Background
Breast cancer is the most common cause of cancer death in women world wide. In the developed world it is estimated that approximately 1 in 11 women will develop the disease over their lifetime. Most new diagnoses are at an early stage of disease (especially in countries with mammographic screening programs), where all macroscopic evidence of malignancy can be removed, and there is a reasonable prospect of long term survival with standard treatments. However, breast cancer can sometimes present as a mass that is large, diffuse or attached to surrounding tissues, making initial surgery very difficult. Such "locally advanced" breast cancer accounts for between 5-30% of all cases of breast cancer, depending on the population group studied (Therasse 2003).
To date the results of treatment of locally advanced breast cancer have been poor, with 5 year survival rates often as low as 30%. Progress in this area has been limited by the relative infrequency of the disease, and resultant lack of clinical trials evaluating its management (Hortobagyi 1998). Furthermore, the definition of what constitutes "locally advanced breast cancer" is broad, and includes those with inoperable stage IIIB, potentially operable T3 tumours, positive supraclavicular lymphadenopathy and inflammatory subtypes. Thirdly chemotherapy, surgery and radiotherapy have often been used in different combinations and sequences across different treatment centres. This variability in disease definition and treatment strategies makes assessment of efficacy very complex.
The aim of this review is to identify and synthesise data from all published randomized trials that compare the effects of different local and systemic therapies on patient outcomes in women with locally advanced breast cancer.
Objectives
1. To assess the impact of different combinations of local therapies and systemic therapies on survival and locoregional disease control in locally advanced breast cancer.
Specifically, for local therapies,
the effect of differing amounts and type of local therapy (surgery and radiotherapy, either alone or in combination)
the effect of different sequences of local therapy (surgery then radiotherapy or vice versa)
the effect of differing amounts and type of local therapy (surgery and radiotherapy, either alone or in combination)
the effect of different sequences of local therapy (surgery then radiotherapy or vice versa)
and for systemic therapies
the effect of differing amounts and duration of treatment (for example, more chemotherapy versus less or chemotherapy with or without endocrine therapy)
the effect of sequence in relation to local therapy (chemotherapy before or after local therapy)
the effect of differing amounts and duration of treatment (for example, more chemotherapy versus less or chemotherapy with or without endocrine therapy)
the effect of sequence in relation to local therapy (chemotherapy before or after local therapy)
2. To determine if overall duration or amount of therapy influences treatment outcome
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials involving
- women with "locally advanced breast cancer" as classified by the investigators
- women with inoperable non-inflammatory breast cancer
- women with inflammatory breast cancer as defined by the investigator
Properly randomized controlled trials that evaluate
- amount of local therapy (surgery, radiotherapy or both)
- amount of systemic therapy (dose, duration, intensity)
- sequence of modalities
Local therapies may include surgery and/or radiotherapy.
Systemic therapies may include chemotherapy and/or endocrine therapy and/or molecularly targeted therapy.
Trials that study a mixed population of women with "early or locally advanced" or "locally advanced or metastatic" disease will be excluded, unless the proportion of patients with locally advanced disease represents the majority (>85%), or patients with locally advanced disease can be identified clearly and outcomes extracted.
Systemic therapies may include chemotherapy and/or endocrine therapy and/or molecularly targeted therapy.
Trials that study a mixed population of women with "early or locally advanced" or "locally advanced or metastatic" disease will be excluded, unless the proportion of patients with locally advanced disease represents the majority (>85%), or patients with locally advanced disease can be identified clearly and outcomes extracted.
Types of participants
Women with "locally advanced breast cancer" as defined above:
Any age of patient
Any menopausal status
Any hormone receptor status (ER or PR)
Any Her 2 status
Any age of patient
Any menopausal status
Any hormone receptor status (ER or PR)
Any Her 2 status
Types of interventions
Interventions include the use of any of:
- Surgery
- Radiotherapy (in the neoadjuvant, definitive or adjuvant setting, using conventional external beam techniques and including the use of boosts, and dose fractionation)
- Chemotherapy (in the neoadjuvant, definitive or adjuvant setting, given systemically, using conventional cytotoxic agents, with or without colony stimulating factors [excluding cytokines or monoclonal antibodies used alone, and high-dose chemotherapy requiring stem cell support])
- Endocrine manoeveres (including anti-oestrogens, oestrogens, androgens, aromatase inhibitors, progestogens and ablations [ovarian , adrenal]
- Molecularly targeted therapy (herceptin)
in single agent, or combined modality comparison.
Types of outcome measures
Primary outcomes
- Overall survival
- Local control (proportion free of local disease progression)
Secondary outcomes
- Disease free survival
- Time to, or proportion with local disease progression
- Time to, or proportion with distant disease progression
- Response rate
- Quality of life
- Toxicity
Subgroup analyses
Will be performed if there are sufficient data to justify them, in particular to identify differences in the effectiveness of treatments between:
Will be performed if there are sufficient data to justify them, in particular to identify differences in the effectiveness of treatments between:
- inflammatory and non-inflammatory subtypes
Search methods for identification of studies
The Cochrane Breast Cancer Group's specialized register will be searched. Trials coded as potentially relevant to locally advanced or inflammatory breast cancer will be assessed by both investigators, first by abstract, then blinded methods section then full manuscript as appropriate. Details of the search strategy applied by the Group to create the register, and the procedure used to code references, are described in the Group's module on the Cochrane Library.
Data collection and analysis
Study selection
Study selection will be undertaken independently by the reviewers (CM and NW), both of whom are content experts. The above selection criteria will be applied to each trial, initially based on title, with the subsequently agreed pool of potentially eligible trials screened with the results section (and any other area where the results appeared) masked. For unpublished trials, available information from conference proceedings will be screened.
Assessment of trial quality
A quality score will be applied to describe the adequacy of allocation concealment:
A. low risk of bias in the randomization process (eg randomization by telephone call to central office).
B. moderate risk of bias (eg sealed envelopes)
C. high risk of bias
D. trials where there was insufficient information to score allocation concealment
A. low risk of bias in the randomization process (eg randomization by telephone call to central office).
B. moderate risk of bias (eg sealed envelopes)
C. high risk of bias
D. trials where there was insufficient information to score allocation concealment
Data extraction
Initial data will be extracted independently by CM and NW. This will include baseline characteristics of the patients, the interventions being tested, tumour response rates, median survivals, and information about toxicity and quality of life. Hazard ratios and confidence intervals will be derived by extracting and combining study estimates according to the method described in Parmar 1998.
Analysis
Results of eligible studies will be statistically synthesised (meta-analysis) if appropriate. It is inevitable that some post hoc judgment will be required, because a number of different questions may be posed, and there may only be one or two trials addressing particular questions. Tumour response rates as reported will be analysed as categorical variables and a pooled relative risk derived if appropriate. It is unlikely that anything other than a narrative review of toxicity and quality of life data will be possible.
Background
Breast cancer is the most common cause of cancer death in women world wide. In the developed world it is estimated that approximately 1 in 11 women will develop the disease over their lifetime. Most new diagnoses are at an early stage of disease (especially in countries with mammographic screening programs), where all macroscopic evidence of malignancy can be removed, and there is a reasonable prospect of long term survival with standard treatments. However, breast cancer can sometimes present as a mass that is large, diffuse or attached to surrounding tissues, making initial surgery very difficult. Such "locally advanced" breast cancer accounts for between 5-30% of all cases of breast cancer, depending on the population group studied (Therasse 2003).
To date the results of treatment of locally advanced breast cancer have been poor, with 5 year survival rates often as low as 30%. Progress in this area has been limited by the relative infrequency of the disease, and resultant lack of clinical trials evaluating its management (Hortobagyi 1998). Furthermore, the definition of what constitutes "locally advanced breast cancer" is broad, and includes those with inoperable stage IIIB, potentially operable T3 tumours, positive supraclavicular lymphadenopathy and inflammatory subtypes. Thirdly chemotherapy, surgery and radiotherapy have often been used in different combinations and sequences across different treatment centres. This variability in disease definition and treatment strategies makes assessment of efficacy very complex.
The aim of this review is to identify and synthesise data from all published randomized trials that compare the effects of different local and systemic therapies on patient outcomes in women with locally advanced breast cancer.
Objectives
1. To assess the impact of different combinations of local therapies and systemic therapies on survival and locoregional disease control in locally advanced breast cancer.
Specifically, for local therapies,
the effect of differing amounts and type of local therapy (surgery and radiotherapy, either alone or in combination)
the effect of different sequences of local therapy (surgery then radiotherapy or vice versa)
the effect of differing amounts and type of local therapy (surgery and radiotherapy, either alone or in combination)
the effect of different sequences of local therapy (surgery then radiotherapy or vice versa)
and for systemic therapies
the effect of differing amounts and duration of treatment (for example, more chemotherapy versus less or chemotherapy with or without endocrine therapy)
the effect of sequence in relation to local therapy (chemotherapy before or after local therapy)
the effect of differing amounts and duration of treatment (for example, more chemotherapy versus less or chemotherapy with or without endocrine therapy)
the effect of sequence in relation to local therapy (chemotherapy before or after local therapy)
2. To determine if overall duration or amount of therapy influences treatment outcome
Methods
Criteria for considering studies for this review
Types of studies
Randomized controlled trials involving
- women with "locally advanced breast cancer" as classified by the investigators
- women with inoperable non-inflammatory breast cancer
- women with inflammatory breast cancer as defined by the investigator
Properly randomized controlled trials that evaluate
- amount of local therapy (surgery, radiotherapy or both)
- amount of systemic therapy (dose, duration, intensity)
- sequence of modalities
Local therapies may include surgery and/or radiotherapy.
Systemic therapies may include chemotherapy and/or endocrine therapy and/or molecularly targeted therapy.
Trials that study a mixed population of women with "early or locally advanced" or "locally advanced or metastatic" disease will be excluded, unless the proportion of patients with locally advanced disease represents the majority (>85%), or patients with locally advanced disease can be identified clearly and outcomes extracted.
Systemic therapies may include chemotherapy and/or endocrine therapy and/or molecularly targeted therapy.
Trials that study a mixed population of women with "early or locally advanced" or "locally advanced or metastatic" disease will be excluded, unless the proportion of patients with locally advanced disease represents the majority (>85%), or patients with locally advanced disease can be identified clearly and outcomes extracted.
Types of participants
Women with "locally advanced breast cancer" as defined above:
Any age of patient
Any menopausal status
Any hormone receptor status (ER or PR)
Any Her 2 status
Any age of patient
Any menopausal status
Any hormone receptor status (ER or PR)
Any Her 2 status
Types of interventions
Interventions include the use of any of:
- Surgery
- Radiotherapy (in the neoadjuvant, definitive or adjuvant setting, using conventional external beam techniques and including the use of boosts, and dose fractionation)
- Chemotherapy (in the neoadjuvant, definitive or adjuvant setting, given systemically, using conventional cytotoxic agents, with or without colony stimulating factors [excluding cytokines or monoclonal antibodies used alone, and high-dose chemotherapy requiring stem cell support])
- Endocrine manoeveres (including anti-oestrogens, oestrogens, androgens, aromatase inhibitors, progestogens and ablations [ovarian , adrenal]
- Molecularly targeted therapy (herceptin)
in single agent, or combined modality comparison.
Types of outcome measures
Primary outcomes
- Overall survival
- Local control (proportion free of local disease progression)
Secondary outcomes
- Disease free survival
- Time to, or proportion with local disease progression
- Time to, or proportion with distant disease progression
- Response rate
- Quality of life
- Toxicity
Subgroup analyses
Will be performed if there are sufficient data to justify them, in particular to identify differences in the effectiveness of treatments between:
Will be performed if there are sufficient data to justify them, in particular to identify differences in the effectiveness of treatments between:
- inflammatory and non-inflammatory subtypes
Search methods for identification of studies
The Cochrane Breast Cancer Group's specialized register will be searched. Trials coded as potentially relevant to locally advanced or inflammatory breast cancer will be assessed by both investigators, first by abstract, then blinded methods section then full manuscript as appropriate. Details of the search strategy applied by the Group to create the register, and the procedure used to code references, are described in the Group's module on the Cochrane Library.
Data collection and analysis
Study selection
Study selection will be undertaken independently by the reviewers (CM and NW), both of whom are content experts. The above selection criteria will be applied to each trial, initially based on title, with the subsequently agreed pool of potentially eligible trials screened with the results section (and any other area where the results appeared) masked. For unpublished trials, available information from conference proceedings will be screened.
Assessment of trial quality
A quality score will be applied to describe the adequacy of allocation concealment:
A. low risk of bias in the randomization process (eg randomization by telephone call to central office).
B. moderate risk of bias (eg sealed envelopes)
C. high risk of bias
D. trials where there was insufficient information to score allocation concealment
A. low risk of bias in the randomization process (eg randomization by telephone call to central office).
B. moderate risk of bias (eg sealed envelopes)
C. high risk of bias
D. trials where there was insufficient information to score allocation concealment
Data extraction
Initial data will be extracted independently by CM and NW. This will include baseline characteristics of the patients, the interventions being tested, tumour response rates, median survivals, and information about toxicity and quality of life. Hazard ratios and confidence intervals will be derived by extracting and combining study estimates according to the method described in Parmar 1998.
Analysis
Results of eligible studies will be statistically synthesised (meta-analysis) if appropriate. It is inevitable that some post hoc judgment will be required, because a number of different questions may be posed, and there may only be one or two trials addressing particular questions. Tumour response rates as reported will be analysed as categorical variables and a pooled relative risk derived if appropriate. It is unlikely that anything other than a narrative review of toxicity and quality of life data will be possible.
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