Subclinical hypothyroidism is defined as an elevated serum thyroid-stimulating hormone (TSH) level with normal free thyroid hormones values. The prevalence of subclinical hypothyroidism is 4% to 8% in the general population, and up to 15% to 18% in women who are over 60 years of age. There is considerable controversy regarding the morbidity, the clinical significance of subclinical hypothyroidism and if these patients should be treated.
Objectives
To assess the effects of thyroid hormone replacement for subclinical hypothyroidism.
Search methods
We searched The Cochrane Library, MEDLINE, EMBASE and LILACS. Ongoing trials databases, reference lists and abstracts of congresses were scrutinized as well.
Selection criteria
All studies had to be randomised controlled trials comparing thyroid hormone replacement with placebo or no treatment in adults with subclinical hypothyroidism. Minimum duration of follow-up was one month.
Data collection and analysis
Two authors independently assessed trial quality and extracted data. We contacted study authors for missing or additional information.
Main results
Twelve trials of six to 14 months duration involving 350 people were included. Eleven trials investigated levothyroxine replacement with placebo, one study compared levothyroxine replacement with no treatment. We did not identify any trial that assessed (cardiovascular) mortality or morbidity. Seven studies evaluated symptoms, mood and quality of life with no statistically significant improvement. One study showed a statistically significant improvement in cognitive function. Six studies assessed serum lipids, there was a trend for reduction in some parameters following levothyroxine replacement. Some echocardiographic parameters improved after levothyroxine replacement therapy, like myocardial relaxation, as indicated by a significant prolongation of the isovolumic relaxation time as well as diastolic dysfunction. Only four studies reported adverse events with no statistically significant differences between groups.
Authors' conclusions
In current RCTs, levothyroxine replacement therapy for subclinical hypothyroidism did not result in improved survival or decreased cardiovascular morbidity. Data on health-related quality of life and symptoms did not demonstrate significant differences between intervention groups.Some evidence indicates that levothyroxine replacement improves some parameters of lipid profiles and left ventricular function.
Differentiated thyroid carcinoma with thyroglobulin positive and radioactive iodine negative metastases has been observed in follow-up studies. The management of this condition remains controversial. Most studies support blind radioactive iodine treatment while others negate this approach.
Objectives
To assess the effects of radioiodine therapy for differentiated thyroid carcinoma with thyroglobulin positive and radioactive iodine negative metastases.
Search methods
Studies were obtained from computerised searches of MEDLINE, EMBASE, The Cochrane Library, China National Infrastructure (CNKI) and paper collections of conferences held in Chinese.
Selection criteria
Randomised controlled clinical trials and prospective controlled clinical trials.
Data collection and analysis
Two authors independently extracted data and interviewed authors of all potentially relevant studies by electronic mail to verify randomisation procedures. One author entered data into a data extraction form and the second one verified the results of this procedure.
Main results
Because of the absence of any suitable randomised or prospective controlled trial in this area, results currently cannot be presented.
Authors' conclusions
The currently available evidence is insufficient to reliably assess the potential of radioiodine treatment for differentiated thyroid carcinoma with thyroglobulin positive and radioactive iodine negative metastases.
Several studies have evaluated the clinical effectiveness of endocrine therapy alone in women aged 70 years or over and who are fit for surgery.
Objectives
To identify and review the evidence from randomised trials comparing primary endocrine therapy (endocrine therapy alone) to surgery, with or without adjuvant endocrine therapy, in the management of women aged 70 years or over with operable breast cancer.
Search methods
For this update, the Cochrane Breast Cancer Group Specialised Register was searched 13th November 2007 using the codes for "early breast cancer", "endocrine therapy", "psychosocial" or "surgery".
Selection criteria
Randomised trials comparing primary endocrine therapy with surgery, with or without adjuvant endocrine therapy, in the management of women aged 70 years or over with early breast cancer and who are fit for surgery.
Data collection and analysis
Studies were assessed for eligibility and quality, and data from published trials were extracted by two independent reviewers. Hazard ratios were derived for time-to-event outcomes, where possible, and a fixed-effect model was used for meta-analysis. Toxicity and quality-of-life data were extracted, where present. Where outcome data were not available, trialists were contacted and unpublished data requested.
Main results
Seven eligible trials were identified of which six had published time-to-event data and one was published only in abstract form with no usable data. The quality of the allocation concealment was adequate in three studies and unclear in the remainder. In each case the endocrine therapy used was tamoxifen.
Data, based on an estimated 869 deaths in 1571 women, were unable to show a statistically significant difference in favour of either surgery or primary endocrine therapy in respect of overall survival. However, there was a statistically significant difference in terms of progression-free survival, which favoured surgery with or without endocrine therapy.
The hazard ratios (HR) for overall survival were: 0.98 (95% confidence interval (CI) 0.74 to 1.30, P value 0.9) for surgery alone versus primary endocrine therapy; 0.86 (95% CI 0.73 to 1.00, P value 0.06) for surgery plus endocrine therapy versus primary endocrine therapy. The HRs for progression-free survival were: 0.55 (95% CI 0.39 to 0.77, P value 0.0006) for surgery alone versus primary endocrine therapy; 0.65 (95% CI 0.53 to 0.81, P value 0.0001) for surgery plus endocrine therapy versus primary endocrine therapy (each comparison based on only one trial). Tamoxifen-related adverse effects included hot flushes, skin rash, vaginal discharge, indigestion, breast pain, sleepiness, headache, vertigo, itching, hair loss, cystitis, acute thrombophlebitis, nausea, and indigestion. Surgery-related adverse effects included paresthesia on the ipsilateral arm and lateral thoracic wall in those who had axillary clearance. One study suggested that those undergoing surgery suffered more psychosocial morbidity at three months postsurgery, although this difference had disappeared by two years.
Authors' conclusions
Primary endocrine therapy should only be offered to women with oestrogen receptor (ER) positive tumours who are unfit for or who refuse surgery. In a cohort of women with significant co-morbid disease and ER-positive tumours it is possible that primary endocrine therapy may be a superior option to surgery. Trials are needed to evaluate the clinical effectiveness of aromatase inhibitors as primary therapy for an infirm older population with ER-positive tumours.
The majority of women diagnosed with breast cancer undergo a multidisciplinary treatment with surgical intervention and radiotherapy or chemotherapy, or both. The importance of timing of tumour removal in relation to the menstrual cycle and its influence on disease-free survival and overall survival has been studied by researchers since 1989 but still remains speculative.
Objectives
To determine if surgery performed either during the follicular or luteal phase of the menstrual cycle affects the overall and disease-free survival of premenopausal breast cancer patients.
Search methods
We searched the Cochrane Breast Cancer Group Trials Register (January 2009), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 1), MEDLINE (1966 to January 2009), EMBASE (1974 to September 2006) and the WHO International Clinical Trials Registry Platform (ICTRP) search portal (July 2010). We checked references of articles and communicated with authors.
Selection criteria
Randomised controlled trials (RCTs) comparing breast surgery during the follicular phase of the menstrual cycle with the luteal phase in premenopausal women. Prospective non-RCTs or observational studies were considered if randomised studies were lacking.
Data collection and analysis
Three authors independently extracted data and assessed trial quality.
Main results
Completed randomised trials were not found. There is one trial that is currently ongoing in Italy; the results have yet to be published.
Two prospective observational studies had data on recurrence-free survival. One study reported an odds ratio for recurrence rate at one year (where > 1 favours the luteal phase) of 0.86 (95% confidence interval (CI) 0.69 to 1.08); 0.87 at two years (95% CI 0.69 to 1.09); 0.95 at three years (95% CI 0.75 to 1.21); 1.12 at four years (95% CI 0.87 to 1.43); and 1.12 at five years (95% CI 0.87 to 1.43). Another study reported a hazard ratio for overall survival of 1.02 (95% CI 0.995 to 1.04, P = 0.14) and for disease-free survival of 1.00 (95% CI 0.98 to 1.02, P = 0.92) at three years based on the last and first menstrual period. The results were not significant. There was no difference in the recurrence rate whether the surgery was done during the follicular or luteal phase of the menstrual cycle.
Authors' conclusions
In the absence of RCTs, this review provides evidence from large prospective observational studies that timing of surgery does not show a significant effect on survival.
After surgery for localised breast cancer, radiotherapy (RT) improves both local control and breast cancer-specific survival. In patients at risk of harbouring micro-metastatic disease, adjuvant chemotherapy (CT) improves 15-year survival. However, the best sequence of administering these two types of adjuvant therapy for early-stage breast cancer is unclear.
Objectives
To determine the effects of different sequencing of adjuvant CT and RT for women with early breast cancer.
Search methods
An updated search was carried out in the Cochrane Breast Cancer Group's Specialised Register (20 May 2011), MEDLINE (14 December 2011), EMBASE (20 May 2011) and World Health Organization (WHO) International Clinical Trials Registry Platform (20 May 2011). Details of the search strategy and methods of coding for the Specialised Register are described in the Group's module in The Cochrane Library. We extracted studies that had been coded as 'early', 'chemotherapy' and 'radiotherapy'.
Selection criteria
We included randomised controlled trials evaluating different sequencing of CT and RT.
Data collection and analysis
We assessed the eligibility and quality of the identified studies and extracted data from the published reports of the included trials. We derived odds ratios (OR) and hazard ratios (HR) from the available numerical data. Toxicity data were extracted, where reported. We used a fixed-effect model for meta-analysis and conducted analyses on the basis of the method of sequencing of the two treatments.
Main results
Three trials reporting two different sequencing comparisons were identified. There were no significant differences between the various methods of sequencing adjuvant therapy for local recurrence-free survival, overall survival, relapse-free survival and metastasis-free survival based on 1166 randomised women in three trials. Concurrent chemoradiation increased anaemia (OR 1.54; 95% confidence interval (CI) 1.10 to 2.15), telangiectasia (OR 3.85; 95% CI 1.37 to 10.87) and pigmentation (OR 15.96; 95% CI 2.06 to 123.68). Treated women did not report worse cosmesis with concurrent chemoradiation but physician-reported assessments did (OR 1.14; 95% CI 0.42 to 3.07). Other measures of toxicity did not differ between the two types of sequencing. On the basis of one trial (244 women), RT before CT was associated with an increased risk of neutropenic sepsis (OR 2.96; 95% CI 1.26 to 6.98) compared with CT before RT, but other measures of toxicity did not differ.
Authors' conclusions
The data included in this review, from three well-conducted randomised trials, suggest that different methods of sequencing CT and RT do not appear to have a major effect on recurrence or survival for women with breast cancer if RT is commenced within seven months after surgery.
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)
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)
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.
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
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])
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:
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
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)
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)
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.
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
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])
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:
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
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.
