Background

Breast cancer is the third most common cancer in Australia, following prostate and bowel cancer, contributing to approximately 12% of new cancer diagnoses in Australia.1 A total of 15,740 new cases were estimated to be diagnosed in 2015, with approximately 3000 breast cancer-related deaths in Australia.1 The lifetime risk of developing breast cancer for a woman is one in eight.1 Risk increases with age and is rare in females aged under 20 years. While it can also occur in males, this is an infrequent event, with one male diagnosed for every 107.6 females (projected estimate for 2015).1 Additional risk factors for breast cancer include hormonal exposure, genetic factors and proliferative breast disease with atypia.2 Survival statistics for breast cancer are improving, likely due to population screening resulting in earlier detection and advances and widespread availability of systemic therapies. The latest Australian figures from 2007 to 2011 show a five-year survival of 90%.3-5

Invasive breast cancer is of epithelial origin. Non-invasive or in situ disease is a pre-malignant condition in which cancer cells are confined within the basement membrane of the epithelium. Once the cancer cells extend beyond the basement membrane into surrounding structures it is then termed "invasive", growing in size and able to spread to other sites via lymphatic channels. Seventy-five per cent of breast lymph channels drain to the ipsilateral axillary lymph nodes, with a minor amount draining through the pectoralis muscle into the medial group of lymph nodes. With axillary lymph node involvement, the cancer is termed "locally advanced".6,7 From here, it may metastasize via lymphatic and hematological spread to other body organs, the most common sites being bone, liver and lung.6,8 The presence of metastases in breast cancer has conventionally been defined as a non-curable disease, with the current standard of treatment aimed at palliative management or disease control (the delay or prevention of disease progression) rather than cure.3,9-15

Metastatic breast cancer is variable in disease extent, ranging from a single metastasis to diffuse disease involving multiple body organs. Oligometastatic disease (OMBC) is a subset of metastatic breast cancer characterized by single or few detectable metastases.3,16,17 The natural history of breast cancer has long been described as a systemic disease. It was first defined by Keynes in 1954 who theorized breast cancer had widespread systemic microscopic dissemination before the primary disease was clinically detectable.16,18 Therefore, treatment of locoregional disease would not affect overall survival. Decades later further understanding of the progression of breast cancer led to it being described as a spectrum of disease: on one hand locoregionally confined, extending to a disease that is systemic at first presentation, and a spectrum of intermediate states in between.17 The clinical oligometastatic state was then introduced by Hellman and Weichselbaum in 1995 who proposed that metastases limited in number and location are unlikely to progress rapidly and are consistent with cells of low malignant potential.9,16 Tumors early in the chain of progression may have metastases limited in number and location because the ability for metastatic growth has not yet become fully acquired and the site for such growth is restricted. With further tumor progression, the metastatic cells develop greater efficiency to seed and grow at distant sites, increasing in location and number.16 Studies show us that those people with fewer metastases have a more prolonged clinical course than those who present with more widespread disease. Therefore, oligometastases should not be interpreted as a definitive sentinel event to widespread metastatic disease.18 From these observations, some researchers have proposed that OMBC may signify less aggressive tumor behavior and be potentially curable with aggressive treatment of the limited metastases.3,9,13,16,19

The true incidence of OMBC is unknown. The available data from chemotherapy trials demonstrate that around 50% of metastatic breast cancer patients have less than two metastases at enrollment and in other trials up to 91% less than four metastases.18 Other reviews quote as little as 1-10% of newly diagnosed metastatic disease.3,14,20 As imaging modalities have become more advanced, such as high-resolution computed tomography with positron emission tomography and magnetic resonance imaging, we have far greater ability to detect metastases. Consequently the number of patients diagnosed with OMBC is likely to increase.19 These recent improvements in imaging technology and accessibility has allowed a "true oligometastatic" state to be diagnosed.21

Modern research has provided understanding of the biology of breast cancer and variability in patterns and rate of growth between individual tumors. Histological assessment gives important insight into individual tumor behavior and associated prognostic information.22 Hellman proposed that oligometastatic disease correlates with the biology of tumor progression. Lower grade tumors have less aggressive growth and smaller sized tumors have less cell numbers for cell seeding and metastases.16,17 Due to extensive education and screening programs, patients more often present with small breast cancers confined to the breast without regional lymph node involvement.23 Biologically locoregional advanced breast cancers and screen-detected breast cancers are different diseases. As the primary disease has changed, so might the behavior of resulting metastatic disease.18

There is a variety of treatments available for breast cancer, which has in part contributed to its improved prognosis, and treatment options continue to increase, especially with the development of targeted therapies.15 Treatment of breast cancer confined to the breast or locoregional disease involving axillary lymph nodes (stage I-III) is typically treated with surgical resection and adjuvant radiotherapy, chemotherapy and/or targeted hormonal therapies.6 Once metastases are present (stage IV) chemotherapy and/or hormonal therapy become the mainstay of treatment, with surgery and radiotherapy used for complications of the disease in a palliative setting, for example, to prevent tumor fungation or in the treatment of painful spinal metastases.10-12,15,18,24 The treatment goals of metastatic breast cancer have traditionally been prolonged survival and improved quality of life.9,13,25

There is currently no clear definition of OMBC, which has made identification and selection of oligometastatic patients for clinical trials difficult. The generally accepted definition is five or less metastases confined to a single organ. Some studies use less than five metastases and metastatic deposits less than 5 cm in size.8,12,15,24,26,27 Other studies further exclude intracranial metastases.15 Improved long-term outcomes have been demonstrated in mostly retrospective studies for metastasectomy in OMBC. This includes surgical resection or local ablative therapies for both primary tumor and distant metastases.3,8-10,14,15,18,24-30 Kobayashi et al.25 conducted a retrospective study of OMBC patients and demonstrated superior prognosis of those treated with aggressive local therapies, achieving overall survival rates of 82% at 10 years and 53% at 20 years. Yoo et al.15 similarly found that high dose radiotherapy to treat limited metastases was associated with better survival. It is unclear whether long-term survival in these patients is due to favorable, less aggressive tumor biology or the effects of therapy.9,12,18 Prospective studies have also been conducted and show promising results but often lack long-term follow-up.12,27

The aim of this systematic review therefore is to assess the effectiveness of aggressive locoregional treatment of OMBC on survival outcomes. A search of PubMed, Cochrane Library, Prospero and JBI Database of Systematic Reviews and Implementation Reports found no current or proceeding systematic review that covered this subject.

Inclusion criteria

Types of participants

This review will consider studies that include all adult women (18 years and older) with OMBC, defined as five or less metastases limited to a single organ. This will include women with newly diagnosed breast cancer and those at relapse (oligorecurrence).31 This includes all hormone receptor and human epidermal growth factor receptor 2 status cancers.

Types of interventions

The current review will consider studies that evaluate effectiveness of intensified multidisciplinary treatment with aggressive locoregional therapies. These include surgical metastasectomy, radiotherapy and thermoablative treatments for both primary tumor and distant metastases.

Comparator

The comparator will be conventional, or standard treatment aimed at disease control and not cure.

Outcomes

The primary outcomes measured will be: overall survival, five-year survival rates and disease-free survival. Secondary outcomes to be assessed will be adverse outcomes associated with intensified treatment regimes.

Types of studies

Randomized and non-randomized controlled trials and prospective and retrospective cohort studies will be considered for inclusion in this review.

Search strategy

The search strategy aims to find both published and unpublished studies. A three-step search strategy will be utilized in this review. An initial limited search of PubMed and Embase will be undertaken followed by an analysis of the text words contained in the title and abstract, and of the index terms used to describe the article.

A second search, using all identified keywords and index terms, will then be undertaken across all included databases.

Third, the reference lists of all identified reports and articles will be searched for additional studies.

Studies published in English which meet the inclusion criteria will be considered for inclusion in this review. Studies published in the last 10 years will be considered for inclusion in this review to assess modern therapeutic techniques and cover a period of modern imaging which accurately identifies a true oligometastatic state.8,15,19,21

The databases to be searched include PubMed and Embase. The search for unpublished studies will include World Health Organization International Clinical Trials Registry Platform, Cochrane Central Register of Controlled Trials and clinicaltrials.gov.

Initial keywords used for search terms will be: "oligometastatic", "breast cancer", "treatment", "survival".

Assessment of methodological quality

Papers selected for review will be assessed by two independent reviewers for methodology validity prior to inclusion in this systematic review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI).32 Any disagreements that arise between the reviewers will be resolved through discussion, or with a third reviewer.

Data extraction

Quantitative data will be extracted from papers included in the review using the standardized data extraction tool from JBI-MAStARI (Appendix I). The data extracted will include specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. Where data are lacking or unclear, attempts will be made to contact study authors by email to provide additional details.

Data synthesis

Quantitative data will, where possible, be pooled in statistical meta-analysis using JBI-MAStARI. All results will be subject to double data entry. Effect sizes expressed as odds ratio (for categorical data) and weighted mean differences (for continuous data) and their 95% confidence intervals will be calculated for analysis. Different forms of aggressive locoregional therapies will be synthesized separately. Heterogeneity will be assessed statistically using the standard Chi-square and also explored using subgroup analyses based on the different study designs and patient age groups included in this review. Where statistical pooling is not possible, the findings will be presented in narrative form, including tables and figures, to aid in data presentation where appropriate.

Appendix I: Data extraction instruments

References