998

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.

Fan 2012

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.

Fountzilas 2004

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.

Fountzilas 2009 A

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.

Fountzilas 2009 B

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.

Hu 2015

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.

Icli 2005

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.

Kolaric 1985

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.

Kolaric 1989

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.

Nielsen 2000

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.

Robert 2006

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.

Stemmler 2011 A

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.

Stemmler 2011 B

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.

Tutt 2014

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.

Valero 2011

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.

Xu 2011 A

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.

Xu 2011 B

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.

5‐FU:5‐fluorouracil
AL: doxorubicin, leucovorin, 5‐fluorouracil, allopurinol
AUC: Area under the curve
bid: Twice a day
C: Carboplatin
CAF: Cyclophosphamide, doxorubicin, fluorouracil
CAP: Cyclophosphamide, adriamycin, Cis‐dichlordiammine platinum
CDDP: Cis‐dichlordiammine platinum
Ce: Cetuximab
CFP: Cyclophosphamide, 5‐Fluorouracil, prednisone
CI: Confidence interval
CIS: Cisplatin
CMF: Cyclophosphamide, methotrexate, fluorouracil
CMFVP: Cyclophosphamide, methotrexate, 5‐fluorouracil, vincristine, prednisolone
CT: X‐ray image made using computerized axial tomography
D: Docetaxel
EcisF: 5‐Fluorouracil, epirubicin, cisplatin
ECOG: Eastern Cooperative Oncology Group
EcycloF: 5‐Fluorouracil, epirubicin, cyclophosphamide
EGFR: Epidermal growth factor receptor
EORTC: European Organisation for Research and Treatment of Cancer
EPI: Epirubicin
EQ‐5D: EuroQol five dimensions questionnaire
EQ VAS: EuroQol visual analogue scale
ER: oestrogen receptor
EUROQOL: The EuroQOL research Group
FAC: 5‐Fluorouracil, adriamycin, cyclophosphamide
FU: 5‐fluorouracil
GemCap: Gemcitabine, capecitabine
GemCarb: Gemcitabine, carboplatin
GemCis: Gemcitabine, cisplatin
GemPac: Gemcitabine, paclitaxel
GemVin: Gemcitabine, vinorelbine
GDoc: Gemcitabine, docetaxel
HeCOG: Hellenic Cooperative Oncology Group
HER2: Human epidermal growth factor receptor 2
HR: Hazard ratio
IHC: Immunohistochemistry
ITT: Intention‐to‐treat
IV: Intravenous
LND: Lonidamine
Max: Maximum
Min: Minimum
MPEMI: Methotrexate + rescue, cisplatin, etoposide, mitomycin
MPEPIV: Methotrexate+ leucovorin rescue; cisplatin, epirubicin, vincristine
MRI: Magnetic resonance imaging
mTNBC: metastatic triple‐negative breast cancer
OS: overall survival
OXA: Oxaliplatin
P: Cisplatin
p.: Page
PCb: Paclitaxel, carboplatin
PE: Cisplatin, etoposide
PFS: progression‐free survival
po: by mouth
PR: Progesterone receptor
Pw: Paclitaxel
q: every
QLQ‐BR23: 23 item quality of life questionnaire
QLQ‐C30: 30 item quality of life questionnaire
QoL: quality of life
RECIST: Response Evaluation Criteria In Solid Tumors
T: Paclitaxel
TCH: Trastuzumab 2 mg/kg + docetaxel 75 mg/m2 + carboplatin
TH: Trastuzumab, docetaxel
TP: Docetaxel, cisplatin
TPa: Trastuzumab, paclitaxel
TPC: Trastuzumab, carboplatin
TTF: Time to treatment failure
TTP: Time to progression
TTPD: Time to progressive disease
TTTF: Time to treatment failure
TX: Docetaxel, capecitabine
VIN: Vinorelbine
VP‐16:Oral etoposide
WBC: White blood cell

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Cartei 1996

Conference abstract only with insufficient data. Attempts to contact authors were unsuccessful. This study was listed as an 'excluded study' in the original version of this review.

Crump 2008

Included 38% participants with locoregional disease. Attempts to contact authors were unsuccessful.

Hogdall 1993

Trial reported only the serum tetranectin levels in relation to survival and response.This study was listed as an 'excluded study' in the original version of this review.

Perez 2001

Trial was registered but never started. Hence, this study has been moved from the 'ongoing studies' section in the original version of this review to the 'excluded studies' of this review update.

Perez 2002

Trial was registered but never started. Hence, this study has been moved from the 'ongoing studies' section in the original version of this review to the 'excluded studies' of this review update.

Somlo 2015

Participants not randomised.

Wang 2008

> 20% participants with locally advanced disease only. Data were not reported separately.

Characteristics of ongoing studies [ordered by study ID]

BRCA

Trial name or title

Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer (BRCA Trial).

Methods

A randomised phase II pilot trial.

Participants

Participants with metastatic genetic breast cancer.

Interventions

Carboplatin vs docetaxel.

Outcomes

Response.

Time to progression.

Toxicity.

Starting date

January 2005.

Estimated primary completion date: 2009.

Contact information

Andrew Tutt, King's College London, email: [email protected].

Notes

Emails sent to the principal investigator in 2015/16 requesting a progress report on the study were not answered.

NCT00201760

Trial name or title

Gemcitabine/Trastuzumab and Gemcitabine/Cisplatin/Trastuzumab in Patients With Metastatic Breast Cancer.

Methods

Randomised phase II study.

Participants

Participants with metastatic breast cancer.

Interventions

Gemcitabine/trastuzumab vs gemcitabine/cisplatin/trastuzumab.

Outcomes

Disease‐free progression.

Response.

Side effects.

Starting date

February 2005.

Estimated study completion date: December 2012.

Contact information

Kari Kendra, MD, email: [email protected].

Notes

Emails sent to the principal investigator in 2015 requesting a progress report on the study were not answered.

Sponsor: Eli Lilly and Company.

NCT00717951

Trial name or title

A Randomised,Multi‐Center Study of Docetaxol Plus Capecitabine or Cisplatin in Anthracycline‐Pretreated Patients With Advanced Breast Cancer.

Methods

Randomised, phase 2, multicentre study.

Participants

Participants with advanced breast cancer.

Interventions

Docetaxel + capecitabine vs docetaxel + cisplatin.

Outcomes

Response.

Time to progression.

Time to treatment failure.

2 year progression‐free survival.

Safety.

QoL.

Starting date

May 2008.

Estimated study completion date: May 2010.

Contact information

Jiang Zefei, Ph.D, emails: [email protected]; [email protected].

Notes

Emails sent to the principal investigator in 2015 requesting a progress report on the study were not answered.

NCT01506609

Trial name or title

The Study Evaluating Efficacy And Tolerability Of Veliparib in Combination With Temozolomide or In Combination With Carboplatin and Paclitaxel Versus Placebo in Subjects With BRCA1 and BRCA2 Mutation and Metastatic Breast Cancer.

Methods

Randomised, phase 2 study.

Participants

Women with BRCA1 or BRCA2 mutation and metastatic breast cancer.

Interventions

Veliparib with temozolomide vs veliparib with carboplatin and paclitaxel vs placebo with carboplatin and paclitaxel.

Outcomes

Progression‐free survival.
Overall survival.
Clinical benefit.
Objective response.
Chemotherapy‐induced peripheral neuropathy.

Starting date

Study start date: January 2012.

Estimated study completion date: May 2016.

Contact information

Stacie P. Shepherd, MD, AbbVie.

Notes

Sponsors and Collaborators: AbbVie (prior sponsor, Abbott).

NCT01898117

Trial name or title

Biomarker Discovery Randomized Phase IIb Trial With Carboplatin‐cyclophosphamide Versus Paclitaxel With or Without Bevacizumab as First‐line Treatment in Advanced Triple Negative Breast Cancer.

Methods

Randomised phase IIb trial.

Participants

Participants with advanced triple‐negative breast cancer.

Interventions

Carboplatin‐cyclophosphamide vs paclitaxel with or without bevacizumab.

Outcomes

Progression‐free survival.

Overall survival.

Toxicity.

Starting date

July 2013.

Estimated primary completion date: December 2019.

Contact information

Sabine C Linn, Prof, MD, email; [email protected].

Notes

NCT02207335

Trial name or title

Trial of Gemcitabine_Capecitabine Versus Gemcitabine_Carboplatin in Breast Cancer.

Methods

A multicentre randomised phase Ⅲ clinical trial.

Participants

Participants with triple‐negative recurrent or metastatic breast cancer.

Interventions

Gemcitabine + capecitabine vs gemcitabine + carboplatin.

Outcomes

Response (RECIST 1.1).

Starting date

December 2013.

Estimated study completion date: December 2016.

Contact information

Zhongsheng Tong, Master, email: [email protected].

Notes

NCT02207361

Trial name or title

Paclitaxel in Combination With Carboplatin Versus Paclitaxel Plus Epirubicin in Metastatic Breast Cancer.

Methods

Randomised prospective clinical trial.

Participants

Participants with metastatic breast cancer.

Interventions

Paclitaxel + carboplatin vs paclitaxel + epirubicin.

Outcomes

Response (RECIST 1.1).

Starting date

December 2013.

Estimated study completion date: December 2016.

Contact information

Zhongsheng Tong, Master, email: [email protected].

Notes

TnAcity

Trial name or title

TnAcity: A phase 2/3 randomised study of weekly nab‐paclitaxel in combination with either gemcitabine or carboplatin vs gemcitabine/carboplatin as first‐line treatment for triple‐negative metastatic breast cancer.

Methods

Phase 2/3 randomised study.

Participants

Women with ER‐, PR‐, and HER2 negative (triple‐negative) metastatic breast cancer.

Interventions

Carboplatin plus gemcitabine vs nab‐paclitaxel plus carboplatin OR gemcitabine.

Outcomes

Progression‐free survival.

Overall survival.

Response.

Duration of response.

Safety.

Starting date

Date of registration: 12/06/2013.

Contact information

Notes

Sponsored by Abraxis BioScience, LLC, a wholly‐owned subsidiary of Celgene Corporation.

BRCA: Breast cancer susceptibility gene
ER: Oestrogen receptor
HER2: Human epidermal growth factor receptor 2
PR: Progesterone receptor
QoL: Quality of life
RECIST:Response Evaluation Criteria In Solid Tumors

Data and analyses

Open in table viewer
Comparison 1. Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

19

2922

HR (95% CI)

0.98 [0.89, 1.07]

Analysis 1.1

Comparison 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), Outcome 1 Overall survival.

Comparison 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), Outcome 1 Overall survival.

1.1 Treatment‐comparisons assessing patients with mTNBC

3

391

HR (95% CI)

0.75 [0.57, 1.00]

1.2 Treatment‐comparisons assessing patients unselected for mTNBC

16

2531

HR (95% CI)

1.01 [0.92, 1.12]

2 Progression‐free survival/time to progression Show forest plot

16

2136

HR (95% CI)

0.85 [0.78, 0.93]

Analysis 1.2

Comparison 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), Outcome 2 Progression‐free survival/time to progression.

Comparison 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), Outcome 2 Progression‐free survival/time to progression.

2.1 Treatment‐comparisons assessing patients with mTNBC

3

391

HR (95% CI)

0.59 [0.49, 0.72]

2.2 Treatment‐comparisons assessing patients unselected for mTNBC

13

1745

HR (95% CI)

0.92 [0.84, 1.01]

3 Objective tumour response rate (assessable participants) Show forest plot

28

4130

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.08, 1.22]

Analysis 1.3

Comparison 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), Outcome 3 Objective tumour response rate (assessable participants).

Comparison 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), Outcome 3 Objective tumour response rate (assessable participants).

3.1 Treatment‐comparisons assessing patients with mTNBC

5

878

Risk Ratio (M‐H, Fixed, 95% CI)

1.33 [1.13, 1.56]

3.2 Treatment‐comparisons assessing patients unselected for mTNBC

23

3252

Risk Ratio (M‐H, Fixed, 95% CI)

1.11 [1.04, 1.19]

Open in table viewer
Comparison 2. Platinum vs non‐platinum regimens (subgroup analysis 2: by type of regimen comparison)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

19

2922

HR (95% CI)

0.98 [0.89, 1.07]

Analysis 2.1

Comparison 2 Platinum vs non‐platinum regimens (subgroup analysis 2: by type of regimen comparison), Outcome 1 Overall survival.

Comparison 2 Platinum vs non‐platinum regimens (subgroup analysis 2: by type of regimen comparison), Outcome 1 Overall survival.

1.1 Regimen A + platinum agent vs regimen A

6

1141

HR (95% CI)

1.08 [0.93, 1.26]

1.2 Regimen A + platinum agent vs regimen B

13

1781

HR (95% CI)

0.92 [0.81, 1.03]

2 Progression‐free survival / time to progression Show forest plot

16

2136

HR (95% CI)

0.85 [0.78, 0.93]

Analysis 2.2

Comparison 2 Platinum vs non‐platinum regimens (subgroup analysis 2: by type of regimen comparison), Outcome 2 Progression‐free survival / time to progression.

Comparison 2 Platinum vs non‐platinum regimens (subgroup analysis 2: by type of regimen comparison), Outcome 2 Progression‐free survival / time to progression.

2.1 Regimen A+platinum agent vs regimen A

6

1087

HR (95% CI)

0.88 [0.78, 1.00]

2.2 Regimen A+platinum agent vs regimen B

10

1049

HR (95% CI)

0.83 [0.74, 0.93]

3 Objective tumour response rate (assessable participants) Show forest plot

28

4130

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.08, 1.22]

Analysis 2.3

Comparison 2 Platinum vs non‐platinum regimens (subgroup analysis 2: by type of regimen comparison), Outcome 3 Objective tumour response rate (assessable participants).

Comparison 2 Platinum vs non‐platinum regimens (subgroup analysis 2: by type of regimen comparison), Outcome 3 Objective tumour response rate (assessable participants).

3.1 Regimen A + platinum agent vs regimen A

9

1519

Risk Ratio (M‐H, Fixed, 95% CI)

1.10 [1.01, 1.21]

3.2 Regimen A + platinum agent vs regimen B

18

2235

Risk Ratio (M‐H, Fixed, 95% CI)

1.22 [1.12, 1.33]

3.3 Single agent platinum vs regimen C

1

376

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.66, 1.17]

Open in table viewer
Comparison 3. Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

19

2922

HR (95% CI)

0.98 [0.89, 1.07]

Analysis 3.1

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 1 Overall survival.

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 1 Overall survival.

1.1 Cisplatin in platinum arm

11

1326

HR (95% CI)

0.91 [0.80, 1.05]

1.2 Carboplatin in platinum arm

8

1596

HR (95% CI)

1.04 [0.91, 1.18]

2 Progression‐free survival/time to progression Show forest plot

16

2136

HR (95% CI)

0.85 [0.78, 0.93]

Analysis 3.2

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 2 Progression‐free survival/time to progression.

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 2 Progression‐free survival/time to progression.

2.1 Cisplatin in platinum arm

11

1369

HR (95% CI)

0.85 [0.76, 0.94]

2.2 Carboplatin in platinum arm

5

767

HR (95% CI)

0.86 [0.75, 0.99]

3 Objective tumour response rate (assessable participants) Show forest plot

28

4130

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.08, 1.22]

Analysis 3.3

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 3 Objective tumour response rate (assessable participants).

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 3 Objective tumour response rate (assessable participants).

3.1 Cisplatin in platinum arm

17

2050

Risk Ratio (M‐H, Fixed, 95% CI)

1.35 [1.24, 1.46]

3.2 Carboplatin in platinum arm

10

1943

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.86, 1.04]

3.3 Oxaliplatin in platinum arm

1

137

Risk Ratio (M‐H, Fixed, 95% CI)

0.85 [0.48, 1.52]

4 Treatment‐related death (safety population) Show forest plot

15

2377

Risk Ratio (M‐H, Fixed, 95% CI)

1.42 [0.73, 2.76]

Analysis 3.4

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 4 Treatment‐related death (safety population).

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 4 Treatment‐related death (safety population).

4.1 Cisplatin in platinum arm

8

1185

Risk Ratio (M‐H, Fixed, 95% CI)

1.39 [0.59, 3.25]

4.2 Carboplatin in platinum arm

6

1055

Risk Ratio (M‐H, Fixed, 95% CI)

1.86 [0.57, 6.05]

4.3 Oxaliplatin in platinum arm

1

137

Risk Ratio (M‐H, Fixed, 95% CI)

0.34 [0.01, 8.16]

5 Nausea/vomiting (safety population) Show forest plot

21

3172

Risk Ratio (M‐H, Fixed, 95% CI)

2.07 [1.69, 2.54]

Analysis 3.5

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 5 Nausea/vomiting (safety population).

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 5 Nausea/vomiting (safety population).

5.1 Cisplatin in platinum arm

14

1731

Risk Ratio (M‐H, Fixed, 95% CI)

2.65 [2.10, 3.34]

5.2 Carboplatin in platinum arm

7

1441

Risk Ratio (M‐H, Fixed, 95% CI)

0.77 [0.47, 1.26]

6 Nephrotoxicity (safety population) Show forest plot

5

632

Risk Ratio (M‐H, Fixed, 95% CI)

3.06 [0.86, 10.84]

Analysis 3.6

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 6 Nephrotoxicity (safety population).

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 6 Nephrotoxicity (safety population).

6.1 Cisplatin in platinum arm

4

561

Risk Ratio (M‐H, Fixed, 95% CI)

3.46 [0.86, 13.97]

6.2 Carboplatin in platinum arm

1

71

Risk Ratio (M‐H, Fixed, 95% CI)

1.56 [0.07, 36.97]

7 Anaemia (safety population) Show forest plot

20

3085

Risk Ratio (M‐H, Fixed, 95% CI)

2.61 [1.90, 3.58]

Analysis 3.7

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 7 Anaemia (safety population).

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 7 Anaemia (safety population).

7.1 Cisplatin in platinum arm

13

1644

Risk Ratio (M‐H, Fixed, 95% CI)

3.72 [2.36, 5.88]

7.2 Carboplatin in platinum arm

7

1441

Risk Ratio (M‐H, Fixed, 95% CI)

1.72 [1.10, 2.70]

8 Hair loss (safety population) Show forest plot

12

1452

Risk Ratio (M‐H, Fixed, 95% CI)

1.41 [1.26, 1.58]

Analysis 3.8

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 8 Hair loss (safety population).

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 8 Hair loss (safety population).

8.1 Cisplatin in platinum arm

9

983

Risk Ratio (M‐H, Fixed, 95% CI)

1.33 [1.15, 1.54]

8.2 Carboplatin in platinum arm

3

469

Risk Ratio (M‐H, Fixed, 95% CI)

1.53 [1.28, 1.84]

9 Leukopenia (safety population) Show forest plot

22

3176

Risk Ratio (M‐H, Fixed, 95% CI)

1.38 [1.21, 1.57]

Analysis 3.9

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 9 Leukopenia (safety population).

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 9 Leukopenia (safety population).

9.1 Cisplatin in platinum arm

15

1866

Risk Ratio (M‐H, Fixed, 95% CI)

1.49 [1.23, 1.81]

9.2 Carboplatin in platinum arm

7

1310

Risk Ratio (M‐H, Fixed, 95% CI)

1.27 [1.07, 1.50]

Open in table viewer
Comparison 4. Platinum vs non‐platinum regimens (subgroup analysis 4: by first‐line therapy)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

19

2922

HR (95% CI)

0.98 [0.89, 1.07]

Analysis 4.1

Comparison 4 Platinum vs non‐platinum regimens (subgroup analysis 4: by first‐line therapy), Outcome 1 Overall survival.

Comparison 4 Platinum vs non‐platinum regimens (subgroup analysis 4: by first‐line therapy), Outcome 1 Overall survival.

1.1 First‐line therapy for > 80% of patients

15

2486

HR (95% CI)

1.00 [0.90, 1.11]

1.2 Second‐ or third‐line therapy for ≥20% of patients

4

436

HR (95% CI)

0.89 [0.73, 1.09]

2 Progression‐free survival/time to progression Show forest plot

16

2136

HR (95% CI)

0.85 [0.78, 0.93]

Analysis 4.2

Comparison 4 Platinum vs non‐platinum regimens (subgroup analysis 4: by first‐line therapy), Outcome 2 Progression‐free survival/time to progression.

Comparison 4 Platinum vs non‐platinum regimens (subgroup analysis 4: by first‐line therapy), Outcome 2 Progression‐free survival/time to progression.

2.1 First‐line therapy for > 80% of patients

11

1565

HR (95% CI)

0.93 [0.83, 1.03]

2.2 Second‐ or third‐line therapy for ≥20% of patients

5

571

HR (95% CI)

0.75 [0.65, 0.86]

3 Objective tumour response rate (assessable participants) Show forest plot

28

4130

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.08, 1.22]

Analysis 4.3

Comparison 4 Platinum vs non‐platinum regimens (subgroup analysis 4: by first‐line therapy), Outcome 3 Objective tumour response rate (assessable participants).

Comparison 4 Platinum vs non‐platinum regimens (subgroup analysis 4: by first‐line therapy), Outcome 3 Objective tumour response rate (assessable participants).

3.1 First‐line therapy for > 80% of patients

20

2983

Risk Ratio (M‐H, Fixed, 95% CI)

1.14 [1.06, 1.21]

3.2 Second‐ or third‐line therapy for ≥20% of patients

8

1147

Risk Ratio (M‐H, Fixed, 95% CI)

1.20 [1.02, 1.42]

Open in table viewer
Comparison 5. Platinum vs non‐platinum regimens (subgroup analysis 5 by anthracycline in regimens)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

19

2922

HR (95% CI)

0.98 [0.89, 1.07]

Analysis 5.1

Comparison 5 Platinum vs non‐platinum regimens (subgroup analysis 5 by anthracycline in regimens), Outcome 1 Overall survival.

Comparison 5 Platinum vs non‐platinum regimens (subgroup analysis 5 by anthracycline in regimens), Outcome 1 Overall survival.

1.1 No anthracycline in platinum or non‐platinum regimens

14

2213

HR (95% CI)

0.94 [0.84, 1.05]

1.2 Platinum + anthracycline vs non‐platinum + anthracycline regimens

3

518

HR (95% CI)

1.09 [0.88, 1.34]

1.3 Platinum + anthracycline vs non‐platinum + non‐anthracycline regimens

2

191

HR (95% CI)

1.12 [0.78, 1.60]

2 Progression‐free survival/time to progression Show forest plot

16

2136

HR (95% CI)

0.85 [0.78, 0.93]

Analysis 5.2

Comparison 5 Platinum vs non‐platinum regimens (subgroup analysis 5 by anthracycline in regimens), Outcome 2 Progression‐free survival/time to progression.

Comparison 5 Platinum vs non‐platinum regimens (subgroup analysis 5 by anthracycline in regimens), Outcome 2 Progression‐free survival/time to progression.

2.1 No anthracycline in platinum or non‐platinum regimens

11

1465

HR (95% CI)

0.80 [0.73, 0.88]

2.2 Platinum+anthracycline vs non‐platinum+anthracycline regimens

4

585

HR (95% CI)

1.05 [0.86, 1.27]

2.3 Platinum+anthracycline vs non‐platinum+non‐anthracycline regimens

1

86

HR (95% CI)

1.23 [0.75, 2.03]

3 Objective tumour response rate (assessable participants) Show forest plot

28

4130

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.08, 1.22]

Analysis 5.3

Comparison 5 Platinum vs non‐platinum regimens (subgroup analysis 5 by anthracycline in regimens), Outcome 3 Objective tumour response rate (assessable participants).

Comparison 5 Platinum vs non‐platinum regimens (subgroup analysis 5 by anthracycline in regimens), Outcome 3 Objective tumour response rate (assessable participants).

3.1 No anthracycline in platinum or non‐platinum regimens

18

2792

Risk Ratio (M‐H, Fixed, 95% CI)

1.10 [1.02, 1.20]

3.2 Platinum+anthracycline vs non‐platinum+anthracycline regimens

6

859

Risk Ratio (M‐H, Fixed, 95% CI)

1.09 [0.97, 1.22]

3.3 Platinum+anthracycline vs non‐platinum+non‐anthracycline regimens

4

479

Risk Ratio (M‐H, Fixed, 95% CI)

1.49 [1.28, 1.74]

Open in table viewer
Comparison 6. Platinum vs non‐platinum regimens (subgroup analysis 6: by taxane in regimens)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

19

2922

HR (95% CI)

0.98 [0.89, 1.07]

Analysis 6.1

Comparison 6 Platinum vs non‐platinum regimens (subgroup analysis 6: by taxane in regimens), Outcome 1 Overall survival.

Comparison 6 Platinum vs non‐platinum regimens (subgroup analysis 6: by taxane in regimens), Outcome 1 Overall survival.

1.1 No taxane in platinum or non‐platinum regimens

9

1092

HR (95% CI)

1.07 [0.93, 1.24]

1.2 Platinum + taxane vs non‐platinum + taxane regimens

6

1255

HR (95% CI)

0.96 [0.82, 1.11]

1.3 Platinum + non‐taxane vs non‐platinum + taxane regimens

4

575

HR (95% CI)

0.85 [0.69, 1.04]

2 Progression‐free survival / time to progression Show forest plot

16

2136

HR (95% CI)

0.85 [0.78, 0.93]

Analysis 6.2

Comparison 6 Platinum vs non‐platinum regimens (subgroup analysis 6: by taxane in regimens), Outcome 2 Progression‐free survival / time to progression.

Comparison 6 Platinum vs non‐platinum regimens (subgroup analysis 6: by taxane in regimens), Outcome 2 Progression‐free survival / time to progression.

2.1 No taxane in platinum or non‐platinum regimens

9

1049

HR (95% CI)

0.92 [0.80, 1.04]

2.2 Platinum + taxane vs non‐platinum + taxane regimens

3

512

HR (95% CI)

0.84 [0.70, 1.00]

2.3 Platinum + non‐taxane vs non‐platinum + taxane regimens

4

575

HR (95% CI)

0.79 [0.69, 0.91]

3 Objective tumour response rate (assessable participants) Show forest plot

28

4130

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.08, 1.22]

Analysis 6.3

Comparison 6 Platinum vs non‐platinum regimens (subgroup analysis 6: by taxane in regimens), Outcome 3 Objective tumour response rate (assessable participants).

Comparison 6 Platinum vs non‐platinum regimens (subgroup analysis 6: by taxane in regimens), Outcome 3 Objective tumour response rate (assessable participants).

3.1 No taxane in platinum or non‐platinum regimens

17

2054

Risk Ratio (M‐H, Fixed, 95% CI)

1.25 [1.15, 1.36]

3.2 Platinum + taxane vs non‐platinum + taxane regimens

6

1152

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.90, 1.12]

3.3 Platinum + non‐taxane vs non‐platinum + taxane regimens

5

924

Risk Ratio (M‐H, Fixed, 95% CI)

1.11 [0.94, 1.30]

Open in table viewer
Comparison 7. Platinum vs non‐platinum regimens (subgroup analysis 7: by trastuzumab in regimens)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

19

2922

HR (95% CI)

0.98 [0.89, 1.07]

Analysis 7.1

Comparison 7 Platinum vs non‐platinum regimens (subgroup analysis 7: by trastuzumab in regimens), Outcome 1 Overall survival.

Comparison 7 Platinum vs non‐platinum regimens (subgroup analysis 7: by trastuzumab in regimens), Outcome 1 Overall survival.

1.1 No trastuzumab in platinum or non‐platinum regimens

17

2463

HR (95% CI)

0.97 [0.88, 1.08]

1.2 Platinum + trastuzumab vs non‐platinum + trastuzumab regimens

2

459

HR (95% CI)

1.00 [0.79, 1.27]

2 Progression‐free survival/time to progression Show forest plot

16

2136

HR (95% CI)

0.85 [0.78, 0.93]

Analysis 7.2

Comparison 7 Platinum vs non‐platinum regimens (subgroup analysis 7: by trastuzumab in regimens), Outcome 2 Progression‐free survival/time to progression.

Comparison 7 Platinum vs non‐platinum regimens (subgroup analysis 7: by trastuzumab in regimens), Outcome 2 Progression‐free survival/time to progression.

2.1 No trastuzumab in platinum or non‐platinum regimens

14

1677

HR (95% CI)

0.84 [0.76, 0.92]

2.2 Platinum+trastuzumab vs non‐platinum+trastuzumab regimens

2

459

HR (95% CI)

0.90 [0.75, 1.08]

3 Objective tumour response rate (assessable participants) Show forest plot

28

4130

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.08, 1.22]

Analysis 7.3

Comparison 7 Platinum vs non‐platinum regimens (subgroup analysis 7: by trastuzumab in regimens), Outcome 3 Objective tumour response rate (assessable participants).

Comparison 7 Platinum vs non‐platinum regimens (subgroup analysis 7: by trastuzumab in regimens), Outcome 3 Objective tumour response rate (assessable participants).

3.1 No trastuzumab in platinum or non‐platinum regimens

26

3687

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.07, 1.23]

3.2 Platinum+trastuzumab vs non‐platinum+trastuzumab regimens

2

443

Risk Ratio (M‐H, Fixed, 95% CI)

1.14 [0.99, 1.31]

Open in table viewer
Comparison 8. Platinum vs non‐platinum regimens (sensitivity analysis 1: excluding selected treatment‐comparisons)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival (restricted to the 12 treatment‐comparisons common to OS and PFS/TTP meta‐analyses) Show forest plot

12

1571

HR (95% CI)

0.92 [0.81, 1.04]

Analysis 8.1

Comparison 8 Platinum vs non‐platinum regimens (sensitivity analysis 1: excluding selected treatment‐comparisons), Outcome 1 Overall survival (restricted to the 12 treatment‐comparisons common to OS and PFS/TTP meta‐analyses).

Comparison 8 Platinum vs non‐platinum regimens (sensitivity analysis 1: excluding selected treatment‐comparisons), Outcome 1 Overall survival (restricted to the 12 treatment‐comparisons common to OS and PFS/TTP meta‐analyses).

2 Progression‐free survival/time to progression (restricted to the 12 treatment‐comparisons common to OS and PFS/TTP meta‐analyses) Show forest plot

12

1571

HR (95% CI)

0.80 [0.73, 0.88]

Analysis 8.2

Comparison 8 Platinum vs non‐platinum regimens (sensitivity analysis 1: excluding selected treatment‐comparisons), Outcome 2 Progression‐free survival/time to progression (restricted to the 12 treatment‐comparisons common to OS and PFS/TTP meta‐analyses).

Comparison 8 Platinum vs non‐platinum regimens (sensitivity analysis 1: excluding selected treatment‐comparisons), Outcome 2 Progression‐free survival/time to progression (restricted to the 12 treatment‐comparisons common to OS and PFS/TTP meta‐analyses).

3 Objective tumour response rate (assessable participants‐ restricted to the 19 treatment‐comparisons in OS meta‐analyses) Show forest plot

19

2685

Risk Ratio (M‐H, Fixed, 95% CI)

1.13 [1.05, 1.22]

Analysis 8.3

Comparison 8 Platinum vs non‐platinum regimens (sensitivity analysis 1: excluding selected treatment‐comparisons), Outcome 3 Objective tumour response rate (assessable participants‐ restricted to the 19 treatment‐comparisons in OS meta‐analyses).

Comparison 8 Platinum vs non‐platinum regimens (sensitivity analysis 1: excluding selected treatment‐comparisons), Outcome 3 Objective tumour response rate (assessable participants‐ restricted to the 19 treatment‐comparisons in OS meta‐analyses).

Open in table viewer
Comparison 9. Platinum vs non‐platinum regimens (sensitivity analysis 2: Progression‐free survival vs. time to progression)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Progression‐free survival vs time to progression Show forest plot

16

2136

HR (95% CI)

0.85 [0.78, 0.93]

Analysis 9.1

Comparison 9 Platinum vs non‐platinum regimens (sensitivity analysis 2: Progression‐free survival vs. time to progression), Outcome 1 Progression‐free survival vs time to progression.

Comparison 9 Platinum vs non‐platinum regimens (sensitivity analysis 2: Progression‐free survival vs. time to progression), Outcome 1 Progression‐free survival vs time to progression.

1.1 Progression‐free survival

9

1324

HR (95% CI)

0.92 [0.82, 1.03]

1.2 Time to progression

7

812

HR (95% CI)

0.78 [0.69, 0.88]

Open in table viewer
Comparison 10. Platinum vs non‐platinum regimens (sensitivity analysis 3: Analyses 1 repeated but with random effects approach)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

19

Hazard Ratio (Random, 95% CI)

0.98 [0.87, 1.11]

Analysis 10.1

Comparison 10 Platinum vs non‐platinum regimens (sensitivity analysis 3: Analyses 1 repeated but with random effects approach), Outcome 1 Overall survival.

Comparison 10 Platinum vs non‐platinum regimens (sensitivity analysis 3: Analyses 1 repeated but with random effects approach), Outcome 1 Overall survival.

1.1 Treatment‐comparisons assessing patients with mTNBC

3

Hazard Ratio (Random, 95% CI)

0.73 [0.51, 1.04]

1.2 Treatment‐comparisons assessing patients unselected for mTNBC

16

Hazard Ratio (Random, 95% CI)

1.02 [0.90, 1.16]

2 Progression‐free survival/time to progression Show forest plot

16

Hazard Ratio (Random, 95% CI)

0.88 [0.76, 1.02]

Analysis 10.2

Comparison 10 Platinum vs non‐platinum regimens (sensitivity analysis 3: Analyses 1 repeated but with random effects approach), Outcome 2 Progression‐free survival/time to progression.

Comparison 10 Platinum vs non‐platinum regimens (sensitivity analysis 3: Analyses 1 repeated but with random effects approach), Outcome 2 Progression‐free survival/time to progression.

2.1 Treatment‐comparisons assessing patients with mTNBC

3

Hazard Ratio (Random, 95% CI)

0.55 [0.38, 0.78]

2.2 Treatment‐comparisons assessing patients unselected for mTNBC

13

Hazard Ratio (Random, 95% CI)

0.96 [0.85, 1.09]

3 Objective tumour response rate (assessable participants) Show forest plot

28

4130

Risk Ratio (M‐H, Random, 95% CI)

1.17 [1.05, 1.30]

Analysis 10.3

Comparison 10 Platinum vs non‐platinum regimens (sensitivity analysis 3: Analyses 1 repeated but with random effects approach), Outcome 3 Objective tumour response rate (assessable participants).

Comparison 10 Platinum vs non‐platinum regimens (sensitivity analysis 3: Analyses 1 repeated but with random effects approach), Outcome 3 Objective tumour response rate (assessable participants).

3.1 Treatment‐comparisons assessing patients with mTNBC

5

878

Risk Ratio (M‐H, Random, 95% CI)

1.60 [1.04, 2.45]

3.2 Treatment‐comparisons assessing patients unselected for mTNBC

23

3252

Risk Ratio (M‐H, Random, 95% CI)

1.13 [1.01, 1.25]

Review update 2016: study flow diagram.
Figuras y tablas -
Figure 1

Review update 2016: study flow diagram.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 2

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

Funnel plot 1: Overall survival (OS). Assessing publication bias and/or small‐study effects. Plot includes all treatment‐comparisons with extractable data for OS. The plot does not show asymmetry (Egger's test P value = 0.98)
Figuras y tablas -
Figure 3

Funnel plot 1: Overall survival (OS). Assessing publication bias and/or small‐study effects. Plot includes all treatment‐comparisons with extractable data for OS. The plot does not show asymmetry (Egger's test P value = 0.98)

Forest plot of comparison: 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), outcome: 1.1 Overall survival.
Figuras y tablas -
Figure 4

Forest plot of comparison: 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), outcome: 1.1 Overall survival.

Forest plot of comparison: 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), outcome: 1.2 Progression‐free survival/time to progression.
Figuras y tablas -
Figure 5

Forest plot of comparison: 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), outcome: 1.2 Progression‐free survival/time to progression.

Forest plot of comparison: 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), outcome: 1.3 Objective tumour response rate (assessable participants).
Figuras y tablas -
Figure 6

Forest plot of comparison: 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), outcome: 1.3 Objective tumour response rate (assessable participants).

Comparison 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), Outcome 1 Overall survival.
Figuras y tablas -
Analysis 1.1

Comparison 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), Outcome 1 Overall survival.

Comparison 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), Outcome 2 Progression‐free survival/time to progression.
Figuras y tablas -
Analysis 1.2

Comparison 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), Outcome 2 Progression‐free survival/time to progression.

Comparison 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), Outcome 3 Objective tumour response rate (assessable participants).
Figuras y tablas -
Analysis 1.3

Comparison 1 Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC), Outcome 3 Objective tumour response rate (assessable participants).

Comparison 2 Platinum vs non‐platinum regimens (subgroup analysis 2: by type of regimen comparison), Outcome 1 Overall survival.
Figuras y tablas -
Analysis 2.1

Comparison 2 Platinum vs non‐platinum regimens (subgroup analysis 2: by type of regimen comparison), Outcome 1 Overall survival.

Comparison 2 Platinum vs non‐platinum regimens (subgroup analysis 2: by type of regimen comparison), Outcome 2 Progression‐free survival / time to progression.
Figuras y tablas -
Analysis 2.2

Comparison 2 Platinum vs non‐platinum regimens (subgroup analysis 2: by type of regimen comparison), Outcome 2 Progression‐free survival / time to progression.

Comparison 2 Platinum vs non‐platinum regimens (subgroup analysis 2: by type of regimen comparison), Outcome 3 Objective tumour response rate (assessable participants).
Figuras y tablas -
Analysis 2.3

Comparison 2 Platinum vs non‐platinum regimens (subgroup analysis 2: by type of regimen comparison), Outcome 3 Objective tumour response rate (assessable participants).

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 1 Overall survival.
Figuras y tablas -
Analysis 3.1

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 1 Overall survival.

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 2 Progression‐free survival/time to progression.
Figuras y tablas -
Analysis 3.2

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 2 Progression‐free survival/time to progression.

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 3 Objective tumour response rate (assessable participants).
Figuras y tablas -
Analysis 3.3

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 3 Objective tumour response rate (assessable participants).

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 4 Treatment‐related death (safety population).
Figuras y tablas -
Analysis 3.4

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 4 Treatment‐related death (safety population).

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 5 Nausea/vomiting (safety population).
Figuras y tablas -
Analysis 3.5

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 5 Nausea/vomiting (safety population).

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 6 Nephrotoxicity (safety population).
Figuras y tablas -
Analysis 3.6

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 6 Nephrotoxicity (safety population).

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 7 Anaemia (safety population).
Figuras y tablas -
Analysis 3.7

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 7 Anaemia (safety population).

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 8 Hair loss (safety population).
Figuras y tablas -
Analysis 3.8

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 8 Hair loss (safety population).

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 9 Leukopenia (safety population).
Figuras y tablas -
Analysis 3.9

Comparison 3 Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm), Outcome 9 Leukopenia (safety population).

Comparison 4 Platinum vs non‐platinum regimens (subgroup analysis 4: by first‐line therapy), Outcome 1 Overall survival.
Figuras y tablas -
Analysis 4.1

Comparison 4 Platinum vs non‐platinum regimens (subgroup analysis 4: by first‐line therapy), Outcome 1 Overall survival.

Comparison 4 Platinum vs non‐platinum regimens (subgroup analysis 4: by first‐line therapy), Outcome 2 Progression‐free survival/time to progression.
Figuras y tablas -
Analysis 4.2

Comparison 4 Platinum vs non‐platinum regimens (subgroup analysis 4: by first‐line therapy), Outcome 2 Progression‐free survival/time to progression.

Comparison 4 Platinum vs non‐platinum regimens (subgroup analysis 4: by first‐line therapy), Outcome 3 Objective tumour response rate (assessable participants).
Figuras y tablas -
Analysis 4.3

Comparison 4 Platinum vs non‐platinum regimens (subgroup analysis 4: by first‐line therapy), Outcome 3 Objective tumour response rate (assessable participants).

Comparison 5 Platinum vs non‐platinum regimens (subgroup analysis 5 by anthracycline in regimens), Outcome 1 Overall survival.
Figuras y tablas -
Analysis 5.1

Comparison 5 Platinum vs non‐platinum regimens (subgroup analysis 5 by anthracycline in regimens), Outcome 1 Overall survival.

Comparison 5 Platinum vs non‐platinum regimens (subgroup analysis 5 by anthracycline in regimens), Outcome 2 Progression‐free survival/time to progression.
Figuras y tablas -
Analysis 5.2

Comparison 5 Platinum vs non‐platinum regimens (subgroup analysis 5 by anthracycline in regimens), Outcome 2 Progression‐free survival/time to progression.

Comparison 5 Platinum vs non‐platinum regimens (subgroup analysis 5 by anthracycline in regimens), Outcome 3 Objective tumour response rate (assessable participants).
Figuras y tablas -
Analysis 5.3

Comparison 5 Platinum vs non‐platinum regimens (subgroup analysis 5 by anthracycline in regimens), Outcome 3 Objective tumour response rate (assessable participants).

Comparison 6 Platinum vs non‐platinum regimens (subgroup analysis 6: by taxane in regimens), Outcome 1 Overall survival.
Figuras y tablas -
Analysis 6.1

Comparison 6 Platinum vs non‐platinum regimens (subgroup analysis 6: by taxane in regimens), Outcome 1 Overall survival.

Comparison 6 Platinum vs non‐platinum regimens (subgroup analysis 6: by taxane in regimens), Outcome 2 Progression‐free survival / time to progression.
Figuras y tablas -
Analysis 6.2

Comparison 6 Platinum vs non‐platinum regimens (subgroup analysis 6: by taxane in regimens), Outcome 2 Progression‐free survival / time to progression.

Comparison 6 Platinum vs non‐platinum regimens (subgroup analysis 6: by taxane in regimens), Outcome 3 Objective tumour response rate (assessable participants).
Figuras y tablas -
Analysis 6.3

Comparison 6 Platinum vs non‐platinum regimens (subgroup analysis 6: by taxane in regimens), Outcome 3 Objective tumour response rate (assessable participants).

Comparison 7 Platinum vs non‐platinum regimens (subgroup analysis 7: by trastuzumab in regimens), Outcome 1 Overall survival.
Figuras y tablas -
Analysis 7.1

Comparison 7 Platinum vs non‐platinum regimens (subgroup analysis 7: by trastuzumab in regimens), Outcome 1 Overall survival.

Comparison 7 Platinum vs non‐platinum regimens (subgroup analysis 7: by trastuzumab in regimens), Outcome 2 Progression‐free survival/time to progression.
Figuras y tablas -
Analysis 7.2

Comparison 7 Platinum vs non‐platinum regimens (subgroup analysis 7: by trastuzumab in regimens), Outcome 2 Progression‐free survival/time to progression.

Comparison 7 Platinum vs non‐platinum regimens (subgroup analysis 7: by trastuzumab in regimens), Outcome 3 Objective tumour response rate (assessable participants).
Figuras y tablas -
Analysis 7.3

Comparison 7 Platinum vs non‐platinum regimens (subgroup analysis 7: by trastuzumab in regimens), Outcome 3 Objective tumour response rate (assessable participants).

Comparison 8 Platinum vs non‐platinum regimens (sensitivity analysis 1: excluding selected treatment‐comparisons), Outcome 1 Overall survival (restricted to the 12 treatment‐comparisons common to OS and PFS/TTP meta‐analyses).
Figuras y tablas -
Analysis 8.1

Comparison 8 Platinum vs non‐platinum regimens (sensitivity analysis 1: excluding selected treatment‐comparisons), Outcome 1 Overall survival (restricted to the 12 treatment‐comparisons common to OS and PFS/TTP meta‐analyses).

Comparison 8 Platinum vs non‐platinum regimens (sensitivity analysis 1: excluding selected treatment‐comparisons), Outcome 2 Progression‐free survival/time to progression (restricted to the 12 treatment‐comparisons common to OS and PFS/TTP meta‐analyses).
Figuras y tablas -
Analysis 8.2

Comparison 8 Platinum vs non‐platinum regimens (sensitivity analysis 1: excluding selected treatment‐comparisons), Outcome 2 Progression‐free survival/time to progression (restricted to the 12 treatment‐comparisons common to OS and PFS/TTP meta‐analyses).

Comparison 8 Platinum vs non‐platinum regimens (sensitivity analysis 1: excluding selected treatment‐comparisons), Outcome 3 Objective tumour response rate (assessable participants‐ restricted to the 19 treatment‐comparisons in OS meta‐analyses).
Figuras y tablas -
Analysis 8.3

Comparison 8 Platinum vs non‐platinum regimens (sensitivity analysis 1: excluding selected treatment‐comparisons), Outcome 3 Objective tumour response rate (assessable participants‐ restricted to the 19 treatment‐comparisons in OS meta‐analyses).

Comparison 9 Platinum vs non‐platinum regimens (sensitivity analysis 2: Progression‐free survival vs. time to progression), Outcome 1 Progression‐free survival vs time to progression.
Figuras y tablas -
Analysis 9.1

Comparison 9 Platinum vs non‐platinum regimens (sensitivity analysis 2: Progression‐free survival vs. time to progression), Outcome 1 Progression‐free survival vs time to progression.

Comparison 10 Platinum vs non‐platinum regimens (sensitivity analysis 3: Analyses 1 repeated but with random effects approach), Outcome 1 Overall survival.
Figuras y tablas -
Analysis 10.1

Comparison 10 Platinum vs non‐platinum regimens (sensitivity analysis 3: Analyses 1 repeated but with random effects approach), Outcome 1 Overall survival.

Comparison 10 Platinum vs non‐platinum regimens (sensitivity analysis 3: Analyses 1 repeated but with random effects approach), Outcome 2 Progression‐free survival/time to progression.
Figuras y tablas -
Analysis 10.2

Comparison 10 Platinum vs non‐platinum regimens (sensitivity analysis 3: Analyses 1 repeated but with random effects approach), Outcome 2 Progression‐free survival/time to progression.

Comparison 10 Platinum vs non‐platinum regimens (sensitivity analysis 3: Analyses 1 repeated but with random effects approach), Outcome 3 Objective tumour response rate (assessable participants).
Figuras y tablas -
Analysis 10.3

Comparison 10 Platinum vs non‐platinum regimens (sensitivity analysis 3: Analyses 1 repeated but with random effects approach), Outcome 3 Objective tumour response rate (assessable participants).

Summary of findings for the main comparison. Platinum‐containing regimens for women with metastatic breast cancer unselected for triple‐negative disease

Platinum compared to non‐platinum chemotherapy regimens for women with metastatic breast cancer unselected for triple‐negative disease

Patient or population: women with metastatic breast cancer unselected for triple‐negative breast cancer (TNBC)
Setting: hospital
Intervention: platinum
Comparison: non‐platinum chemotherapy regimens

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants (treatment‐ comparisons)

Quality of the evidence
(GRADE)

Comments

Risk with non‐platinum chemotherapy regimens

Risk with platinum

Overall survival ‐ trials of metastatic breast cancer participants unselected for TNBC

1‐year risk of death

HR 1.01
(0.92 to 1.12)

2531 (16)

⊕⊕⊕⊕
HIGH3

Heterogeneity: P = 0.09, I2=34%

310 per 1,000 1

313 per 1,000
(289 to 340)2

2‐year risk of death

540 per 1,000 1

543 per 1,000
(510 to 581)2

Progression‐free survival/time to progression (randomised participants) ‐ trials of metastatic breast cancer participants unselected for TNBC

1‐year risk of progression or death

HR 0.92
(0.84 to 1.01)

1745 (13)

⊕⊕⊕⊝
MODERATE4

Heterogeneity: P = 0.08, I2=38%

737 per 1,000 1

707 per 1,000
(674 to 740)2

2‐year risk of progression or death

891 per 1,000 1

869 per 1,000
(844 to 893)2

Objective tumour response rate (assessable participants) ‐ trials of metastatic breast cancer participants unselected for TNBC

493 per 1,000 5

547 per 1,000
(512 to 586)

RR 1.11
(1.04 to 1.19)

3252 (23)

⊕⊕⊝⊝
LOW4,6

Heterogeneity: P = 0.0002, I2=58%

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio; HR: Hazard ratio;

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Estimated from the average of non‐platinum group Kaplan‐Meier probabilities from the three highest weighted non‐TNBC treatment‐comparisons for this outcome

2 Estimated as 1000*(1‐S(t)HR) where S(t) is the estimated probability of survival for non‐platinum participants and HR is the pooled hazard ratio (Davies 1998)

3 Quality of evidence for OS was not downgraded for blinding because this outcome is unlikely to be affected by non‐blinding.

4 Downgraded quality of evidence one level for 'indirectness' because this outcome is a surrogate endpoint of questionable validity for assessing the more important outcome of OS in the context of metastatic breast cancer (Burzykowski 2008)

5 Estimated from all 23 non‐TNBC treatment‐comparisons in the review

6 Downgraded quality of evidence one level for 'inconsistency' because there was substantial evidence of heterogeneity across studies (P < 0.05)

Figuras y tablas -
Summary of findings for the main comparison. Platinum‐containing regimens for women with metastatic breast cancer unselected for triple‐negative disease
Summary of findings 2. Platinum‐containing regimens for women with metastatic triple‐negative breast cancer

Platinum compared to non‐platinum chemotherapy regimens for women with metastatic triple‐negative breast cancer

Patient or population: women with metastatic triple‐negative breast cancer (mTNBC)
Setting: hospital
Intervention: platinum
Comparison: non‐platinum chemotherapy regimens

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants (treatment‐ comparisons)

Quality of the evidence
(GRADE)

Comments

Risk with non‐platinum chemotherapy regimens

Risk with platinum

Overall survival ‐ trials of mTNBC participants

1‐year risk of death

HR 0.75
(0.57 to 1.00)

391 (3)

⊕⊕⊝⊝
LOW3,4,5

Heterogeneity: P = 0.23, I2 = 32%

485 per 1,000 1

392 per 1,000
(315 to 485)2

2‐year risk of death

655 per 1,000 1

550 per 1,000
(455 to 655)2

Progression‐free survival/time to progression (randomised participants) ‐ trials of mTNBC participants

1‐year risk of death

HR 0.59
(0.49 to 0.72)

391 (3)

⊕⊕⊝⊝
LOW4,6

Heterogeneity: P = 0.07, I2 = 67%

894 per 1,000 1

733 per 1,000
(667 to 801)2

2‐year risk of death

987 per 1,000 1

922 per 1,000
(879 to 955)2

Objective tumour response rate (assessable participants) ‐ trials of mTNBC participants

354 per 1,0007

470 per 1,000
(400 to 552)

RR 1.33
(1.13 to 1.56)

878 (5)

⊕⊕⊝⊝
LOW6,8

Heterogeneity: P = 0.0010, I2 = 78%

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio; HR: Hazard ratio;

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Estimated from the average of non‐platinum group Kaplan‐Meier probabilities from the three TNBC treatment‐comparisons contributing data for pooling on this outcome

2 Estimated as 1000*(1‐S(t)HR) where S(t) is the estimated probability of survival for non‐platinum participants and HR is the pooled hazard ratio (Davies 1998)

3 Downgraded quality of evidence one level for 'imprecision' because the confidence interval for the pooled estimate is wide and crosses or nearly crosses unity

4 Downgraded quality of evidence one level for 'suspected publication bias' because Tutt 2014 is a large study with 376 participants but has so far only reported median OS/PFS times. As a consequence, the study did not contribute to the pooled HR estimates for OS or PFS/TTP. The reported median OS/PFS times in Tutt 2014 were similar between platinum and non‐platinum regimens. Hence, it seems likely that if HRs from Tutt 2014 were able to be included in pooled HR estimates, these pooled estimates would be considerably closer to the null.

5 Quality of evidence for OS was not downgraded for blinding because this outcome is unlikely to be affected by non‐blinding.

6 Downgraded quality of evidence one level for 'indirectness' because this outcome is a surrogate endpoint of questionable validity for assessing the more important outcome of OS in the context of metastatic breast cancer (Burzykowski 2008)

7Estimated from all five TNBC treatment‐comparisons in the review

8 Downgraded quality of evidence one level for 'inconsistency' because there was substantial evidence of heterogeneity across studies (P < 0.05)

Figuras y tablas -
Summary of findings 2. Platinum‐containing regimens for women with metastatic triple‐negative breast cancer
Summary of findings 3. Platinum‐containing regimens and toxicity profile

Platinum compared to non‐platinum chemotherapy regimens for nausea/vomiting, anaemia, hair loss and leukopenia

Patient or population: women with metastatic breast cancer
Setting: hospital
Intervention: platinum
Comparison: non‐platinum chemotherapy regimens

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No. of participants (treatment‐ comparisons)

Quality of the evidence
(GRADE)

Comments

Risk with non‐platinum chemotherapy regimens

Risk with platinum

Nausea/vomiting* grade 3 or 4 (safety population) by type of platinum agent in platinum regimen

Carboplatin

(RR 0.77, 95% CI 0.47 to 1.26)

1441 (7)

⊕⊕⊕⊝
MODERATE2

Test for carboplatin/cisplatin subgroup difference: P < 0.0001

Heterogeneity among carboplatin studies: P = 0.30, I2 = 17%

Heterogeneity among cisplatin studies: P = 0.010, I2 = 32%

80 per 1,000 1

62 per 1,000
(59 to 101)

Cisplatin

(RR 2.65, 95% CI 2.10 to 3.34)

1747 (14)

⊕⊕⊕⊝
MODERATE3

80 per 1,000 1

210 per 1,000
(167 to 266)

Anaemia grade 3 or 4 (safety population) by type of platinum agent in platinum regimen

Carboplatin

(RR 1.72, 95% CI 1.10 to 2.70)

1441 (7)

⊕⊕⊕⊕
HIGH

Test for carboplatin/cisplatin subgroup difference: P = 0.02

Heterogeneity among carboplatin studies: P = 0.67, I2 = 0%

Heterogeneity among cisplatin studies: P = 0.50, I2 = 0%

33 per 1,000 1

57 per 1,000
(36 to 89)

Cisplatin

(RR 3.72, 95% CI 2.36 to 5.88)

1644 (13)

⊕⊕⊕⊕

HIGH

33 per 1,000 1

123 per 1,000
(78 to 194)

Hair loss grade 3 or 4 (safety population)

Carboplatin or cisplatin

(RR 1.41, 95% CI 1.26 to 1.58)

1452 (13)

⊕⊕⊕⊕
HIGH

Test for carboplatin/cisplatin subgroup difference: P = 0.23

Heterogeneity: P = 0.10, I2 = 40%

264 per 1,000 1

372 per 1,000
(333 to 417)

Leukopenia** grade 3 or 4 (safety population)

Carboplatin or cisplatin

(RR 1.38, 95% CI 1.21 to 1.57)

3176 (22)

⊕⊕⊕⊝
MODERATE3

Test for carboplatin/cisplatin subgroup difference: P = 0.22

Heterogeneity: P = 0.0002, I2 = 60%

179 per 1,000 1

247 per 1,000 (217 to 281)

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio; HR: Hazard ratio;

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1 Estimated from all treatment‐comparisons (cisplatin and carboplatin) contributing data for pooling for this outcome

2 Downgraded quality of evidence one level for 'imprecision' because the confidence interval for the pooled estimate is wide and does not rule out 'no effect'

3 Downgraded quality of evidence one level for 'inconsistency' because there was substantial evidence of heterogeneity across studies (P < 0.05)

*data on vomiting was included if data on nausea/vomiting was reported separately

**data on neutropenia was included if data on leukopenia was not reported

Figuras y tablas -
Summary of findings 3. Platinum‐containing regimens and toxicity profile
Table 1. Platinum agents

Generic name

Other names

Carboplatin

Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, Nealorin, Novoplatinum, Paraplat, Paraplatin AQ, Paraplatin, Paraplatine, Platinwas, Ribocarbo

Cisplatin

Abiplatin, Blastolem, Briplatin,CACP, CDDP, cis‐DDP, cis‐diamminedichloridoplatinum, cis‐diamminedichloro platinum (II), cis‐diamminedichloroplatinum, Cis‐dichloroammine Platinum (II), Cismaplat, Cisplatina, cis‐platinous diamine dichloride, cis‐platinum II diamine dichloride, cis‐platinum II, cis‐platinum, Cisplatyl, Citoplatino, Citosin, CPDD, Cysplatyna, DDP, DDP, Lederplatin, Metaplatin, Neoplatin, PDD, Peyrone's Chloride, Peyrone's Salt, Placis, Platamine, Platiblastin, Platiblastin‐S, Platinex, Platinol‐ AQ, Platinol, Platinol‐AQ VHA Plus, Platinol‐AQ, Platinoxan, platinum diamminodichloride, Platiran, Platistin, Platosin

Oxaliplatin

Ai Heng, Aiheng, diaminocyclohexane oxalatoplatinum, oxalatoplatin, oxalatoplatinum, oxaliplatine, Eloxatin, Dacotin, Dacplat, Eloxatine, 1‐OHP, L‐OHP, oxaliplatin medac

Figuras y tablas -
Table 1. Platinum agents
Table 2. Chemotherapeutic Agents (adapted from Table 1.1 in The Chemotherapy Source Book)

Type of Agent

Action

Includes

Agents that damage the DNA template

by alkylation: nitrogen mustards

cyclophosphamide, melphalan, ifosfamide, chlorambucil

by alkylation: nitrosureas

carmustine (BCNU), lomustine (CCNU)

by alkylation: other agents

thiotepa, mitomycin C

by platinum coordination cross‐linking

cisplatin, carboplatin

antibiotics

doxorubicin, daunorubicin, mitoxantrone, idarubicin, epirubicin, amsacrine

podophyllotoxins

etoposide, teniposide

by intercalation

dactinomycin, mithramycin

by uncertain mechanisms

bleomycin

Spindle poisons

vinca alkaloids

vincristine, vinblastine, vendesine, vinorelbine

taxanes

taxol, taxotere

Antimetabolites

thymidylate synthase

5‐fluorouracil

dihydrofolate reductase

methotrexate

Figuras y tablas -
Table 2. Chemotherapeutic Agents (adapted from Table 1.1 in The Chemotherapy Source Book)
Table 3. Number of treatment‐comparisons included in meta‐analyses by subgroup and three outcomes

Outcome

Subgroup

Treatment‐

comparisons

N

Overall

survival

n (% of N)

Progression

‐free

survival/time to

progression

n (% of N)

Objective

response

rate

n (% of N)

Overall:

28

19 (68%)

16 (57%)

28 (100%)

Type of platinum agent in platinum arm:

Cisplatin in platinum arm

17

11 (65%)

11 (65%)

17 (100%)

Carboplatin in platinum arm

10

8 (80%)

5 (50%)

10 (100%)

Oxaliplatin in platinum arm

1

(0%)

(0%)

1 (100%)

Type of regimen comparison:

Regimen A + platinum agent vs regimen A

9

6 (67%)

6 (67%)

9 (100%)

Regimen A + platinum agent vs regimen B

18

13 (72%)

10 (56%)

18 (100%)

Single agent platinum vs regimen C

1

(0%)

(0%)

1 (100%)

First‐line therapy:

First‐line therapy for > 80% of participants

20

15 (75%)

11 (55%)

20 (100%)

Second‐ or third‐line therapy for ≥ 20% of participants

8

4 (50%)

5 (63%)

8 (100%)

Participant selection for mTNBC:

Participants with mTNBC

5

3 (60%)

3 (60%)

5 (100%)

Participants unselected for mTNBC

23

16 (70%)

13 (57%)

23 (100%)

Anthracycline in regimens:

No anthracycline in platinum or non‐platinum regimens

18

14 (78%)

11 (61%)

18 (100%)

Platinum + anthracycline vs non‐platinum + anthracycline regimens

6

3 (50%)

4 (67%)

6 (100%)

Platinum + anthracycline vs non‐platinum + non‐anthracycline regimens

4

2 (50%)

1 (25%)

4 (100%)

Taxane in regimens:

No taxane in platinum or non‐platinum regimens

17

9 (53%)

9 (53%)

17 (100%)

Platinum + taxane vs non‐platinum + taxane regimens

6

6 (100%)

3 (50%)

6 (100%)

Platinum + non‐taxane vs non‐platinum + taxane regimens

5

4 (80%)

4 (80%)

5 (100%)

Trastuzumab in regimens:

No trastuzumab in platinum or non‐platinum regimens

26

17 (65%)

14 (54%)

26 (100%)

Platinum + trastuzumab vs non‐platinum + trastuzumab regimens

2

2 (100%)

2 (100%)

2 (100%)

Figuras y tablas -
Table 3. Number of treatment‐comparisons included in meta‐analyses by subgroup and three outcomes
Table 4. Summary of regimens included in the analysis

Trials ID

Arm 1 (platinum‐containing)

Arm 2 (control)

First‐line therapy for > 80% of participants

Majority participants anthracycline‐naive

Regimen A + platinum vs regimen A

Berruti 2002 A

Epi + Cis (epirubicin+cisplatin)

Epi (epirubicin)

Y

Y

Berruti 2002 B

Epi + Cis + LND (epirubicin+cisplatin+lonidamine)

Epi + LND (epirubicin + lonidamine)

Y

Y

Bhattacharyya 2009

Endoxan 50 mg per day at 10 am and methotrexate 2.5 mg twice a day at 9 am and 5 pm and with 'cisplatinum'

Endoxan 50 mg per day at 10 am and methotrexate 2.5 mg twice a day at 9 am and 5 pm

N

N

Carey 2012

C + Cb (Cetuximab + carboplatin)

C (Cetuximab with carboplatin added after progression)

N

N

Costanza 1999

CBDA + CAF (carboplatin + cycloheximide + doxorubicin + fluorouracil + methotrexate)

CAF (cycloheximide + doxorubicin + fluorouracil)

(methotrexate substituted after total doxorubicin ‐ 540 mg)

Y

Unclear

Fountzilas 2009 A

PCb (paclitaxel + carboplatin)

Pw (paclitaxel)

Y

N

Nielsen 2000

Epi + Cis (epirubicin + cisplatin)

Epi (epirubicin)

Y

Y

Robert 2006

TPC (trastuzumab + paclitaxel + carboplatin)

TP (trastuzumab + paclitaxel)

Y

Unclear

Valero 2011

TCH (trastuzumab + docetaxel + carboplatin)

TH (trastuzumab + docetaxel)

Y

N

Regimen A + platinum vs regimen B

Amadori 2013

(pemetrexed + carboplatin)

(vinorelbine + gemcitabine)

N

N

Cocconi 1991

MPEPIV(a) or MPEMi (b) (a: methotrexate, leucovorin, cisplatin, epirubicin, vincristine; b: methotrexate, leucovorin, cisplatin, etoposide, mitomycin)

CMF (cyclophosphamide, methotrexate, fluorouracil)

Y

Y

Cocconi 1996

Etop + Cis (etoposide + cisplatin)

CMF (cyclophosphamide, methotrexate, fluorouracil)

Y

Unclear

Cocconi 1999

PE + CMF + AL (cisplatin + etoposide + doxorubicin + cyclophosphamide, methotrexate + fluorouracil, lecovorin + allopurinol)

CMF (cyclophosphamide, methotrexate, fluorouracil)

Y

Unclear

Creagan 1984

CFP + CAP (cyclophosphamide + doxorubicin + cis‐dichlordiammine + CFP)

CFP (cyclophosphamide + fluorouracil + prednisone)

Y

Y

Delaloge 2004

OXA (oxaliplatin + 5‐flurouracil)

VIN (vinorelbine)

N

N

Eisen 1998

EcisF (5‐flurouracil + epirubicin + cisplatin)

EcycloF (5‐flurouracil + epirubicin + cyclophosphamide)

Y

Y

Fan 2012

TP (docetaxel + cisplatin)

TX (docetaxel + capecitabine)

Y

N

Fountzilas 2004

Epi + Pcb (epirubicin + carboplatin)

Epi + P (epirubicin + paclitaxel)

Y

Y (54%)

Fountzilas 2009 B

PCb (paclitaxel + carboplatin)

GDoc (docetaxel + gemcitabine)

Y

N

Hu 2015

(cisplatin + gemcitabine)

(paclitaxel + gemcitabine)

Y

N

Icli 2005

Etop + Cis (etoposide + cisplatin)

P (paclitaxel)

N

N

Kolaric 1985

CAP (cyclophosphamide + doxorubicin + platinum)

CMFVP (cyclophosphamide + methotrexate + 5‐fluorouracil + vincristine + prednisone)

Y

Y

Kolaric 1989

CAP (cyclophosphamide + doxorubicin +platinum)

FAC (5‐flurouracil + doxorubicin +

cyclophosphamide)

Y

Y

Stemmler 2011 A

GemCis (gemcitabine + cisplatin)

GemVin (gemcitabine + vinorelbine)

N

N

Stemmler 2011 B

GemCis (gemcitabine + cisplatin)

GemCap (gemcitabine + capecitabine)

N

N

Xu 2011 A

GemCis (gemcitabine + cisplatin)

GemPac (gemcitabine + paclitaxel)

Y

N

Xu 2011 B

GemCarb (gemcitabine + carboplatin)

GemPac (gemcitabine + paclitaxel)

Y

N

Single agent platinum vs regimen C

Tutt 2014

C (carboplatin)

D (docetaxel)

N

Unclear

Figuras y tablas -
Table 4. Summary of regimens included in the analysis
Table 5. Summary of outcomes for included trials

Trial ID

Extractable OS data for HR estimation1

Median OS time2

Extractable PFS/TTP data for HR estimation1

Median PFS/TTP time2

Overall response

Treatment‐related deaths

Grade III & IV Toxicity

Accrual3

Regimen A + platinum vs regimen A

Berruti 2002 A

NR

Y

Y

Y

Y

Y

Nausea/vomiting

Nephrotoxicity

Anaemia

Leukopenia

185

Berruti 2002 B

NR

Y

Y

Y

Y

Y

Nausea/vomiting

Nephrotoxicity

Anaemia

Leukopenia

186

Bhattacharyya 2009

NR

Y

NR

Y

Y

NR

NR

126

Carey 2012

Y

Y

Y

NR

Y

NR

Not extractable

102

Costanza 1999

Y

Y

NR

NR

Y

Y

Nausea/vomiting

Anaemia

Leukopenia

221

Fountzilas 2009 A

Y

Y

NR

NR

Y

Y

Nausea/vomiting

Anaemia

Hair loss

Leukopenia

204

Nielsen 2000

Y

Y

Y

Y

Y

Y

Nausea/vomiting

Leukopenia

155

Robert 2006

Y

Y

Y

Y

Y

NR

Nausea/vomiting

Anaemia

Leukopenia

196

Valero 2011

Y

Y

Y

Y

Y

Y

Nausea/vomiting

Anaemia

263

Regimen A + platinum vs regimen B

Amadori 2013

NR

NR

Y

Y

Y

Y

Leukopenia

135

Cocconi 1991

Y

Y

NR

Y

Y

NR

Anaemia

Leukopenia

140

Cocconi 1999

Y

Y

NR

Y

Y

NR

Nausea/vomiting

Anaemia

Hair loss

Leukopenia

105

Cocconi 1996

NR

Y

NR

Y

Y

DU

Not extractable

169

Creagan 1984

Y

Y

Y

Y

Y

NR

Nausea/vomiting

Hair loss

Leukopenia

86

Delaloge 2004

NR

Y

NR

Y

Y

Y

Not extractable

137

Eisen 1998

NR

Y

Y

Y

Y

DU

Nausea/vomiting

Anaemia

Hair loss

Leukopenia

59

Fan 2012

Y

Y

Y

Y

Y

Y

Nausea/vomiting

Anaemia

Leukopenia

53

Fountzilas 2004

Y

NR

NR

NR

Y

NR

Nausea/vomiting

Anaemia

Leukopenia

327

Fountzilas 2009 B

Y

Y

NR

NR

Y

Y

Nausea/vomiting

Anaemia

Hair loss

Leukopenia

212

Hu 2015

Y

NR

Y

Y

Y

Y

Nausea/vomiting

Anaemia

Hair loss

Leukopenia

236

Icli 2005

Y

Y

Y

NR

Y

Y

Nausea/vomiting

Anaemia

Leukopenia

193

Kolaric 1985

NR

NR

NR

NR

Y

NR

Nausea/vomiting

Nephrotoxicity

Anaemia

Hair loss

Leukopenia

123

Kolaric 1989

Y

Y

NR

NR

Y

Y

Nausea/vomiting

Anaemia

Hair loss

Leukopenia

142

Stemmler 2011 A

Y

Y

Y

Y

Y

NR

Nausea/vomiting

Anaemia

Hair loss

Leukopenia

69

Stemmler 2011 B

Y

Y

Y

Y

Y

NR

Nausea/vomiting

Anaemia

Hair loss

Leukopenia

72

Xu 2011 A

Y

Y

Y

Y

Y

Y

Nausea/vomiting

Nephrotoxicity

Anaemia

Hair loss

Leukopenia

75

Xu 2011 B

Y

Y

Y

Y

Y

Y

Nausea/vomiting

Nephrotoxicity

Anaemia

Hair loss

Leukopenia

71

Single agent platinum vs regimen C

Tutt 2014

NR

Y

NR

Y

Y

NR

NR

376

1 Sufficient data reported to estimate a HR for pooling as outlined by Parmar 1998 and Tierney 2007; this includes Kapalan‐Meier curve, HR and standard error/confidence interval or logrank statistics

2 Trials that did not explicitly report median time were classified as NR here regardless of estimable median time from Kaplan‐Meier curve

3 Accrual numbers represent the maximum numbers of participants in the trial (not study) that were included in the analyses of OS, PFS/TTP or OR (assessable participants).

*NR = not reported, DU = deaths unexplained, Y = data reported.

Figuras y tablas -
Table 5. Summary of outcomes for included trials
Comparison 1. Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

19

2922

HR (95% CI)

0.98 [0.89, 1.07]

1.1 Treatment‐comparisons assessing patients with mTNBC

3

391

HR (95% CI)

0.75 [0.57, 1.00]

1.2 Treatment‐comparisons assessing patients unselected for mTNBC

16

2531

HR (95% CI)

1.01 [0.92, 1.12]

2 Progression‐free survival/time to progression Show forest plot

16

2136

HR (95% CI)

0.85 [0.78, 0.93]

2.1 Treatment‐comparisons assessing patients with mTNBC

3

391

HR (95% CI)

0.59 [0.49, 0.72]

2.2 Treatment‐comparisons assessing patients unselected for mTNBC

13

1745

HR (95% CI)

0.92 [0.84, 1.01]

3 Objective tumour response rate (assessable participants) Show forest plot

28

4130

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.08, 1.22]

3.1 Treatment‐comparisons assessing patients with mTNBC

5

878

Risk Ratio (M‐H, Fixed, 95% CI)

1.33 [1.13, 1.56]

3.2 Treatment‐comparisons assessing patients unselected for mTNBC

23

3252

Risk Ratio (M‐H, Fixed, 95% CI)

1.11 [1.04, 1.19]

Figuras y tablas -
Comparison 1. Platinum vs non‐platinum regimens (subgroup analysis 1: by treatment‐comparisons assessing mTNBC)
Comparison 2. Platinum vs non‐platinum regimens (subgroup analysis 2: by type of regimen comparison)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

19

2922

HR (95% CI)

0.98 [0.89, 1.07]

1.1 Regimen A + platinum agent vs regimen A

6

1141

HR (95% CI)

1.08 [0.93, 1.26]

1.2 Regimen A + platinum agent vs regimen B

13

1781

HR (95% CI)

0.92 [0.81, 1.03]

2 Progression‐free survival / time to progression Show forest plot

16

2136

HR (95% CI)

0.85 [0.78, 0.93]

2.1 Regimen A+platinum agent vs regimen A

6

1087

HR (95% CI)

0.88 [0.78, 1.00]

2.2 Regimen A+platinum agent vs regimen B

10

1049

HR (95% CI)

0.83 [0.74, 0.93]

3 Objective tumour response rate (assessable participants) Show forest plot

28

4130

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.08, 1.22]

3.1 Regimen A + platinum agent vs regimen A

9

1519

Risk Ratio (M‐H, Fixed, 95% CI)

1.10 [1.01, 1.21]

3.2 Regimen A + platinum agent vs regimen B

18

2235

Risk Ratio (M‐H, Fixed, 95% CI)

1.22 [1.12, 1.33]

3.3 Single agent platinum vs regimen C

1

376

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.66, 1.17]

Figuras y tablas -
Comparison 2. Platinum vs non‐platinum regimens (subgroup analysis 2: by type of regimen comparison)
Comparison 3. Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

19

2922

HR (95% CI)

0.98 [0.89, 1.07]

1.1 Cisplatin in platinum arm

11

1326

HR (95% CI)

0.91 [0.80, 1.05]

1.2 Carboplatin in platinum arm

8

1596

HR (95% CI)

1.04 [0.91, 1.18]

2 Progression‐free survival/time to progression Show forest plot

16

2136

HR (95% CI)

0.85 [0.78, 0.93]

2.1 Cisplatin in platinum arm

11

1369

HR (95% CI)

0.85 [0.76, 0.94]

2.2 Carboplatin in platinum arm

5

767

HR (95% CI)

0.86 [0.75, 0.99]

3 Objective tumour response rate (assessable participants) Show forest plot

28

4130

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.08, 1.22]

3.1 Cisplatin in platinum arm

17

2050

Risk Ratio (M‐H, Fixed, 95% CI)

1.35 [1.24, 1.46]

3.2 Carboplatin in platinum arm

10

1943

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.86, 1.04]

3.3 Oxaliplatin in platinum arm

1

137

Risk Ratio (M‐H, Fixed, 95% CI)

0.85 [0.48, 1.52]

4 Treatment‐related death (safety population) Show forest plot

15

2377

Risk Ratio (M‐H, Fixed, 95% CI)

1.42 [0.73, 2.76]

4.1 Cisplatin in platinum arm

8

1185

Risk Ratio (M‐H, Fixed, 95% CI)

1.39 [0.59, 3.25]

4.2 Carboplatin in platinum arm

6

1055

Risk Ratio (M‐H, Fixed, 95% CI)

1.86 [0.57, 6.05]

4.3 Oxaliplatin in platinum arm

1

137

Risk Ratio (M‐H, Fixed, 95% CI)

0.34 [0.01, 8.16]

5 Nausea/vomiting (safety population) Show forest plot

21

3172

Risk Ratio (M‐H, Fixed, 95% CI)

2.07 [1.69, 2.54]

5.1 Cisplatin in platinum arm

14

1731

Risk Ratio (M‐H, Fixed, 95% CI)

2.65 [2.10, 3.34]

5.2 Carboplatin in platinum arm

7

1441

Risk Ratio (M‐H, Fixed, 95% CI)

0.77 [0.47, 1.26]

6 Nephrotoxicity (safety population) Show forest plot

5

632

Risk Ratio (M‐H, Fixed, 95% CI)

3.06 [0.86, 10.84]

6.1 Cisplatin in platinum arm

4

561

Risk Ratio (M‐H, Fixed, 95% CI)

3.46 [0.86, 13.97]

6.2 Carboplatin in platinum arm

1

71

Risk Ratio (M‐H, Fixed, 95% CI)

1.56 [0.07, 36.97]

7 Anaemia (safety population) Show forest plot

20

3085

Risk Ratio (M‐H, Fixed, 95% CI)

2.61 [1.90, 3.58]

7.1 Cisplatin in platinum arm

13

1644

Risk Ratio (M‐H, Fixed, 95% CI)

3.72 [2.36, 5.88]

7.2 Carboplatin in platinum arm

7

1441

Risk Ratio (M‐H, Fixed, 95% CI)

1.72 [1.10, 2.70]

8 Hair loss (safety population) Show forest plot

12

1452

Risk Ratio (M‐H, Fixed, 95% CI)

1.41 [1.26, 1.58]

8.1 Cisplatin in platinum arm

9

983

Risk Ratio (M‐H, Fixed, 95% CI)

1.33 [1.15, 1.54]

8.2 Carboplatin in platinum arm

3

469

Risk Ratio (M‐H, Fixed, 95% CI)

1.53 [1.28, 1.84]

9 Leukopenia (safety population) Show forest plot

22

3176

Risk Ratio (M‐H, Fixed, 95% CI)

1.38 [1.21, 1.57]

9.1 Cisplatin in platinum arm

15

1866

Risk Ratio (M‐H, Fixed, 95% CI)

1.49 [1.23, 1.81]

9.2 Carboplatin in platinum arm

7

1310

Risk Ratio (M‐H, Fixed, 95% CI)

1.27 [1.07, 1.50]

Figuras y tablas -
Comparison 3. Platinum vs non‐platinum regimens (subgroup analysis 3: by type of platinum agent in platinum arm)
Comparison 4. Platinum vs non‐platinum regimens (subgroup analysis 4: by first‐line therapy)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

19

2922

HR (95% CI)

0.98 [0.89, 1.07]

1.1 First‐line therapy for > 80% of patients

15

2486

HR (95% CI)

1.00 [0.90, 1.11]

1.2 Second‐ or third‐line therapy for ≥20% of patients

4

436

HR (95% CI)

0.89 [0.73, 1.09]

2 Progression‐free survival/time to progression Show forest plot

16

2136

HR (95% CI)

0.85 [0.78, 0.93]

2.1 First‐line therapy for > 80% of patients

11

1565

HR (95% CI)

0.93 [0.83, 1.03]

2.2 Second‐ or third‐line therapy for ≥20% of patients

5

571

HR (95% CI)

0.75 [0.65, 0.86]

3 Objective tumour response rate (assessable participants) Show forest plot

28

4130

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.08, 1.22]

3.1 First‐line therapy for > 80% of patients

20

2983

Risk Ratio (M‐H, Fixed, 95% CI)

1.14 [1.06, 1.21]

3.2 Second‐ or third‐line therapy for ≥20% of patients

8

1147

Risk Ratio (M‐H, Fixed, 95% CI)

1.20 [1.02, 1.42]

Figuras y tablas -
Comparison 4. Platinum vs non‐platinum regimens (subgroup analysis 4: by first‐line therapy)
Comparison 5. Platinum vs non‐platinum regimens (subgroup analysis 5 by anthracycline in regimens)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

19

2922

HR (95% CI)

0.98 [0.89, 1.07]

1.1 No anthracycline in platinum or non‐platinum regimens

14

2213

HR (95% CI)

0.94 [0.84, 1.05]

1.2 Platinum + anthracycline vs non‐platinum + anthracycline regimens

3

518

HR (95% CI)

1.09 [0.88, 1.34]

1.3 Platinum + anthracycline vs non‐platinum + non‐anthracycline regimens

2

191

HR (95% CI)

1.12 [0.78, 1.60]

2 Progression‐free survival/time to progression Show forest plot

16

2136

HR (95% CI)

0.85 [0.78, 0.93]

2.1 No anthracycline in platinum or non‐platinum regimens

11

1465

HR (95% CI)

0.80 [0.73, 0.88]

2.2 Platinum+anthracycline vs non‐platinum+anthracycline regimens

4

585

HR (95% CI)

1.05 [0.86, 1.27]

2.3 Platinum+anthracycline vs non‐platinum+non‐anthracycline regimens

1

86

HR (95% CI)

1.23 [0.75, 2.03]

3 Objective tumour response rate (assessable participants) Show forest plot

28

4130

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.08, 1.22]

3.1 No anthracycline in platinum or non‐platinum regimens

18

2792

Risk Ratio (M‐H, Fixed, 95% CI)

1.10 [1.02, 1.20]

3.2 Platinum+anthracycline vs non‐platinum+anthracycline regimens

6

859

Risk Ratio (M‐H, Fixed, 95% CI)

1.09 [0.97, 1.22]

3.3 Platinum+anthracycline vs non‐platinum+non‐anthracycline regimens

4

479

Risk Ratio (M‐H, Fixed, 95% CI)

1.49 [1.28, 1.74]

Figuras y tablas -
Comparison 5. Platinum vs non‐platinum regimens (subgroup analysis 5 by anthracycline in regimens)
Comparison 6. Platinum vs non‐platinum regimens (subgroup analysis 6: by taxane in regimens)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

19

2922

HR (95% CI)

0.98 [0.89, 1.07]

1.1 No taxane in platinum or non‐platinum regimens

9

1092

HR (95% CI)

1.07 [0.93, 1.24]

1.2 Platinum + taxane vs non‐platinum + taxane regimens

6

1255

HR (95% CI)

0.96 [0.82, 1.11]

1.3 Platinum + non‐taxane vs non‐platinum + taxane regimens

4

575

HR (95% CI)

0.85 [0.69, 1.04]

2 Progression‐free survival / time to progression Show forest plot

16

2136

HR (95% CI)

0.85 [0.78, 0.93]

2.1 No taxane in platinum or non‐platinum regimens

9

1049

HR (95% CI)

0.92 [0.80, 1.04]

2.2 Platinum + taxane vs non‐platinum + taxane regimens

3

512

HR (95% CI)

0.84 [0.70, 1.00]

2.3 Platinum + non‐taxane vs non‐platinum + taxane regimens

4

575

HR (95% CI)

0.79 [0.69, 0.91]

3 Objective tumour response rate (assessable participants) Show forest plot

28

4130

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.08, 1.22]

3.1 No taxane in platinum or non‐platinum regimens

17

2054

Risk Ratio (M‐H, Fixed, 95% CI)

1.25 [1.15, 1.36]

3.2 Platinum + taxane vs non‐platinum + taxane regimens

6

1152

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.90, 1.12]

3.3 Platinum + non‐taxane vs non‐platinum + taxane regimens

5

924

Risk Ratio (M‐H, Fixed, 95% CI)

1.11 [0.94, 1.30]

Figuras y tablas -
Comparison 6. Platinum vs non‐platinum regimens (subgroup analysis 6: by taxane in regimens)
Comparison 7. Platinum vs non‐platinum regimens (subgroup analysis 7: by trastuzumab in regimens)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

19

2922

HR (95% CI)

0.98 [0.89, 1.07]

1.1 No trastuzumab in platinum or non‐platinum regimens

17

2463

HR (95% CI)

0.97 [0.88, 1.08]

1.2 Platinum + trastuzumab vs non‐platinum + trastuzumab regimens

2

459

HR (95% CI)

1.00 [0.79, 1.27]

2 Progression‐free survival/time to progression Show forest plot

16

2136

HR (95% CI)

0.85 [0.78, 0.93]

2.1 No trastuzumab in platinum or non‐platinum regimens

14

1677

HR (95% CI)

0.84 [0.76, 0.92]

2.2 Platinum+trastuzumab vs non‐platinum+trastuzumab regimens

2

459

HR (95% CI)

0.90 [0.75, 1.08]

3 Objective tumour response rate (assessable participants) Show forest plot

28

4130

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.08, 1.22]

3.1 No trastuzumab in platinum or non‐platinum regimens

26

3687

Risk Ratio (M‐H, Fixed, 95% CI)

1.15 [1.07, 1.23]

3.2 Platinum+trastuzumab vs non‐platinum+trastuzumab regimens

2

443

Risk Ratio (M‐H, Fixed, 95% CI)

1.14 [0.99, 1.31]

Figuras y tablas -
Comparison 7. Platinum vs non‐platinum regimens (subgroup analysis 7: by trastuzumab in regimens)
Comparison 8. Platinum vs non‐platinum regimens (sensitivity analysis 1: excluding selected treatment‐comparisons)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival (restricted to the 12 treatment‐comparisons common to OS and PFS/TTP meta‐analyses) Show forest plot

12

1571

HR (95% CI)

0.92 [0.81, 1.04]

2 Progression‐free survival/time to progression (restricted to the 12 treatment‐comparisons common to OS and PFS/TTP meta‐analyses) Show forest plot

12

1571

HR (95% CI)

0.80 [0.73, 0.88]

3 Objective tumour response rate (assessable participants‐ restricted to the 19 treatment‐comparisons in OS meta‐analyses) Show forest plot

19

2685

Risk Ratio (M‐H, Fixed, 95% CI)

1.13 [1.05, 1.22]

Figuras y tablas -
Comparison 8. Platinum vs non‐platinum regimens (sensitivity analysis 1: excluding selected treatment‐comparisons)
Comparison 9. Platinum vs non‐platinum regimens (sensitivity analysis 2: Progression‐free survival vs. time to progression)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Progression‐free survival vs time to progression Show forest plot

16

2136

HR (95% CI)

0.85 [0.78, 0.93]

1.1 Progression‐free survival

9

1324

HR (95% CI)

0.92 [0.82, 1.03]

1.2 Time to progression

7

812

HR (95% CI)

0.78 [0.69, 0.88]

Figuras y tablas -
Comparison 9. Platinum vs non‐platinum regimens (sensitivity analysis 2: Progression‐free survival vs. time to progression)
Comparison 10. Platinum vs non‐platinum regimens (sensitivity analysis 3: Analyses 1 repeated but with random effects approach)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall survival Show forest plot

19

Hazard Ratio (Random, 95% CI)

0.98 [0.87, 1.11]

1.1 Treatment‐comparisons assessing patients with mTNBC

3

Hazard Ratio (Random, 95% CI)

0.73 [0.51, 1.04]

1.2 Treatment‐comparisons assessing patients unselected for mTNBC

16

Hazard Ratio (Random, 95% CI)

1.02 [0.90, 1.16]

2 Progression‐free survival/time to progression Show forest plot

16

Hazard Ratio (Random, 95% CI)

0.88 [0.76, 1.02]

2.1 Treatment‐comparisons assessing patients with mTNBC

3

Hazard Ratio (Random, 95% CI)

0.55 [0.38, 0.78]

2.2 Treatment‐comparisons assessing patients unselected for mTNBC

13

Hazard Ratio (Random, 95% CI)

0.96 [0.85, 1.09]

3 Objective tumour response rate (assessable participants) Show forest plot

28

4130

Risk Ratio (M‐H, Random, 95% CI)

1.17 [1.05, 1.30]

3.1 Treatment‐comparisons assessing patients with mTNBC

5

878

Risk Ratio (M‐H, Random, 95% CI)

1.60 [1.04, 2.45]

3.2 Treatment‐comparisons assessing patients unselected for mTNBC

23

3252

Risk Ratio (M‐H, Random, 95% CI)

1.13 [1.01, 1.25]

Figuras y tablas -
Comparison 10. Platinum vs non‐platinum regimens (sensitivity analysis 3: Analyses 1 repeated but with random effects approach)