Timing of breast surgery in premenopausal breast cancer patients

Abstract

Background

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.

Plain language summary

Timing of surgery for premenopausal women with breast cancer

Breast cancer is one of the most common causes of mortality and morbidity and the majority of women diagnosed with breast cancer undergo treatment which includes surgical intervention, radiotherapy or chemotherapy, or both. This review attempted to ascertain if the timing of tumour removal in relation to different stages of the menstrual cycle has an impact on overall survival or disease‐free survival in premenopausal breast cancer patients. The follicular stage of the menstrual cycle relates to days 0 to 14, prior to ovulation. The luteal phase relates to days 15 to 35, after ovulation. If small changes in the timing of surgery could predictably improve the survival rates, any inconvenience and complexity is a small price to pay for the benefit. There were no completed randomised controlled trials comparing surgery performed during the follicular phase and the luteal phase of the menstrual cycle. We identified one ongoing randomised multicentre study and three prospective observational studies.

Of the three prospective observational studies, one reported no survival differences between menstrual cycle groups after stratification by lymph node status at a mean follow‐up of 48 months. The results showed a lack of prognostic value (recurrence‐free survival and overall survival) of timing of surgery in relation to the menstrual period or to oestrogen and progesterone levels in premenopausal breast carcinoma patients. One study gave no data on mean survival time or recurrence‐free survival and the third study reported no significant difference in the overall survival of patients when surgery was done in either the follicular or luteal phase of the menstrual cycle.

A large randomised controlled trial would be ideal to establish the influence of timing of surgery in relation to the menstrual cycle (follicular phase or luteal phase) on the prognosis of breast cancer. However, in the absence of this, the information available from the prospective observational studies shows that there is no difference in disease‐free survival and overall survival in non‐metastatic breast cancer patients irrespective of whether the surgery was done during the follicular or the luteal phase.

Background

Description of the condition

Breast cancer is one of the most common causes of mortality and morbidity among women in both the developed and the developing world (Ferlay 2004; Sasco 2001). The majority of women diagnosed with breast cancer undergo a multidisciplinary treatment which includes surgical intervention and radiotherapy or chemotherapy, or both. Surgery may consist of either lumpectomy or wide excision with removal of some or all the axillary lymph nodes, or a total mastectomy (which is the removal of the entire breast with some or all the axillary nodes). However, depending on the stage of the disease and the treatment given, the disease may recur, and is incurable once the person has distant metastases, although treatment will support some women to live with the recurrent disease for some years (Montazeri 2008; Recht 1999).

Description of the intervention

In 1989, Hrushesky 1989 suggested that the timing of breast cancer surgery in relation to the phase of the menstrual cycle might affect long‐term and disease‐free survival in premenopausal women with operable breast cancer. This hypothesis was formulated by their earlier studies conducted in mice. Ratajczak 1988 reported that surgical cure was most frequent in mice when the operation was performed before and during the span of ovulation when there was a rhythmic surge of oestrogen. Fatal metastatic disease occurred when the primary tumour was resected at the time of metestrus in mice, which is comparable to the time around menstruation in women, a time of rhythmic oestrogen withdrawal.

The menstrual cycle can be divided into two phases, the follicular phase (days 0 to 14) and the luteal phase (days 15 to 35). The follicular phase is characterised by a pre‐ovulatory rise and fall of the hormone oestrogen in the absence of progesterone, followed by ovulation. The subsequent luteal phase is characterised by an increase in oestrogen and a concurrent rise in progesterone. Biologists have documented robust rhythmic changes in the breast during the menstrual cycle and have suggested that circulating hormones at the time of surgery may have potential implications for the success of a surgical intervention (Hagen 1998; Kurebayashi 1995; Pujol 2001).

How the intervention might work

Researchers have suggested different explanations for the biological mechanism. Firstly, during the follicular phase low serum progesterone might decrease cell adhesiveness thereby increasing the chances of cell seeding at operation. Secondly, increased secretion of growth factors in the follicular phase is believed to increase the chance of cancer cells being implanted in other organs. A possible mediator might be insulin‐like growth factor I (IGF‐I), a potent mitogen for breast cancer cells, since stimulation of IGF‐I expression by oestrogens has been reported (Lippman 1986; Murphy 1990). Thirdly, decreased activity of natural killer cells may favour metastases during the follicular phase of the cycle (Sulke 1985; White 1982).

Why it is important to do this review

The importance of timing of breast cancer surgery in relation to the menstrual cycle and its effect on survival rate still remains speculative. The notion that surgery during the luteal phase improves survival outcomes is shown to be inconsistent in the retrospective and prospective studies conducted so far (Chaudhry 2006). In addition, other factors such as menstrual pattern, lymph node status, hormone receptor expression (oestrogen receptor (ER) and progesterone receptor (PR) status), tumour grading and differentiation, tumour size and types of treatments may also influence the survival rate (Badwe 1999; Badwe 2000; Fish 1998; Hortobagi 2002). Obviously if small changes in the timing of surgery could predictably improve the survival rates, the inconvenience and complexity is a small price to pay relative to the benefit. This review evaluated whether the timing of surgery can influence the overall and disease‐free survival of premenopausal women with operable breast cancer, keeping in view the fact that the above mentioned factors may also influence the outcome.

Objectives

To determine if surgery (lumpectomy, wide excision with removal of some or all the axillary lymph nodes, or a total mastectomy) performed either during the follicular or the luteal phase of the menstrual cycle affects the overall survival and disease‐free survival of premenopausal women with breast cancer.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled studies comparing breast surgery during the follicular and luteal phases of the menstrual cycle in premenopausal women with breast cancer.

Prospective, non‐randomised controlled trials were also considered where randomised studies were lacking. In the absence of trials, prospective observational studies were considered for a narrative description of the evidence available.

Types of participants

Premenopausal women with operable breast cancer.

Types of interventions

Breast surgery during the follicular or the luteal phase of the menstrual cycle. This included:

• Lumpectomy (surgical removal of a lump or wide local excision);

• Mastectomy (surgical removal of the full breast to remove cancerous tissue); or

• Quadrantectomy (removal of part of the breast).

Patients treated with pre or postradiotherapy or chemotherapy, or both, were included. Other characteristics of patients (for example age, nodal status, ER and PR status, tumour grading and differentiation, tumour size) which may influence the survival rate were considered during the selection of trials.

Types of outcome measures

Primary outcomes

1. Overall survival rate (OS), the percentage of women who survived for a defined period of time in the study

2. Disease‐free survival or recurrence (DFS), the length of time after treatment with no disease

3. Median survival time, the time from diagnosis or treatment at which half of the patients with breast cancer were either found or expected to be still alive

4. Median disease‐free survival time, the time after treatment at which half of the patients were free of breast cancer

5. Disease recurrence rate

Secondary outcomes

No secondary outcome measures were considered for this review.

Search methods for identification of studies

Independent searches of the following databases were completed by two authors (MS, MY).

Electronic searches

The databases were searched on the dates stated using the search strategies indicated.

(a) Cochrane Breast Cancer Group Specialised Register. The Specialised Register, maintained by the Cochrane Breast Cancer Group, was searched (20th January 2009). Details of the search strategies used by the group for the identification of studies and the procedure used to code references are outlined in the group's module (http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/BREASTCA/frame.html). Studies with text words 'tim* of surgery', 'tim* of mastectomy', 'tim* of lumpectomy' and 'tim* of breast surgery' on the Specialised Register were extracted for consideration.
(b) Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 1 2009); see Appendix 1.
(c) MEDLINE (January 1966 to January 2009); see Appendix 2.
(d) EMBASE (1974 to September 2006); see Appendix 3.
(e) CANCERLIT using Dialog Datastar (1974 to March 2003); see Appendix 4. This database ceased to be updated from 2003.
(f) WHO International Clinical Trials Registry Platform (ICTRP) search portal (performed search 16 July 2010); see Appendix 5.

Searching other resources

(1) References from published studies

References (bibliographies) of articles were checked for any unknown trials, which were not indexed in the databases.

(2) Unpublished literature

Attempts were made to obtain unpublished trial data from the respective authors. Some authors were consulted to find out if they knew of any published or unpublished randomised controlled trials pertaining to the timing of breast surgery in premenopausal women that had not been identified by us.

(3) Conference proceedings

We searched conference websites for abstracts of presentations. These conferences included the European Society of Mastology (EUSOM) and the Annual meeting of the American Society of Clinical Oncology (ASCO) (from 2006 to July 2010).

(4) Language restrictions

No language restrictions were imposed.

Data collection and analysis

Selection of studies

Three authors (MS, KLW and MY) independently examined the abstracts of studies identified by the search strategy. The results of searches conducted after 2006 were independently examined by two authors (VB and MS). Full publications were retrieved for qualifying abstracts. Discrepancies were resolved by discussion.

Data extraction and management

Two review authors (MS and MY) extracted information on participants, methods, interventions, outcomes and results; and evaluated the methodological quality of each trial. Trial quality was assessed according to methods outlined in section 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).

The following features were considered.

1. Method of randomisation.

2. Method of allocation concealment.

3. Blinding of participants, surgeons and outcome assessors.

4. Completeness of follow up.

Data were extracted using methods outlined in section 7 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008) by two authors (MS and MY) working independently. Discrepancies were resolved by discussion.

Assessment of risk of bias in included studies

The allocation concealment for each study was scored A (adequate), B (unclear), C (inadequate) or D (not used) according to the rating system outlined in the Cochrane Handbook for Systematic Reviews of Interventions, section 6.3 (Higgins 2008).

Trials in which it was explicit that there was concealment of allocation, blinding of outcome assessment, handling of drop outs and withdrawals and with intention‐to‐treat (ITT) analysis were considered to be of high quality (Juni 1999).

Measures of treatment effect

Presentation of statistical data included the odds ratio (OR) or hazard ratio (HR) for binary data with the 95% confidence interval (CI).

Unit of analysis issues

Overall survival and recurrence‐free survival data were extracted from the Kaplan Meier curves at predetermined time points. Median survival times and published P values from Kaplan Meier curves were also extracted whenever possible.

Dealing with missing data

When there were missing data in the study reports, attempts were made to contact the investigators for further information.

Assessment of heterogeneity

We were unable to calculate pooled treatment effects from the identified studies as the information gathered was insufficient. Therefore, we did not perform heterogeneity tests.

Assessment of reporting biases

Publication bias evaluation using funnel plots was not attempted as only limited numbers of studies were identified. An attempt was made to identify any selective reporting of outcomes in the studies. If so, the authors were contacted.

Data synthesis

Due to the limited data that were extracted, fixed‐effect and random‐effects models were not used to pool data. The data obtained from Kaplan Meier curves on the recurrence of disease and disease‐free survival were entered into RevMan 5 (RevMan 2008) to generate Peto ORs and 95% CIs. When there was insufficient information available, we recorded the percentages that were reported in the study into the table.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis and the investigation of heterogeneity were not performed owing to the limitations of the available data.

Sensitivity analysis

Sensitivity analysis was not performed owing to the limitations of the available data.

Results

Description of studies

See table: Characteristics of included studies.

Results of the search

We did not find any completed randomised controlled trials comparing surgery (that is lumpectomy, partial mastectomy or full mastectomy) performed during either the follicular or the luteal phase of the menstrual cycle. We found an abstract of one randomised multicentre study (11 Italian centres, all members of the Italian Breast Oncology Group) presented at an oncology conference (The European Society of Mastology) in 1997 (Galimberti 1997). According to this report, 216 patients were recruited with 94 patients operated on during the follicular phase and 122 patients during the luteal phase. Later an updated report was published (Zurrida 2001) indicating the number of patients randomised and their clinical characteristics. Details of which are in the table of Ongoing studies. This report did not include analysis of the outcomes of interest. Unsuccessful attempts have been made to contact the author to obtain the current status of the trial.

We found three prospective observational studies (Grant 2009; Pujol 2001; Thorpe 2008). Prior to publication of Thorpe 2008, the study results were presented at the American Society of Clinical Oncology meeting in 2005 (Sainsbury 2005a). Similarly, preliminary study details and results of Grant 2009 were presented in the American Society of Clinical Oncology Annual Meeting Proceedings in 2004 (Grant 2004).

Included studies

The study by Pujol (Pujol 2001) analysed 487 premenopausal patients with non‐metastatic primary breast carcinoma, of which 360 patients were eligible for analysis. Patients had a tumour size of either T1, T2, T3 or T4 with the majority of the patients having T2. Lymph node involvement was either N 0, 1 to 2 or > 2, with the majority of the patients having no lymph node involvement; the Scarff‐Bloom‐Richardson (SBR) grade was 1, 2 or 3, with the majority of the patients with SBR grade 2. The seriousness of breast cancer is determined by the SBR grade, which depends upon the three histological parameters: nuclear pleomorphism, mitotic score and tubular differentiation.

Patients who were excluded from the study included those with preoperative radiotherapy or chemotherapy, metastasis, had used oral contraceptives less than one month before surgery, perimenopausal women and pregnant women. Patients however had radiotherapy or chemotherapy post surgery depending on the oestrogen receptor (ER) status and node involvement. In this study, serum estradiol, progesterone, follicular stimulating hormone and luteinising hormone levels were assayed on the day of surgery to define the menstrual cycle phase. Patients were then followed up for a mean period of 48 months.

The study by Thorpe 2008 recruited 611 patients to the Intervention, Timing and Surgery (ITS) study between February 1993 and December 2000. This was a multicentre study conducted across 24 UK sites and one Italian site. The median age of patients was 43 years (range 19 to 55 years). The last menstrual period (LMP) was categorised according to the menstrual cycle phase definitions of Senie 1991 (follicular phase: 0 to 14 days; luteal phase: 15 to 36 days); Badwe 1991 (follicular phase: 3 to 12 days; luteal phase: 0 to 2 days); and Hrushesky 1989 (perimenstrual: 0 to 6 days and 21 to 32 days; mid‐cycle: 7 to 20 days). Patients were categorised as being in either the follicular or the luteal phase of their menstrual cycle at the time of intervention using the LMP, first menstrual period after surgery (FMP), hormonal profile at the time of the intervention as well as menstrual cycle length and variation, in order to identify as accurately as possible the patient's phase of the menstrual cycle at the time of intervention. This categorisation was performed by an independent expert who was blinded to the patients’ outcomes. To ensure that each menstrual cycle group had an adequate number of patients (that is 60 to 65 patients per group) and number of events for the analysis, 412 patients were recruited to the primary analysis group. These patients had regular cycles and no oral contraceptives were taken six months prior to entering the study.

The types of surgery included excision biopsy, lumpectomy and mastectomy. The majority of patients had a lumpectomy (47.8%), followed by a mastectomy (33.5%) and an excision biopsy (18%). Fourteen per cent of the tumours were grade I, 42% were grade II and 40% were grade III while 51% were node positive.

In the study by Grant 2009 (North Central Cancer Treatment Group, N9431) 1118 women were initially enrolled (from July 1996 until December 2001), of which the eligible cohort comprised of 834 women who had stages I and II breast cancer and had either single (720 women) or two surgical procedures (114 women). At the time of the surgical procedure, 230 patients (28%) were classified to be at the luteal phase (serum progesterone (Pg) level ≥ 5 ng/ml) and 363 patients (44%) were in the follicular phase (serum Pg level ≤ 3 ng/ml, before cycle day 21). Approximately 241 patients were categorised as other (17% were anovulatory, for 9% of patients the luteal phase was unclear, 2% had oligoovulatory, 1% had persistent corpus luteum and another 1% had contradictory information and could not be classified).

Excluded studies

The retrospective studies and surveys excluded from this review were: Cooper 1999; Fentiman 2002; Gnant 1992; Goldhirsch 1997; Harlap 1998; Jager 1995; Milella 1999; Mondini 1997; Normura 1999; Saad 1994; Takeda 2001; Veronesi 1994). One further study was excluded (Sainsbury 2005a) because it was a conference presentation given prior to the full publication of Thorpe 2008. See Characteristics of excluded studies.

Risk of bias in included studies

The main bias of this review was the lack of randomised controlled trials on the topic. Although this review identified one incomplete randomised controlled trial, the method of randomisation and other methodological qualities of this trial could not be verified owing to the incomplete information in the abstract. Furthermore, the relevant outcomes were not reported.

In one prospective observational study, patients were entered into the trial (from 1992 to 1995) after obtaining informed consent from the patients. It was a single centre study conducted at the Montpellier Cancer Center, France (Pujol 2001).

Initially 487 premenopausal patients were selected but only 360 were eligible for the study. Twenty‐six per cent (127/487) of the patients were excluded as they did not meet the eligibility criteria. The sample size calculation was performed a priori and 354 patients were estimated to have a power of 90%. The study had 186 patients who underwent surgery during the follicular phase, 24 patients during their ovulatory phase and 150 patients during the luteal phase.

The hormonal phase of the menstrual cycle was determined on the day of the surgery; however potential bias may have occurred in assigning the patients to a definite time for surgery due to prior knowledge of the patients' characteristics. If the assignment of patients to a definite time for surgery had been handled by an independent person, not involved the study, it may have resulted in less bias during the assignment to surgery. Similar bias may have occurred in the Grant 2009 study.

There was no blinding of patients or surgeons in the study (Pujol 2001). During the length of the study (48 months), only two patients were lost to follow up.

Allocation

Allocation concealment was assessed in the one identified randomised controlled trial (Galimberti 1997) but the information provided was inadequate.

Blinding

Blinding was assessed in the one identified randomised controlled trial (Galimberti 1997) but the information provided was inadequate. In Pujol 2001 there was no blinding of patients or surgeons in the study however this would not have influenced the study outcomes because overall survival and disease‐free survival are objective measures. In Thorpe 2008 patients were accurately classified as being in either the follicular or the luteal phase of their menstrual cycle at the time of intervention by using LMP, FMP and hormonal profiles at the time of intervention as well as menstrual cycle length and variation. This classification was performed by an independent expert who was blinded to the patients’ outcomes.

Selective reporting

All available data were reported.

Other potential sources of bias

There were no other potential sources of bias.

Effects of interventions

This review did not identify any randomised controlled trials. However, there was one ongoing randomised controlled trial (Galimberti 1997; Zurrida 2001) focusing on the time of surgery for operable breast cancer. This trial was being undertaken in Italy and no results have been published to date. The status of this trial will be assessed when we next update the review.

While writing our protocol, we did not set a priori conditions for studies of lower quality in the case of insufficient evidence from randomised controlled trials. However, considering the importance of this question and the current knowledge gaps, we felt it was worthwhile to include a narrative description of the evidence from the existing prospective studies.

We did not find any controlled clinical trials. Three prospective observational studies involving a cohort of patients who underwent surgical procedures at different phases of the menstrual cycle were identified (Grant 2009; Pujol 2001; Thorpe 2008). Pujol 2001 had relevant data on recurrence‐free survival at one, two, three, four and five years. The data were extracted from the Kaplan Meier curves (comparisons 1:01 and 1:02). The recurrence, where an OR > 1 favours the luteal phase at one year was: OR 0.86 (95% CI 0.69 to 1.08), two years: OR 0.87 (95% CI 0.69 to 1.09), three years: OR 0.95 (95% CI 0.75 to 1.21), four years: OR 1.12 (95% CI 0.87 to 1.43), and five years: OR 1.12 (95% CI 0.87 to 1.43) (refer to Analysis 1.1). The study reported that the risk of recurrence was similar whether surgery was completed during the follicular or the luteal phase; patients had non‐metastatic breast cancer with a tumour size > 2 cm (T1, T2, T3, T4) with or without node involvement (N0, N1, N2, N3) and a SBR grade 1, 2 or 3.

1.1. Analysis.

Comparison 1: Follicular phase versus luteal phase, Outcome 1: Recurrence

The study also reported that there were no survival differences between menstrual cycle groups when stratified by lymph node status (Analysis 1.3). The results showed a lack of prognostic value (that is recurrence‐free survival and overall survival) of timing of surgery in relation to the menstrual period or oestrogen and progesterone concentrations in premenopausal breast carcinoma patients.

1.3. Analysis.

Comparison 1: Follicular phase versus luteal phase, Outcome 3: Disease‐free Survival

Disease‐free Survival
Study	DFS at 1 year	DFS at 2 years	DFS at 3 years	DFS at 4 years	DFS at 5 years	HR (adjusted)	95% CI	N (No.of patients)
Overall
Grant 2009					Follicular: 82.7% (95% CI 78.7% to 86.8%) Luteal: 82.1% (95% CI 77.1% to 87.5%) Indeterminate phase: 79.2% (95% CI 73.9% to 84.7%)	0.88	0.62 to 1.26	0.498
Pujol 2001	Follicular: 93% Luteal: 92% Ovulatory: 95%	Follicular: 87.5% Luteal: 86% Ovulatory:87%	Follicular:80% Luteal:79% Ovulatory:87%	Follicular: 75% Luteal: 77.5% Ovulatory: 87%	Follicular: 75% Luteal: 77.5% Ovulatory:81%	Not mentioned	Not mentioned	0.46
ER negative (Follicular vs Luteal)
Grant 2009						0.532	0.31 to 0.93	171
Pujol 2001	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported
ER positive (Follicular vs Luteal)
Grant 2009						1.16	0.72 to 1.87	416
Pujol 2001	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported
New Subgroup

In addition, there was no relationship between the menstrual phase at time of surgery and tumour size, cathepsin D level, SBR grade, progesterone receptor status and the number of positive lymph nodes. In the multivariate analysis, the lack of lymph node involvement, presence of progesterone receptors and low concentrations of luteinising hormone predicted a longer overall survival independent of other factors (lymph node status: RR 2.6, 95% CI 1.6 to 4.2, P < 0.01; progesterone status: RR 0.4, 95% CI 0.2 to 1.0, P = 0.06; luteinising hormone concentration: RR 3.6, 95% CI 1.4 to 9.0, P < 0.01). There was no difference in survival between the different menstrual groups even after stratification by lymph node status.

In Thorpe 2008, the median follow up was 59 months (inter‐quartile range 43 to 78 months). In this analysis, timing of surgery during the menstrual cycle had no significant impact on the three‐year overall survival (hazard ratio (HR) 1.02, 95% CI 0.995 to 1.04, P = 0.14) and three‐year disease‐free survival (HR 1.00, 95% CI 0.98 to 1.02, P = 0.92). The study attributed the insignificant result as possibly due to 97% of patients receiving some form of adjuvant therapy. When menstrual cycle was categorised into follicular or luteal phase according to the hormone profiles with LMP and FMP data, 17.7% of patients (73/412) could not be identified as being either in the follicular or the luteal phase and 19.9% of patients (82/412) did not have hormonal data for their first operation and one patient received neoadjuvant therapy only during the primary analysis group. Therefore only 256 patients (62%) were included in the analysis. The study reported no significant difference in the overall survival of patients when surgery was done in the follicular or the luteal phase of the menstrual cycle. The data extrapolated from the graph showed that at three years the proportion of patients who were at risk was 87% in the luteal phase compared to 82.8% in the follicular phase.

Similar results were also reported by a recent, large prospective study by Grant 2009. Overall survival and disease‐free survival did not differ with respect to the menstrual phase at surgery for patients classified as in the follicular or luteal menstrual phase or in an indeterminate category. Five‐year OS rates were 91.9% (95% CI 89.1% to 94.8%), 92.2% (95% CI 88.7% to 95.9%) and 91.8% (95% CI 88.2% to 95.5%); and the 5‐year DFS rates were 82.7% (95% CI 78.7% to 86.8%), 82.1% (95% CI 77.1% to 87.5%) and 79.2% (95% CI 73.9% to 84.7%) among women who had surgery during the follicular, luteal or indeterminate phases, respectively. The HR for DFS (follicular versus luteal) was 0.88 (95% CI 0.62 to 1.26, P = 0.498). The authors also performed an analysis based on nodal disease, ER status, adjuvant radiation therapy, adjuvant chemotherapy and menstrual phase at surgery. They reported that there was no association with DFS (adjusted HR 0.83, 95% CI 0.58 to 1.19, P = 0.319; n = 587). Based on the ER status (ER‐positive and ER‐negative cohorts) the HRs differed for the follicular versus luteal phases (ER‐positive cohort: HR 1.16, 95% CI 0.72 to 1.87; ER‐negative cohort: HR 0.53, 95% CI 0.31 to 0.93).

Overall survival (OS) did not differ when the analysis was adjusted for nodal disease and ER tumour status (follicular versus luteal HR 1.0, 95% CI 0.58 to 1.71, P = 0.985). For patients with an ER‐positive status (n = 417) the HR was 1.46 (95% CI 0.68 to 3.16) compared to the ER‐negative patient group (n = 173) with an HR of 0.78 (95% CI 0.36 to 1.68), however the results were insignificant.

Discussion

Although a large randomised controlled trial would have been ideal to establish the influence of timing of surgery in relation to the menstrual cycle (follicular phase or luteal phase) on the prognosis of breast cancer, the information currently available from the prospective observational studies shows that there is no difference in disease‐free survival and overall survival in non‐metastatic breast cancer patients irrespective of whether the surgery was done during the follicular or the luteal phase. There was also no significant difference in the overall survival and disease‐free survival based on the nodal disease and ER status of the patients.

Data from various excluded retrospective studies showed conflicting results. Some studies reported that premenopausal patients operated on during the luteal phase had a significantly better prognosis than patients operated on during the follicular phase (Cooper 1999; Goldhirsch 1997; Saad 1994; Veronesi 1994) whereas other studies suggested no benefit (Gnant 1992; Harlap 1998; Jager 1995; Milella 1999; Mondini 1997) or favoured surgery during the follicular phase of the menstrual cycle (Normura 1999; Sainsbury 1991; Takeda 2001). Some studies reported that the beneficial effect observed during the follicular phase was restricted to patients with node‐positive disease while other studies found that the phase interacted with oestrogen receptor (ER) or progesterone (PR) status or with tumour size (Milella 1999).

Another study (Fentiman 2002) was designed to study prognostic factors of early breast cancer and part of this study included the timing of surgery. Blood was taken and frozen serum stored from 471 premenopausal patients. For 289 patients, this was undertaken during four days of surgery and the last menstrual period (LMP) was known in 81% (234/289) of the patients. Both estradiol (E2) and progesterone (P) were measured by radioimmunoassay. For those patients with the known LMP, there was no relationship between the phase of the cycle and serum E2 because of wide inter‐individual variations, but P values showed a correlation for 92% of patients in the follicular phase (≤ 4 ng/mL‐1) and 56% of those patients in the putative luteal phase (≥ 4 ng/mL‐1).

One of the limitations in these studies is that the menstrual history data are often inaccurate and therefore unreliable; studies lack adequate procedures to record hormonal assessment before the surgery, which may potentially lead to misclassification of the patient's menstrual phase. Various treatments (radiotherapy and chemotherapy) are given pre and postsurgery, which may further influence outcome. It was reported by Pujol 2001 that discrepancies existed between hormonal measures and the dates of the LMP. If hormonal measurements were not taken, 16% of the population would have been misclassified as in the follicular phase and 36% in the luteal phase. According to Pujol 2001, the high incidence of misclassification is due to a higher incidence of an anovulatory cycle in aging premenopausal women. Another reason is the variations in the definitions (that is cut off points) of follicular and luteal phases in the current literature, which can lead to false positive results. It is therefore important for researchers in this field to standardise the cut off points during the menstrual cycle and also use hormonal measurements to define phases of the menstrual cycle in future studies.

In Thorpe 2008, the menstrual cycle was categorised into the follicular or the luteal phase according to hormonal profiles and LMP and FMP data and only 256 patients (62.1%) were included in the analysis. This was due to either unavailable hormonal data or the incorrect identification of the follicular or the luteal phase of the menstrual cycle. In the recent study of Grant 2009, 29% of the patients were classified as indeterminate.

The findings from the retrospective studies have resulted in uncertainty and confusion amongst surgeons and patients. However the results obtained from prospective studies show that it is unlikely that there is a difference in overall survival and disease‐free survival in patients undergoing surgery during the follicular or the luteal phases of the menstrual cycle.

Summary of main results

No randomised controlled trials or controlled clinical trials were included in the analysis for this review. We identified three prospective observational trials. All three trials reported no relationship between the menstrual phase during which surgery was undertaken and overall survival or recurrent‐free survival. Pujol 2001 had relevant data on recurrence‐free survival at one, two, three, four and five years and results showed that the risk of recurrence was similar whether the surgery was undertaken during the follicular or the luteal phase for patients with non‐metastatic breast cancer with tumour size >2 cm (T1,T2, T3, T4), with or without node involvement (N0, N1, N2, N3), and SBR grade 1, 2 or 3. Thorpe 2008 reported no difference in the overall survival when surgery was done during either the follicular or the luteal phase of the menstrual cycle. Data extrapolated from their graph showed that at three years, the proportion of patients at risk was 82.8% during the follicular phase and 87% during the luteal phase. Similar results were also reported by Grant 2009, showing that the results from prospective studies are consistent in their findings.

Overall completeness and applicability of evidence

This review highlighted the lack of complete and applicable evidence concerning the time of breast surgery in premenopausal breast cancer patients. One conference abstract of a randomised controlled trial (a multicentre study) was identified which recruited 216 patients, however no results were reported and our attempts to contact the author and ascertain the current state of the trial were unsuccessful.

Quality of the evidence

This review draws attention to the lack of randomised controlled trials on the timing of breast surgery in premenopausal breast cancer patients and thus identifies a lack of high quality evidence. However, the limited evidence available from non‐randomised prospective studies provides a good indication of the direction of the evidence.

Potential biases in the review process

There is no potential bias in the review process.

Agreements and disagreements with other studies or reviews

None identified.

Authors' conclusions

Implications for practice.

There is currently no evidence indicating that timing of surgery during the follicular or the luteal phase of the menstrual cycle can benefit patients with regard to overall and recurrence‐free survival. Evidence from three prospective observational studies shows that there is no difference in overall and disease‐free survival for non‐metastatic or metastatic breast cancer patients whether the surgery was done during the follicular or luteal phase of the menstrual cycle. Therefore, scheduling of breast cancer operations based on the menstrual cycle is not justified unless further evidence is forthcoming.

Implications for research.

It would have been ideal if a high quality randomised controlled trial had been completed in order to solve the controversy surrounding whether or not the timing of surgery influences the patient's overall and disease‐free survival.

It is vital that researchers discuss and standardise an acceptable definition for the follicular and the luteal phases of the menstrual cycle before embarking on a trial. Since there is a potential for misclassifying the menstrual phases, confirmation should be done by taking hormonal measurements in future trials.

Some researchers believe that a beneficial effect is dependent on the oestrogen receptor (ER) and progesterone receptor (PR) positive or negative status, tumour size, node involvement and metastases, hence it is important to note these patient characteristics in a trial so that a stratified analysis can be done.

It would also be worthwhile to investigate if delaying surgery would pose any further harm to patients.

What's new

Date	Event	Description
6 February 2018	Review declared as stable	Only one small cohort study has been conducted since review publication and this study is unlikely to change the overall findings of the review. Therefore we do not expect to update this review.

History

Protocol first published: Issue 3, 2002
Review first published: Issue 5, 2011

Date	Event	Description
22 June 2011	Amended	Amended author name of LW Khin.

Appendices

Appendix 1. Appendix 1

The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library 2010, Issue 1.

The search terms used were:

#1 Breast neoplasm (MESH)exp
#2 Breast Cancer
#3 ( #1 OR #2)
#4 follicular OR follicle*
#5 luteal OR lutenizing*
#6 menstrual*
#7 #3 AND ( #4 OR #5 OR #6)
#8 timing OR time*
#9 ( #7 AND #8)

Appendix 2. Appendix 2

MEDLINE (January 1966 to January 2009) 
This database was searched using PubMed and Web of Knowledge.The search terms used were:

(a)

#1 Breast neoplasm[MESH]
#2 Breast Cancer
#3 ( #1 OR #2)
#4 follicular OR follicle*
#5 luteal OR lutenizing*
#6 menstrual*
#7 #3 AND ( #4 OR #5 OR #6)
#8 timing OR time*
#9 ( #7 AND #8)
(b) (menstru* and prognos* and (breast* cancer))

Appendix 3. Appendix 3

EMBASE (1974 to September 2006) 
This database was searched using Dialog Datastar.
The search terms used were:
#1 Breast neoplasm [MESH]
#2 Breast Cancer
#3 ( #1 OR #2)
#4 follicular OR follicle$
#5 luteal OR lutenizing$
#6 menstrual*
#7 #3 AND ( #4 OR #5 OR #6)
#8 timing OR time$
#9 ( #7 AND #8)

EMBASE was not searched after 2006 as the authors did not have access to the database.

Appendix 4. Appendix 4

CANCERLIT (1974 to March 2003 using Dialog Datastar). This database ceased updating in 2003.

The search terms used were:
 #1 Breast neoplasm{MESH]
#2 Breast Cancer
#3 ( #1 OR #2)
#4 follicular OR follicle*
#5 luteal OR lutenizing*
#6 menstrual*
#7 #3 AND ( #4 OR #5 OR #6)
#8 timing OR time*
#9 ( #7 AND #8)

Appendix 5. Appendix 5

Host: http://apps.who.it/trialsearch/
16 July 2010

Advanced search (with Recruitment set at ALL):
Search 1.
Condition field: breast cancer OR breast carcinoma OR breast neoplasm
Intervention field: timing of mastectomy OR timing of mastectomies OR timing of lumpectomy OR timing of lumpectomies OR timing of breast surgery OR timing of breast surgeries

Data and analyses

Comparison 1. Follicular phase versus luteal phase.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Recurrence	1		Peto Odds Ratio (Exp[(O‐E) / V], Fixed, 95% CI)	Totals not selected
1.1.1 At 1 year	1		Peto Odds Ratio (Exp[(O‐E) / V], Fixed, 95% CI)	Totals not selected
1.1.2 At 2 years	1		Peto Odds Ratio (Exp[(O‐E) / V], Fixed, 95% CI)	Totals not selected
1.1.3 At 3 years	1		Peto Odds Ratio (Exp[(O‐E) / V], Fixed, 95% CI)	Totals not selected
1.1.4 At 4 years	1		Peto Odds Ratio (Exp[(O‐E) / V], Fixed, 95% CI)	Totals not selected
1.1.5 At 5 years	1		Peto Odds Ratio (Exp[(O‐E) / V], Fixed, 95% CI)	Totals not selected
1.2 Overall Survival	1		Other data	No numeric data
1.2.1 Overall	1		Other data	No numeric data
1.2.2 ER tumour status/Nodal disease	1		Other data	No numeric data
1.2.3 ER negative (follicular versus Luteal)	1		Other data	No numeric data
1.2.4 ER positive (Follicular versus Luteal)	1		Other data	No numeric data
1.3 Disease‐free Survival	2		Other data	No numeric data
1.3.1 Overall	2		Other data	No numeric data
1.3.2 ER negative (Follicular vs Luteal)	2		Other data	No numeric data
1.3.3 ER positive (Follicular vs Luteal)	2		Other data	No numeric data
1.3.4 New Subgroup	0		Other data	No numeric data

1.2. Analysis.

Comparison 1: Follicular phase versus luteal phase, Outcome 2: Overall Survival

Overall Survival
Study	OS at 1 year	OS at 2 years	OS at 3 years	OS at 4 years	OS at 5 years	Hazard ratio	95% Confidence interval	P value
Overall
Grant 2009					Follicular: 91.9% (95% CI 89.1% t0 94.8%) Luteal: 92.2% (95% CI 88.7% to 95.9%) Indeterminate phase: 91.8% (95% CI 88.2% to 95.5%)	1.10	0.64 to 1.88	0.732
ER tumour status/Nodal disease
Grant 2009						1.00	0.58 to 1.71	0.985
ER negative (follicular versus Luteal)
Grant 2009						0.780	0.36 to 1.68
ER positive (Follicular versus Luteal)
Grant 2009						1.46	0.68 to 3.36

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Grant 2009.

Study characteristics
Methods	‐Prospective observational phase III clinical trial ‐Dates of accrual: July 1996 to December 2001 ‐Randomisation: not randomised ‐Blinding: not blinded ‐ITT: not mentioned ‐Median follow up: 6.6 years
Participants	‐834 women comprised the study cohort: 230 (28%) in the luteal phase; 363 (44%) in the follicular phase; and 241 grouped as other ‐Median age (years): luteal (42, range 28‐52); follicular (42, range 22‐54); other (42, range 23‐53) ‐Premenopausal women who had regular menstrual cycles of 21 to 35 days duration ‐Pathology: stage I‐II breast cancer including patients with ductal carcinoma ‐Chemotherapy and/or radiotherapy were allowed in accordance with internationally accepted criteria, as per investigator’s discretion ‐Eligibility required serum be drawn within 1 calendar day of the lumpectomy or mastectomy for women who underwent a one‐stage procedure and within 1 calendar day of each stage for women who underwent a two‐stage procedure
Interventions	Surgical treatment consisted of an open biopsy followed by a mastectomy or breast conserving surgery with or without sentinel node biopsy and/or axillary nodal dissection. Fine needle aspirates and core or stereotactic needle biopsies were allowed before the definitive procedure
Outcomes	‐Disease‐free survival (which was defined as the time from registration to the recurrence of tumour at any local, regional, or distant location) ‐Detection of a second primary cancer ‐Death as a result of any cause without documentation of recurrence ‐Overall survival (which was defined as time from registration to death as a result of any cause)
Notes	Out of the 1118 women enrolled onto this trial, National Surgical Adjuvant Breast and Bowel Project (NSABP) enrolled 69.3%, North Central Cancer Treatment Group (NCCTG) enrolled 16.5% and International Breast Cancer Study Group (IBCSG) enrolled 14.2%

Pujol 2001.

Study characteristics
Methods	‐Monocentric prospective study ‐Dates of accrual: 1992 to 1995 ‐Randomisation: not randomised ‐Blinding: not blinded ‐Baseline comparability achieved ‐ITT: not mentioned ‐Mean follow up was 48 months
Participants	‐487 patients (360 eligible) ‐Consecutive premenopausal women with primary breast carcinoma ‐No preoperative radiotherapy or chemotherapy, metastasis, use of oral contraceptives or pregnancies ‐Perimenopausal women (patients with last regular menses occurring ≤ 6 months earlier) and menopausal women (patients with their last regular menses > 6 months earlier) were excluded
Interventions	‐Surgery carried out during the follicular phase compared to surgery during the luteal phase ‐The types of surgery undergone by patients included mastectomy or sector resection followed by radiotherapy
Outcomes	‐Relapse‐free survival (RFS) between the different phases of the cycle ‐Overall survival (OS) between the different phases of the cycle RFS and OS were defined as survival until recurrence or death from breast carcinoma or censorship at the last check up before the study closing date (October 1995)
Notes	Out of the 487 patients, 127 patients were not eligible as they had preoperative radiotherapy or chemotherapy (35), metastasis (17), use of oral contraceptives less than 1 month before surgery (14), perimenopausal (60), and pregnancy (1) 2 patients were lost to follow up Co‐interventions: Patients with ER‐positive and lymph node positive status received a combination of adjuvant chemotherapy with endocrine therapy Patients with ER‐positive and no lymph node involvement received endocrine therapy, generally consisting of a combination of ovariectomy and tamoxifen for 5 years Patients with ER‐negative and lymph node negative status were recommended for adjuvant chemotherapy (6 courses of CMF) when poor prognostic indicators were present (such as grade 3 and/or tumour size > 3cm) Baseline comparability: There was a higher mean ER level in the follicular phase than in the ovulatory period and the luteal phase (P=0.02) There was also a trend toward a higher proportion of ER‐positive tumours in the follicular phase (65%) than in the ovulatory (62%) and luteal phases (57%), but the difference did not reach statistical significance (P=0.14)

Thorpe 2008.

Study characteristics
Methods	‐Multicentre prospective, observational study ‐Randomisation: not randomised ‐Reported 3‐year survival rates ‐Median follow up 59 months
Participants	Premenopausal women with suspected operable primary breast cancer
Interventions	Timing of surgery
Outcomes	The primary endpoint: overall survival (OS), with disease‐free survival (DFS) at 3 years Secondary endpoint: local recurrence‐free survival and systemic recurrence‐free survival at 3 years
Notes	LMP was categorised according to the menstrual cycle phase definitions of Senie 1991 (follicular: days 0 to 14; luteal: days 15 to 36), Badwe 1991 (follicular: days 3 to 12; luteal: days 0 to 2 and 13 to 32) and Hrushesky 1989 (perimenstrual: days 0 to 6 and 21 to 32; mid‐cycle: days 7 to 20)

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Cooper 1999	A retrospective study which focused mainly on evaluating the survival of premenopausal breast carcinoma patients in relation to oestrogen receptor and progesterone receptor status of the primary tumour, and with little focus on menstrual cycle timing of surgery
Fentiman 2002	A retrospective review of the data
Gnant 1992	A retrospective study that evaluated a combined two‐centre series of 385 premenopausal women operated on for stage I/II breast cancer with a median follow up of five years for a possible impact on outcome of the date of their LMP before surgery
Goldhirsch 1997	A retrospective study. 1554 patients from the IBCSG trial VI were considered for this study, 1475 patients (94.9%) were eligible but only 1033 were evaluable (70.0%). Premenopausal women that had a histologically proven, node positive unilateral breast cancer with either ER‐positive or ER‐negative status. Surgery in the follicular phase compared to surgery in the luteal phase. The types of surgery undergone included: total mastectomy with axillary clearance or breast conserving procedure (quadrantectomy or lumpectomy) with axillary lymph node clearance and subsequent local radiotherapy. Disease‐free survival (defined as the length of time from date of randomisation to any relapse (including ipsilateral breast recurrence), the appearance of a second primary cancer (including contralateral breast cancer) or death whichever occurred first between the different phases of the cycle Co‐ intervention: Each patient received one of the following:(A) CMF x 6 on months 1 to 6, (B) CMF x 6 plus 3 single courses of reintroduction CMF given on months 9, 12 and 15, (C) CMF x 3 on months 1 to 3, (D) CMF x 3 plus 3 single courses of reintroduction CMF given on months 6, 9 and 12 75% of patients were randomised to receive at least 6 cycles of CMF
Harlap 1998	An epidemiologic survey of 614 premenopausal patients who had surgery for invasive, non‐metastatic breast carcinoma
Jager 1995	A retrospective study of 710 premenopausal women with primary breast cancer who had documented day of last menstrual bleeding, size of primary tumour and number of lymph node metastases
Milella 1999	A retrospective study of five years that analysed the impact of the timing of surgery during menstrual cycle on disease‐free and overall survival of 248 premenopausal patients with stage I/II breast cancer who underwent surgery followed by anthracycline containing adjuvant chemotherapy
Mondini 1997	A review of the records of 165 premenopausal breast cancer women consecutively operated on from 1977 until 1991
Normura 1999	A retrospective cohort of a randomised study of adjuvant endocrine, chemotherapy and chemo‐endocrine therapy, where the correlation between timing of mastectomy and relapse‐free survival and overall survival in 721 premenopausal patients with early breast cancer were investigated
Saad 1994	A retrospective study which involved analysis of the data of 96 premenopausal patients who underwent primary surgery for operable breast carcinoma between 1975 and 1988 to determine effects of different factors on the prognosis
Takeda 2001	A retrospective study evaluating the timing of surgery in relation to menstrual phase as might affect the progress of disease, in 28 premenopausal women with operable breast cancer
Veronesi 1994	A retrospective study of 1175 premenopausal women whose date of LMP was known were followed up for up to 20 years (average 8 years) after surgery for breast cancer

CMF: cyclophosphamide, methotrexate and fluorouracil combination chemotherapy

Characteristics of ongoing studies [ordered by study ID]

Galimberti 1997.

Study name	Prognosis of breast cancer according to timing of surgery and menstrual phase
Methods	Multicenter study Prospective study: self‐randomised by the phase of their menstrual cycle on the day of surgery
Participants	In 1997, 94 patients were operated on during the follicular phase and 122 during the luteal phase. Of the follicular phase patients, 50 patients received conservative surgery and 19 patients underwent a mastectomy; amongst the luteal phase patients, 62 received conservative surgery and 28 underwent a mastectomy. Pathological data for patients in the follicular phase are: T1 = 34, T2 = 34, T3 = 1; for the luteal phase: T1 = 49, T2 = 38, T3 = 3. Axillary nodes were involved in 35 follicular phase patients and 53 luteal phase patients. The other cases were N0. Oestrogen receptors were positive in 35 in the follicular phase and 39 in the luteal phase and the data are still being elaborated on for a further 22. In 2001, further data were published in a review by Zurrida (2001). It included 768 patients were operated for breast cancer and data were available for 711 patients. Patients who underwent surgery during the luteal phase = 389 and during the follicular phase = 322.
Interventions	Breast cancer surgery at the luteal phase versus the follicular phase. The breast surgery included conservative or demolitive (simultaneous breast reconstruction but always with axillary dissection). Patients who underwent sentinel node biopsy were included provided they eventually received complete axillary dissection.
Outcomes	Disease‐free survival and long‐term survival. No data reported.
Starting date	February 1995. Recruitment appears to be ongoing.
Contact information	Istituto Europeo di Oncologia, Via G Ripamonti 435, Milano, Italy
Notes	Contacted authors on several occasions (last date of contact 11/03/11) and we have not received a response

NCT00005079.

Study name	Timing of Menstrual Cycle and Surgery in Treating Premenopausal Women With Stage I, Stage II, or Stage III Breast Cancer
Methods	Prospective multicentre study, other details are unclear
Participants	Premenopausal women with histologically confirmed stage I, II, or III primary breast cancer undergoing breast surgery
Interventions	Timing of surgery based on menstrual cycle.
Outcomes	Disease recurrence, progression and death
Starting date	1999
Contact information	Rebecca and John Moores UCSD Cancer Center, La Jolla, California, United States, 92093‐0658
Notes

Differences between protocol and review

We had intended in the protocol that the review would only include randomised controlled studies. In the absence of published randomised studies, the evidence was gathered from prospective non‐randomised studies and a narrative synthesis provided.

Contributions of authors

Miny Samuel (MS) prepared the protocol, undertook searches, designed the data extraction form, extracted the data and wrote the first draft of the review and addressed comments from reviewers and editors.
Khin Lay Wai (KLW) prepared the protocol, designed the data extraction form, extracted the data from some of the studies and commented on the final review.
Wei‐Sean Yong (WY) commented on the protocol and the final review.
Victoria K Brennan (VB) updated the searches, reviewed the second draft of the review, addressed comments and the final review.

Sources of support

Internal sources

• Research Triangle Institute‐Health Solutions, UK

• Singapore General Hospital, Singapore

External sources

• No sources of support supplied

Declarations of interest

We certify that we have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter of this review (for example through employment, consultancy, stock ownership, honoraria, expert testimony).

Stable (no update expected for reasons given in 'What's new')