cochrane database of systematic reviews (reviews) || combination versus sequential single agent...

Combination versus sequential single agent chemotherapy for

metastatic breast cancer (Review)

Dear RF, McGeechan K, Jenkins MC, Barratt A, Tattersall MHN, Wilcken N

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2013, Issue 12

http://www.thecochranelibrary.com

Combination versus sequential single agent chemotherapy for metastatic breast cancer (Review)

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

19DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Overall survival, Outcome 1 Overall survival (all trials). . . . . . . . . . . . . 50

Analysis 2.1. Comparison 2 Progression-free survival, Outcome 1 Progression-free survival (all trials). . . . . . . 51

Analysis 3.1. Comparison 3 Overall response, Outcome 1 Overall response (all trials). . . . . . . . . . . . 52

Analysis 4.1. Comparison 4 Treatment-related deaths, Outcome 1 Treatment-related deaths (all trials). . . . . . 53

Analysis 5.1. Comparison 5 Neutropenia, Outcome 1 Neutropaenia. . . . . . . . . . . . . . . . . . 54

Analysis 6.1. Comparison 6 Febrile neutropenia, Outcome 1 Febrile neutropenia. . . . . . . . . . . . . 55

Analysis 7.1. Comparison 7 Nausea and vomiting, Outcome 1 Nausea and vomiting. . . . . . . . . . . . 56

Analysis 8.1. Comparison 8 Overall survival - risk of bias, Outcome 1 Overall survival - risk of bias. . . . . . . 57

Analysis 9.1. Comparison 9 Progression-free survival - risk of bias, Outcome 1 Progression-free survival - risk of bias. 58

Analysis 10.1. Comparison 10 Overall response - risk of bias, Outcome 1 Overall response - risk of bias. . . . . . 59

Analysis 11.1. Comparison 11 Treatment-related deaths - risk of bias, Outcome 1 Treatment-related deaths - risk of bias. 60

Analysis 12.1. Comparison 12 Neutropenia - risk of bias, Outcome 1 Neutropaenia - risk of bias. . . . . . . . 61

Analysis 13.1. Comparison 13 Febrile neutropenia - risk of bias, Outcome 1 Febrile neutropenia - risk of bias. . . . 62

Analysis 14.1. Comparison 14 Nausea and vomiting - risk of bias, Outcome 1 Nausea and vomiting - risk of bias. . 63

Analysis 15.1. Comparison 15 Overall survival - line of chemotherapy, Outcome 1 Overall survival - line of chemotherapy. 64

Analysis 16.1. Comparison 16 Progression-free survival - line of chemotherapy, Outcome 1 Progression free survival - line

of chemotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Analysis 17.1. Comparison 17 Overall response - line of chemotherapy, Outcome 1 Overall response - subgroup analysis,

line of chemotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

Analysis 18.1. Comparison 18 Treatment-related deaths - line of chemotherapy, Outcome 1 Treatment-related deaths - line

of chemotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Analysis 19.1. Comparison 19 Neutropenia - line of chemotherapy, Outcome 1 Neutropaenia - line of chemotherapy. 68

Analysis 20.1. Comparison 20 Febrile neutropenia - line of chemotherapy, Outcome 1 Febrile neutropenia - line of

chemotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

Analysis 21.1. Comparison 21 Nausea and vomiting - line of chemotherapy, Outcome 1 Nausea and vomiting - line of

chemotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

Analysis 22.1. Comparison 22 Overall survival - schema 1 versus schema 2, Outcome 1 Overall survival - Schema 1 versus

Schema 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Analysis 23.1. Comparison 23 Progression-free survival - schema 1 versus schema 2, Outcome 1 Progression-free survival -

Schema 1 versus Schema 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

Analysis 24.1. Comparison 24 Overall response - schema 1 versus schema 2, Outcome 1 Overall response - Schema 1 versus

Schema 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

iCombination versus sequential single agent chemotherapy for metastatic breast cancer (Review)


Analysis 25.1. Comparison 25 Treatment-related deaths - schema 1 versus schema 2, Outcome 1 Treatment-related deaths -


Analysis 26.1. Comparison 26 Neutropenia - schema 1 versus schema 2, Outcome 1 Neutropaenia - subgroup analysis,


Analysis 27.1. Comparison 27 Febrile neutropenia - schema 1 versus schema 2, Outcome 1 Febrile neutropenia - Schema 1

versus Schema 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

Analysis 28.1. Comparison 28 Nausea and vomiting - schema 1 versus schema 2, Outcome 1 Nausea and vomiting -


Analysis 29.1. Comparison 29 Overall survival - relative dose intensity, Outcome 1 Overall survival - relative dose

intensity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

Analysis 30.1. Comparison 30 Progression-free survival - relative dose intensity, Outcome 1 Progression-free survival -

relative dose intensity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Analysis 31.1. Comparison 31 Overall response - relative dose intensity, Outcome 1 Overall response - relative dose

intensity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

Analysis 32.1. Comparison 32 Treatment-related deaths - relative dose intensity, Outcome 1 Treatment-related deaths -

relative dose intensity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

Analysis 33.1. Comparison 33 Neutropenia - relative dose intensity, Outcome 1 Neutropaenia - relative dose intensity. 82

Analysis 34.1. Comparison 34 Febrile neutropenia - relative dose intensity, Outcome 1 Febrile neutropenia - relative dose

intensity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

Analysis 35.1. Comparison 35 Nausea and vomiting - relative dose intensity, Outcome 1 Nausea and vomiting - relative

dose intensity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

84ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

88APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

90WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

91CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

91DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

91SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

91DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

91NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

92INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiCombination versus sequential single agent chemotherapy for metastatic breast cancer (Review)


[Intervention Review]

Combination versus sequential single agent chemotherapy formetastatic breast cancer

Rachel F Dear1, Kevin McGeechan2, Marisa C Jenkins2, Alexandra Barratt2, Martin HN Tattersall1, Nicholas Wilcken1,3

1Sydney Medical School, The University of Sydney, Sydney, Australia. 2Sydney School of Public Health, The University of Sydney,

Sydney, Australia. 3Medical Oncology, Westmead and Nepean Hospitals, Westmead, Australia

Contact address: Rachel F Dear, Sydney Medical School, The University of Sydney, Blackburn Building D06, Sydney, NSW, 2006,

Australia. [email protected].

Editorial group: Cochrane Breast Cancer Group.

Publication status and date: Edited (no change to conclusions), published in Issue 1, 2014.

Review content assessed as up-to-date: 31 October 2013.

Citation: Dear RF, McGeechan K, Jenkins MC, Barratt A, Tattersall MHN, Wilcken N. Combination versus sequential single

agent chemotherapy for metastatic breast cancer. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD008792. DOI:

10.1002/14651858.CD008792.pub2.


A B S T R A C T

Background

Combination chemotherapy can cause greater tumour cell kill if the drug dose is not compromised, while sequential single agent

chemotherapy may allow for greater dose intensity and treatment time, potentially meaning greater benefit from each single agent. In

addition, sequentially using single agents might cause less toxicity and impairment of quality of life, but it is not known whether this

might compromise survival time.

Objectives

To assess the effect of combination chemotherapy compared to the same drugs given sequentially in women with metastatic breast

cancer.

Search methods

We searched the Cochrane Breast Cancer Group Specialised Register, using the search terms “advanced breast cancer” and “chemother-

apy”, MEDLINE and EMBASE on 31 October 2013. The World Health Organization International Clinical Trials Registry Platform

and ClinicalTrials.gov were also searched (22 March 2012).

Selection criteria

Randomised controlled trials of combination chemotherapy compared to the same drugs used sequentially in women with metastatic

breast cancer in the first-, second- or third-line setting.

Data collection and analysis

Two authors independently extracted data from published trials. Hazard ratios (HR) were derived from time-to-event outcomes where

possible, and a fixed-effect model was used for meta-analysis. Response rates were analysed as dichotomous variables (risk ratios (RR)),

and toxicity and quality of life data were extracted where available.

1Combination versus sequential single agent chemotherapy for metastatic breast cancer (Review)


mailto:[email protected]

Main results

Twelve trials reporting on nine treatment comparisons (2317 patients randomised) were identified. The majority of trials (10 trials)

had an unclear or high risk of bias. Time-to-event data were collected for nine trials for overall survival and eight trials for progression-

free survival. All 12 trials reported results for tumour response. In the 12 trials there were 1023 deaths in 2317 women randomised.

There was no difference in overall survival, with an overall HR of 1.04 (95% confidence interval (CI) 0.93 to 1.16; P = 0.45), and no

significant heterogeneity. This result was consistent in the four subgroups analysed (risk of bias, line of chemotherapy, type of schema

of chemotherapy, and relative dose intensity). In particular, there was no difference in survival according to the type of schema of

chemotherapy, that is whether chemotherapy was given on disease progression or after a set number of cycles. In the eight trials that

reported progression-free survival, 678 women progressed out of the 886 women randomised. The combination arm had a higher risk

of progression than the sequential arm (HR 1.16; 95% CI 1.03 to 1.31; P = 0.01) with no significant heterogeneity. This result was

consistent in all subgroups. Overall tumour response rates were higher in the combination arm (RR 1.16; 95% CI 1.06 to 1.28; P

= 0.001) but there was significant heterogeneity for this outcome across the trials. In the seven trials that reported treatment-related

deaths, there was no significant difference between the two arms, although the CIs were very wide due to the small number of events

(RR 1.53; 95% CI 0.71 to 3.29; P = 0.28). The risk of febrile neutropenia was higher in the combination arm (RR 1.32; 95% CI

1.06 to 1.65; P = 0.01). There was no statistically significant difference in the risk of neutropenia, nausea and vomiting, or treatment-

related deaths. Overall quality of life showed no difference between the two groups, but only three trials reported this outcome.

Authors’ conclusions

Sequential single agent chemotherapy has a positive effect on progression-free survival, whereas combination chemotherapy has a higher

response rate and a higher risk of febrile neutropenia in metastatic breast cancer. There is no difference in overall survival time between

these treatment strategies, both overall and in the subgroups analysed. In particular, there was no difference in survival according to

the schema of chemotherapy (giving chemotherapy on disease progression or after a set number of cycles) or according to the line of

chemotherapy (first-line versus second- or third-line). Generally this review supports the recommendations by international guidelines

to use sequential monotherapy unless there is rapid disease progression.

P L A I N L A N G U A G E S U M M A R Y

Combination (several drugs at the same time) versus sequential chemotherapy (same drugs given one after the other) for

metastatic breast cancer

Metastatic breast cancer is not currently a curable disease but one that can be very effectively treated with chemotherapy, endocrine

therapy and targeted therapies. Average survival is about two years but some women live for many years longer. It is important to

investigate the best way to give chemotherapy to treat metastatic breast cancer in order to optimise survival and quality of life and to

minimise the side effects from treatment.

This review investigated whether giving a combination of drugs at the same time was more effective than giving the same drugs one at

a time (sequential treatment).

A literature search conducted in October 2013 resulted in 12 randomised controlled studies with 2317 patients that could be included

in the analysis. The patients had metastatic breast cancer and either they had not been treated or had received one or two treatments

after their diagnosis of metastatic breast cancer. The primary outcomes were overall survival and progression-free survival (time from

randomisation to the time of disease progression). Secondarily, we compared the degree the tumour shrunk in response to chemotherapy

(overall response rate), toxicity and quality of life.

There was no difference in overall survival between the two groups but we found that when drugs were given one at a time there was

more time before the tumours grew back again (longer progression-free survival). However, combination chemotherapy caused tumours

to shrink more, although this did not result in longer survival than when using sequential chemotherapy. Rates of febrile neutropenia

(infection) were higher in the combination arm but there was no difference in the rates of neutropenia (low white blood cells). There

was no difference in quality of life between the two groups but there were only three trials that reported this information. Quality of

life should be included as an outcome in future trials addressing this question. Overall, the studies did not consistently report the way

patients were randomised and this may be a source of bias in the results.

Generally this review supports the recommendations by international guidelines to use sequential monotherapy unless there is rapid

disease progression.



B A C K G R O U N D

Description of the condition

Breast cancer is the most common type of cancer and the second

leading cause of cancer deaths in women. In 2002, there were over

1.1 million new cases and approximately 410,000 deaths from

breast cancer, worldwide (Ferlay 2004).

If breast cancer becomes metastatic, it is treatable but not cur-

able. The aims of treatment include improving survival and qual-

ity of life. There has never been a randomised trial comparing

systemic therapy to best supportive care to demonstrate that sys-

temic therapy can improve survival in women with metastatic

breast cancer. Despite this, data from single institution series and

population-based registries show that the survival of patients with

metastatic breast cancer has improved over time, from approxi-

mately 16 months in the early 1990s to beyond 24 months in

2001 (Chia 2007; Giordano 2004), although some women may

live for many years (Hayes 1995). This improvement coincides

with the availability of new systemic agents (taxanes, aromatase

inhibitors, trastuzumab and capecitabine) and a higher propor-

tion of women with metastatic breast cancer receiving systemic

therapy (Chia 2007). While longer survival cannot be attributed

conclusively to the use of improved systemic therapies it is be-

lieved they have contributed. The optimal combination, sequence

and timing of systemic agents for metastatic breast cancer remains

unresolved. Selection of treatment is based on consideration of

the site of recurrence, symptoms, anticipated response to treat-

ment, expected toxicities, quality of life and patient preference.

Ultimately most women with metastatic breast cancer will receive

chemotherapy because they have hormone receptor negative dis-

ease, their disease has become refractory to endocrine therapy, they

are symptomatic, or they have rapidly progressive visceral disease

(Hortobagyi 1996).

Description of the intervention

Combination chemotherapy can achieve several important objec-

tives that are less probable with single agent chemotherapy. Com-

bination therapy firstly provides increased cell kill within the range

of acceptable toxicity for each drug, as long as dosing is not com-

promised and the tumour is sensitive to each drug; secondly used

with an heterogeneous tumour cell population it increases the

probability of some cells being responsive compared with a single

agent; and thirdly the combination may delay the development of

drug resistance if there is rapid cell kill and a reduced cell mass.

The scheduling of multiple drug regimens may influence both the

effectiveness and toxicity of the regimen. The Goldie and Cold-

man model predicts that drug resistant cells may be present even

in small tumours (Goldie 1982). They propose alternating non

cross-resistant drug combinations as early as possible as a means

of eliminating resistant clones. Norton and Day predicted that

the sequential use of drug combinations would outperform al-

ternating cycles because no two combinations were likely to be

strictly non-cross resistant or have equal cell killing capacity (Day

1986; Norton 1991). In the adjuvant setting, a randomised trial

observed that four three-week cycles of doxorubicin followed by

eight three-week cycles of cyclophosphamide methotrexate fluo-

rouracil (CMF) in women with high-risk primary breast cancer

(four or more positive lymph nodes) was more effective than an

alternating schedule of doxorubicin and CMF in terms of disease-

free and overall survival (Bonadonna 1995).

A potential limitation of the effectiveness of combination chemo-

therapy is that dose levels of the component drugs may need to

be reduced to limit toxicity. Another limitation of combination

treatment is that it may use non-cross resistant agents rapidly. In

contrast, these agents given as sequential monotherapy may al-

low for more cycles of effective treatment. The use of sequential

monotherapy may allow for greater dose intensity and allow for

a treatment approach that gets maximum time and benefit from

each agent.

Optimal dosing of chemotherapy is challenging because of the

different effects on normal and tumour tissues. Most cancer che-

motherapeutic agents show a steep dose-response curve in the lin-

ear phase of tumour growth. A reduction in drug dose when the

tumour is in this linear phase of the dose-response curve almost

always results in a reduction in the probability of cure before a

reduction in antitumour activity is observed. This observation has

led cancer clinicians and researchers to conclude that when cure

is a reasonable treatment expectation, increasing the dose inten-

sity of treatment will increase the rate and duration of tumour

response and improve the survival rate (Hryniuk 1987). How-

ever, there are limitations to the effectiveness of dose intensity, as

demonstrated by the use of high-dose chemotherapy. A Cochrane

Review (Farquhar 2008) of six randomised trials comparing high-

dose chemotherapy and autograft with conventional chemother-

apy for women with metastatic breast cancer demonstrated no

statistically significant evidence of benefit in overall survival. In-

creased dose intensity also comes at a cost of increased toxicity

to normal tissues. If palliation is the primary goal of treatment,

and anticipated survival is limited, then toxicity and quality of life

become important factors when deciding on a treatment regimen.

Combination therapy can also refer to the combination of chemo-

therapy with a biological agent. This regimen is most commonly

used in women with human epidermal growth factor receptor 2-

positive (HER2-positive) metastatic breast cancer, for example a

taxane and trastuzumab or capecitabine and lapatinib. This re-

view focuses only on the combination of chemotherapeutic agents

compared to the same agents given as sequential monotherapy.

How the intervention might work



The question of interest is whether patients receiving combination

chemotherapy regimens have better health outcomes, including

longer survival and less toxicity, than for sequential single agent

chemotherapy. Sequential single agent use has evolved to main-

tain dose intensity while limiting toxicity, and without sacrificing

survival. Sequential therapy may refer to the consecutive admin-

istration of single agents with each agent introduced after disease

progression or it may refer to a planned sequence of single agents

given without interruption between the regimens.

Why it is important to do this review

The comparison of combination chemotherapy with the same

agents given sequentially as monotherapy is a clinically important

question that addresses a common clinical scenario facing medi-

cal oncologists treating women with metastatic breast cancer. This

is because the role of combination chemotherapy in metastatic

breast cancer is still unresolved. Combination chemotherapy is

often given to obtain a response in immediately life-threatening

circumstances whereas sequential monotherapy is given for less

urgent treatment needs. A Cochrane review showed that combina-

tion chemotherapy gave a statistically significant improvement in

response rate, time to progression and overall survival but was more

toxic compared to single agent chemotherapy (Carrick 2009). Few

studies included in this review formally compared women’s quality

of life between combination and single agent therapy. While the

review by Carrick et al tested the benefit of two agents given in

combination compared to a single agent it did not address the ben-

efit of two agents given in combination versus the same drugs given

as sequential monotherapy. It is not known if it is more beneficial

to give a combination of drugs at the same time or to give the same

drugs as single agents administered sequentially. Furthermore, re-

garding sequential single agents, there is still debate about whether

single agents should be given until disease progression (when the

drugs are changed) or whether a planned sequence of single agents

should be given that involves changing the drug before resistance

develops and disease progression occurs (see Objectives).

O B J E C T I V E S

To assess the effect of combination chemotherapy compared to

the same drugs given sequentially in women with metastatic breast

cancer.

We compared the use of single chemotherapy agents given se-

quentially with regimens using a combination of the same agents

for the management of women with metastatic breast cancer to

determine their effect on survival. This involved examining two

different chemotherapy schemata:

• schema 1: the combination given until disease progression

versus sequential single agents given on disease progression, e.g.

cycles of combination AB until disease progression versus cycles

of drug A until disease progression followed by cycles of drug B

until disease progression;

• schema 2: the combination given for a set number of cycles

versus sequential single agents given as a set number of cycles,

e.g. eight cycles of AB versus four cycles of A followed by four

cycles of B.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomised controlled clinical trials that compared a combina-

tion of drugs with the same single chemotherapy agents given se-

quentially for women with metastatic breast cancer.

Types of participants

Women diagnosed with all types of advanced (metastatic) breast

cancer. Metastatic breast cancer was defined as stage IV by the

TNM classification of malignant tumours. Adults aged 18 years

and above were included.

Types of interventions

The intervention was any chemotherapy regimen containing a

combination of chemotherapeutic agents given as first-line or sec-

ond-line and third-line treatment.

The comparison was sequential single agent use of the drugs in the

combination chemotherapy regimen given as first-line or second-

line and third-line treatment. The sequential single agents may

have been administered according to either schema 1 or schema 2

as described under Objectives.

Trials were excluded that included a single agent chemotherapeutic

agent alone (drug A alone).

Types of outcome measures

Primary outcomes

1. Overall survival

2. Progression-free survival (or time to progression)



Secondary outcomes

1. Tumour response rate

2. Quality of life measures

3. Toxicity

Outcome definitions

1. Overall survival (OS): time from date randomised to date

of death (any cause).

2. Progression-free survival (PFS): time from date randomised

to date of progression or death from any cause. We used time to

progression (TTP) (time from randomisation to date of

progression) when PFS was not reported.

3. Overall response rate (RR): the percentage of patients with

a complete or partial response. Complete and partial responses

were defined according to Response Evaluation Criteria in Solid

Tumors (RECIST) criteria (Therasse 2000). That is, a complete

response was the disappearance of all target lesions and a partial

response was at least a 30% decrease in the sum of the longest

diameter of target lesions. The composite response rate was used

for sequential single agent chemotherapy. This was calculated as

the percentage of patients responding at some point during any

of the single agent regimens.

4. Quality of life was defined as an expression of well-being

and measured using a validated scale (e.g. Short Form-36 (SF-

36), European Organisation for Research and Treatment of

Cancer (EORTC), Functional Assessment of Cancer Therapy

(FACT)).

5. Toxicities: restricted in our analyses to serious side effects as

classified by the World Health Organization (WHO) or

National Cancer Institution Criteria (NCIC) grading 3 or more.

Search methods for identification of studies

See: Breast Cancer Group methods used in reviews.

Only trials published in English were included.

Electronic searches

We searched the following databases.

1. The Cochrane Breast Cancer Group (CBCG) Specialised

Register (searched on 31 October 2013). Details of search

strategies used by the CBCG for the identification of studies and

the procedures used to code references are outlined in the

CBCG’s module at www.mrw.interscience.wiley.com/cochrane/

clabout/articles/BREASTCA/frame.html). Trials with the key

words ’advanced breast cancer’, ’metastatic breast cancer’,

’combination chemotherapy’, ’sequential single agent

chemotherapy’ and ’single agent chemotherapy’ were extracted

and considered for inclusion in the review.

2. MEDLINE (via OvidSP) (searched on 31 October 2013),

see Appendix 1.

3. EMBASE (via Embase.com) (searched on 31 October

2013), see Appendix 2.

4. The WHO International Clinical Trials Registry Platform

(ICTRP) search portal (http://apps.who.int/trialsearch/

Default.aspx) for prospectively registered and ongoing trials

(searched on 22 March 2012), see Appendix 3.

5. ClinicalTrials.gov (http://clinicaltrials.gov/ct2/search/

advanced) (searched on 22 March 2012), see Appendix 4.

Searching other resources

(a) Bibliography searching

We tried to identify further studies from reference lists of identified

relevant trials or reviews. A copy of the full article for each reference

reporting a potentially eligible trial was obtained, where possible.

Where this was not possible, we attempted to make contact with

the authors to provide additional information.

(b) Handsearching of journals

We handsearched the database of abstracts on the treatment of

metastatic breast cancer from the annual meetings of the American

Society of Clinical Oncology (1987 to 2000; 2003) and San An-

tonio Breast Cancer Conference (1981 to 2002). A list of journals

currently being handsearched by The Cochrane Collaboration is

available at the US Cochrane Center Handsearch master list page

(http://us.cochrane.org/master-list).

Data collection and analysis

We performed the analysis in accordance with the guidelines pub-

lished in the Cochrane Handbook for Systematic Reviews of Inter-

ventions Version 5.1.0 (Higgins 2011).

Selection of studies

Two authors (RD, MT) independently screened the results of the

search. We applied the selection criteria described above to each

trial and recorded any reasons for exclusion. A full copy of trials

likely to be included in the review were retrieved and read. For un-

published trials, we assessed the available information from con-

ference proceedings. Any discrepancies were resolved by a third

author. Only manuscripts published in English were included.

Data extraction and management

Data were extracted from trial publications by two authors (RD,

MT). A standardised data extraction form was used to record de-

tails of study design, participants, setting, interventions, follow-

up, quality components, efficacy outcomes, toxicity and quality of



http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/BREASTCA/frame.html




http://apps.who.int/trialsearch/Default.aspx





http://clinicaltrials.gov/ct2/search/advanced






http://us.cochrane.org/master-list





life. The form is available from the authors upon request. A third

author (NW) was available to resolve any discrepancies regarding

the extraction of quantitative data and a fourth author (AB) was

available to resolve any discrepancies regarding the assessment of

the quality of the randomised controlled trials. When a trial was

presented in abstract form, we sought further information, as nec-

essary, from the internet, contacting the authors, or checking for

the next best available resource or publication.

In the case of published papers, we also contacted the authors for

additional information if it was not reported in the paper. For

studies with more than one publication, we extracted data from

all the publications, however we considered the final or updated

version of the trial as the primary reference.

Assessment of risk of bias in included studies

Quality assessment was based on the assessment of a list of proce-

dures related to the design and reporting of trials that are known

to minimise the risk of bias. Therefore, trials were assessed by the

degree they addressed each of the following items.

Random sequence generation

1. Low risk: if the allocation sequence was generated by a

computer or random number table. Drawing of lots, tossing of a

coin, shuffling of cards or throwing dice were considered as

adequate if a person who was not otherwise involved in the

recruitment of participants performed the procedure.

2. Unclear risk: if the trial was described as randomised but

the method used for the allocation sequence generation was not

described.

3. High risk: if the trial used a system involving dates, names,

admittance numbers or alternating allocation.

Allocation concealment

1. Low risk: if the allocation of patients involved a central

independent unit; sequentially numbered identical drug

containers; or serially numbered, sealed, opaque envelopes.

2. Unclear risk: if the trial was described as randomised but

the method used to conceal the allocation was not described.

3. High risk: if the allocation sequence was known to the

investigators who assigned participants; the envelopes did not

have all three safeguards; or if a non-random sequence was used.

Blinding of participants, personnel and outcome assessors

1. Low risk: if the trial was described as double-blind or

single-blind i.e. double-blind (method described and technique

used meant that neither the participant nor the care provider or

assessor knew which treatment was given) and single-blind

(participant or care provider or assessor was aware of the

treatment given).

2. Unclear risk: if the trial was described as double-blind or

single-blind but the method of blinding was not described.

3. High risk: if the trial was open label (all parties were aware

of the treatment).

Incomplete outcome data addressed

The completeness of outcome data were described for each main

outcome. The description included whether attrition and exclu-

sions were reported, the numbers in each intervention group (com-

pared with total randomised participants), reasons for attrition

and exclusions and any re-inclusions in the analysis.

1. Low risk: no missing data; or reasons for missing data were

not related to outcome, were balanced across groups with similar

reasons or numbers of participants missing, or plausible effect

size was not enough to change observed effect.

2. Unclear risk: attrition and exclusions reported but reasons

were not included.

3. High risk: incomplete outcome data were not addressed.

Free of selective outcome reporting

We stated how the possibility of selective outcome reporting was

examined by the review authors and what was found.

1. Low risk: all pre-specified outcomes were reported in a pre-

specified way.

2. Unclear risk: expected outcomes were reported but not pre-

specified.

3. High risk: outcomes were not reported as planned or

expected; or the outcomes were reported in a way they could not

be used in the review, e.g. only direction of effect and

significance.

Other sources of bias

Comments were made regarding the following.

• If the treatment groups were similar at baseline regarding

the most important prognostic factors.

• If the trial was stopped early using a data-dependent process

(including formal stopping rule).

• If analysis was by intention to treat (or enough data were

provided to replicate such an analysis i.e. number of withdrawals,

dropouts and losses to follow-up in each group).

We contacted authors of the primary trial reports, when necessary,

to clarify data and provide missing information. We entered the

characteristics and outcomes of the included trials and details of

the excluded trials into our database.

Each selected study was assessed as low, unclear or high risk of

bias based on assessments of the domains described above (ran-

dom sequence generation, allocation concealment, blinding, in-

complete data addressed, free of selective outcome reporting and

other sources of bias). Since the selected studies had different levels



of risk of bias (with most being of high or unclear risk of bias),

we conducted a primary analysis including all trials and then per-

formed a sensitivity analysis to show how the conclusions were

affected if studies of unclear or high risk of bias were excluded.

Measures of treatment effect

We extracted the hazard ratio (HR) and associated variances for

overall survival and progression-free survival (or time to progres-

sion) directly from the trial publications.

We obtained a pooled HR through the generic inverse variance ap-

proach, from the log HR and the standard error of the log HR, us-

ing fixed-effect and random-effects models along with assessments

of heterogeneity (Deeks 2006). The pooled HR represented the

overall risk of an event on combination chemotherapy regimens

compared to single agent sequential chemotherapy.

We reported ratios of treatment effects for time-to-event outcomes

so that HRs less than 1.0 favoured combination chemotherapy

regimens and values greater than 1.0 favoured single agent sequen-

tial chemotherapy regimens. The forest plots for overall survival

and progression-free survival presented the hazard ratio (HR) and

95% confidence interval (CI).

We analysed an indicator of response as a dichotomous variable

(complete or partial response versus stable disease or no response)

and derived a pooled relative risk (RR). We reported responses on

an intention-to-treat basis. If the majority of trials only reported

results based on assessable (not randomised) patients, we used as-

sessable responses. We reported ratios of treatment effects for re-

sponse so that risk ratios (RRs) more than 1.0 favoured combi-

nation chemotherapy regimens and values less than 1.0 favoured

single agent sequential chemotherapy regimens.

Unit of analysis issues

Four trials were three-arm studies (Cresta 2004; Koroleva 2001;

Sledge 2003; Soto 2006). Two out of three of the arms in each of

these trials were combined. For Cresta 2004, there was one com-

bination arm of doxorubicin and docetaxel, a single agent arm

where these two drugs were given on an alternating schedule, and

another single agent arm where the drugs were given sequentially.

The two single agent arms were combined in this trial. In Koroleva

2001 there were two combination arms using doxorubicin and

docetaxel but at different doses, and one sequential single agent

arm. The two combination arms were combined in this trial. In

Sledge 2003 there was one combination arm that included dox-

orubicin and paclitaxel, one single agent arm that started with

doxorubicin, and another single agent arm that began treatment

with paclitaxel. The two single agent arms were combined in this

arm. In Soto 2006 there was one sequential single agent arm that

included capecitabine followed by a taxane (either docetaxel or

paclitaxel), a combination arm that included capecitabine and do-

cetaxel, and another combination arm that included capecitabine

and paclitaxel. The two combination arms were combined in this

trial.

Dealing with missing data

If data were missing, we made multiple attempts to contact the

original investigators. This was successful in the case of four studies

(Alba 2004; Fountzilas 2001; Park 2010; Sledge 2003). When

we were unable to obtain data, two authors extracted data from

published Kaplan-Meier curves (Tierney 2007). If there was a

discrepancy between authors, we took an average of the two values

at each time point and used the averaged values to generate a new

HR. To allow for premature follow-up, we adjusted the numbers

at risk based upon estimated minimum and maximum follow-up

times. If these were not reported we estimated minimum follow-

up using the estimated time taken to complete treatment. We

estimated maximum follow-up using the last event reported in

the relevant time-to-event curve. We have presented these follow-

up estimates in the Characteristics of included studies table under

’Notes’.

Assessment of heterogeneity

We included all outcomes available from the individual studies in

the meta-analysis with heterogeneity reported by the Q (Chi2) and

the I2 statistics. Statistical significance of the Q statistic was judged

as P < 0.10 because of the low statistical power of the test. The I2 statistic indicates the per cent variability due to between-study

(or inter-study) variability, as opposed to within-study (or intra-

study) variability. An I2 statistic greater than 50% was considered

large (Higgins 2002), however this was considered alongside the

magnitude and direction of effects and the P value from the Chi2

test for heterogeneity.

Assessment of reporting biases

Reporting bias was assessed using the Cochrane Collaboration’s

assessment tool (Table 8.6a) in the Cochrane Handbook for System-

atic Reviews of Interventions (Higgins 2011).

Data synthesis

We used a fixed-effect model for meta-analysis. HRs and RRs were

calculated with a generic inverse variance fixed-effect model anal-

ysis. Response rates were analysed as dichotomous variables and

we derived a pooled relative risk. We used the Mantel-Haenszel

method with zero-cell corrections for the analysis of treatment-

related deaths because this was a rare event, however we used the

inverse variance method to pool the RRs for the other toxicity

outcomes (neutropenia, febrile neutropenia and nausea and vom-

iting) because these outcomes are not rare events. We also analysed

all toxicity outcomes using conditional logistic regression.



Subgroup analysis and investigation of heterogeneity

As outlined in the protocol, we pre-specified three subgroups. We

extracted data on these subgroups from all trial publications, where

available.

1. Schedule of single agent: schema 1 versus schema 2 (see

Objectives).

2. Dose of chemotherapy: trials where the dose used in the

combination regimen was the same as the doses of the single

agents compared to trials where the doses were not equivalent in

the two arms of the study.

3. Line of chemotherapy for metastatic breast cancer (first-line

versus second-line or third-line chemotherapy).

Sensitivity analysis

A sensitivity analysis comparing the outcomes using studies at low

risk of bias with outcomes of studies of unclear or high risk of

bias was performed. Trials were assessed for quality by the degree

to which they addressed the following seven domains: random

sequence generation, allocation concealment, blinding of partic-

ipants and personnel, blinding of outcome assessors, incomplete

outcome data, selective outcome reporting, and if the analysis was

by intention to treat. Each selected study was assessed as low, un-

clear or high risk of bias based on assessing each of these domains.

If the majority of the seven categories (that is four or more out of

seven) were considered at unclear or high risk of bias the trial was

considered to be at risk of bias.

R E S U L T S

Description of studies

See: Characteristics of included studies and Characteristics of

excluded studies.

Results of the search

We searched the Cochrane Breast Cancer Group Specialised Reg-

ister, EMBASE, MEDLINE, the WHO ICTRP and ClinicalTri-

als.gov. From these databases 2299 were coded as references to

studies of advanced breast cancer and chemotherapy (Figure 1).

Of these 160 were duplicate studies, leaving 2139 remaining stud-

ies. Of these 18 were trials that compared combination chemo-

therapy with drugs given as sequential single agents. Two were

excluded because the drugs given in the sequential arm were dif-

ferent from those in the combination arm. Two studies (Campone

2013; Zhang 2013) were categorised as ’study awaiting classifica-

tion’ because the trials were completed but with insufficient data

for inclusion at present. The results from these two small trials will

be included in an updated version of this review. The remaining

14 references reported the results of 14 randomised trials. One

report (Chlebowski 1989) combined the results from two separate

but similar trials, both of which were reported earlier (Chlebowski

1979; Smalley 1976). Both of these publications were therefore

excluded from the review. The 12 eligible trials reported on nine

treatment comparisons, summarised in Table 1. The details of the

chemotherapy protocols used are detailed in Table 2. The trials

included in the forest plots are labelled by primary author and

date of publication. Nine of the trials were published in full while

three were only available in abstract form.



Figure 1. Results of search strategy applied 31 October 2013 for combination versus sequential single agent

chemotherapy for metastatic breast cancer.



Of the 12 eligible trials, only one allowed crossover from one arm

to the other. This occurred in Sledge 2003 between the two single

agent arms but did not include the combination arm. At the time

of progression, patients in the doxorubicin arm crossed over to

paclitaxel, and those in the paclitaxel arm crossed over to doxoru-

bicin. These two single agent arms were therefore equivalent to

two sequential single agent arms and were analysed as such in this

review.

Risk of bias in included studies

See: ’Risk of bias’ graph (Figure 2).

Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as

percentages across all included studies.

Allocation

Sequence generation was clearly reported in three trials (Baker

1974; Conte 2004; Fountzilas 2001) and was unclear in the re-

maining nine trials (Alba 2004; Beslija 2006; Chlebowski 1989;

Cresta 2004; Koroleva 2001; Park 2010; Sledge 2003; Soto 2006;

Tomova 2010). Two trials had adequate allocation concealment

(Chlebowski 1989; Conte 2004). In nine trials allocation con-

cealment was unclear (Alba 2004; Beslija 2006; Cresta 2004;

Fountzilas 2001; Koroleva 2001; Park 2010; Sledge 2003; Soto

2006; Tomova 2010). However, in all of these trials there were

no large differences in baseline characteristics between the two

treatment arms. In one trial (Baker 1974) there was no allocation

concealment: “all patients treated with chemotherapy during this

time period were entered onto the study, despite the fact that the

physician might have known which branch the patient would be

entered into prior to the initiation of therapy...this...probably ac-

counted for the difference in size of the two divisions”.

Blinding

In all but one trial it was unclear if there was blinding of partic-

ipants or personnel. In the one trial where it was clear, there was

not blinding of study personnel (Baker 1974). In two trials there

was blinding of outcome assessors (Fountzilas 2001; Park 2010)

but in the remaining 10 trials it was unclear if there was blinding

of the outcome assessors.



Incomplete outcome data

Completeness of outcome data was adequate in 10 trials. The

remaining two trials (Koroleva 2001; Soto 2006) reported attrition

rates or exclusions but reasons were not provided so complete

reporting of outcomes was judged as unclear.

Selective reporting

For eight trials, completeness of all outcome data was adequate

for use in the review. Outcome data were either directly extracted

from the paper (Beslija 2006; Park 2010), provided after contact-

ing the authors (Alba 2004; Fountzilas 2001; Sledge 2003) or

calculated from Kaplan-Meier curves in the case of HRs (Baker

1974; Conte 2004; Tomova 2010). In one trial the majority of

outcomes had adequate completeness although there was one out-

come which was unclear, progression-free survival (Chlebowski

1989). The remaining three trials had inadequate completeness of

outcome data for both overall and progression-free survival (Cresta

2004; Koroleva 2001; Soto 2006). Only the direction of effect

and P value were provided in these trials. All trials reported the

response rate and toxicity. Only three trials reported quality of life

(Conte 2004; Park 2010; Sledge 2003).

Three trials in the review were in the form of abstracts (Beslija

2006; Koroleva 2001; Soto 2006) so in the background section

they hypothesised that combination chemotherapy prolongs over-

all survival, progression-free survival and response rate, which im-

plied that these were pre-specified outcomes. Toxicity was not usu-

ally pre-specified. The abstracts did not describe how the outcomes

were reported and this was not explained in the methods section.

However, reporting of outcomes was adequate in Beslija 2006 but

not in Koroleva 2001 or Soto 2006.

Other potential sources of bias

The main other potential source of bias was that in seven trials

the analysis was not by intention to treat (Baker 1974; Conte

2004; Koroleva2001; Park 2010, Sledge2003; Soto 2006; Tomova

2010). To overcome this problem, when we extracted the data

from these trials we analysed the results by intention to treat.

Effects of interventions

The ratios of treatment effects for time-to-event outcomes were

reported so that hazard ratios (HRs) less than 1.0 favoured the

combination arm and HRs more than 1.0 favoured the sequential

arm. We have reported ratios of treatment effects for response so

that a risk ratio (RR) of more than 1.0 favoured the combination

arm.

Of the 12 trials, the primary outcome in most trials (eight out

of 12) was the objective response rate (Beslija 2006; Conte 2004;

Cresta 2004; Fountzilas 2001; Koroleva 2001; Park 2010; Sledge

2003; Soto 2006). In two trials the primary outcome was overall

survival (Baker 1974; Chlebowski 1989); in one trial the primary

outcome was time to progression (Tomova 2010); and in one trial

the primary outcome was toxicity (Alba 2004). Most trials had a

superiority design, although one trial used a noninferiority design

(Conte 2004). See: the Characteristics of included studies, Table

1 on treatment comparisons used in the included studies, and

Table 2 detailing the chemotherapy regimens used in the included

studies.

The results for the pooled data, from all trials that had extractable

data, are detailed first followed by four subgroup analyses.

All trials

Overall survival - all trials

There are 12 trials in this review, which included nine treatment

comparisons. A total of 2317 women were randomised. Time-

to-event data were extractable for overall survival from nine tri-

als, which included nine treatment comparisons. This represented

77% of all patients randomised (1786/2317). There were 1023

deaths in 2317 women randomised. The overall HR for overall

survival was 1.04 (95% CI 0.93 to 1.16; P = 0.45) (Figure 3) and

there was no statistically significant heterogeneity (I2 = 24%; P =

0.23).



Figure 3. Forest plot of comparison: 1 Overall survival, outcome: 1.1 Overall survival (all trials).

Progression-free survival - all trials

Progression-free survival data were available from eight trials,

which included eight treatment comparisons. This represented

68% of all patients randomised (1564/2317). There were 678

women who progressed out of 886 randomised. Combination che-

motherapy had a higher risk of progression than sequential single

agent chemotherapy with an overall HR of 1.16 (95% CI 1.03 to

1.31; P = 0.01) (Figure 4) and there was no statistically significant

heterogeneity (I2 = 26%; P = 0.22).

Figure 4. Forest plot of comparison: 2 Progression-free survival, outcome: 2.1 Progression-free survival (all

trials).



Overall tumour response rate - all trials

Tumour response rates for assessable patients were available for

all 12 trials in the review. This represented 92% of all patients

randomised (2140/2317). Combination chemotherapy was asso-

ciated with a higher overall tumour response rate compared to se-

quential single agent chemotherapy with an RR of 1.16 (95% CI

1.06 to 1.28; P = 0.001) (Figure 5). There was statistically signifi-

cant heterogeneity for this outcome across the trials (I2 = 72%; P

< 0.0001).

Figure 5. Forest plot of comparison: 3 Overall response, outcome: 3.1 Overall response (all trials).

Toxicity - all trials

Treatment-related deaths were reported in seven trials. This rep-

resented 39% of all patients randomised (902/2317). There were

24 treatment-related deaths of which 16 occurred in the combi-

nation arm and eight occurred in the sequential arm. This was not

statistically significant (RR 1.53; 95% CI 0.71 to 3.29; P = 0.28)

(Analysis 4.1). There was no statistically significant heterogeneity

(I2 = 29%; P = 0.22).

All 12 trials provided extractable data on grade III or IV toxic-

ity. Of these, 12 reported on neutropenia or leukopenia (2351

patients), nine on febrile neutropenia (2328 patients), and eight

on nausea and vomiting (1719 patients). Regarding neutropenia

and leukopenia, data on grade III or IV leukopenia was included

if neutropenia was not reported (Baker 1974; Chlebowski 1989;

Tomova 2010). In trials where the toxicity was described as ’se-

vere’ we assumed they assessed toxicity similarly to the trials with

toxicity grade III or IV using the WHO criteria (Baker 1974;

Chlebowski 1989).

There was no difference in the risk of neutropenia or leukopenia

(RR 0.94; 95% CI 0.87 to 1.02; P = 0.12) (Analysis 5.1) but

there was significant heterogeneity between trials (I2 = 78%; P

<0.00001). However, combination chemotherapy was associated

with an increased likelihood of febrile neutropenia (RR 1.32; 95%

CI 1.06 to 1.65; P = 0.01) (Analysis 6.1). There was no significant

heterogeneity (I2 = 42%; P = 0.09). There was no difference in the

risk of nausea and vomiting (RR 0.88; 95% CI 0.57 to 1.34; P =

0.55) (Analysis 7.1) and there was no significant heterogeneity (I2 = 0%; P = 0.58).

When the toxicity outcomes were analysed using conditional lo-

gistic regression the results were similar to those provided by the

Mantel-Haenszel method for treatment-related deaths and the in-

verse variance method for the other toxicity measures (neutrope-

nia, febrile neutropenia, and nausea and vomiting).



Quality of life - all trials

Quality of life data were reported in three trials. This represented

25% of all patients randomised (589/2317). Two of these trials

used the European Organisation for Research and Treatment of

Cancer (EORTC) Quality of Life Questionnaire (QLQ C-30)

(Conte 2004; Park 2010) and one used FACT-B (Sledge 2003) to

measure quality of life. In Conte 2004 emotional functioning was

better in the combination arm (score differences 3.53; 95% CI -

6.99 to -0.06). There was no significant difference for the seven

symptom scales or for financial impact. In Park 2010 there was no

difference in baseline subscale scores between the two arms, and no

significant difference in symptom scale scores during treatment.

However, the combination arm had statistically better scores in

role functioning, social functioning, and global health compared

to the sequential arm (P < 0.05). In Sledge 2003 there was no

statistically significant difference between treatment arms on any

quality of life subscales.

Subgroup analyses

Low versus high or unclear risk of bias

We conducted a pre-specified subgroup analysis to investigate the

treatment effect in trials with a low risk of bias compared to the

trials considered at high or unclear risk of bias. In total, there were

two trials considered low risk of bias and 10 trials with a high or

unclear risk of bias.

Overall survival

Data for overall survival were available for both trials with a low risk

of bias. In the trials with a low risk of bias, there was no difference

in overall survival between the combination and sequential arms,

with a HR of 1.21 (95% CI 0.93 to 1.58; P = 0.16) (Analysis 8.1),

and no significant heterogeneity (I2 = 0%; P = 0.93).

Data for overall survival was available for seven out of the 10 trials

with a high or unclear risk of bias. In these trials there was no

difference in overall survival, with a HR of 1.01 (95% CI 0.90 to

1.14; P = 0.85) (Analysis 8.1), and no significant heterogeneity (I2 = 34%; P = 0.17).

A test for interaction between the two groups for overall survival

revealed no significant interaction (P = 0.23).

Progression-free survival

Data for progression-free survival were available for both trials

with a low risk of bias. In the trials with a low risk of bias there

was no difference in progression-free survival, with a HR of 1.15

(95% CI 0.94 to 1.41; P = 0.17) (Analysis 9.1), and no significant


Data for progression-free survival was available for six of the 10

trials with a high or unclear risk of bias. In these trials there was

a higher risk of progression in the combination arm compared to

the sequential arm with a HR of 1.17 (95% CI 1.01 to 1.35, P =

0.03) (Analysis 9.1) and no significant heterogeneity (I2 = 45%;

P = 0.11).

A test for interaction between the two groups for progression-free

survival revealed no significant interaction (P = 0.93).

Overall response

Data for overall response rate were available for both trials with

a low risk of bias. There was no difference in overall tumour re-

sponse, with a HR of 0.91 (95% CI 0.76 to 1.10; P = 0.35)

(Analysis 10.1), and no significant heterogeneity (I2 = 49%; P =

0.16).

Tumour response data were available for all 10 trials with a high or

unclear risk of bias. There was a higher overall tumour response rate

in these trials for the combination arm compared to the sequential

arm with a HR of 1.26 (95% CI 1.13 to 1.39; P < 0.0001) (

Analysis 10.1) but there was significant heterogeneity (I2 = 70%;

P = 0.0005).

A test for interaction between the two group for overall tumour

response revealed a significant interaction (P = 0.004).

Treatment-related deaths

Data were available for one out of the two trials with a low risk of

bias. In this trial with a low risk of bias (Conte 2004) there were

three deaths in the combination arm compared to one death in

the sequential arm with no difference in treatment-related deaths

(HR 2.60; 95% CI 0.28 to 24.60; P = 0.40) (Analysis 11.1).

Data were available for six out of the 10 trials with a high or

unclear risk of bias. In these trials there were 13 deaths in the

combination arm and seven deaths in the sequential arm. There

was no statistically significant difference, with a HR of 1.41 (95%

CI 0.62 to 3.20; P = 0.42) (Analysis 11.1), and no significant


A test for interaction between the two groups for treatment-related

deaths revealed no significant interaction (P = 0.61).

Neutropenia

Data were available for both trials with a low risk of bias. In these

two trials with a low risk of bias there was a decreased risk of

neutropenia in the sequential arm compared to the combination

arm (RR 0.62; 95% CI 0.50 to 0.76; P < 0.00001) (Analysis

12.1) however there was significant heterogeneity (I2 = 91%; P =

0.0006).

Data were available for all 10 trials with a high or unclear risk of

bias. In these trials there was no difference in the rates of neutrope-

nia (RR 1.00; 95% CI 0.92 to 1.09; P = 0.98) (Analysis 12.1)

however there was significant heterogeneity (I2 = 59%; P = 0.009).

A test for interaction between the two groups for neutropenia

revealed a significant interaction (P < 0.0001).



Febrile neutropenia

Data were available for both of the trials with a low risk of bias.

In these two trials with a low risk of bias there was no significant

difference in the rates of febrile neutropenia (RR 1.60; 95% CI

0.72 to 3.57; P = 0.25) (Analysis 13.1) and there was no significant


Data were available for seven out of the 10 trials with a high

or unclear risk of bias. In these trials there was an increased risk

of febrile neutropenia in the combination arm compared to the

sequential arm (RR 1.30; 95% CI 1.03 to 1.64; P = 0.03) (Analysis

13.1) but with significant heterogeneity (I2 = 54%; P = 0.04).

A test for interaction between the two groups for febrile neutrope-

nia revealed no significant interaction (P = 0.63).

Nausea and vomiting

Data were available for one out of the two trials with a low risk

of bias. This trial showed no difference in the rates of nausea and

vomiting (RR 1.03; 95% CI 0.21 to 4.99; P = 0.97) (Analysis

14.1).

Data were available for seven out of the 10 trials with a high or

unclear risk of bias. In these trials there was no difference in the

rates of nausea and vomiting (RR 0.87; 95% CI 0.56 to 1.35; P =

0.52) (Analysis 14.1) and no significant heterogeneity (I2 = 0%;

P = 0.46).

A test for interaction between the two groups for nausea and vom-

iting revealed no significant interaction (P = 0.83).

First-line versus second-line or third-line chemotherapy


treatment effect in trials of first-line chemotherapy compared to

trials of second-line or third-line chemotherapy. In total, there

were nine trials with first-line chemotherapy and three trials for

second-line or third-line chemotherapy.

Overall survival

Data were available for seven out of nine trials with first-line che-

motherapy. In the trials of first-line chemotherapy there was no

difference in overall survival between the combination and sequen-

tial arms, with a HR of 1.04 (95% CI 0.93 to 1.18; P = 0.47)


0.17).

Data were available for two out of the three trials of second- or

third-line chemotherapy. In these trials there was no difference in

overall survival, with a HR of 1.03 (95% CI 0.76 to 1.40; P =

0.84) (Analysis 15.1), and no significant heterogeneity (I2 = 28%;

P = 0.24).




Data were available for six out of nine trials of first-line chemo-

therapy. In the trials of first-line chemotherapy there was a higher

risk of progression in the combination arm compared to the se-

quential arm with a HR of 1.16 (95% CI 1.02 to 1.31; P = 0.02)

(Analysis 16.1) and no significant heterogeneity (I2 = 44%; P =

0.11).


third-line chemotherapy. In these trials there was no difference

in progression-free survival, with a HR of 1.25 (95% CI 0.80 to

1.95; P = 0.33) (Analysis 16.1), and no significant heterogeneity

(I2 = 0%; P = 0.52).



Overall response

Data were available for all nine trials investigating first-line che-

motherapy. In these trials of first-line chemotherapy there was ev-

idence of a difference in overall tumour response rate in the com-

bination arm compared to the sequential arm, with a HR 1.10

(95% CI 1.00 to 1.22; P = 0.05) (Analysis 17.1), but there was

significant heterogeneity (I2 = 74%; P = 0.0001).

Data were available for all three trials of second- or third-line

chemotherapy. In these trials there was a higher overall tumour

response rate in the combination compared to the sequential arm

with a HR of 1.54 (95% CI 1.22 to 1.93; P = 0.0002) (Analysis

17.1) and there was no significant heterogeneity (I2 = 0%; P =

0.40).

A test for interaction between the two groups for overall tumour

response revealed a significant interaction (P = 0.009).


Data were available for five of the nine trials of first-line che-

motherapy. In the trials of first-line chemotherapy there were 14

deaths in the combination arm and six deaths in the sequential

arm but this was not statistically different (HR 1.72; 95% CI 0.70

to 4.18; P = 0.23) (Analysis 18.1) and there was no significant



third-line chemotherapy. In these trials there were two deaths in

the combination arm and two deaths in the sequential arm and this

was not statistically different (HR 1.06; 95% CI 0.23 to 4.94; P

= 0.94) (Analysis 18.1) and there was no significant heterogeneity

(I2 = 59%; P = 0.12).



Neutropenia

Data were available for all nine trials of first-line chemotherapy.

In the trials of first-line chemotherapy there was no difference in



rates of neutropenia (RR 0.96; 95% CI 0.87 to 1.05; P = 0.39)

(Analysis 19.1) but there was significant heterogeneity between

the trials (I2 = 81%; P < 0.00001).


chemotherapy. In these trials there were higher rates of neutropenia

in the sequential arm compared to the combination arm (RR 0.64;

95% CI 0.48 to 0.85; P = 0.002) (Analysis 19.1) and there was

no significant heterogeneity (I2 = 0%; P = 0.62).


revealed a significant interaction (P = 0.007).

Febrile neutropenia

Data were available for seven out of nine trials of first-line chemo-

therapy. In these trials there were higher rates of febrile neutrope-

nia in the combination arm compared to the sequential arm (RR

1.34; 95% CI 1.07 to 1.68; P = 0.01) (Analysis 20.1) and there

was significant heterogeneity (I2 = 48%; P = 0.07).


third-line chemotherapy. In these trials there was no difference in

the rates of febrile neutropenia (RR 0.86; 95% CI 0.24 to 3.15;

P = 0.82) (Analysis 20.1) and no significant heterogeneity (I2 =

43%; P = 0.18).



Nausea and vomiting

Data were available for five out of nine trials of first-line chemo-

therapy. There was no difference in the rate of nausea and vom-

iting (RR 0.85; 95% CI 0.55 to 1.33; P = 0.48) (Analysis 21.1)

and no significant heterogeneity (I2 = 0%; P = 0.53).


chemotherapy. There was no difference in the rate of nausea and

vomiting (RR 1.25; 95% CI 0.27 to 5.74; P = 0.78) (Analysis

21.1) and no significant heterogeneity (I2 = 25%; P = 0.25).



Chemotherapy given on disease progression (schema 1)

versus chemotherapy given for a set number of cycles

(schema 2)


treatment effect in trials where the combination or sequential arms

were given until disease progression (schema 1) compared to trials

where the combination or sequential arms were given for a set

number of cycles (schema 2). In total, there were six trials that

used schema 1 and six trials that used schema 2.

Overall survival

Data were available for five out of the six trials that used schema

1. In trials where chemotherapy was given on disease progression

there was no difference in overall survival, with a HR of 0.98

(95% CI 0.86 to 1.12; P = 0.77) (Analysis 22.1), and there was

no significant heterogeneity (I2 = 47%; P = 0.11).

Data were available for four out of the six trials that used schema

2. In trials where chemotherapy was given for a set number of

cycles there was no difference in overall survival, with a HR of

1.22 (95% CI 0.99 to 1.49; P = 0.06) (Analysis 22.1), and there

was no significant heterogeneity (I2 = 0%; P = 1.00).




Data were available for four out of the six trials that used schema


there was a higher risk of progression in the combination arm

compared to the sequential arm with a HR of 1.20 (95% CI

1.03 to 1.40; P = 0.02) (Analysis 23.1) but there was significant


Data were available for four out of the six trials that used schema 1.

In trials where chemotherapy was given for a set number of cycles

there was no difference in progression-free survival, with a HR of

1.12 (95% CI 0.94 to 1.33; P = 0.22) (Analysis 23.1), and there

was no significant heterogeneity (I2 = 0%; P = 0.84).



Overall response

Data were available for all six trials that used schema 1. In trials

where chemotherapy was given on disease progression there was a

higher overall tumour response in the combination arm compared

to the sequential arm with a HR of 1.46 (95% CI 1.28 to 1.65; P

< 0.00001) (Figure 6) but there was significant heterogeneity (I2

= 58%; P = 0.04).



Figure 6. Forest plot of comparison: 24 Overall response - schema 1 versus schema 2, outcome: 24.1

Overall response - schema 1 versus schema 2.


where chemotherapy was given for a set number of cycles there

was no significant difference in overall tumour response in the

combination compared to the sequential arm, with a HR of 0.92

(95% CI 0.80 to 1.04; P = 0.19) (Figure 6), and there was no



response revealed a significant interaction (P < 0.00001).


Data were available for three out of the six trials that used schema


there were nine deaths in the combination arm and seven deaths

in the sequential arm, with no significant difference in treatment-

related deaths (HR of 0.94; 95% CI 0.36 to 2.44; P = 0.90)

(Analysis 25.1) and no significant heterogeneity (I2 = 58%; P =

0.09).

Data were available for four out of the six trials that used schema 2.


there were seven deaths in the combination arm and one death in

the sequential arm, with no significant difference (HR 4.00; 95%

CI 0.87 to 18.35; P = 0.07) (Analysis 25.1) and no significant




Neutropenia


where chemotherapy was given on disease progression there was

no difference in the rates of neutropenia (RR 0.99; 95% CI 0.87

to 1.14; P = 0.92) (Analysis 26.1) and there was significant het-

erogeneity (I2 = 47%; P = 0.09).



was no difference in the rates of neutropenia (RR 0.92; 95% CI

0.84 to 1.01; P = 0.07) (Analysis 26.1) but there was significant

heterogeneity (I2 = 88%; P < 0.00001).



Febrile neutropenia



Data were available for three out of six trials that used schema 1. In

trials where chemotherapy was given on disease progression there

was an increased risk of febrile neutropenia in the combination

arm compared to the sequential arm (RR 1.76; 95% CI 1.14 to

2.73; P = 0.01) (Analysis 27.1) and no significant heterogeneity

(I2 = 19%; P = 0.29).



was no difference in the risk of febrile neutropenia (RR 1.19;

95% CI 0.92 to 1.55; P =0.18) (Analysis 27.1) and no significant




Nausea and vomiting

Data were available for three out of six trials that used schema 1. In

trials where chemotherapy was given on disease progression there

was no difference in the risk of nausea and vomiting (RR 0.75;

95% CI 0.39 to 1.46; P = 0.40) (Analysis 28.1) and no significant


Data were available for five out of six trials that used schema 2.


there was no difference in the risk of nausea and vomiting (RR

0.98; 95% CI 0.56 to 1.71; P = 0.94) (Analysis 28.1) and no




Relative dose intensity


treatment effect in trials that contained arms with a similar relative

dose intensity (RDI) compared to trials where there was a different

RDI. In total, there were three trials with a similar RDI and three

trials with a different RDI.

Overall survival

Data were available for two out of the three trials with a similar

RDI between the combination and sequential arms. In the trials

with a similar RDI between arms there was no difference in overall

survival, with a HR of 1.23 (95% CI 0.93 to 1.62; P = 0.15)


0.96).

Data were available for two out of the three trials with a different

RDI. There was no difference in overall survival, with a HR of

1.03 (95% CI 0.76 to 1.40; P = 0.84) (Analysis 29.1), and no





Data were available for two out of the three trials with a similar

RDI. There was no difference in progression, with a HR of 1.15



Data were available for two out of the three trials with a different

RDI. There was no difference in progression, with a HR of 1.25





Overall response

Data were available for all three trials with a similar RDI between

the combination and sequential arms. There was no difference in

overall tumour response, with a HR of 0.88 (95% CI 0.72 to 1.07;

P = 0.20) (Analysis 31.1), and no significant heterogeneity (I2 =

0%; P = 0.43).

Data were available for all three trials with a different RDI between

the combination and sequential arms. There was no difference in

overall tumour response, with a HR of 0.93 (95% CI 0.72 to 1.20;

P = 0.55) Analysis 31.1), and no significant heterogeneity (I2 =

46%; P = 0.16).


response revealed no significant interaction (P = 0.76).


Data were available for one out of three trials with a similar RDI.

In this trial with a similar RDI in the combination and sequential

arms there were no treatment-related deaths in either arm.

Data were available for all three trials with a different RDI between

the combination and sequential arms. There were four deaths in

the combination arm and two deaths in the sequential arm but this

was not statistically significant, with a HR of 1.66 (95% CI 0.45

to 6.10; P = 0.44) (Analysis 32.1), and was without significant


A test for interaction was not applicable.

Neutropenia

Data were available for all three trials with a similar RDI. There was

no difference in the rates of neutropenia (RR 1.08; 95% CI 0.97

to 1.20; P = 0.15) (Analysis 33.1) and no significant heterogeneity

(I2 = 60%; P = 0.08).

Data were available for all three trials with a different RDI. In trials

with differing RDIs there were higher rates of neutropenia in the

sequential arm compared to the combination arm (RR 0.67; 95%

CI 0.51 to 0.87; P = 0.003) (Analysis 33.1) and no significant


A test for interaction revealed a significant difference for neutrope-

nia between the two groups (P = 0.001).



Febrile neutropenia

Data were available for all three trials with a similar RDI. There

was a higher rate of febrile neutropenia in the combination arm

compared to the sequential arm (RR 2.36; 95% CI 1.21 to 4.62; P

= 0.01) (Analysis 34.1) and there was no significant heterogeneity

(I2 = 36%; P = 0.21).

Data were available for all three trials with a different RDI. In trials

with differing RDIs there was no difference in the rates of febrile

neutropenia (RR 1.07; 95% CI 0.80 to 1.42; P = 0.66) (Analysis

34.1) and no significant heterogeneity (I2 = 0%; P = 0.39).

A test for interaction revealed a significant difference for febrile

neutropenia between the two groups (P = 0.03).

Nausea and vomiting

Data were available for all three trials with a similar RDI. There

was no difference in the rates of nausea and vomiting (RR 1.14;



Data were available for all three trials with a different RDI. There

was no difference in the rates of nausea and vomiting (RR 0.86;





D I S C U S S I O N

Summary of main results

There was no statistically significant benefit in overall survival for

combination compared to sequential single agent chemotherapy

in the first-, second- or third-line treatment of metastatic breast

cancer. This result was consistent in the four subgroups analysed

(that is trials judged as high versus low risk of bias, first-line versus

second- or third-line, schema 1 versus schema 2, and similar versus

different dose intensity). In particular, there was no difference in

outcome according to the type of sequential schema of chemo-

therapy.

The review demonstrated that combination therapy had a higher

risk of progression than sequential therapy (HR 1.16; 95% CI

1.03 to 1.31; P = 0.01), with no significant heterogeneity. Again,

this result was consistent in all subgroups. Even if there was a sug-

gestion of a higher risk of progression in one subgroup compared

to another (for example in trials with a high or unclear risk of bias,

in trials of first-line chemotherapy, and trials where treatment was

changed on disease progression), a test for interaction in each of

these instances did not reveal a statistically significant interaction

for these subgroups.

Overall tumour response rates were higher for combination ther-

apy compared to sequential therapy (RR 1.16; 95% CI 1.06 to

1.28; P = 0.001) but there was significant heterogeneity for this

outcome across the trials. In trials with a high or unclear risk of

bias there was a higher rate of tumour response (RR 1.26; 95% CI

1.13 to 1.39; P < 0.0001) than in the two trials which had a low

risk of bias (RR 0.91; 95% CI 0.76 to 1.10; P = 0.35), however

there was significant heterogeneity in the trials of high or unclear

risk of bias. A test for interaction revealed a difference between

these two groups (P = 0.004). There was evidence of an effect of

combination chemotherapy on tumour response rate for trials of

first-line chemotherapy (RR 1.10; 95% 1.00 to 1.22; P = 0.05)

but there was significant heterogeneity. The effect was greater in

trials of second- or third-line chemotherapy (RR 1.54; 95% CI

1.22 to 1.93; P = 0.0002) and the test for interaction revealed a

difference in these subgroups (P = 0.009). The effect on tumour

response was greater in trials where chemotherapy was changed on

disease progression (schema 1, RR 1.46; 95% CI 1.28 to 1.65; P

< 0.00001) but with significant heterogeneity compared to trials

where chemotherapy was given for a set number of cycles (schema

2, RR 0.92; 95% CI 0.80 to 1.04; P = 0.19). The test for interac-

tion confirmed a difference between schema 1 and schema 2 (P <

0.00001).

As aforementioned, there was no difference in overall survival or

progression-free survival according to the schema of chemother-

apy drugs given. Given this result, it seems preferable to use com-

bination chemotherapy, and change treatment on disease progres-

sion (schema 1), in the setting of rapidly progressive disease when

a greater response rate is desired.

In the seven trials that reported treatment-related deaths, there

were 16 deaths for combination therapy compared to eight deaths

for sequential therapy but there was no statistically significant dif-

ference (RR 1.53; 95% CI 0.71 to 3.29; P = 0.28). The confidence

interval was wide due to the small number of events.

The risk of febrile neutropenia was higher for combination therapy

(RR 1.32; 95% CI 1.06 to 1.65; P = 0.01). This outcome was

consistent amongst all subgroups, although there was a higher risk

of febrile neutropenia in trials with a similar RDI (RR 2.36; 95%

CI 1.21 to 4.62; P = 0.01) compared to trials where there was a

different dose intensity (RR 1.07; 95% CI 0.80 to 1.42; P = 0.66),

and the test of interaction between these groups was significant (P

= 0.03).

Overall, there was no significant difference in the risk of neu-

tropenia (RR 0.94; 95% CI 0.87 to 1.02; P = 0.12) but there was

significant heterogeneity between these trials (P < 0.00001). The

risk of neutropenia was lower for combination therapy than for

sequential therapy in trials which had a low risk of bias (RR 0.62;

95% CI 0.50 to 0.76; P < 0.00001) compared to those with a

high risk of bias (RR 1.00; 95% CI 0.92 to 1.09; P = 0.98) and

the test for interaction between these groups was significant (P <

0.0001). There was significant heterogeneity between the trials in

both of these subgroups. Neutropenia rates were also lower for the

combination therapy compared to the sequential therapy in trials

of second- or third-line chemotherapy (RR 0.64; 95% CI 0.48 to



0.85; P = 0.002) compared to trials of first-line chemotherapy (RR

0.96; 95% CI 0.87 to 1.05; P = 0.39). The test of interaction be-

tween these groups was significant (P = 0.007). Neutropenia rates

were lower in the combination therapy compared to the sequential

therapy in trials using a different RDI (RR 0.67; 95% CI 0.51

to 0.87; P = 0.003) compared to trials that used a similar RDI

(RR 1.08; 95% CI 0.97 to 1.20; P = 0.15). The test of interaction

between these groups was significant (P = 0.001).

There was no significant difference in the risk of nausea and vomit-

ing between the combination and sequential single agent therapies

(RR 0.88; 95% CI 0.57 to 1.37; P = 0.55) and this was consistent

across all subgroups analysed.

Quality of life was only measured in three out of the 12 trials

in this review. In Sledge 2003 there was no difference in quality

of life between the two arms, however in Conte 2004 and Park

2010 there was a suggestion of a better quality of life in some

domains in the combination arm compared to the sequential arm.

In Conte 2004 the trend towards inferior quality of life in the

sequential arm was thought to be due to the higher doses of the

single agents, which caused more haematological and neurological

toxicity. In Park 2010 increased functional scores (role function,

social function) and global health in the combination arm were

postulated to be due to the better response rate in the combination

arm. This is consistent with studies of quality of life in the palliative

setting where quality of life was related to how responsive the

tumour was to chemotherapy (Modi 2002; Shin 2008).

Overall completeness and applicability ofevidence

While data for overall and progression-free survival could be ex-

tracted for the majority of trials (nine of 12 trials for overall sur-

vival, eight of 12 trials for progression-free survival), the evidence

would be more complete if these data were available for all trials.

In the trials where the data were missing, two were published in

abstract form (Koroleva 2001; Soto 2006). In Cresta 2004, HRs

were not published for overall survival or progression-free survival,

and survival curves were not included in the paper. Chlebowski

1989 did not publish a HR for progression-free survival, or include

a survival curve. Despite some missing data, the evidence is still

applicable to clinical practice because survival data were available

for the majority of trials and the results in the subgroup analyses

were consistent with the overall HRs. All trials provided data on

tumour response and neutropenia. There was a paucity of quality

of life data, which means it is not possible to generalise about the

effect of combination versus sequential single agent chemotherapy

on quality of life.

Quality of the evidence

The majority of trials (10 out of 12) were classified as having an

unclear or high risk of bias. For most of these trials this classifi-

cation was made because it was not clearly explained in the trial

methods if factors such as randomisation and blinding were done

properly. Randomisation and blinding make up four out of a to-

tal of seven factors on which the risk of bias is assessed (random

sequence generation, allocation concealment, blinding of partici-

pants and personnel, and blinding of outcome assessment). As a

result, there was a tendency for most trials to score poorly for risk

of bias. While unclear risk is categorised with a high risk of bias it

may be that this is an unfair assumption and randomisation may

in fact have been done properly. Also, blinding is rarely feasible in

chemotherapy trials. The risk of bias in the randomised controlled

trials included in this review may therefore be overestimated and

the quality of the trials may be better than this scoring system

implies.

Potential biases in the review process

There were no potential biases in the review process.

Agreements and disagreements with otherstudies or reviews

The higher overall tumour response rate for combination ther-

apy is consistent with other reviews of combination chemotherapy

in metastatic breast cancer (Butters 2011; Carrick 2009). Butters

2011 aimed to assess the effect of adding a chemotherapy drug,

or drugs, to an established chemotherapy regimen in metastatic

breast cancer and demonstrated an advantage for tumour response

for adding one or more drugs, but there was no difference in overall

survival or time to progression. There was more toxicity with the

addition of one or more drugs to a regimen. Carrick 2009 aimed to

assess the effect of combination chemotherapy compared to single

agent chemotherapy in metastatic breast cancer and found that

combination chemotherapy had superior overall survival, time to

progression and response rates, but more toxicity. Both of these

Cochrane reviews found a high rate of toxicity for neutropenia,

alopecia and nausea and vomiting. Febrile neutropenia was not

analysed separately. Our review found higher rates of febrile neu-

tropenia for combination therapy but no overall difference in the

rates of neutropenia or nausea and vomiting. We did not analyse

rates of alopecia. The higher risk of detection of neutropenia for

sequential therapy compared to combination therapy in some sub-

groups is likely due to the higher doses of the single agents used.

A U T H O R S ’ C O N C L U S I O N S



Implications for practice

Combination chemotherapy does not provide a survival benefit

compared to sequential single agent chemotherapy. It is notable

that there was no difference in outcome according to the treat-

ment strategy of sequential single agents; the single agents can ei-

ther be changed on disease progression, or planned sequences of

the single agents can be administered. Sequential single agent che-

motherapy has a positive effect on progression-free survival while

combination chemotherapy produces a higher tumour response

rate. Combination chemotherapy also has a higher risk of febrile

neutropenia, with no overall difference in rates of neutropenia

or nausea and vomiting. This review supports the recommenda-

tions by international guidelines to use sequential monotherapy

in most clinical scenarios unless there is rapid clinical progression,

life-threatening visceral metastases, or need for rapid symptom

or disease control, where combination chemotherapy is preferred

(Cardoso 2009; Cardoso 2012).

Implications for research

Future trials need to provide good quality evidence so that the

best treatment decisions can be made for women with metastatic

breast cancer. More research is needed to determine the impact of

combination therapy versus sequential single agent chemotherapy

on quality of life, and also potentially include the outcome Q-

TWIST (quality-adjusted time without symptoms of disease and

toxicity), which is clearly an important goal in the treatment of

metastatic breast cancer.

A C K N O W L E D G E M E N T S

We would like to thank Fergus Tai for his work identifying studies

through the Cochrane Breast Cancer Group Specialised Register.

We would also like to thank Melina Willson for her advice during

the review process.

R E F E R E N C E S

References to studies included in this review

Alba 2004 {published data only}∗ Alba E, Martin M, Ramos M, Adrover E, Balil A, Jara C, et

al.Multicenter randomized trial comparing sequential with

concomitant administration of doxorubicin and docetaxel

as first-line treatment of metastatic breast cancer: a Spanish

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Vaitkevicius VK. Evaluation of combination vs. sequential

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M, Banjin A, et al.Randomized trial of sequence vs.

combination of capecitabine (X) and docetaxel (T): XT vs.

T followed by X after progression as first-line therapy for

patients (pts) with metastatic breast cancer (MBC). Journal

of Clinical Oncology 2006;24(18 Suppl):571.

Chlebowski 1989 {published data only}∗ Chlebowski RT, Smalley RV, Weiner JM, Irwin LE,

Bartolucci AA, Bateman JR. Combination versus sequential

single agent chemotherapy in advanced breast cancer:

association with metastatic sites and long-term survival.

British Journal of Cancer 1989;59(2):227–30.

Conte 2004 {published data only}∗ Conte PF, Guarneri V, Bruzzi P, Prochilo T, Salvadori

B, Bolognesi A, et al.Concomitant versus sequential

administration of epirubicin and paclitaxel as first-line

therapy in metastatic breast carcinoma. Cancer 2004;101

(4):704–12.

Cresta 2004 {published data only}∗ Cresta S, Grasselli G, Mansutti A, Martoni A, Lelli G,

Capri G, et al.A randomized phase II study of combination,

alternating and sequential regimens of doxorubicin and

docetaxel as first-line chemotherapy for women with

metastatic breast cancer. Annals of Oncology 2004;15(3):

433–9.

Fountzilas 2001 {published data only}∗ Fountzilas G, Papadimitriou C, Dafni U, Bafaloukos D,

Skarlos D, Moulopoulos LA, et al.Dose-dense sequential

chemotherapy with epirubicin and paclitaxel versus the

combination, as first-line chemotherapy, in advanced breast

cancer: a randomized study conducted by the Hellenic

Cooperative Oncology Group. Journal of Clinical Oncology

2001;19(8):2232–9.

Koroleva 2001 {published data only}∗ Koroleva I, Wojtukiewicz M, Zaluski J, Arzumanov A,

Biakhov M, Gad-El-Mawla N, et al.Preliminary results of a

phase II randomized trial of Taxotere (T) and doxorubicin

(A) given in combination or sequentially as first line

chemotherapy (CT) for metastatic breast cancer (MBC).

American Society of Clinical Oncology 2001;20:abstract 117.

Park 2010 {published data only}∗ Park IH, Ro J, Lee KS, Kim SN, Yun YH, Nam BH. Phase

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breast cancer. Investigational New Drugs 2010;28(5):

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Rowinsky EK, et al.Phase III trial of doxorubicin, paclitaxel,

and the combination of doxorubicin and paclitaxel as

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21(4):588–92.

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Timcheva C, Wiltschke C, et al.Concomitant docetaxel

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Campone 2013 {published data only}

Campone M, Dobrovolskaya N, Tjulandin S, Chen SC,

Fourie S, Mefti F, et al.A three-arm randomized phase

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plus capecitabine in patients with metastatic breast cancer

previously treated with anthracyclines. The Breast Journal

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Alba 2004

Methods Accrual dates: December 1999 to December 2001

Sample size: 144

Number of centres: multicentre - 23 sites in Spain

Randomisation method: randomisation done centrally but not reported how randomi-

sation was achieved

Baseline comparability: no significant imbalance reported

Participants Female

Age range: 31-78 years (median 58 in sequential arm, 61 in combination arm)

MBC

First-line chemotherapy

Interventions AT versus A→T

Arm I: (AT) doxorubicin + docetaxel

Arm II: (A→T) doxorubicin followed by docetaxel

Outcomes Toxicity (primary outcome)

Overall response rate (CR + PR)

Duration of response (for responding patients, calculated from the date of first objective

response until the time of progression)

TTP

OS

Notes Schema 2

Follow-up: minimum 0.36 months, maximum 35.59 months

Patients stratified prospectively based on previous administration of anthracyclines and

study centre

Combination arm: 67% completed 6 cycles. Withdrawals mainly due to adverse events.

Less than 95% relative dose intensity

Sequential arm: 81% completed 6 cycles. Greater than 95% relative dose intensity

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk 2- unclear

Allocation concealment (selection bias) Unclear risk 2- unclear

Blinding of participants and personnel

(performance bias)

All outcomes




Alba 2004 (Continued)

Blinding of outcome assessment (detection

bias)

All outcomes


Incomplete outcome data (attrition bias)

All outcomes

Low risk 1- no missing data

Selective reporting (reporting bias) Low risk 1- all pre-specified outcomes are reported

Other bias Low risk Treatment groups were similar at baseline

The trial was not stopped early

Analysis was by intention to treat

Baker 1974

Methods Accrual dates: October 1969 to March 1971

Sample size: 89

Number of centres: 1 site in the United States of America

Randomisation method: randomisation “based upon the last digit of their admission

number to the service”

Baseline comparability: different sample size of 2 arms (more in combination than se-

quential arm) but no difference in Karnofsky Performance Scale (KPS), age, menopausal

status or disease-free interval

Participants Female

Age range: 26-77 years (53 in combination arm, median 54 in sequential arm)

MBC


Interventions FCV versus F→C→ V

Arm I: (FCV) 5-FU + cyclophosphamide + vincristine

Arm II: (F→C→ V) 5-FU followed by cyclophosphamide followed by vincristine

Outcomes Response

Duration of response

Overall survival

Notes Schema 1

Follow-up: minimum 18 months, maximum 36 months

6/52 (12%) patients in combination arm, and 7/37 (19%) in sequential arm died prior

to 30 days from the onset of the study

The median number of cycles received by the combination arm was not given

In sequential arm, 30/37 (81%) received second cycle of 5FU, 25/30 (83%) received

cyclophosphamide, and 12/25 (40%) received vincristine. The median number of cycles

of each drug was not reported

Risk of bias



Baker 1974 (Continued)



bias)

Low risk “Women were randomly allocated to one

of two branches of the study based upon

the last digit of their admission number to

the service”

Allocation concealment (selection bias) High risk 3- No. “All patients treated with chemo-

therapy during this time period were en-

tered onto the study, despite the fact that

the physician might have known which

branch the patient would be entered into

prior to the initiation of therapy.”


(performance bias)

All outcomes

High risk 3- No. All parties aware of treatment


bias)

All outcomes



All outcomes



Other bias High risk Treatment groups had different numbers of

patients, but were well balanced for baseline

characteristics


Analysis was not by intention to treat

Beslija 2006

Methods Accrual dates: not reported in abstract

Sample size: 100

Number of centres: not reported in abstract

Randomisation method: not reported in abstract


Participants Female

Age range: 29-64 years (48 in combination arm, median 52 in sequential arm)

MBC




Beslija 2006 (Continued)

Interventions XT versus X→T

Arm I: (XT) capecitabine + docetaxel

Arm II: (T→X) docetaxel followed by capecitabine

Outcomes Toxicity

Overall response rate (CR + PR)

TTP

OS

Notes Schema 1

Follow-up: not reported, not calculated because abstract only

100% had prior adjuvant anthracyclines

All patients had a good performance status - 100% had median KPS 100

X monotherapy data were not considered in the RR or TTP analyses but were included

for OS and safety (number not reported)

In the T→X arm, 74% crossed over to X on progression

Median number of cycles given in the combination and sequential arms not reported

Risk of bias



bias)


Allocation concealment (selection bias) Unclear risk 2- unclear


(performance bias)

All outcomes



bias)

All outcomes



All outcomes


Selective reporting (reporting bias) Low risk 1- yes: all pre-specified outcomes are re-

ported in a pre-specified way

Other bias Low risk In the abstract report available, pre-speci-

fied outcomes were reported

The treatment groups were similar at base-

line

It is not reported if the trial was stopped

early

The analysis was by intention to treat



Chlebowski 1989

Methods Accrual dates: 1971 and 1973

Sample size: 237 (126 from WCSG and 111 from SECSG)

Number of centres: unknown but multicentre (USA) - Western Cancer Study Group

(WCSG) and Southeastern Cancer Study Group (SECSG)

Randomisation method: randomisation done centrally, but exact method not reported


Participants Female

Age range: median age 55 years

MBC


Interventions CMFTP or CMFVP versus F→C→TP→M or F→M→C→V→P

Arm I: (CMFTP or CMFVP) cyclophosphamide + 5-fluorouracil + methotrexate +

triiodothyronine OR vincristine + prednisone

Arm II: (F→C→TP→M) 5-fluorouracil followed by cyclophosphamide followed by

triiodothyronine plus prednisone followed by methotrexate OR (F→M→C→V→P)

5-fluorouracil followed by methotrexate followed by cyclophosphamide followed by

vincristine followed by prednisone

Outcomes Overall survival

Response rate


Toxicity

Notes Schema 1


This report is a combined analysis from the WCSG trial (reported separately by Chle-

bowski in 1979) and the SECSG trial (reported by Smalley 1976). These trials were

initiated at the same time and had similar patient eligibility, chemotherapy protocols

(except WCSG used triiodothyronine and SECSG used vincristine) and response criteria

121/126 on WCSG were available for toxicity and response assessment

101/111 on SECSG were available for toxicity and response assessment

Median number of cycles for each arm not reported

Risk of bias



bias)


Allocation concealment (selection bias) Low risk 1- adequate


(performance bias)

All outcomes




Chlebowski 1989 (Continued)


bias)

All outcomes



All outcomes


Selective reporting (reporting bias) Unclear risk 3- progression-free survival was not re-

ported in a way that it could be used in the

review

Other bias Low risk Treatment groups were similar at baseline



Conte 2004

Methods Accrual dates: December 1996 and June 2001

Sample size: 202

Number of centres: multicentre, 18 centres (15 Italian, 3 Spanish)

Randomisation method: central randomisation by phone call “a separate randomisation

list for each centre was prepared with permuted blocks of varying size in random se-

quence”


Participants Female

Age range: 30-73, median 58

MBC


Interventions EP versus E→P

Arm I: (EP) epirubicin + paclitaxel

Arm II: (E→P) epirubicin followed by paclitaxel

Outcomes Objective response rate (i.e. ORR = CR + PR). CR disappearance of all clinical evidence

of tumour, determined by 2 observations not less than 4 weeks apart; PR- ≥50% decrease

in the sum of the products of the largest dimension of the target lesions; SD- response less

than PR or progression less than PD for ≥4 weeks; PD ≥25% increase in the product

of measured lesions and/or new lesions

Overall survival (date of randomisation to date of death or last follow-up)

Progression-free survival (date of randomisation to date of death or PD)

Toxicity

Quality of life (QLQ-C30)

Pharmacoeconomic profile

Notes Schema 2

Randomised phase 3 trial




Conte 2004 (Continued)

Noninferiority design where the combination (Arm I) was considered the standard (con-

trol) arm

2 patients in combination arm and 2 patients in sequential arm withdrew and were lost

to follow up immediately after randomisation

Patients who had disease progression during combination chemotherapy or when receiv-

ing paclitaxel in the sequential arm were released from the study. If disease progression

occurred while on epirubicin, patients were given paclitaxel 250 mg/m2

Based on cost of chemo drugs- sequential arm 37% less expensive than combination

arm- full analysis to be reported separately

60/106 (57%) of combination arm and 60/92 (65%) completed planned treatment; 15/

106 (14%) in combination arm versus 31/92 (34%) in sequential arm completed all

cycles without protocol modifications (P = 0.001)

Median of 8 courses (range 0 to 8) was given in both treatment arms

Risk of bias



bias)

Low risk 1- adequate

Allocation concealment (selection bias) Low risk 1- adequate


(performance bias)

All outcomes

Unclear risk 2- not reported


bias)

All outcomes



All outcomes


Selective reporting (reporting bias) Low risk 1- all pre-specified outcomes reported

Other bias High risk Treatment groups similar at baseline for im-

portant prognostic factors

Trial was stopped early before the planned

sample size of 266 was reached because the

sequential arm was associated with not a

decreased but possibly an increased toxicity

(neutropenia and neuropathy)

The analysis was not by intention to treat



Cresta 2004

Methods Accrual dates: November 1996 to January 2000

Sample size: 123

Number of centres: multicentre, 9 centres

Randomisation method: not reported


Participants Female

Age range: 24-69. Median age 53 years

MBC


Interventions AT versus alternating T then A versus sequential A→T


Arm II: (sequential A→T) doxorubicin followed by docetaxel

Arm III: (alternating T then A) docetaxel followed by doxorubicin

Outcomes Rate of complete response

Overall response

Time to progression

Survival

Safety

Notes Schema 2

Randomised phase 2 study

Follow-up: not reported

123 enrolled, 121 received study treatment. Of 123 enrolled patients, 13 didn’t meet

eligibility criteria (5 from Arm I, 2 from Arm II, and 6 from Arm III)

Median relative dose intensity for each arm ≥ 0.9 for each drug

Median total dose of doxorubicin: Arm I 460 mg/m2, Arm II 297 mg/m2, Arm III 294

mg/m2

Discontinuation due to adverse events: Arm I 7 patients, Arm II 5 patients, Arm III 2

patients

Median number of cycles received by each arm not reported

Risk of bias



bias)


Allocation concealment (selection bias) Unclear risk 2- not reported


(performance bias)

All outcomes




Cresta 2004 (Continued)


bias)

All outcomes



All outcomes


Selective reporting (reporting bias) High risk 3- outcomes were not reported in a way that

they could be used in the review (hazard

ratio not reported, nor was a Kaplan-Meier

curve reported)

Other bias Low risk 1- treatment groups similar at baseline re-

garding important prognostic factors



Fountzilas 2001

Methods Accrual dates: October 1997 to May 1999

Sample size: 183

Number of centres: unknown (Greece)

Randomisation method:done at central office and based on a random number list, strat-

ification


Participants Female

Age range: 26-77 years (median 57.5 years)

MBC


Interventions Arm I: EP versus E→P

Arm I (EP) epirubicin + paclitaxel

Arm II (E→P) epirubicin followed by paclitaxel (dose dense)

Outcomes Overall response rate

Complete response rate (complete disappearance of all clinical symptoms and signs of

disease for at least 4 weeks)

Time to progression

Overall survival (from start of chemotherapy to date of death or last follow-up)

Toxicity

Notes Schema 2

Randomised phase 2

Follow-up: minimum 6 months, maximum 84.5 months

Median relative dose intensity in both groups was similar (96-97)

80% completed planned combination therapy, 85% completed planned sequential ther-

apy



Fountzilas 2001 (Continued)

Risk of bias



bias)

Low risk 1- adequate



(performance bias)

All outcomes



bias)

All outcomes

Low risk 1- all imaging reviewed by 3 independent

radiologists at the end of the study


All outcomes



Other bias Low risk 1- treatment groups similar at baseline re-




Koroleva 2001

Methods Accrual dates: August 1997 to August 2000

Sample size: 193

Number of centres: unknown (Europe)



Participants Female

Age range: 21-70 (median 51 years)

MBC


Interventions AT versus AT (different drug doses) versus T→A


Arm II: docetaxel then doxorubicin

Arm III: (AT, different drug doses) doxorubicin + docetaxel

Outcomes Response rate

Toxicity

Time to progression



Koroleva 2001 (Continued)

Overall survival

Notes Schema 2


Follow-up: not reported, not able to calculate because abstract only

Abstract only

Median relative dose intensity in both groups similar (97.9)

Median number of cycles received by each arm not reported

Risk of bias



bias)




(performance bias)

All outcomes



bias)

All outcomes



All outcomes

Unclear risk 2- attrition data reported (193 patients ran-

domised, but data available for only 177

patients, and only 131 patients evaluated

for response) but reasons not included




curve reported)

Other bias High risk 1- treatment groups similar at baseline re-






Park 2010

Methods Accrual dates: April 2004 to December 2006

Sample size: 82

Number of centres: not reported (Korea)



Participants Female

Age range: 27-77 (median 53 years)

MBC

Third-line chemotherapy and beyond (prior treatment with anthracyclines and taxanes)

Interventions GV versus G→V

Arm I: (GV) gemcitabine + vinorelbine

Arm II: (G→V) gemcitabine → vinorelbine

Outcomes Response rate (proportion with a complete or partial tumour response)

Time to treatment failure (from date of entry to date of progression, death, withdrawal

etc)

Overall survival (survival from date of randomisation to date of death or last follow-up)

Quality of life (EORTC QLQ C-30, validated Korean version)

Notes Schema 1


Follow-up: minimum 1 month, maximum 55.4 months

81 patients evaluable for treatment efficacy and safety

The mean delivered doses higher in sequential arm, but higher relative dose intensity in

combination arm

In the sequential arm, 33/40 (83%) crossed over to vinorelbine

In the combination arm the median number of cycles of GV was 4. In the sequential

arm, the median number of cycles of gemcitabine was 2.5, and the median number of

cycles of vinorelbine was 2

Risk of bias



bias)




(performance bias)

All outcomes



bias)

All outcomes

Low risk 1- all imaging was reviewed by an indepen-

dent radiologist



Park 2010 (Continued)


All outcomes







Sledge 2003

Methods Accrual dates: February 1993 and September 1995

Sample size: 739

Number of centres: not reported (USA)

Randomisation method:

Baseline comparability:no significant imbalance reported

Participants Female

Age range: 25-79 years (median 56 years combination, 58 in doxorubicin arm, 56 in

paclitaxel arm)

MBC


Interventions AP versus A versus P

Arm I: (AP) doxorubicin + paclitaxel

Arm II: (A) doxorubicin (→ paclitaxel)

Arm III: (P) paclitaxel (→ doxorubicin)

Outcomes Response rate (complete response and partial response)

Time to treatment failure (date of study entry to date of disease progression pr date)

Overall survival (date of study entry to death or date of last follow-up)

Quality of life (FACT-B, at baseline and week 16)

Notes Schema 1


Follow-up: minimum 0.13 months, maximum 75.17 months

8 patients not eligible for inclusion (duplicate registration n = 3, became ineligible n = 3,

patient needed radiotherapy n = 1, doctor preference n = 1), therefore 731 randomised,

then 33 excluded

In the sequential arm, the overall rate of crossover was 57% (58% from doxorubicin to

paclitaxel, and 56% from paclitaxel to doxorubicin)

The median number of cycles given in each arm was not reported

Risk of bias




Sledge 2003 (Continued)


bias)




(performance bias)

All outcomes



bias)

All outcomes



All outcomes







Soto 2006

Methods Accrual dates:

Sample size: 368 enrolled, 277 evaluable

Number of centres: unknown (Mexico)



Participants Female

Age range: not reported in abstract

MBC

Second-line chemotherapy (prior anthracyclines)

Interventions XT versus X→T

Arm I: (XT) capecitabine + docetaxel

Arm II: (X→T) capecitabine → docetaxel or paclitaxel

Arm III: (X→P) capecitabine + paclitaxel



Overall survival

Toxicity

Median doses



Soto 2006 (Continued)

Notes Schema 1


Median follow-up 15.5 months (minimum and maximum follow-up not reported)

Abstract only

In sequential arm 58/91 (64%) received the sequential taxane (the remainder did not

either because still on X, or had a CR, or had a rapid PD)

Risk of bias



bias)




(performance bias)

All outcomes



bias)

All outcomes



All outcomes

Unclear risk 2- exclusions reported (“91 patients still on

therapy or not evaluable”) but reason in-

complete (e.g. why the patients were not

evaluable)




curve reported)







Tomova 2010

Methods Accrual dates: September 2002 to March 2006

Sample size: 100

Number of centres: 14 centres in 7 countries



Participants Female

Median age 53 years in combination arm, 55 years in sequential arm

MBC

Second-line chemotherapy (prior anthracyclines)

Interventions TG versus T→ G

Arm I: (TG) docetaxel + gemcitabine

Arm II: (T→G) docetaxel → gemcitabine


Response duration

Time to progression

Overall survival

Toxicity

Notes Schema 2



Sample size calculated to be 430, but due to poor recruitment the trial was closed after

100 patients were randomised

26% completed the combination treatment TG and 28% completed the sequential

treatment T→G

Risk of bias



bias)




(performance bias)

All outcomes



bias)

All outcomes



All outcomes




Tomova 2010 (Continued)


Other bias High risk 3- the trial was stopped early due to poor

recruitment


CR: complete response

KPS: Karnofsky Performance Scale

MBC: metastatic breast cancer

OS: overall survival

PD: progressive disease

PR: partial response

RR: response rate

TTP: time to progression

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Chlebowski 1979 The results of this study were updated and included in Chlebowski 1989 (which also includes the updated results

from Smalley 1976)

Smalley 1976 The results of this study were updated and included in Chlebowski 1989 (which also includes the updated results

from Chlebowski 1979)

Characteristics of studies awaiting assessment [ordered by study ID]

Campone 2013

Methods Accrual dates: June 2005 to April 2008

Sample size: 139 patients

Randomised multicentre study

Participants MBC

Previously treated with anthracyclines

Interventions Arm I: vinorelbine + capecitabine

Arm II: vinorelbine capecitabine

Arm II: docetaxel + capecitabine



Campone 2013 (Continued)

Outcomes Disease control rate

Safety profile

Response rate


Duration of disease control

Duration of stable disease


Time to treatment failure

Overall survival

Notes Study results published in May-June 2013. Awaiting additional trial data from the trialists

Zhang 2013

Methods Accrual dates: August 2007 to December 2010

Sample size: 60

Randomised multicentre phase II study

Participants MBC

First-line therapy

Interventions Arm I: vinorelbine + capecitabine

Arm II: vinorelbine → capecitabine

Outcomes Progression-free survival

Time to treatment failure

Quality of life

Time to progression

Overall survival

Notes Study results published 2 October 2013. Awaiting additional trial data from the trialists

See: http://clinicaltrials.gov/show/NCT00629148



http://clinicaltrials.gov/show/NCT00629148





D A T A A N D A N A L Y S E S

Comparison 1. Overall survival

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Overall survival (all trials) 9 1786 Hazard Ratio (Fixed, 95% CI) 1.04 [0.93, 1.16]

Comparison 2. Progression-free survival


studies

No. of


1 Progression-free survival (all

trials)

8 1564 Hazard Ratio (Fixed, 95% CI) 1.16 [1.03, 1.31]

Comparison 3. Overall response


studies

No. of


1 Overall response (all trials) 12 2140 Risk Ratio (IV, Fixed, 95% CI) 1.16 [1.06, 1.28]

Comparison 4. Treatment-related deaths


studies

No. of


1 Treatment-related deaths (all

trials)

7 902 Risk Ratio (M-H, Fixed, 95% CI) 1.53 [0.71, 3.29]



Comparison 5. Neutropenia


studies

No. of


1 Neutropaenia 12 Risk Ratio (Fixed, 95% CI) 0.94 [0.87, 1.02]

Comparison 6. Febrile neutropenia


studies

No. of


1 Febrile neutropenia 9 Risk Ratio (Fixed, 95% CI) 1.32 [1.06, 1.65]

Comparison 7. Nausea and vomiting


studies

No. of


1 Nausea and vomiting 8 Risk Ratio (Fixed, 95% CI) 0.88 [0.57, 1.34]

Comparison 8. Overall survival - risk of bias


studies

No. of


1 Overall survival - risk of bias 9 Hazard Ratio (Fixed, 95% CI) 1.04 [0.93, 1.16]

1.1 Low risk of bias 2 Hazard Ratio (Fixed, 95% CI) 1.21 [0.93, 1.58]

1.2 High/unclear risk of bias 7 Hazard Ratio (Fixed, 95% CI) 1.01 [0.90, 1.14]

Comparison 9. Progression-free survival - risk of bias


studies

No. of


1 Progression-free survival - risk of

bias

8 Hazard Ratio (Fixed, 95% CI) 1.16 [1.03, 1.31]

1.1 Low risk of bias 2 Hazard Ratio (Fixed, 95% CI) 1.15 [0.94, 1.41]

1.2 High/unclear risk of bias 6 Hazard Ratio (Fixed, 95% CI) 1.17 [1.01, 1.35]



Comparison 10. Overall response - risk of bias


studies

No. of


1 Overall response - risk of bias 12 2140 Risk Ratio (IV, Fixed, 95% CI) 1.16 [1.06, 1.28]

1.1 Low risk of bias 2 381 Risk Ratio (IV, Fixed, 95% CI) 0.91 [0.76, 1.10]

1.2 High/unclear risk of bias 10 1759 Risk Ratio (IV, Fixed, 95% CI) 1.26 [1.13, 1.39]

Comparison 11. Treatment-related deaths - risk of bias


studies

No. of


1 Treatment-related deaths - risk

of bias


1.1 Low risk of bias 1 198 Risk Ratio (M-H, Fixed, 95% CI) 2.60 [0.28, 24.60]

1.2 High/unclear risk of bias 6 704 Risk Ratio (M-H, Fixed, 95% CI) 1.41 [0.62, 3.20]

Comparison 12. Neutropenia - risk of bias


studies

No. of


1 Neutropaenia - risk of bias 12 Risk Ratio (Fixed, 95% CI) 0.94 [0.87, 1.02]

1.1 Low risk of bias 2 Risk Ratio (Fixed, 95% CI) 0.62 [0.50, 0.76]

1.2 High/unclear risk of bias 10 Risk Ratio (Fixed, 95% CI) 1.00 [0.92, 1.09]

Comparison 13. Febrile neutropenia - risk of bias


studies

No. of


1 Febrile neutropenia - risk of bias 9 Risk Ratio (Fixed, 95% CI) 1.32 [1.06, 1.65]





Comparison 14. Nausea and vomiting - risk of bias


studies

No. of


1 Nausea and vomiting - risk of

bias

8 Risk Ratio (Fixed, 95% CI) 0.88 [0.57, 1.34]



Comparison 15. Overall survival - line of chemotherapy


studies

No. of


1 Overall survival - line of

chemotherapy


1.1 First line chemotherapy 7 Hazard Ratio (Fixed, 95% CI) 1.04 [0.93, 1.18]

1.2 Second/third line

chemotherapy


Comparison 16. Progression-free survival - line of chemotherapy


studies

No. of


1 Progression free survival - line of

chemotherapy


1.1 First line chemotherapy 6 Hazard Ratio (Fixed, 95% CI) 1.16 [1.02, 1.31]


chemotherapy


Comparison 17. Overall response - line of chemotherapy


studies

No. of


1 Overall response - subgroup

analysis, line of chemotherapy

12 2140 Risk Ratio (IV, Fixed, 95% CI) 1.16 [1.06, 1.28]

1.1 First line chemotherapy 9 1778 Risk Ratio (IV, Fixed, 95% CI) 1.10 [1.00, 1.22]


chemotherapy




Comparison 18. Treatment-related deaths - line of chemotherapy


studies

No. of


1 Treatment-related deaths - line

of chemotherapy


1.1 First line chemotherapy 5 722 Risk Ratio (M-H, Fixed, 95% CI) 1.72 [0.70, 4.18]


chemotherapy


Comparison 19. Neutropenia - line of chemotherapy


studies

No. of


1 Neutropaenia - line of

chemotherapy


1.1 First-line chemotherapy 9 Risk Ratio (Fixed, 95% CI) 0.96 [0.87, 1.05]

1.2 Second/third-line

chemotherapy


Comparison 20. Febrile neutropenia - line of chemotherapy


studies

No. of


1 Febrile neutropenia - line of

chemotherapy




chemotherapy


Comparison 21. Nausea and vomiting - line of chemotherapy


studies

No. of


1 Nausea and vomiting - line of

chemotherapy




chemotherapy




Comparison 22. Overall survival - schema 1 versus schema 2


studies

No. of


1 Overall survival - Schema 1

versus Schema 2


1.1 Schema 1 5 Hazard Ratio (Fixed, 95% CI) 0.98 [0.86, 1.12]


Comparison 23. Progression-free survival - schema 1 versus schema 2


studies

No. of


1 Progression-free survival -

Schema 1 versus Schema 2




Comparison 24. Overall response - schema 1 versus schema 2


studies

No. of


1 Overall response - Schema 1

versus Schema 2


1.1 Schema 1 6 1344 Risk Ratio (IV, Fixed, 95% CI) 1.46 [1.28, 1.65]

1.2 Schema 2 6 796 Risk Ratio (IV, Fixed, 95% CI) 0.92 [0.80, 1.04]

Comparison 25. Treatment-related deaths - schema 1 versus schema 2


studies

No. of


1 Treatment-related deaths -

Schema 1 versus Schema 2


1.1 Schema 1 3 379 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.36, 2.44]

1.2 Schema 2 4 523 Risk Ratio (M-H, Fixed, 95% CI) 4.00 [0.87, 18.35]



Comparison 26. Neutropenia - schema 1 versus schema 2


studies

No. of


1 Neutropaenia - subgroup

analysis, Schema 1 versus

Schema 2


1.1 Schema 1 6 Risk Ratio (Fixed, 95% CI) 0.99 [0.87, 1.14]


Comparison 27. Febrile neutropenia - schema 1 versus schema 2


studies

No. of


1 Febrile neutropenia - Schema 1

versus Schema 2




Comparison 28. Nausea and vomiting - schema 1 versus schema 2


studies

No. of


1 Nausea and vomiting - Schema

1 versus Schema 2




Comparison 29. Overall survival - relative dose intensity


studies

No. of


1 Overall survival - relative dose

intensity


1.1 Similar dose intensity 2 Hazard Ratio (Fixed, 95% CI) 1.23 [0.93, 1.62]

1.2 Different dose intensity 2 Hazard Ratio (Fixed, 95% CI) 1.03 [0.76, 1.40]



Comparison 30. Progression-free survival - relative dose intensity


studies

No. of


1 Progression-free survival -

relative dose intensity


1.1 Similar dose intensity 2 Hazard Ratio (Fixed, 95% CI) 1.15 [0.91, 1.45]

1.2 Different dose intensity 2 Hazard Ratio (Fixed, 95% CI) 1.25 [0.80, 1.95]

Comparison 31. Overall response - relative dose intensity


studies

No. of


1 Overall response - relative dose

intensity


1.1 Similar dose intensity 3 355 Risk Ratio (IV, Fixed, 95% CI) 0.88 [0.72, 1.07]

1.2 Different dose intensity 3 324 Risk Ratio (IV, Fixed, 95% CI) 0.93 [0.72, 1.20]

Comparison 32. Treatment-related deaths - relative dose intensity


studies

No. of


1 Treatment-related deaths -

relative dose intensity


1.1 Similar dose intensity 1 82 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

1.2 Different dose intensity 3 324 Risk Ratio (M-H, Fixed, 95% CI) 1.66 [0.45, 6.10]

Comparison 33. Neutropenia - relative dose intensity


studies

No. of


1 Neutropaenia - relative dose

intensity


1.1 Similar dose intensity 3 Risk Ratio (Fixed, 95% CI) 1.08 [0.97, 1.20]

1.2 Different dose intensity 3 Risk Ratio (Fixed, 95% CI) 0.67 [0.51, 0.87]



Comparison 34. Febrile neutropenia - relative dose intensity


studies

No. of


1 Febrile neutropenia - relative

dose intensity




Comparison 35. Nausea and vomiting - relative dose intensity


studies

No. of


1 Nausea and vomiting - relative

dose intensity




Analysis 1.1. Comparison 1 Overall survival, Outcome 1 Overall survival (all trials).

Review: Combination versus sequential single agent chemotherapy for metastatic breast cancer

Comparison: 1 Overall survival

Outcome: 1 Overall survival (all trials)

Study or subgroup Combination Sequential log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio

N N (SE) IV,Fixed,95% CI IV,Fixed,95% CI

Alba 2004 69 75 0.2151 (0.2634) 4.5 % 1.24 [ 0.74, 2.08 ]

Baker 1974 46 30 0.3716 (0.2606) 4.6 % 1.45 [ 0.87, 2.42 ]

Beslija 2006 50 50 -0.6387 (0.3182) 3.1 % 0.53 [ 0.28, 0.99 ]

Chlebowski 1989 129 93 -0.1054 (0.1282) 19.2 % 0.90 [ 0.70, 1.16 ]

Conte 2004 106 92 0.174 (0.2355) 5.7 % 1.19 [ 0.75, 1.89 ]

Fountzilas 2001 90 93 0.1989 (0.1667) 11.3 % 1.22 [ 0.88, 1.69 ]

Park 2010 41 40 -0.1744 (0.235) 5.7 % 0.84 [ 0.53, 1.33 ]

Sledge 2003 230 453 0.0488 (0.0901) 38.8 % 1.05 [ 0.88, 1.25 ]

0.01 0.1 1 10 100

Favours combination Favours sequential

(Continued . . . )



(. . . Continued)Study or subgroup Combination Sequential log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio


Tomova 2010 46 53 0.1989 (0.211) 7.1 % 1.22 [ 0.81, 1.84 ]

Total (95% CI) 100.0 % 1.04 [ 0.93, 1.16 ]

Heterogeneity: Chi2 = 10.54, df = 8 (P = 0.23); I2 =24%

Test for overall effect: Z = 0.76 (P = 0.45)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100


Analysis 2.1. Comparison 2 Progression-free survival, Outcome 1 Progression-free survival (all trials).


Comparison: 2 Progression-free survival

Outcome: 1 Progression-free survival (all trials)

Study or subgroup Combination Sequential log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio


Alba 2004 69 75 0.0296 (0.1827) 10.7 % 1.03 [ 0.72, 1.47 ]

Baker 1974 46 30 0.239 (0.2295) 6.8 % 1.27 [ 0.81, 1.99 ]

Beslija 2006 50 50 -0.6033 (0.2865) 4.3 % 0.55 [ 0.31, 0.96 ]

Conte 2004 106 92 0.0862 (0.139) 18.5 % 1.09 [ 0.83, 1.43 ]

Fountzilas 2001 90 93 0.2151 (0.1579) 14.3 % 1.24 [ 0.91, 1.69 ]

Park 2010 41 40 0.2776 (0.2429) 6.0 % 1.32 [ 0.82, 2.12 ]

Sledge 2003 230 453 0.2469 (0.0962) 38.5 % 1.28 [ 1.06, 1.55 ]

Tomova 2010 46 53 -0.1625 (0.6415) 0.9 % 0.85 [ 0.24, 2.99 ]

Total (95% CI) 100.0 % 1.16 [ 1.03, 1.31 ]




0.01 0.1 1 10 100




Analysis 3.1. Comparison 3 Overall response, Outcome 1 Overall response (all trials).


Comparison: 3 Overall response

Outcome: 1 Overall response (all trials)

Study or subgroup Combination Sequential Risk Ratio Weight Risk Ratio

n/N n/N IV,Fixed,95% CI IV,Fixed,95% CI

Alba 2004 35/69 46/75 9.6 % 0.83 [ 0.62, 1.11 ]

Baker 1974 20/46 16/30 3.8 % 0.82 [ 0.51, 1.30 ]

Beslija 2006 34/50 20/50 5.5 % 1.70 [ 1.15, 2.51 ]

Chlebowski 1989 61/129 20/93 4.5 % 2.20 [ 1.43, 3.38 ]

Conte 2004 62/106 53/92 14.8 % 1.02 [ 0.80, 1.29 ]

Cresta 2004 26/41 25/41 7.3 % 1.04 [ 0.74, 1.46 ]

Fountzilas 2001 38/90 51/93 9.0 % 0.77 [ 0.57, 1.04 ]

Koroleva 2001 23/47 24/43 5.3 % 0.88 [ 0.59, 1.30 ]

Park 2010 11/41 5/40 0.9 % 2.15 [ 0.82, 5.62 ]

Sledge 2003 108/230 159/453 24.1 % 1.34 [ 1.11, 1.61 ]

Soto 2006 67/91 42/91 12.9 % 1.60 [ 1.24, 2.06 ]

Tomova 2010 14/46 15/53 2.2 % 1.08 [ 0.58, 1.98 ]

Total (95% CI) 986 1154 100.0 % 1.16 [ 1.06, 1.28 ]

Total events: 499 (Combination), 476 (Sequential)




0.01 0.1 1 10 100

Favours sequential Favours combination



Analysis 4.1. Comparison 4 Treatment-related deaths, Outcome 1 Treatment-related deaths (all trials).


Comparison: 4 Treatment-related deaths

Outcome: 1 Treatment-related deaths (all trials)

Study or subgroup Combination Sequential Risk Ratio Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Alba 2004 2/69 0/75 5.43 [ 0.27, 111.12 ]

Baker 1974 1/46 3/30 0.22 [ 0.02, 1.99 ]

Chlebowski 1989 8/129 2/93 2.88 [ 0.63, 13.27 ]

Conte 2004 3/106 1/92 2.60 [ 0.28, 24.60 ]

Cresta 2004 0/41 0/41 0.0 [ 0.0, 0.0 ]

Park 2010 0/41 2/40 0.20 [ 0.01, 3.94 ]

Tomova 2010 2/46 0/53 5.74 [ 0.28, 116.67 ]

Total (95% CI) 478 424 1.53 [ 0.71, 3.29 ]





0.1 0.2 0.5 1 2 5 10




Analysis 5.1. Comparison 5 Neutropenia, Outcome 1 Neutropaenia.


Comparison: 5 Neutropenia

Outcome: 1 Neutropaenia

Study or subgroup log [Risk Ratio] Risk Ratio Weight Risk Ratio

(SE) IV,Fixed,95% CI IV,Fixed,95% CI

Alba 2004 0.2012 (0.4564) 0.7 % 1.22 [ 0.50, 2.99 ]

Baker 1974 -0.401 (0.3887) 1.0 % 0.67 [ 0.31, 1.43 ]

Beslija 2006 -0.1542 (0.5192) 0.6 % 0.86 [ 0.31, 2.37 ]

Chlebowski 1989 2.0716 (0.7517) 0.3 % 7.94 [ 1.82, 34.64 ]

Conte 2004 -0.579 (0.1119) 12.0 % 0.56 [ 0.45, 0.70 ]

Cresta 2004 0.1248 (0.0838) 21.5 % 1.13 [ 0.96, 1.34 ]

Fountzilas 2001 0.9201 (0.424) 0.8 % 2.51 [ 1.09, 5.76 ]

Koroleva 2001 0.0168 (0.0734) 28.0 % 1.02 [ 0.88, 1.17 ]

Park 2010 -0.2871 (0.3571) 1.2 % 0.75 [ 0.37, 1.51 ]

Sledge 2003 0.0007 (0.0736) 27.8 % 1.00 [ 0.87, 1.16 ]

Soto 2006 0.2014 (0.8268) 0.2 % 1.22 [ 0.24, 6.18 ]

Tomova 2010 -0.507 (0.16) 5.9 % 0.60 [ 0.44, 0.82 ]

Total (95% CI) 100.0 % 0.94 [ 0.87, 1.02 ]

Heterogeneity: Chi2 = 50.97, df = 11 (P<0.00001); I2 =78%



0.01 0.1 1 10 100




Analysis 6.1. Comparison 6 Febrile neutropenia, Outcome 1 Febrile neutropenia.


Comparison: 6 Febrile neutropenia

Outcome: 1 Febrile neutropenia



Alba 2004 0.0749 (0.1498) 57.2 % 1.08 [ 0.80, 1.45 ]

Beslija 2006 -0.1542 (0.5192) 4.8 % 0.86 [ 0.31, 2.37 ]

Conte 2004 0.238 (0.5665) 4.0 % 1.27 [ 0.42, 3.85 ]

Cresta 2004 1.7671 (0.6384) 3.1 % 5.85 [ 1.68, 20.46 ]

Fountzilas 2001 0.7259 (0.5943) 3.6 % 2.07 [ 0.64, 6.62 ]

Koroleva 2001 0.2955 (0.5534) 4.2 % 1.34 [ 0.45, 3.98 ]

Park 2010 1.0739 (1.1331) 1.0 % 2.93 [ 0.32, 26.97 ]

Sledge 2003 0.7129 (0.2523) 20.2 % 2.04 [ 1.24, 3.34 ]

Tomova 2010 -0.7746 (0.812) 1.9 % 0.46 [ 0.09, 2.26 ]

Total (95% CI) 100.0 % 1.32 [ 1.06, 1.65 ]




0.01 0.1 1 10 100




Analysis 7.1. Comparison 7 Nausea and vomiting, Outcome 1 Nausea and vomiting.


Comparison: 7 Nausea and vomiting

Outcome: 1 Nausea and vomiting

Study or subgroup log [Risk Ratio] Risk Ratio Risk Ratio


Alba 2004 -0.2843 (0.4003) 0.75 [ 0.34, 1.65 ]

Cresta 2004 -0.2478 (0.5596) 0.78 [ 0.26, 2.34 ]

Fountzilas 2001 0.0328 (0.803) 1.03 [ 0.21, 4.99 ]

Koroleva 2001 1.5864 (1.0322) 4.89 [ 0.65, 36.95 ]

Park 2010 0 (0) 0.0 [ 0.0, 0.0 ]

Sledge 2003 -0.2777 (0.3632) 0.76 [ 0.37, 1.54 ]

Soto 2006 -0.3094 (0.9039) 0.73 [ 0.12, 4.32 ]

Tomova 2010 1.7483 (1.5363) 5.74 [ 0.28, 116.68 ]

Total (95% CI) 0.88 [ 0.57, 1.34 ]

Heterogeneity: Chi2 = 4.70, df = 6 (P = 0.58); I2 =0.0%



0.1 0.2 0.5 1 2 5 10




Analysis 8.1. Comparison 8 Overall survival - risk of bias, Outcome 1 Overall survival - risk of bias.


Comparison: 8 Overall survival - risk of bias

Outcome: 1 Overall survival - risk of bias

Study or subgroup log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio


1 Low risk of bias

Conte 2004 0.174 (0.2355) 5.7 % 1.19 [ 0.75, 1.89 ]

Fountzilas 2001 0.1989 (0.1667) 11.3 % 1.22 [ 0.88, 1.69 ]

Subtotal (95% CI) 17.0 % 1.21 [ 0.93, 1.58 ]



2 High/unclear risk of bias

Alba 2004 0.2151 (0.2634) 4.5 % 1.24 [ 0.74, 2.08 ]

Baker 1974 0.3716 (0.2606) 4.6 % 1.45 [ 0.87, 2.42 ]

Beslija 2006 -0.6387 (0.3182) 3.1 % 0.53 [ 0.28, 0.99 ]

Chlebowski 1989 -0.1054 (0.1282) 19.2 % 0.90 [ 0.70, 1.16 ]

Park 2010 -0.1744 (0.235) 5.7 % 0.84 [ 0.53, 1.33 ]

Sledge 2003 0.0488 (0.0901) 38.8 % 1.05 [ 0.88, 1.25 ]

Tomova 2010 0.1989 (0.211) 7.1 % 1.22 [ 0.81, 1.84 ]

Subtotal (95% CI) 83.0 % 1.01 [ 0.90, 1.14 ]



Total (95% CI) 100.0 % 1.04 [ 0.93, 1.16 ]



Test for subgroup differences: Chi2 = 1.43, df = 1 (P = 0.23), I2 =30%

0.01 0.1 1 10 100




Analysis 9.1. Comparison 9 Progression-free survival - risk of bias, Outcome 1 Progression-free survival -

risk of bias.


Comparison: 9 Progression-free survival - risk of bias

Outcome: 1 Progression-free survival - risk of bias



1 Low risk of bias

Conte 2004 0.0862 (0.139) 18.5 % 1.09 [ 0.83, 1.43 ]

Fountzilas 2001 0.2151 (0.1579) 14.3 % 1.24 [ 0.91, 1.69 ]

Subtotal (95% CI) 32.8 % 1.15 [ 0.94, 1.41 ]




Alba 2004 0.0296 (0.1827) 10.7 % 1.03 [ 0.72, 1.47 ]

Baker 1974 0.239 (0.2295) 6.8 % 1.27 [ 0.81, 1.99 ]

Beslija 2006 -0.6033 (0.2865) 4.3 % 0.55 [ 0.31, 0.96 ]

Park 2010 0.2776 (0.2429) 6.0 % 1.32 [ 0.82, 2.12 ]

Sledge 2003 0.2469 (0.0962) 38.5 % 1.28 [ 1.06, 1.55 ]

Tomova 2010 -0.1625 (0.6415) 0.9 % 0.85 [ 0.24, 2.99 ]

Subtotal (95% CI) 67.2 % 1.17 [ 1.01, 1.35 ]



Total (95% CI) 100.0 % 1.16 [ 1.03, 1.31 ]



Test for subgroup differences: Chi2 = 0.01, df = 1 (P = 0.93), I2 =0.0%

0.01 0.1 1 10 100




Analysis 10.1. Comparison 10 Overall response - risk of bias, Outcome 1 Overall response - risk of bias.


Comparison: 10 Overall response - risk of bias

Outcome: 1 Overall response - risk of bias



1 Low risk of bias

Conte 2004 62/106 53/92 14.8 % 1.02 [ 0.80, 1.29 ]

Fountzilas 2001 38/90 51/93 9.0 % 0.77 [ 0.57, 1.04 ]

Subtotal (95% CI) 196 185 23.8 % 0.91 [ 0.76, 1.10 ]





Alba 2004 35/69 46/75 9.6 % 0.83 [ 0.62, 1.11 ]

Baker 1974 20/46 16/30 3.8 % 0.82 [ 0.51, 1.30 ]

Beslija 2006 34/50 20/50 5.5 % 1.70 [ 1.15, 2.51 ]

Chlebowski 1989 61/129 20/93 4.5 % 2.20 [ 1.43, 3.38 ]

Cresta 2004 26/41 25/41 7.3 % 1.04 [ 0.74, 1.46 ]

Koroleva 2001 23/47 24/43 5.3 % 0.88 [ 0.59, 1.30 ]

Park 2010 11/41 5/40 0.9 % 2.15 [ 0.82, 5.62 ]

Sledge 2003 108/230 159/453 24.1 % 1.34 [ 1.11, 1.61 ]

Soto 2006 67/91 42/91 12.9 % 1.60 [ 1.24, 2.06 ]

Tomova 2010 14/46 15/53 2.2 % 1.08 [ 0.58, 1.98 ]

Subtotal (95% CI) 790 969 76.2 % 1.26 [ 1.13, 1.39 ]




Total (95% CI) 986 1154 100.0 % 1.16 [ 1.06, 1.28 ]





0.01 0.1 1 10 100




Analysis 11.1. Comparison 11 Treatment-related deaths - risk of bias, Outcome 1 Treatment-related deaths

- risk of bias.


Comparison: 11 Treatment-related deaths - risk of bias

Outcome: 1 Treatment-related deaths - risk of bias



1 Low risk of bias

Conte 2004 3/106 1/92 2.60 [ 0.28, 24.60 ]

Subtotal (95% CI) 106 92 2.60 [ 0.28, 24.60 ]


Heterogeneity: not applicable



Alba 2004 2/69 0/75 5.43 [ 0.27, 111.12 ]

Baker 1974 1/46 3/30 0.22 [ 0.02, 1.99 ]

Chlebowski 1989 8/129 2/93 2.88 [ 0.63, 13.27 ]

Cresta 2004 0/41 0/41 0.0 [ 0.0, 0.0 ]

Park 2010 0/41 2/40 0.20 [ 0.01, 3.94 ]

Tomova 2010 2/46 0/53 5.74 [ 0.28, 116.67 ]

Subtotal (95% CI) 372 332 1.41 [ 0.62, 3.20 ]




Total (95% CI) 478 424 1.53 [ 0.71, 3.29 ]





0.1 0.2 0.5 1 2 5 10




Analysis 12.1. Comparison 12 Neutropenia - risk of bias, Outcome 1 Neutropaenia - risk of bias.


Comparison: 12 Neutropenia - risk of bias

Outcome: 1 Neutropaenia - risk of bias



1 Low risk of bias

Conte 2004 -0.579 (0.1119) 12.0 % 0.56 [ 0.45, 0.70 ]

Fountzilas 2001 0.9201 (0.424) 0.8 % 2.51 [ 1.09, 5.76 ]

Subtotal (95% CI) 12.9 % 0.62 [ 0.50, 0.76 ]


Test for overall effect: Z = 4.45 (P < 0.00001)


Alba 2004 0.2012 (0.4564) 0.7 % 1.22 [ 0.50, 2.99 ]

Baker 1974 -0.401 (0.3887) 1.0 % 0.67 [ 0.31, 1.43 ]

Beslija 2006 -0.1542 (0.5192) 0.6 % 0.86 [ 0.31, 2.37 ]

Chlebowski 1989 2.0716 (0.7517) 0.3 % 7.94 [ 1.82, 34.64 ]

Cresta 2004 0.1248 (0.0838) 21.5 % 1.13 [ 0.96, 1.34 ]

Koroleva 2001 0.0168 (0.0734) 28.0 % 1.02 [ 0.88, 1.17 ]

Park 2010 -0.2871 (0.3571) 1.2 % 0.75 [ 0.37, 1.51 ]

Sledge 2003 0.0007 (0.0736) 27.8 % 1.00 [ 0.87, 1.16 ]

Soto 2006 0.2014 (0.8268) 0.2 % 1.22 [ 0.24, 6.18 ]

Tomova 2010 -0.507 (0.16) 5.9 % 0.60 [ 0.44, 0.82 ]

Subtotal (95% CI) 87.1 % 1.00 [ 0.92, 1.09 ]



Total (95% CI) 100.0 % 0.94 [ 0.87, 1.02 ]




0.01 0.1 1 10 100




Analysis 13.1. Comparison 13 Febrile neutropenia - risk of bias, Outcome 1 Febrile neutropenia - risk of bias.


Comparison: 13 Febrile neutropenia - risk of bias

Outcome: 1 Febrile neutropenia - risk of bias



1 Low risk of bias

Conte 2004 0.238 (0.5665) 4.0 % 1.27 [ 0.42, 3.85 ]

Fountzilas 2001 0.7259 (0.5943) 3.6 % 2.07 [ 0.64, 6.62 ]

Subtotal (95% CI) 7.6 % 1.60 [ 0.72, 3.57 ]




Alba 2004 0.0749 (0.1498) 57.2 % 1.08 [ 0.80, 1.45 ]

Beslija 2006 -0.1542 (0.5192) 4.8 % 0.86 [ 0.31, 2.37 ]

Cresta 2004 1.7671 (0.6384) 3.1 % 5.85 [ 1.68, 20.46 ]

Koroleva 2001 0.2955 (0.5534) 4.2 % 1.34 [ 0.45, 3.98 ]

Park 2010 1.0739 (1.1331) 1.0 % 2.93 [ 0.32, 26.97 ]

Sledge 2003 0.7129 (0.2523) 20.2 % 2.04 [ 1.24, 3.34 ]

Tomova 2010 -0.7746 (0.812) 1.9 % 0.46 [ 0.09, 2.26 ]

Subtotal (95% CI) 92.4 % 1.30 [ 1.03, 1.64 ]



Total (95% CI) 100.0 % 1.32 [ 1.06, 1.65 ]




0.01 0.1 1 10 100




Analysis 14.1. Comparison 14 Nausea and vomiting - risk of bias, Outcome 1 Nausea and vomiting - risk of

bias.


Comparison: 14 Nausea and vomiting - risk of bias

Outcome: 1 Nausea and vomiting - risk of bias



1 Low risk of bias

Fountzilas 2001 0.0328 (0.803) 1.03 [ 0.21, 4.99 ]

Subtotal (95% CI) 1.03 [ 0.21, 4.99 ]




Alba 2004 -0.2843 (0.4003) 0.75 [ 0.34, 1.65 ]

Cresta 2004 -0.2478 (0.5596) 0.78 [ 0.26, 2.34 ]

Koroleva 2001 1.5864 (1.0322) 4.89 [ 0.65, 36.95 ]

Park 2010 0 (0) 0.0 [ 0.0, 0.0 ]

Sledge 2003 -0.2777 (0.3632) 0.76 [ 0.37, 1.54 ]

Soto 2006 -0.3094 (0.9039) 0.73 [ 0.12, 4.32 ]

Tomova 2010 1.7483 (1.5363) 5.74 [ 0.28, 116.68 ]

Subtotal (95% CI) 0.87 [ 0.56, 1.35 ]



Total (95% CI) 0.88 [ 0.57, 1.34 ]




0.1 0.2 0.5 1 2 5 10




Analysis 15.1. Comparison 15 Overall survival - line of chemotherapy, Outcome 1 Overall survival - line of

chemotherapy.


Comparison: 15 Overall survival - line of chemotherapy

Outcome: 1 Overall survival - line of chemotherapy



1 First line chemotherapy

Alba 2004 0.2151 (0.2634) 4.5 % 1.24 [ 0.74, 2.08 ]

Baker 1974 0.3716 (0.2606) 4.6 % 1.45 [ 0.87, 2.42 ]

Beslija 2006 -0.6387 (0.3182) 3.1 % 0.53 [ 0.28, 0.99 ]

Chlebowski 1989 -0.1054 (0.1282) 19.2 % 0.90 [ 0.70, 1.16 ]

Conte 2004 0.174 (0.2355) 5.7 % 1.19 [ 0.75, 1.89 ]

Fountzilas 2001 0.1989 (0.1667) 11.3 % 1.22 [ 0.88, 1.69 ]

Sledge 2003 0.0488 (0.0901) 38.8 % 1.05 [ 0.88, 1.25 ]

Subtotal (95% CI) 87.2 % 1.04 [ 0.93, 1.18 ]



2 Second/third line chemotherapy

Park 2010 -0.1744 (0.235) 5.7 % 0.84 [ 0.53, 1.33 ]

Tomova 2010 0.1989 (0.211) 7.1 % 1.22 [ 0.81, 1.84 ]

Subtotal (95% CI) 12.8 % 1.03 [ 0.76, 1.40 ]



Total (95% CI) 100.0 % 1.04 [ 0.93, 1.16 ]




0.01 0.1 1 10 100




Analysis 16.1. Comparison 16 Progression-free survival - line of chemotherapy, Outcome 1 Progression free

survival - line of chemotherapy.


Comparison: 16 Progression-free survival - line of chemotherapy

Outcome: 1 Progression free survival - line of chemotherapy




Alba 2004 0.0296 (0.1827) 10.7 % 1.03 [ 0.72, 1.47 ]

Baker 1974 0.239 (0.2295) 6.8 % 1.27 [ 0.81, 1.99 ]

Beslija 2006 -0.6033 (0.2865) 4.3 % 0.55 [ 0.31, 0.96 ]

Conte 2004 0.0862 (0.139) 18.5 % 1.09 [ 0.83, 1.43 ]

Fountzilas 2001 0.2151 (0.1579) 14.3 % 1.24 [ 0.91, 1.69 ]

Sledge 2003 0.2469 (0.0962) 38.5 % 1.28 [ 1.06, 1.55 ]

Subtotal (95% CI) 93.1 % 1.16 [ 1.02, 1.31 ]




Park 2010 0.2776 (0.2429) 6.0 % 1.32 [ 0.82, 2.12 ]

Tomova 2010 -0.1625 (0.6415) 0.9 % 0.85 [ 0.24, 2.99 ]

Subtotal (95% CI) 6.9 % 1.25 [ 0.80, 1.95 ]



Total (95% CI) 100.0 % 1.16 [ 1.03, 1.31 ]




0.01 0.1 1 10 100




Analysis 17.1. Comparison 17 Overall response - line of chemotherapy, Outcome 1 Overall response -

subgroup analysis, line of chemotherapy.


Comparison: 17 Overall response - line of chemotherapy

Outcome: 1 Overall response - subgroup analysis, line of chemotherapy




Alba 2004 35/69 46/75 9.6 % 0.83 [ 0.62, 1.11 ]

Baker 1974 20/46 16/30 3.8 % 0.82 [ 0.51, 1.30 ]

Beslija 2006 34/50 20/50 5.5 % 1.70 [ 1.15, 2.51 ]

Chlebowski 1989 61/129 20/93 4.5 % 2.20 [ 1.43, 3.38 ]

Conte 2004 62/106 53/92 14.8 % 1.02 [ 0.80, 1.29 ]

Cresta 2004 26/41 25/41 7.3 % 1.04 [ 0.74, 1.46 ]

Fountzilas 2001 38/90 51/93 9.0 % 0.77 [ 0.57, 1.04 ]

Koroleva 2001 23/47 24/43 5.3 % 0.88 [ 0.59, 1.30 ]

Sledge 2003 108/230 159/453 24.1 % 1.34 [ 1.11, 1.61 ]

Subtotal (95% CI) 808 970 83.9 % 1.10 [ 1.00, 1.22 ]





Park 2010 11/41 5/40 0.9 % 2.15 [ 0.82, 5.62 ]

Soto 2006 67/91 42/91 12.9 % 1.60 [ 1.24, 2.06 ]

Tomova 2010 14/46 15/53 2.2 % 1.08 [ 0.58, 1.98 ]

Subtotal (95% CI) 178 184 16.1 % 1.54 [ 1.22, 1.93 ]




Total (95% CI) 986 1154 100.0 % 1.16 [ 1.06, 1.28 ]





0.01 0.1 1 10 100




Analysis 18.1. Comparison 18 Treatment-related deaths - line of chemotherapy, Outcome 1 Treatment-

related deaths - line of chemotherapy.


Comparison: 18 Treatment-related deaths - line of chemotherapy

Outcome: 1 Treatment-related deaths - line of chemotherapy




Alba 2004 2/69 0/75 5.43 [ 0.27, 111.12 ]

Baker 1974 1/46 3/30 0.22 [ 0.02, 1.99 ]

Chlebowski 1989 8/129 2/93 2.88 [ 0.63, 13.27 ]

Conte 2004 3/106 1/92 2.60 [ 0.28, 24.60 ]

Cresta 2004 0/41 0/41 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 391 331 1.72 [ 0.70, 4.18 ]





Park 2010 0/41 2/40 0.20 [ 0.01, 3.94 ]

Tomova 2010 2/46 0/53 5.74 [ 0.28, 116.67 ]

Subtotal (95% CI) 87 93 1.06 [ 0.23, 4.94 ]




Total (95% CI) 478 424 1.53 [ 0.71, 3.29 ]





0.1 0.2 0.5 1 2 5 10




Analysis 19.1. Comparison 19 Neutropenia - line of chemotherapy, Outcome 1 Neutropaenia - line of

chemotherapy.


Comparison: 19 Neutropenia - line of chemotherapy

Outcome: 1 Neutropaenia - line of chemotherapy



1 First-line chemotherapy

Alba 2004 0.2012 (0.4564) 1.0 % 1.22 [ 0.50, 2.99 ]

Baker 1974 -0.401 (0.3887) 1.4 % 0.67 [ 0.31, 1.43 ]

Beslija 2006 -0.1542 (0.5192) 0.8 % 0.86 [ 0.31, 2.37 ]

Chlebowski 1989 2.0716 (0.7517) 0.4 % 7.94 [ 1.82, 34.64 ]

Conte 2004 -0.579 (0.1119) 16.5 % 0.56 [ 0.45, 0.70 ]

Cresta 2004 0.1248 (0.0838) 29.5 % 1.13 [ 0.96, 1.34 ]

Fountzilas 2001 0.9201 (0.424) 1.2 % 2.51 [ 1.09, 5.76 ]

Koroleva 2001 0.0168 (0.0734) 38.4 % 1.02 [ 0.88, 1.17 ]

Sledge 2003 0.2012 (0.4564) 1.0 % 1.22 [ 0.50, 2.99 ]

Subtotal (95% CI) 90.0 % 0.96 [ 0.87, 1.05 ]



2 Second/third-line chemotherapy

Park 2010 -0.2871 (0.3571) 1.6 % 0.75 [ 0.37, 1.51 ]

Soto 2006 0.2014 (0.8268) 0.3 % 1.22 [ 0.24, 6.18 ]

Tomova 2010 -0.507 (0.16) 8.1 % 0.60 [ 0.44, 0.82 ]

Subtotal (95% CI) 10.0 % 0.64 [ 0.48, 0.85 ]



Total (95% CI) 100.0 % 0.92 [ 0.84, 1.01 ]




0.01 0.1 1 10 100




Analysis 20.1. Comparison 20 Febrile neutropenia - line of chemotherapy, Outcome 1 Febrile neutropenia -

line of chemotherapy.


Comparison: 20 Febrile neutropenia - line of chemotherapy

Outcome: 1 Febrile neutropenia - line of chemotherapy




Alba 2004 0.0749 (0.1498) 57.2 % 1.08 [ 0.80, 1.45 ]

Beslija 2006 -0.1542 (0.5192) 4.8 % 0.86 [ 0.31, 2.37 ]

Conte 2004 0.238 (0.5665) 4.0 % 1.27 [ 0.42, 3.85 ]

Cresta 2004 1.7671 (0.6384) 3.1 % 5.85 [ 1.68, 20.46 ]

Fountzilas 2001 0.7259 (0.5943) 3.6 % 2.07 [ 0.64, 6.62 ]

Koroleva 2001 0.2955 (0.5534) 4.2 % 1.34 [ 0.45, 3.98 ]

Sledge 2003 0.7129 (0.2523) 20.2 % 2.04 [ 1.24, 3.34 ]

Subtotal (95% CI) 97.1 % 1.34 [ 1.07, 1.68 ]




Park 2010 1.0739 (1.1331) 1.0 % 2.93 [ 0.32, 26.97 ]

Tomova 2010 -0.7746 (0.812) 1.9 % 0.46 [ 0.09, 2.26 ]

Subtotal (95% CI) 2.9 % 0.86 [ 0.24, 3.15 ]



Total (95% CI) 100.0 % 1.32 [ 1.06, 1.65 ]




0.01 0.1 1 10 100




Analysis 21.1. Comparison 21 Nausea and vomiting - line of chemotherapy, Outcome 1 Nausea and

vomiting - line of chemotherapy.


Comparison: 21 Nausea and vomiting - line of chemotherapy

Outcome: 1 Nausea and vomiting - line of chemotherapy




Alba 2004 -0.2843 (0.4003) 0.75 [ 0.34, 1.65 ]

Cresta 2004 -0.2478 (0.5596) 0.78 [ 0.26, 2.34 ]

Fountzilas 2001 0.0328 (0.803) 1.03 [ 0.21, 4.99 ]

Koroleva 2001 1.5864 (1.0322) 4.89 [ 0.65, 36.95 ]

Sledge 2003 -0.2777 (0.3632) 0.76 [ 0.37, 1.54 ]

Subtotal (95% CI) 0.85 [ 0.55, 1.33 ]




Park 2010 0 (0) 0.0 [ 0.0, 0.0 ]

Soto 2006 -0.3094 (0.9039) 0.73 [ 0.12, 4.32 ]

Tomova 2010 1.7483 (1.5363) 5.74 [ 0.28, 116.68 ]

Subtotal (95% CI) 1.25 [ 0.27, 5.74 ]



Total (95% CI) 0.88 [ 0.57, 1.34 ]




0.1 0.2 0.5 1 2 5 10




Analysis 22.1. Comparison 22 Overall survival - schema 1 versus schema 2, Outcome 1 Overall survival -

Schema 1 versus Schema 2.


Comparison: 22 Overall survival - schema 1 versus schema 2

Outcome: 1 Overall survival - Schema 1 versus Schema 2



1 Schema 1

Baker 1974 0.3716 (0.2606) 4.6 % 1.45 [ 0.87, 2.42 ]

Beslija 2006 -0.6387 (0.3182) 3.1 % 0.53 [ 0.28, 0.99 ]

Chlebowski 1989 -0.1054 (0.1282) 19.2 % 0.90 [ 0.70, 1.16 ]

Park 2010 -0.1744 (0.235) 5.7 % 0.84 [ 0.53, 1.33 ]

Sledge 2003 0.0488 (0.0901) 38.8 % 1.05 [ 0.88, 1.25 ]

Subtotal (95% CI) 71.4 % 0.98 [ 0.86, 1.12 ]



2 Schema 2

Alba 2004 0.2151 (0.2634) 4.5 % 1.24 [ 0.74, 2.08 ]

Conte 2004 0.174 (0.2355) 5.7 % 1.19 [ 0.75, 1.89 ]

Fountzilas 2001 0.1989 (0.1667) 11.3 % 1.22 [ 0.88, 1.69 ]

Tomova 2010 0.1989 (0.211) 7.1 % 1.22 [ 0.81, 1.84 ]

Subtotal (95% CI) 28.6 % 1.22 [ 0.99, 1.49 ]



Total (95% CI) 100.0 % 1.04 [ 0.93, 1.16 ]




0.01 0.1 1 10 100




Analysis 23.1. Comparison 23 Progression-free survival - schema 1 versus schema 2, Outcome 1

Progression-free survival - Schema 1 versus Schema 2.


Comparison: 23 Progression-free survival - schema 1 versus schema 2

Outcome: 1 Progression-free survival - Schema 1 versus Schema 2



1 Schema 1

Baker 1974 0.239 (0.2295) 6.8 % 1.27 [ 0.81, 1.99 ]

Beslija 2006 -0.6033 (0.2865) 4.3 % 0.55 [ 0.31, 0.96 ]

Park 2010 0.2776 (0.2429) 6.0 % 1.32 [ 0.82, 2.12 ]

Sledge 2003 0.2469 (0.0962) 38.5 % 1.28 [ 1.06, 1.55 ]

Subtotal (95% CI) 55.7 % 1.20 [ 1.03, 1.40 ]



2 Schema 2

Alba 2004 0.0296 (0.1827) 10.7 % 1.03 [ 0.72, 1.47 ]

Conte 2004 0.0862 (0.139) 18.5 % 1.09 [ 0.83, 1.43 ]

Fountzilas 2001 0.2151 (0.1579) 14.3 % 1.24 [ 0.91, 1.69 ]

Tomova 2010 -0.1625 (0.6415) 0.9 % 0.85 [ 0.24, 2.99 ]

Subtotal (95% CI) 44.3 % 1.12 [ 0.94, 1.33 ]



Total (95% CI) 100.0 % 1.16 [ 1.03, 1.31 ]




0.01 0.1 1 10 100




Analysis 24.1. Comparison 24 Overall response - schema 1 versus schema 2, Outcome 1 Overall response -

Schema 1 versus Schema 2.


Comparison: 24 Overall response - schema 1 versus schema 2

Outcome: 1 Overall response - Schema 1 versus Schema 2



1 Schema 1

Baker 1974 20/46 16/30 3.8 % 0.82 [ 0.51, 1.30 ]

Beslija 2006 34/50 20/50 5.5 % 1.70 [ 1.15, 2.51 ]

Chlebowski 1989 61/129 20/93 4.5 % 2.20 [ 1.43, 3.38 ]

Park 2010 11/41 5/40 0.9 % 2.15 [ 0.82, 5.62 ]

Sledge 2003 108/230 159/453 24.1 % 1.34 [ 1.11, 1.61 ]

Soto 2006 67/91 42/91 12.9 % 1.60 [ 1.24, 2.06 ]

Subtotal (95% CI) 587 757 51.7 % 1.46 [ 1.28, 1.65 ]




2 Schema 2

Alba 2004 35/69 46/75 9.6 % 0.83 [ 0.62, 1.11 ]

Conte 2004 62/106 53/92 14.8 % 1.02 [ 0.80, 1.29 ]

Cresta 2004 26/41 25/41 7.3 % 1.04 [ 0.74, 1.46 ]

Fountzilas 2001 38/90 51/93 9.0 % 0.77 [ 0.57, 1.04 ]

Koroleva 2001 23/47 24/43 5.3 % 0.88 [ 0.59, 1.30 ]

Tomova 2010 14/46 15/53 2.2 % 1.08 [ 0.58, 1.98 ]

Subtotal (95% CI) 399 397 48.3 % 0.92 [ 0.80, 1.04 ]




Total (95% CI) 986 1154 100.0 % 1.16 [ 1.06, 1.28 ]





0.01 0.1 1 10 100




Analysis 25.1. Comparison 25 Treatment-related deaths - schema 1 versus schema 2, Outcome 1

Treatment-related deaths - Schema 1 versus Schema 2.


Comparison: 25 Treatment-related deaths - schema 1 versus schema 2

Outcome: 1 Treatment-related deaths - Schema 1 versus Schema 2



1 Schema 1

Baker 1974 1/46 3/30 0.22 [ 0.02, 1.99 ]

Chlebowski 1989 8/129 2/93 2.88 [ 0.63, 13.27 ]

Park 2010 0/41 2/40 0.20 [ 0.01, 3.94 ]

Subtotal (95% CI) 216 163 0.94 [ 0.36, 2.44 ]




2 Schema 2

Alba 2004 2/69 0/75 5.43 [ 0.27, 111.12 ]

Conte 2004 3/106 1/92 2.60 [ 0.28, 24.60 ]

Cresta 2004 0/41 0/41 0.0 [ 0.0, 0.0 ]

Tomova 2010 2/46 0/53 5.74 [ 0.28, 116.67 ]

Subtotal (95% CI) 262 261 4.00 [ 0.87, 18.35 ]




Total (95% CI) 478 424 1.53 [ 0.71, 3.29 ]





0.1 0.2 0.5 1 2 5 10




Analysis 26.1. Comparison 26 Neutropenia - schema 1 versus schema 2, Outcome 1 Neutropaenia -

subgroup analysis, Schema 1 versus Schema 2.


Comparison: 26 Neutropenia - schema 1 versus schema 2

Outcome: 1 Neutropaenia - subgroup analysis, Schema 1 versus Schema 2



1 Schema 1

Baker 1974 -0.401 (0.3887) 1.0 % 0.67 [ 0.31, 1.43 ]

Beslija 2006 -0.1542 (0.5192) 0.6 % 0.86 [ 0.31, 2.37 ]

Chlebowski 1989 2.0716 (0.7517) 0.3 % 7.94 [ 1.82, 34.64 ]

Park 2010 -0.2871 (0.3571) 1.2 % 0.75 [ 0.37, 1.51 ]

Sledge 2003 0.0007 (0.0736) 27.8 % 1.00 [ 0.87, 1.16 ]

Soto 2006 0.2014 (0.8268) 0.2 % 1.22 [ 0.24, 6.18 ]

Subtotal (95% CI) 31.1 % 0.99 [ 0.87, 1.14 ]



2 Schema 2

Alba 2004 0.2012 (0.4564) 0.7 % 1.22 [ 0.50, 2.99 ]

Conte 2004 -0.579 (0.1119) 12.0 % 0.56 [ 0.45, 0.70 ]

Cresta 2004 0.1248 (0.0838) 21.5 % 1.13 [ 0.96, 1.34 ]

Fountzilas 2001 0.9201 (0.424) 0.8 % 2.51 [ 1.09, 5.76 ]

Koroleva 2001 0.0168 (0.0734) 28.0 % 1.02 [ 0.88, 1.17 ]

Tomova 2010 -0.507 (0.16) 5.9 % 0.60 [ 0.44, 0.82 ]

Subtotal (95% CI) 68.9 % 0.92 [ 0.84, 1.01 ]



Total (95% CI) 100.0 % 0.94 [ 0.87, 1.02 ]




0.01 0.1 1 10 100




Analysis 27.1. Comparison 27 Febrile neutropenia - schema 1 versus schema 2, Outcome 1 Febrile

neutropenia - Schema 1 versus Schema 2.


Comparison: 27 Febrile neutropenia - schema 1 versus schema 2

Outcome: 1 Febrile neutropenia - Schema 1 versus Schema 2



1 Schema 1

Beslija 2006 -0.1542 (0.5192) 4.8 % 0.86 [ 0.31, 2.37 ]

Park 2010 1.0739 (1.1331) 1.0 % 2.93 [ 0.32, 26.97 ]

Sledge 2003 0.7129 (0.2523) 20.2 % 2.04 [ 1.24, 3.34 ]

Subtotal (95% CI) 25.9 % 1.76 [ 1.14, 2.73 ]



2 Schema 2

Alba 2004 0.0749 (0.1498) 57.2 % 1.08 [ 0.80, 1.45 ]

Conte 2004 0.238 (0.5665) 4.0 % 1.27 [ 0.42, 3.85 ]

Cresta 2004 1.7671 (0.6384) 3.1 % 5.85 [ 1.68, 20.46 ]

Fountzilas 2001 0.7259 (0.5943) 3.6 % 2.07 [ 0.64, 6.62 ]

Koroleva 2001 0.2955 (0.5534) 4.2 % 1.34 [ 0.45, 3.98 ]

Tomova 2010 -0.7746 (0.812) 1.9 % 0.46 [ 0.09, 2.26 ]

Subtotal (95% CI) 74.1 % 1.19 [ 0.92, 1.55 ]



Total (95% CI) 100.0 % 1.32 [ 1.06, 1.65 ]




0.01 0.1 1 10 100




Analysis 28.1. Comparison 28 Nausea and vomiting - schema 1 versus schema 2, Outcome 1 Nausea and

vomiting - Schema 1 versus Schema 2.


Comparison: 28 Nausea and vomiting - schema 1 versus schema 2

Outcome: 1 Nausea and vomiting - Schema 1 versus Schema 2



1 Schema 1

Park 2010 0 (0) 0.0 [ 0.0, 0.0 ]

Sledge 2003 -0.2777 (0.3632) 0.76 [ 0.37, 1.54 ]

Soto 2006 -0.3094 (0.9039) 0.73 [ 0.12, 4.32 ]

Subtotal (95% CI) 0.75 [ 0.39, 1.46 ]



2 Schema 2

Alba 2004 -0.2843 (0.4003) 0.75 [ 0.34, 1.65 ]

Cresta 2004 -0.2478 (0.5596) 0.78 [ 0.26, 2.34 ]

Fountzilas 2001 0.0328 (0.803) 1.03 [ 0.21, 4.99 ]

Koroleva 2001 1.5864 (1.0322) 4.89 [ 0.65, 36.95 ]

Tomova 2010 1.7483 (1.5363) 5.74 [ 0.28, 116.68 ]

Subtotal (95% CI) 0.98 [ 0.56, 1.71 ]



Total (95% CI) 0.88 [ 0.57, 1.34 ]




0.1 0.2 0.5 1 2 5 10




Analysis 29.1. Comparison 29 Overall survival - relative dose intensity, Outcome 1 Overall survival -

relative dose intensity.


Comparison: 29 Overall survival - relative dose intensity

Outcome: 1 Overall survival - relative dose intensity



1 Similar dose intensity

Alba 2004 0.2151 (0.2634) 15.8 % 1.24 [ 0.74, 2.08 ]

Fountzilas 2001 0.1989 (0.1667) 39.6 % 1.22 [ 0.88, 1.69 ]

Subtotal (95% CI) 55.4 % 1.23 [ 0.93, 1.62 ]



2 Different dose intensity

Park 2010 -0.1744 (0.235) 19.9 % 0.84 [ 0.53, 1.33 ]

Tomova 2010 0.1989 (0.211) 24.7 % 1.22 [ 0.81, 1.84 ]

Subtotal (95% CI) 44.6 % 1.03 [ 0.76, 1.40 ]



Total (95% CI) 100.0 % 1.14 [ 0.92, 1.39 ]




0.01 0.1 1 10 100




Analysis 30.1. Comparison 30 Progression-free survival - relative dose intensity, Outcome 1 Progression-

free survival - relative dose intensity.


Comparison: 30 Progression-free survival - relative dose intensity

Outcome: 1 Progression-free survival - relative dose intensity




Alba 2004 0.0296 (0.1827) 33.5 % 1.03 [ 0.72, 1.47 ]

Fountzilas 2001 0.2151 (0.1579) 44.8 % 1.24 [ 0.91, 1.69 ]

Subtotal (95% CI) 78.3 % 1.15 [ 0.91, 1.45 ]




Park 2010 0.2776 (0.2429) 18.9 % 1.32 [ 0.82, 2.12 ]

Tomova 2010 -0.1625 (0.6415) 2.7 % 0.85 [ 0.24, 2.99 ]

Subtotal (95% CI) 21.7 % 1.25 [ 0.80, 1.95 ]



Total (95% CI) 100.0 % 1.17 [ 0.95, 1.44 ]




0.01 0.1 1 10 100




Analysis 31.1. Comparison 31 Overall response - relative dose intensity, Outcome 1 Overall response -

relative dose intensity.


Comparison: 31 Overall response - relative dose intensity

Outcome: 1 Overall response - relative dose intensity




Cresta 2004 26/41 25/41 21.2 % 1.04 [ 0.74, 1.46 ]

Fountzilas 2001 38/90 51/93 26.2 % 0.77 [ 0.57, 1.04 ]

Koroleva 2001 23/47 24/43 15.5 % 0.88 [ 0.59, 1.30 ]

Subtotal (95% CI) 178 177 62.9 % 0.88 [ 0.72, 1.07 ]





Alba 2004 35/69 46/75 28.0 % 0.83 [ 0.62, 1.11 ]

Park 2010 11/41 5/40 2.6 % 2.15 [ 0.82, 5.62 ]

Tomova 2010 14/46 15/53 6.5 % 1.08 [ 0.58, 1.98 ]

Subtotal (95% CI) 156 168 37.1 % 0.93 [ 0.72, 1.20 ]




Total (95% CI) 334 345 100.0 % 0.90 [ 0.77, 1.05 ]





0.01 0.1 1 10 100




Analysis 32.1. Comparison 32 Treatment-related deaths - relative dose intensity, Outcome 1 Treatment-

related deaths - relative dose intensity.


Comparison: 32 Treatment-related deaths - relative dose intensity

Outcome: 1 Treatment-related deaths - relative dose intensity




Cresta 2004 0/41 0/41 0.0 [ 0.0, 0.0 ]

Subtotal (95% CI) 41 41 0.0 [ 0.0, 0.0 ]





Alba 2004 2/69 0/75 5.43 [ 0.27, 111.12 ]

Park 2010 0/41 2/40 0.20 [ 0.01, 3.94 ]

Tomova 2010 2/46 0/53 5.74 [ 0.28, 116.67 ]

Subtotal (95% CI) 156 168 1.66 [ 0.45, 6.10 ]




Total (95% CI) 197 209 1.66 [ 0.45, 6.10 ]





0.1 0.2 0.5 1 2 5 10




Analysis 33.1. Comparison 33 Neutropenia - relative dose intensity, Outcome 1 Neutropaenia - relative

dose intensity.


Comparison: 33 Neutropenia - relative dose intensity

Outcome: 1 Neutropaenia - relative dose intensity




Cresta 2004 0.1248 (0.0838) 37.0 % 1.13 [ 0.96, 1.34 ]

Fountzilas 2001 0.9201 (0.424) 1.4 % 2.51 [ 1.09, 5.76 ]

Koroleva 2001 0.0168 (0.0734) 48.2 % 1.02 [ 0.88, 1.17 ]

Subtotal (95% CI) 86.6 % 1.08 [ 0.97, 1.20 ]




Alba 2004 0.2012 (0.4564) 1.2 % 1.22 [ 0.50, 2.99 ]

Park 2010 -0.2871 (0.3571) 2.0 % 0.75 [ 0.37, 1.51 ]

Tomova 2010 -0.507 (0.16) 10.1 % 0.60 [ 0.44, 0.82 ]

Subtotal (95% CI) 13.4 % 0.67 [ 0.51, 0.87 ]



Total (95% CI) 100.0 % 1.01 [ 0.92, 1.12 ]




0.01 0.1 1 10 100




Analysis 34.1. Comparison 34 Febrile neutropenia - relative dose intensity, Outcome 1 Febrile neutropenia

- relative dose intensity.


Comparison: 34 Febrile neutropenia - relative dose intensity

Outcome: 1 Febrile neutropenia - relative dose intensity




Cresta 2004 1.7671 (0.6384) 4.4 % 5.85 [ 1.68, 20.46 ]

Fountzilas 2001 0.7259 (0.5943) 5.1 % 2.07 [ 0.64, 6.62 ]

Koroleva 2001 0.2955 (0.5534) 5.9 % 1.34 [ 0.45, 3.98 ]

Subtotal (95% CI) 15.4 % 2.36 [ 1.21, 4.62 ]




Alba 2004 0.0749 (0.1498) 80.4 % 1.08 [ 0.80, 1.45 ]

Park 2010 1.0739 (1.1331) 1.4 % 2.93 [ 0.32, 26.97 ]

Tomova 2010 -0.7746 (0.812) 2.7 % 0.46 [ 0.09, 2.26 ]

Subtotal (95% CI) 84.6 % 1.07 [ 0.80, 1.42 ]



Total (95% CI) 100.0 % 1.21 [ 0.93, 1.57 ]




0.01 0.1 1 10 100




Analysis 35.1. Comparison 35 Nausea and vomiting - relative dose intensity, Outcome 1 Nausea and

vomiting - relative dose intensity.


Comparison: 35 Nausea and vomiting - relative dose intensity

Outcome: 1 Nausea and vomiting - relative dose intensity




Cresta 2004 -0.2478 (0.5596) 0.78 [ 0.26, 2.34 ]

Fountzilas 2001 0.0328 (0.803) 1.03 [ 0.21, 4.99 ]

Koroleva 2001 1.5864 (1.0322) 4.89 [ 0.65, 36.95 ]

Subtotal (95% CI) 1.14 [ 0.50, 2.60 ]




Alba 2004 -0.2843 (0.4003) 0.75 [ 0.34, 1.65 ]

Park 2010 0 (0) 0.0 [ 0.0, 0.0 ]

Tomova 2010 1.7483 (1.5363) 5.74 [ 0.28, 116.68 ]

Subtotal (95% CI) 0.86 [ 0.40, 1.83 ]



Total (95% CI) 0.98 [ 0.56, 1.71 ]




0.1 0.2 0.5 1 2 5 10


A D D I T I O N A L T A B L E S

Table 1. Summary of treatment comparisons

Combination Sequential Number of trials

doxorubicin + docetaxel doxorubicin → docetaxel Alba 2004

Cresta 2004(included alternating regimen)

Koroleva 2001 (included 2 combination

arms with different doses)



Table 1. Summary of treatment comparisons (Continued)

5-fluorouracil + cyclophosphamide + vin-

cristine

5-fluorouracil → cyclophosphamide →

vincristine

Baker 1974

capecitabine + docetaxel or paclitaxel capecitabine → docetaxel or paclitaxel Beslija 2006

Soto 2006

5-fluorouracil + cyclophosphamide + pred-

nisone + thyroxine or vincristine

5-fluorouracil → cyclophosphamide →

thyroxine or vincristine → prednisone

Chlebowski 1989

epirubicin + paclitaxel epirubicin → paclitaxel Conte 2004

epirubicin + paclitaxel dose dense epirubicin→ paclitaxel Fountzilas 2001

gemcitabine + vinorelbine gemcitabine → vinorelbine Park 2010

doxorubicin + paclitaxel doxorubicin → paclitaxel or paclitaxel →

doxorubicin

Sledge 2003

docetaxel + gemcitabine docetaxel → gemcitabine Tomova 2010

Table 2. Chemotherapy details

Trial name Arm I Arm II

Alba 2004 Arm I: AT=

Doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 both

on day 1.

Cycles repeated every 21 days for 6 cycles.

If prior anthracyclines:

given 3 cycles of AT at above doses followed by 3 cycles

of docetaxel 100 mg/m2

Arm II: A→T=

Doxorubicin 75 mg/m2 intravenously day 1 for 3 cycles

followed by docetaxel 100 mg/m2 intravenously day 1

for 3 cycles

If prior anthracyclines given 2 cycles of doxorubicin 75

mg/m2 followed by 4 cycles of docetaxel 100 mg/m2.

Cycles repeated every 21 days

Baker 1974 Arm I: FCV=

5-fluorouracil 7.5 mg/kg intravenously days 1-5 plus

cyclophosphamide 4 mg/kg intravenously days 1 to 5

plus vincristine 0.015 mg/kg intravenously days 1 and

8

Cycles repeated every 28 days until disease progression

Arm II: F→C→V=

5-fluorouracil 15 mg/kg intravenously days 1 to 5 every

28 days until disease progression then

cyclophosphamide 8 mg/kg intravenously days 1 to 5

every 28 days until disease progression then

vincristine 0.02 mg/kg intravenously weekly until dis-

ease progression

Beslija

2006

Arm I: XT=

Capecitabine (Xeloda, X) 1250 mg/m2 twice daily

orally from days 1 to 14 and docetaxel (Taxotere, T) 75

mg/m2 intravenously day 1.

Cycle repeated every 21 days until disease progression

Arm II: T→X=

Docetaxel 100 mg/m2 intravenously day 1 until disease

progression then

capecitabine 1250 mg/m2 twice daily orally from days

1 to 14 until disease progression




Table 2. Chemotherapy details (Continued)

Chlebowski 1989 WCSG Arm I: CMFTP=

Cyclophosphamide 2 mg/kg/day orally, plus 5-fluo-

rouracil 15 mg/kg every 2 weeks intravenously from

day 1, plus methotrexate 30 mg/m2 every 2 weeks in-

travenously beginning on day 8, plus prednisone 0.5

mg/kg/day orally, plus triiodothyronine 0.005 mg daily.

Cycle repeated until disease progression

SECSG Arm I:

Cyclophosphamide 400 mg/m2 intravenously day 1

every 28 days, plus 5-fluorouracil 400 mg/m2 intra-

venously day 1 and day 8 every 28 days, plus methotrex-

ate 30 mg/m2 intravenously day 1 and day 8 every 28

days, plus vincristine 1 mg/m2 intravenously day 1 and

day 8 every 28 days, plus prednisone 80mg orally daily

from days 1 to 7 every 28 days. Cycle repeated until

disease progression

or

Cyclophosphamide 100 mg orally daily, plus 5-

fluorouracil 400 mg/m2 intravenously weekly, plus

methotrexate 20 mg/m2 orally weekly, plus vincristine

1 mg/m2 intravenously weekly, plus prednisone 45 mg

orally daily for 14 days, then 30 mg daily for 14 days

then 15 mg daily for 28 days. Cycle repeated until dis-

ease progression

WCSG Arm II: F→C→TP→M=

5-fluorouracil 15 mg/kg weekly intravenously from day

1 for a minimum of 4 weeks until disease progression

then

cyclophosphamide 2 mg/kg/day orally for a minimum

of 4 weeks until disease progression then

triiodothyronine 0.005 mg daily plus prednisone 0.5

mg/kg/day for a minimum of 6 weeks until disease pro-

gression then

methotrexate 30 mg/m2 intravenously weekly for a

minimum of 4 weeks

SECSG Arm II: F→MC→V→P=

5-fluorouracil 600 mg/m2 intravenously weekly until

disease progression then

methotrexate 20 mg/m2 orally biweekly until disease

progression then

cyclophosphamide 100 mg/m2 orally daily until disease

progression then

vincristine 1 mg/m2 intravenously weekly until disease

progression then

prednisone 45 mg orally daily for 14 days then 30 mg

daily for 14 days then 15 mg daily for 30 days

Conte

2004

Arm I: EP=

Epirubicin 90 mg/m2 plus paclitaxel 200 mg/m2 intra-

venously day 1.

Cycles repeated every 21 days for 8 cycles

Arm II: E→P=

Epirubicin 120 mg/m2 intravenously day 1 for 4 cycles

then

paclitaxel 250 mg/m2 intravenously day 1 for 4 cycles.


Cresta

2003

Arm I: AT=

Doxorubicin 60 mg/m2 plus docetaxel 60 mg/m2 in-

travenously day.


Arm II: A→T (sequential regimen)=

Doxorubicin 75 mg/m2 intravenously on day 1 for 4

cycles followed by docetaxel 75 mg/m2 intravenously

on day 1 for 4 cycles. Cycles repeated every 21 days.

Maximum 8 cycles

Arm III: T then A (alternating regimen)=

Docetaxel 100 mg/m2 intravenously on day 1 for 4

cycles alternating with doxorubicin 75 mg/m2 intra-

venously on day 1 for 4 cycles. Cycles repeated every

21 days. Maximum 8 cycles

Fountzilas

2001

Arm I: P=

Epirubicin 80 mg/m2 plus paclitaxel 175 mg/m2 intra-

venously day 1.


Arm II: E→P

Epirubicin 110 mg/m2 intravenously day 1 for 4 cycles

followed by

paclitaxel 225 mg/m2 intravenously day 1 for 4 cycles.

Cycles repeated every 14 days with G-CSF support

(dose dense regimen)



Table 2. Chemotherapy details (Continued)

Koroleva

2001

Arm I: AT=


travenously day 1.


Arm II: T→A=

Docetaxel 100 mg/m2 intravenously day 1 for 4 cycles

followed by

doxorubicin 75 mg/m2 intravenously day 1 for 4 cycles.

Cycles repeated every 21 days.

Arm III: AT=


travenously day 1.


Park

2010

Arm I: GV=

Gemcitabine 1,000 mg/m2 plus vinorelbine 25 mg/m2 intravenously days 1 and 8.


Arm II: G→V=

Gemcitabine 1,200 mg/m2 intravenously on days 1 and

8 until disease progression then

vinorelbine 30 mg/m2 intravenously days 1 and 8 until

disease progression.


Sledge

2003

Arm I: AT=

Doxorubicin 50 mg/m2 plus paclitaxel 150 mg/m2 over

24 hours intravenously day 1.


Arm II: A (→P)=

Doxorubicin 60 mg/m2 intravenously day 1 for a max-

imum of 8 cycles. If disease progressed crossed over to

paclitaxel 175 mg/m2 intravenously over 24 hours on

day 1.


Arm III: P (→A)=

Paclitaxel 175 mg/m2 intravenously over 24 hours on

day 1. If disease progressed crossed over to doxorubicin

60 mg/m2 intravenously day 1.


Soto

2006

Arm I: XT=

Capecitabine 825 mg/m2 twice daily orally from days

1 to 14 plus docetaxel 75 mg/m2 intravenously on day

1 until disease progression.


Arm II: X→T (docetaxel or paclitaxel)=

Capecitabine 1250 mg/m2 twice daily orally days 1 to

14 until disease progression then

docetaxel 100 mg/m2 or paclitaxel 175 mg/m2 intra-

venously on day 1 until disease progression.


Arm III: XP=

Capecitabine 825 mg/m2 twice daily orally from days 1

to 14 plus paclitaxel 175 mg/m2 intravenously on day

1 until disease progression.


Tomova

2010

Arm I: TG=

Docetaxel 75 mg/m2 intravenously on day 1 plus gem-

citabine 1,000 mg/m2 intravenously on days 1 and 8.


Arm II: T→G=

Docetaxel 100 mg/m2 intravenously on day 1 for 4

cycles followed by

gemcitabine 1,250 mg/m2 intravenously on days 1 and

1 for 4 cycles.




A P P E N D I C E S

Appendix 1. MEDLINE via OvidSP

1 randomised controlled trial.pt.

2 randomized controlled trial.pt.

3 controlled clinical trial.pt.

4 randomized.ab.

5 randomised.ab.

6 placebo.ab.

7 randomly.ab.

8 trial.ab.

9 groups.ab.

10 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9

11 exp Breast Neoplasms/

12 metastatic breast cancer$.ti,ab,tw.

13 metastatic breast neoplas$.ti,ab,tw.

14 metastatic breast tumour$.ti,ab,tw.

15 metastatic breast tumor$.ti,ab,tw.

16 metastatic breast carcinoma$.ti,ab,tw.

17 advance$ breast cancer$.ti,ab,tw.

18 advance$ breast neoplas$.ti,ab,tw.

19 advance$ breast tumour$.ti,ab,tw.

20 advance$ breast tumor$.ti,ab,tw.

21 advance$ breast carcinoma$.ti,ab,tw.

22 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21

23 11 and 22



(Continued)

24 exp Drug Therapy, Combination/

25 combination chemotherapy.mp.

26 sequential single agent chemotherapy.mp.

27 (sequential adj6 single adj6 agent adj6 chemotherap$).mp.

28 24 or 25 or 26 or 27

29 10 and 23 and 28

30 Animals/

31 Humans/

32 30 not 31

33 29 not 32

Appendix 2. EMBASE via Embase.com

1. random* OR factorial* OR crossover* OR cross NEXT/1 over* OR placebo* OR (doubl* AND blind*) OR (singl* AND

blind*) OR assign* OR allocat* OR volunteer*OR ’crossover procedure’/exp OR ’double blind procedure’/exp OR ’randomized

controlled trial’/exp OR ’single blind procedure’/exp

2. ’breast cancer’/exp

3. advance* NEAR/6 ’breast neoplasm’

4. advance* NEAR/6 ’breast carcinoma’

5. advance* NEAR/6 ’breast cancer’

6. advance* NEAR/6 ’breast tumour’

7. advance* NEAR/6 ’breast tumor’

8. metastatic NEAR/6 ’breast cancer’

9. metastatic NEAR/6 ’breast neoplasm’

10. metastatic NEAR/6 ’breast carcinoma’

11. metastatic NEAR/6 ’breast tumour’

12. metastatic NEAR/6 ’breast tumor’

13. #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12

14. #2 AND #13

15. ’chemotherapy’/exp OR chemotherapy

16. chemotherap*

17. combin* NEAR/6 chemotherap*

18. sequen* NEAR/6 ’single agent’

19. #16 AND #18

20. #15 OR #16 OR #17 OR #19

21. #1 AND #14 AND #20

22. #21 AND [humans]/lim AND [embase]/lim



Appendix 3. WHO ICTRP

Basic search:

1. advanced breast cancer AND combination chemotherap*

2. advanced breast cancer AND sequential single agent chemotherapy

3. advanced breast cancer AND sequential single chemotherapy

4. advanced breast cancer AND sequential chemotherapy

5. advanced breast cancer AND single agent chemotherapy

6. metastatic breast cancer AND combination chemotherap*

7. metastatic breast cancer AND sequential single agent chemotherapy

8. metastatic breast cancer AND sequential single chemotherapy

9. metastatic breast cancer AND sequential chemotherapy

10. metastatic breast cancer AND single agent chemotherapy

Advanced search:

1. Title: Combination versus sequential single agent chemotherapy for metastatic breast cancer

Recruitment Status: ALL

2. Condition: advanced breast cancer OR metastatic breast cancer

Intervention: combination chemotherap*



Intervention: sequential single agent chemotherapy



Intervention: combination versus single sequential chemotherapy


Appendix 4. ClinicalTrials.gov

Advanced search:

1. Conditions: metastatic breast cancer

Interventions: combination chemotherapy


Interventions: sequential single agent chemotherapy


Interventions: combination versus sequential single agent chemotherapy

4. Conditions: advanced breast cancer

Interventions: combination chemotherapy


Interventions: sequential single agent chemotherapy


Interventions: combination versus sequential single agent chemotherapy



W H A T ’ S N E W

Last assessed as up-to-date: 31 October 2013.

Date Event Description

21 January 2014 Amended Corrected labels for Analysis 10.1, 17.1, 24.1 (Figure 6) and 31.1, and also the number of participants

in the Beslija trial for the outcome overall response

C O N T R I B U T I O N S O F A U T H O R S

Rachel Dear (RD), Martin Tattersall (MT) and Nicholas Wilcken (NW) conceived the study objective. RD wrote the review, which

was reviewed and revised by MT, Alexandra Barratt (AB), NW, Kevin McGeechan (KMcG), and Marisa Jenkins (MJ).

D E C L A R A T I O N S O F I N T E R E S T

None

S O U R C E S O F S U P P O R T

Internal sources

• Nil, Not specified.

External sources

• Nil, Not specified.

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

In the protocol we proposed only including first and second-line chemotherapy trials. Our review includes a trial of third-line chemo-

therapy (Park 2010, prior treatment with anthracyclines or taxanes) because the paper met all our other eligibility criteria.

A pre-specified secondary outcome in the protocol was stable disease. We have not reported this outcome because overall tumour

response rate (which includes complete response and partial response) is a more commonly reported outcome that can then be compared

to other similar reviews on this topic.

Another pre-specified outcome in the protocol was “QTWIST” (quality-adjusted time without symptoms of disease and toxicity). We

have not reported this in our review because this outcome was not reported in any of the trials included in this review, and toxicity data

were not consistently reported so that time with side effects from chemotherapy could not accurately be extracted.

In the review, the ’Human’ limit in the MEDLINE search strategy and the ’Randomised controlled trial’ limit in the EMBASE search

strategy were revised.



N O T E S

Two studies (Campone 2013; Zhang 2013) were categorised under the section ’Characteristics of studies awaiting classification’ because

the trials were completed but with insufficient data for inclusion at present. The results from these two small trials will be included in

an updated version of this review.

I N D E X T E R M S

Medical Subject Headings (MeSH)

Antineoplastic Agents [∗administration & dosage; adverse effects]; Antineoplastic Combined Chemotherapy Protocols [∗ administration

& dosage; adverse effects]; Breast Neoplasms [∗drug therapy; mortality; pathology]; Disease Progression; Disease-Free Survival; Nausea

[chemically induced]; Neutropenia [chemically induced]; Randomized Controlled Trials as Topic; Vomiting [chemically induced]

MeSH check words

Female; Humans



cochrane database of systematic reviews (reviews) || combination versus sequential single agent...

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