Abstract
Introduction
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions after breast-conserving surgery for ductal carcinoma in situ? What are the effects of treatments for primary operable breast cancer? What are the effects of interventions in locally advanced breast cancer (stage IIIB)? We searched: Medline, Embase, The Cochrane Library and other important databases up to February 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 79 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding chemotherapy (cyclophosphamide/methotrexate/ fluorouracil and/or anthracycline and/or taxane-based regimens), or hormonal treatment to radiotherapy; adjuvant treatments (aromatase inhibitors, adjuvant anthracycline regimens, tamoxifen); axillary clearance; axillary dissection plus sentinel node dissection; axillary radiotherapy; axillary sampling; combined chemotherapy plus tamoxifen; chemotherapy plus monoclonal antibody (trastuzumab); extensive surgery; high-dose chemotherapy; hormonal treatment; less extensive mastectomy; less than whole breast radiotherapy plus breast conserving surgery; multimodal treatment; ovarian ablation; primary chemotherapy; prolonged adjuvant combination chemotherapy; radiotherapy (after breast-conserving surgery, after mastectomy, plus tamoxifen after breast-conserving surgery, to the internal mammary chain, and to the ipsilateral supraclavicular fossa, and total nodal radiotherapy); sentinel node biopsy; and standard chemotherapy regimens.
Key Points
Breast cancer affects at least 1 in 10 women in the UK, but most present with primary operable disease, which has an 80% 5-year survival rate overall.
In women with ductal carcinoma in situ, radiotherapy reduces local recurrence and invasive carcinoma after breast-conserving surgery, but may not improve survival.
In women with primary operable breast cancer, survival may be increased by full surgical excision, tamoxifen, chemotherapy, radiotherapy, ovarian ablation or trastuzumab (in women who overexpress HER2/neu oncogene).
Incomplete excision may increase the risk of local recurrence, but less-extensive mastectomy that excises all local disease is as effective as radical mastectomy at prolonging survival, with better cosmetic results.
Axillary clearance (removal of all axillary lymph nodes) achieves local disease control, but has not been shown to increase survival, and can cause arm lymphoedema.
Sentinel lymph node biopsy or 4-node sampling may adequately stage the axilla with less morbidity compared with axillary clearance.
Adjuvant tamoxifen reduces the risk of recurrence and death in women with oestrogen-positive tumours, but adverse effects begin to outweigh benefit after 5 years of treatment.
Primary chemotherapy may facilitate successful breast-conserving surgery instead of mastectomy. Adjuvant combination chemotherapy improves survival compared with no chemotherapy, with greatest benefit likely with anthracycline-based regimens at standard doses for 4-6 months.
Radiotherapy decreases recurrence and mortality after breast-conserving surgery. Post-mastectomy radiotherapy for women who are node-positive or at high risk of recurrence decreases recurrence and mortality, but may increase mortality in node-negative women.
Adjuvant aromatase inhibitors improve disease-free survival compared with tamoxifen, but their effect on overall survival is unclear.Adjuvant taxoid regimens may improve disease-free survival over standard anthracycline-based therapy.
In women with locally advanced breast cancer, radiotherapy may be as effective as surgery or tamoxifen at increasing survival and local disease control.
Adding tamoxifen or ovarian ablation to radiotherapy increases survival compared with radiotherapy alone, but adding chemotherapy may not reduce recurrence or mortality compared with radiotherapy alone.
Chemotherapy alone, while widely used, does not improve survival in women with locally advanced breast cancer.
About this condition
Definition
This review examines the effects of treatment for non-metastatic, primary breast cancer. Ductal carcinoma in situ is a non-invasive tumour characterised by the presence of malignant cells in the breast ducts, but with no evidence that they breach the basement membrane and invade into periductal connective tissues. Invasive breast cancer occurs when cancer cells spread beyond the basement membrane, which covers the underlying connective tissue in the breast. This tissue is rich in blood vessels and lymphatic channels capable of carrying cancer cells beyond the breast. Invasive breast cancer can be separated into three main groups: early invasive breast cancer, locally advanced breast cancer, and metastatic breast cancer (see review on breast cancer [metastatic]). Operable breast cancer is apparently restricted to the breast and to local lymph nodes, and can be removed surgically. Although women do not have overt metastases at the time of staging, they remain at risk of local recurrence, and of metastatic spread. They can be divided into those with tumours greater than 4 cm or with multifocal cancers that are usually treated by mastectomy, and those with tumours less than 4 cm cancers that can be treated by breast-conserving surgery. Locally advanced breast cancer is defined according to the TNM staging system of the UICC as stage IIIB (includes T4 a-d; N2 disease, but absence of metastases [see table 1 ]). It is a disease presentation with clinical or histopathological evidence of skin and/or chest-wall involvement, and/or axillary nodes matted together by tumour extension. Metastatic breast cancer is presented in a separate review (see review on breast cancer [metastatic]).
Table 1.
Staging of breast cancer (the individual terms are explained in the glossary) (see text).
| TNM | Stage | |||
| Non-invasive | Tis | N0 | M0 | 0 |
| Early invasive | T1-2 | N0-1 | M0 | I, II A or B |
| T3 | N0 | M0 | II B | |
| Advanced | ||||
| Locally advanced | Tany | N2 | M0 | III A |
| T3 | N1-2 | M0 | III A | |
| T4 | N0-3 | M0 | III B | |
| Tany | N3 | M0 | III B | |
| Metastatic | Tany | Nany | M1 | IV |
Incidence/ Prevalence
Breast cancer affects 1/10-1/11 women in the UK and causes about 21,000 deaths a year. Prevalence is about five times higher, with over 100,000 women in the UK living with breast cancer at any one time. Of the 36,000 new cases of breast cancer each year in England and Wales, most will present with primary operable disease.
Aetiology/ Risk factors
The risk of breast cancer increases with age, doubling every 10 years up to the menopause. Risk factors include an early age at menarche, older age at menopause, older age at birth of first child, family history, atypical hyperplasia, excess alcohol intake, radiation exposure to developing breast tissue, oral contraceptive use, postmenopausal HRT, and postmenopausal obesity. Risk in different countries varies fivefold. The cause of breast cancer in most women is unknown. About 5% of breast cancers can be attributed to mutations in the genes BRCA1 and BRCA2, but the contribution to inherited breast cancer of other genes, including Chk2, ATM, p53, and PTEN, is currently less well established.
Prognosis
Non-metastatic carcinoma of the breast is potentially curable. The risk of relapse depends on various clinicopathological features, of which axillary node involvement, tumour grade, tumour size, and oestrogen receptor status are the most prognostically important. Of women with operable disease, 80% are alive 5 years after diagnosis and treatment (adjuvant treatment is given to most women after surgery). Risk of recurrence is highest during the first 5 years, but the risk remains even 15-20 years after surgery. Recurrence at 10 years, according to one large systematic review, is 60-70% in node-positive women, and 25-30% in node negative women. The prognosis for disease-free survival at 5 years is worse for stage IIIB (33%) than that for stage IIIA (71%). Overall survival at 5 years is 44% for stage IIIB and 84% for stage IIIA. Poor survival and high rates of local recurrence characterise locally advanced breast cancer.
Aims of intervention
To improve survival; to prevent local or regional node recurrence; to obtain prognostic information on the type and extent of tumour and the status of the axillary lymph nodes; to optimise cosmetic results and minimise psychosocial impact; to minimise adverse effects of treatment; and to maximise quality of life.
Outcomes
Survival; rates of local and regional recurrence; rates of mastectomy after breast-conserving treatment; rates of development of metastases; cosmetic outcomes; quality of life; incidence of adverse effects of treatment, including upper-limb lymphoedema.
Methods
BMJ Clinical Evidence search and appraisal January 2007. The following databases were used to identify studies for this review: Medline 1966 to January 2007, Embase 1980 to January 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2006, Issue 4. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE). Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the authors for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for evaluation in this review were: published systematic reviews and RCTs in any language, any level of blinding, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. The authors also identified data by personal communication with experts in the field, and through hand searches. Abstracts of studies that were considered to be fundamental to clinical practice and new developments were included in comments sections. Phase 3 randomised published data are included. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).
Table.
GRADE evaluation of interventions for breast cancer (non-metastatic)
| Important outcomes | Treatment success, mortality, adverse effects | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of interventions after breast-conserving surgery for ductal carcinoma in situ? | |||||||||
| 3, 1 paper (2862) | Treatment success | Radiotherapy v no radiotherapy | 4 | 0 | 0 | 0 | 0 | High | |
| 3, 1 paper (2862) | Mortality | Radiotherapy v no radiotherapy | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1, 1 paper (1804) | Treatment success | Tamoxifen plus radiotherapy v placebo | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1, 1 paper (1804) | Mortality | Tamoxifen plus radiotherapy v placebo | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (523) | Treatment success | Tamoxifen plus radiotherapy v radiothera py | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| What are the effects of treatments for primary operable breast cancer? | |||||||||
| 1 (5187 | Mortality | Adjuvant aromatase inhibitors v placebo | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 2, 2 papers (14068) | Treatment success | Adjuvant aromatase inhibitors v tamoxifen | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 2, 2 papers (14068) | Mortality | Adjuvant aromatase inhibitors v tamoxifen | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 47 (18000) | Treatment success | Adjuvant combination chemotherapy v no chemotherapy | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 47 (18000) | Mortality | Adjuvant combination chemotherapy v no chemotherapy | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| not reported (3454) | Treatment success | Different treatment durations compared with each other ( prolonged adjuvant combination chemotherapy) | 4 | 0 | 0 | 0 | 0 | High | |
| not reported (3454) | Mortality | Different treatment durations compared with each other ( prolonged adjuvant combination chemotherapy) | 4 | 0 | 0 | 0 | 0 | High | |
| 2 (3877) | Treatment success | Different doses compared with each other (enhancedose regimens of adjuvant combination chemotherapy) | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 2 (3877) | Mortality | Different doses compared with each other (enhancedose regimens of adjuvant combination chemotherapy) | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 11 (5942) | Treatment success | Anthracycline regimens compared with standard CMF regimens | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 11 (5942) | Mortality | Anthracycline regimens compared with standard CMF regimens | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 55 (37000) | Treatment success | Adjuvant tamoxifen v placebo | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 55 (37000) | Mortality | Adjuvant tamoxifen v placebo | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (3887) | Treatment success | Durations of treatment compared with each other (adjuvant tamoxifen) | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (3887) | Mortality | Durations of treatment compared with each other (adjuvant tamoxifen) | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (3387) | Treatment success | Trastuzumab v observation (after chemotherapy) | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (3387) | Mortality | Trastuzumab v observation (after chemotherapy) | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 2 (3351) | Treatment success | Trastuzumab v observation (during chemotherapy) | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 2 (3351) | Mortality | Trastuzumab v observation (during chemotherapy) | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 6 (at least 3490 women) | Treatment success | Adjuvant taxoid regimens v standard anthracycline based regimens | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 6 (at least 3490 women) | Mortality | Adjuvant taxoid regimens v standard anthracycline based regimens | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 5 (2090) | Mortality | Supraradical, radical, and total mastectomy compared with each other | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 4 (1296) | Mortality | Radical/total mastectomy v simple mastectomy | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (1079) | Mortality | Radical mastectomy v total mastectomy with or without axillary radiotherapy | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 6 (3107) | Treatment success | Mastectomy v breast conservation | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 6 (4438) | Mortality | Mastectomy v breast conservation | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (701) | Mortality | Radical mastectomy v quandrantectomy plus radiotherapy | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (1851) | Mortality | Lumpectomy with or without radiotherapy v total mastectomy | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (237) | Mortality | Modified radical mastectomy v lumpectomy plus axillary dissection plus radiotherapy | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (705) | Treatment success | Different extents of local excision compared with each other | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 12 (2102) | Treatment success | Ovarian ablation v no ablation | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 12 (2102) | Mortality | Ovarian ablation v no ablation | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 10 (7311) | Treatment success | Breast-conserving surgery plus radiotherapy v breast-conserving surgery alone | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 10 (7311) | Mortality | Breast-conserving surgery plus radiotherapy v breast-conserving surgery alone | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 8 (3531) | Treatment success | Breast-conserving surgery plus radiotherapy v mastectomy | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 7 (3294) | Mortality | Breast-conserving surgery plus radiotherapy v mastectomy | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 3 (2073) | Treatment success | Breast-conserving surgery plus radiotherapy v breast-conserving surgery plus tamoxifen | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 3 (2071) | Mortality | Radiotherapy plus tamoxifen v tamoxifen alone (after breast-conserving surgery) | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 36 (10982) | Treatment success | Radiotherapy after mastectomy v mastectomy alone (in women at high risk of local recurrence) | 4 | −1 | −1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for heterogeneity between RCTs |
| 36 (10982) | Mortality | Radiotherapy after mastectomy v mastectomy alone (in women at high risk of local recurrence) | 4 | −1 | −1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for heterogeneity between RCTs |
| 36 (5195) | Treatment success | Radiotherapy after mastectomy v mastectomy alone (in women not at high risk of local recurrence) | 4 | −1 | −1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for heterogeneity between RCTs |
| 36 (5195) | Mortality | Radiotherapy after mastectomy v mastectomy alone (in women not at high risk of local recurrence) | 4 | −1 | −1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for heterogeneity between RCTs |
| 4 (2802) | Treatment success | Primary chemotherapy v adjuvant chemotherapy | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 5 (3216) | Mortality | Primary chemotherapy v adjuvant chemotherapy | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 26 (not reported) | Treatment success | Radiotherapy after mastectomy v mastectomy alone in women at high risk of local recurrence | 4 | −2 | −1 | 0 | 0 | Very low | Quality points deducted for incomplete reporting of results and for inclusion of RCTs without total nodal radiation. Consistency point deducted for heterogeneity between RCTs |
| 26 (not reported) | Mortality | Radiotherapy after mastectomy v mastectomy alone in women at high risk of local recurrence | 4 | −2 | −2 | 0 | 0 | Very low | Quality points deducted for incomplete reporting of results and for inclusion of RCTs without total nodal radiation. Consistency point deducted for conflicting results and for heterogeneity between RCTs |
| 1 (466) | Mortality | Axillary clearance v axillary sampling | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 8 (4370) | Treatment success | Axillary clearance v axillary radiotherapy | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 8 (4370) | Mortality | Axillary clearance v axillary radiotherapy | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (448) | Treatment success | Standard v dose intensified anthracycline based regimens | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (448) | Mortality | Standard v dose intensified anthracycline based regimens | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (174) | Treatment success | FAC regimen (fluorouracil, adriamycin [doxorubicin], and cyclophosphamide) v single agent paclitaxel | 4 | −2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (174) | Mortality | FAC regimen (fluorouracil, adriamycin [doxorubicin], and cyclophosphamide) v single agent paclitaxel | 4 | −2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (101) | Treatment success | MPEMi (methotrexate, cisplatin, etoposide, mitomycin C), MPEpiE (methotrexate, cisplatin, epirubicin, etoposide), and MPEpiV (methotrexate, cisplatin, epirubicin, vincristine) regimens v each other | 4 | −2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 2 (2515) | Treatment success | Sequencing of anthracycline based chemotherapy and docetaxel | 4 | −2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and for no long term results |
| 1 (73) | Treatment success | Intra-arterial v intravenous administration | 4 | −2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 2 (876) | Treatment success | Less than whole-breast radiotherapy v whole breast radiotherapy | 4 | 0 | −1 | 0 | 0 | Moderate | Consistency point deducted for conflicting results |
| 1 (168) | Mortality | Less than whole-breast radiotherapy v whole breast radiotherapy | 4 | −1 | −1 | 0 | 0 | Moderate | Quality point deducted for sparse data and conflicting results |
| 1 (270) | Treatment success | Radiotherapy to the internal mammary chain v nointernal mammary chain irradiation | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (270) | Mortality | Radiotherapy to the internal mammary chain v nointernal mammary chain irradiation | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (1375) | Treatment success | Radiotherapy v no radiotherapy to the ipsilateral supraclavicular fossa | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 2 (498) | Treatment success | Sentinel node biopsy plus total axillary dissection v with sentinel node biopsy alone | 4 | −2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and for uncertainty about follow-up |
| 1 (200) | Mortality | Sentinel node biopsy plus total axillary dissection v with sentinel node biopsy alone | 4 | −2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting of results and for uncertainty about follow-up |
| at least 6 RCTs (at least 3015 women) | Mortality | High-dose chemotherapy plus autologous stem cell transplantation v conventional chemotherapy | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 13 (5064) | Adverse effects | High-dose chemotherapy plus autologous stem cell transplantation v conventional chemotherapy | 4 | 0 | 0 | 0 | +2 | High | Effect size points added for RR greater than 5 |
| What are the effects of interventions in locally advanced breast cancer (stage III B)? | |||||||||
| 4 (3599) | Treatment success | Post-operative radiotherapy (in women also receiving postoperative systemic treatment) v no radiotherapy | 4 | −2 | 0 | −1 | 0 | Low | Quality poinst deducted for incomplete reporting of results and for weak methods. Directness points deducted for inclusion of women with different disease severities |
| 4 (3599) | Mortality | Post-operative radiotherapy (in women also receiving postoperative systemic treatment) v no radiotherapy | 4 | −2 | 0 | −1 | 0 | Low | Quality poinst deducted for incomplete reporting of results and for weak methods. Directness points deducted for inclusion of women with different disease severities |
| 2 (219) | Treatment success | Surgery alone v radiotherapy alone | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 2 (219) | Mortality | Surgery v radiotherapy | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 1 (143) | Mortality | Low-dose radiotherapy v tamoxifen | 4 | −2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 3 (580) | Treatment success | Systemic treatment plus radiotherapy v radiotherapy | 4 | −1 | −1 | −1 | 0 | Very low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Directness points deducted for inclusion of women with less locally advanced breast cancer |
| 3 (580) | Mortality | Systemic treatment plus radiotherapy v radiotherapy | 4 | −1 | −1 | −1 | 0 | Very low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results. Directness points deducted for inclusion of women with less locally advanced breast cancer |
| 1, 1 publication (107) | Treatment success | Multimodal treatment v hormone treatment | 4 | −1 | −1 | 0 | +1 | Moderate | Quality point deducted for sparse data. Consistency point deducted for different results at different end points. Effect size point added for OR 2–5 |
| 1 (101) | Mortality | Adjuvant chemotherapy v primary plus adjuvant chemotherapy | 4 | −1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
Type of evidence: 4 = RCT; 2 = Observational Consistency: similarity of results across studies Directness: generalisability of population or outcomes Effect size: based on relative risk or odds ratio
Glossary
- Adjuvant treatment
(also known as postoperative chemotherapy) This usually refers to systemic chemotherapy, hormonal treatment, or both, given to people after removal of a primary tumour (in this case, surgery for early breast cancer), with the aim of killing any remaining micrometastatic tumour cells and thus preventing recurrence.
- Anthracyclines
These are also known as cytotoxic antibiotics, and are used as adjuvant treatment with radiotherapy. Examples of anthracyclines are aclarubicin, daunorubicin, adriamycin (doxorubicin), epirubicin, and idarubicin.
- Axillary clearance
Clearance of level I, II, and usually level III axillary lymph nodes. Level I nodes are lateral to the pectoralis minor muscle, level II nodes are under it, and level III nodes are medial to it at the apex of the axilla.
- Axillary radiotherapy
This usually includes irradiation of the supraclavicular fossa. Irradiation of this area incorporates some underlying lung, which increases the risk of radiation pneumonitis. By increasing the volume of the lung irradiated, compared with chest wall or breast radiotherapy alone, the risk of acute pneumonitis is increased.
- Axillary sampling
Aims to remove the four largest, most easily palpable axillary lymph nodes for histological examination.
- Brachial plexopathy
Damage — usually permanent and often progressive — to the brachial plexus. It may arise from radiotherapy as a delayed or late event. It may also be caused by tumour infiltration.
- Brachytherapy
Delivery of a radiation dose over a short distance either from a low-energy x ray source, a low-energy electron source, or a radioactive source.
- Breast-conserving surgery
Surgery consisting of lumpectomy (minimal cancer-free margins), wide local excision (wider free margins), or segmental or quadrant resection (usually with wide-free margins).
- CMF (classical)
Chemotherapy regimen containing cyclophosphamide, methotrexate, and fluorouracil.
- Combination chemotherapy
Two or more cytotoxic drugs given intravenously every 3–4 weeks for 4–6 months.
- Disease-free survival
Means being alive with no local or distant recurrence or contralateral disease.
- Early invasive breast cancer
(stage I or II) is M0 with T1 or T2 (tumour diameter ≤ 5 cm, no involvement of skin or chest wall) and N0 or N1 (mobile axillary nodes); or M0 with T3 (tumour diameter over 5 cm , no skin or chest wall involvement), but only N0.
- FAC
Chemotherapy regimen containing fluorouracil, adriamycin (doxorubicin), and cyclophosphamide.
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Less than whole-breast radiotherapy
The delivery of radiotherapy by either temporary internal placement of a radiation source or by external beam treatment to part of the breast (area of wide local excision after breast-conserving surgery).
- Locally advanced breast cancer
Operable locally advanced breast cancer (stage III A) is T3 (tumours more than 5 cm) and N1 (non-matted involved axillary nodes). Locally advanced breast cancer (stage III B) is M0 with T4 (skin or chest wall infiltration by tumour), N2 (matted axillary nodes)/N3 (internal mammary node involvement) disease, or both, not classified as non-invasive or early invasive breast cancer. Metastatic breast cancer (stage IV) is M1 (any supraclavicular fossa node involvement or distant metastases to bone, lung, liver, etc.) with any combination of tumour and node parameters.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Lumpectomy
Removal of tumour with a 1 cm margin (macroscopically) around the palpable cancer.
- Milan regimen
A sequential regimen of single agent anthracycline followed by CMF.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Modified radical mastectomy
Modified radical mastectomy is a total mastectomy with removal of all axillary nodes from level I medial to the pectoralis minor, level II underneath the pectoralis minor, and up to the apex and including level III nodes medial to the pectoralis minor but below the axillary vein up to the first rib. Traditionally, a modified radical mastectomy included excision of the pectoralis minor, but most surgeons performing a modified radical mastectomy nowadays preserve the pectoralis minor.
- Ovarian ablation
Surgical, medical, or radiation induced suppression of ovarian function in premenopausal women.
- Overall objective response rate
The proportion of treated people in whom a complete response (disappearance of all known lesions on 2 separate measurements at least 4 weeks apart), or partial response ( more than 50% reduction in the size of lesions) is observed.
- Primary chemotherapy
(also known as neoadjuvant or preoperative chemotherapy) involves the use of chemotherapy to treat breast cancer before loco-regional treatment (surgery and or radiotherapy) to the breast to downstage large primary cancers which would require mastectomy to improve chances of survival.
- Quadrantectomy
Tumour excised with ≥ 2 cm of normal surrounding breast tissue and with a segment of breast tissue from the periphery of the breast to the nipple.
- Radical mastectomy
Removal of the breast and pectoralis major and minor muscles and axillary contents.
- Radiotherapy
Part of initial local and regional treatment. In early stage disease, it may be an adjunct to surgery; in locally advanced disease (T4, N2), it may be the sole locoregional treatment. Radiotherapy may be delivered to the breast or postmastectomy chest wall, as well as to the lymphatic areas of the axilla, supraclavicular fossa, or internal mammary node chain.
- Sentinel node biopsy
A procedure whereby the first nodes in the draining lymphatic basin are removed and examined by a pathologist for cancer cells.
- Simple mastectomy
Removal of the breast tissue, usually in association with an ellipse of skin which includes the nipple and areolar complex. Dissection continues down to, but does not usually include, the pectoral fascia. It includes removal of the axillary tail of the breast. Lymph nodes are not usually removed other than by an additional procedure.
- Supraradical mastectomy
Removal of breast, pectoralis major and minor muscles, axillary contents, and internal mammary chain of nodes.
- Systemic therapy
Use of oral or intravenous treatments which affect the whole body.
- TNM staging system
See “staging of breast cancer”, above.
- Total mastectomy
Surgery to remove the entire breast.
- Total nodal irradiation
Radiotherapy to the regional lymph nodes, including supraclavicular, infraclavicular, axillary nodes, and internal mammary nodes in the upper intercostal spaces.
- UICC
International Union against Cancer.
- Very low-quality evidence
Any estimate of effect is very uncertain.
See review on breast cancer (metastatic).
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
Contributor Information
Justin Stebbing, Chelsea and Westminister Hospital, London, UK.
Geoff Delaney, Cancer Therapy Centre, Liverpool Hospital, Liverpool, UK.
Professor Alistair Thompson, Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
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