Tumour bed boost radiotherapy for women after breast conserving surgery
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of tumour bed boost radiotherapy after breast conserving surgery (BCS) and whole breast irradiation (WBI) for the treatment of invasive breast cancer.
Background
Description of the condition
Breast cancer is the most common cancer in women worldwide with nearly 1.7 million new cases diagnosed in 2012 (Globocan). It represents about 12% of all new cancer cases in both sexes and 25% of all cancer cases in women (Globocan). Data from the World Health Organization (WHO) mortality and population database indicate that breast cancer accounted for the largest number of predicted cancer deaths in women in Europe (the estimated age‐standardised (world) breast cancer mortality rate was 14.6/100,000 women in 2013) (Malvezzi 2013). Without (neo‐)adjuvant therapy, up to 30% of node‐negative and up to 70% of node‐positive breast cancers in women will recur locally or spread to another organ after surgery (Darby 2011; EBCTCG 2005).
Several unfavourable risk factors have been reported for local breast cancer recurrence after primary therapy, and predictive tools that can estimate breast cancer risk have been established. Besides nodal status, the risk factors can include: the omission of radiotherapy/hormonal therapy/chemotherapy, young age, presence of lymphovascular invasion, presence of ductal carcinoma in situ (DCIS), high histologic grade, large tumour diameter and positive or dubious surgical margins (Darby 2011; Sanghani 2010; van Werkhoven 2011).
Description of the intervention
Breast conserving therapy (BCT), involving breast conserving surgery (BCS) followed by whole breast irradiation (WBI) and optionally a boost to the tumour bed, is a standard therapeutic option for women with early‐stage breast cancer. Randomised controlled trials (RCTs) have shown that local control rates and survival in women who have had BCT are comparable to women who have had a mastectomy (Fisher 2002; Litière 2012). A boost to the tumour bed means that an extra dose of radiation is applied that covers the initial tumour site where the cancer is most likely to return. The rationale for a boost of radiotherapy to the tumour bed is twofold: firstly, local recurrence is mostly at the site of the primary tumour because remaining microscopic tumour cells are most likely situated there, and secondly, radiation can eliminate these causative microscopic tumour cells.
The main goal of adjuvant radiotherapy (that is, WBI and an optional boost to the tumour bed) after BCS is to decrease local recurrence and to permit breast conservation with minimal treatment‐induced side effects. The necessity of adjuvant radiotherapy has been demonstrated by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). The meta‐analysis conducted by the EBCTCG showed a reduction in the 10‐year first recurrence rate from 35% to 19.3%, and a breast cancer survival gain of 3.8% at 15 years when adding adjuvant radiotherapy (Darby 2011).
The standard radiotherapy technique is to treat the whole breast with a total radiation dose of 42 to 50 Gray (Gy) with an optional tumour bed boost. The boost continues to be used in women at high risk of local recurrence, but is less widely accepted for women at lower risk. Reasons for questioning the boost are twofold. Firstly, the boost brings higher treatment costs. Secondly, the potential adverse events are not negligible. The short‐term side effects include fatigue, breast oedema, skin erythema and hyperpigmentation, while the long‐term risks include radiation pneumonitis, rib fractures, cardiac toxicity and radiation‐induced second cancers. The National Comprehensive Cancer Network recommends a boost in women at higher risk for recurrence (NCCN ‐ guidelines version 1.2016). This can be achieved by external beam radiotherapy with doses of 10 to 16 Gy, or by interstitial brachytherapy. European guidelines advise a boost to the tumour bed in women with at least one of the following risk factors: age up to 50 years, grade 3 tumours, extensive DCIS, vascular invasion, and possibly in cases of non‐radical tumour excision (Senkus 2015).
How the intervention might work
After the initial treatment, a local recurrence can occur where residual microscopic cancerous cells grow back at the original site of the breast cancer. The medical literature reveals that between 44% and 90% of local recurrences are located in or near the primary tumour bed (Bartelink 2007; Kuerer 2004; Vaidya 2010) and these numbers correlate well with pathological findings from Holland et al (Holland 1985). To eliminate residual microscopic cancerous cells, an additional tumour bed boost is advocated and gives a further 50% reduction in local recurrence (Bartelink 2015; van Werkhoven 2011).
Ionising radiation consists of high‐energy particles whose ionising tracks deposit energy in cells. The total ionising radiation dose, D, is measured in energy per unit mass. Radiation mainly damages chromatin, for example causing DNA double strand breaks (DSBs). An acute dose of 1 Gy makes many thousands of ionisations in the cell's nucleus, of which a small minority quickly induce DSBs. Most DSBs are repaired within the next half hour, and a few are misrepaired. At a typical dose of several Gy, at least one misrepair usually occurs, and this misrepair can be enough to kill the cell at the next cycle of cell division. This is called 'indirect' cell death. Irradiation can also 'directly' form other kinds of lethal lesions, such as lethal point mutations, meaning that the effect is unrepairably lethal and not prone to repair or misrepair.
The effect of radiation on tumours is presented in the linear quadratic (LQ) model which quantifies the effects of both unrepairable damage and repairable damage susceptible to misrepair (Kellerer 1972). The model is based on the concept of a biologically effective dose (BED) that represents the physical dose required for a given effect. BED = D [1+d/(α/β)]‐γTt/α where D is the dose per fraction, α and β are the LQ parameters, γ = ln(2)/Tpot and Tpot is the potential doubling time, and Tt is the treatment time (Fowler 1989).
Improved tumour control requires an increased radiation dose within the dose‐response range of any residual tumour burden. The effect of radiation on the tumour (based on α/β) in breast tissue is no longer 10 Gy as historically assumed, but around 4 Gy (Hennequin 2013; START 2008). With this in mind, existing dose‐schedules for local tumour control should be reconsidered by calculating all BEDs of the regimens used in studies in breast cancer.
Why it is important to do this review
With the introduction of the CT‐scan and 3D‐therapy planning in radiotherapy over a decade ago, research has focused on optimising treatment techniques. Today, the tumour bed in breast tissue can be irradiated using a whole set of treatment techniques that includes conventional radiation, 3D‐conformal radiation, intensity‐modulated radiation, intra‐operative radiation or proton irradiation. The radiation oncologist also has a broad choice of fractionation schemes (that is, delivering the total dose in different numbers or sizes of doses per fraction) ‐ normofractionation (the standard regimen for breast irradiation equals 50 Gy in 25 fractions of 2 Gy, 5 days a week), hypofractionation (that is, the total dose of radiation is divided into larger doses per fraction) or even single fraction radiotherapy ‐ and a wide range of treatment times.
Even though research has provided a wide variety of treatment options, no consensus has been reached on the necessity of and consequently the indications for the boost to the tumour bed. The absolute size of the benefit of the tumour bed boost is linked to the baseline risk of local recurrence; the highest benefit is recorded in the highest risk groups (Bartelink 2015). The effect of the boost dose seems to be independent of tumour characteristics such as grade or stage and adjuvant systemic treatment (Bartelink 2015). However, it may be dependent on age and surgical margin status.
It is important to clearly determine those women who will benefit from having a boost to the tumour bed. In this review, we will try to help practitioners weigh up the benefit of better local control and survival against an increase in side effects (e.g. fibrosis ‐ scarring of connective tissue), the inconvenience of a longer treatment time and higher cost.
Objectives
To assess the effects of tumour bed boost radiotherapy after breast conserving surgery (BCS) and whole breast irradiation (WBI) for the treatment of invasive breast cancer.
Methods
Criteria for considering studies for this review
Types of studies
All parallel group randomised controlled trials (RCTs) comparing the addition and the omission of breast cancer tumour bed boost radiotherapy.
Types of participants
Women with a histological diagnosis of invasive breast cancer for the first time (not recurrent or metastatic disease) with no prior history of malignant disease (other than basal cell carcinoma of the skin).
We will only include studies in which women have been treated with BCS. BCS could include lumpectomy and wide local excision or quadrantectomy, with or without axillary dissection, axillary sampling or sentinel node biopsy. Women will not be excluded based on age, race, tumour size or histological type.
Types of interventions
All women with BCS (lumpectomy, quadrantectomy or segmental mastectomy) followed by WBI (any standard schedule). We will compare women who have received an additional boost to the tumour bed with women who have not received a boost. The boost can be delivered with external beam radiation (electrons or photons) or with interstitial brachytherapy.
We will exclude women who have received intraoperative radiotherapy.
We will allow systemic treatments such as hormones, chemotherapy or monoclonal antibodies as long as they are applied equally to participants in each arm of the trial.
Types of outcome measures
Primary outcomes
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Local control, defined as the time (from randomisation) until the development of any local recurrence during follow‐up (time‐to‐event outcome). We define local recurrence as recurrence in the ipsilateral breast (i.e. the breast in which cancer had been diagnosed), the skin and parenchyma. We will recalculate the BED of the tumour bed volume according to the LQ model taking into account the α/β value of breast cancer cells, the total treatment time and the potential doubling time.
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Acute toxicity related to radiotherapy, i.e. any toxic events occurring in the breast, skin, lung and heart within six months of completion of radiotherapy. Acute toxicity will be classified according to the scales used by authors and, if possible, converted to the score from the National Cancer Institute Common Toxicity Criteria (NCI‐CTCAE v4.0).
Secondary outcomes
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Overall survival, defined as the time from randomisation to death from any cause during follow‐up.
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Disease‐free survival, defined as the time from randomisation to relapse (local or distant) during follow‐up.
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Late toxicity related to radiotherapy, i.e. any toxic event occurring more than six months after radiotherapy. These will be classified according to the scales used by the authors, otherwise we will consider grade 3 or 4 toxic events according to the National Cancer Institute Common Toxicity Criteria (NCI‐CTCAE v4.0). In this review, we will extract data at 5, 10, 15 and 20 years.
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Cosmesis, scored according to the Harvard scale in four classes: excellent, good, fair and poor (Harris 1979).
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Quality of life, classified according to validated scales used by the trial authors or current scores on the EORTC Quality of Life scale (EORTC QoL).
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Treatment costs. These will be classified according to the scales used by the trial authors.
Search methods for identification of studies
Electronic searches
We will search the following databases:
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The Cochrane Breast Cancer Group's (CBCG's) Specialised Register. 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). Trials with the key words "randomized controlled trial, breast cancer, breast‐conserving therapy, radiotherapy and boost" will be extracted from the Register and considered for inclusion in the review.
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MEDLINE (via OvidSP). See Appendix 1.
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EMBASE (via EMBASE.com). See Appendix 2.
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CENTRAL. See Appendix 3.
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The WHO International Clinical Trials Registry Platform (ICTRP) search portal (http://apps.who.int/trialsearch/Default.aspx) for all prospectively registered and ongoing trials. See Appendix 4.
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Clinicaltrials.gov (http://clinicaltrials.gov/). See Appendix 5.
Searching other resources
Bibliographic searching
We will search reference lists of all included trials and relevant (systematic) reviews to identify other studies.
Conference proceedings
We will search the European Society of Radiotherapy and Oncology Annual Meeting, the St. Gallen Oncology Conferences, and the American Society for Radiation Oncology Annual Meeting.
Data collection and analysis
Selection of studies
Two authors (IK and CW) will independently scan the title, abstract and keywords of every record identified in the search. We will assess the full articles if the information suggests that the study may meet our inclusion criteria (according to types of studies, participants, and interventions). We will resolve differences in assessment by discussion and, in cases of disagreement, we will consult a third review author (TD). A copy of the full article for each reference reporting a potentially‐eligible trial will be obtained. Where this is not possible, we will attempt to contact authors to request additional information. In cases where data are limited, or information on study methods is limited, we will request further information from the study authors.
We will include studies in English, French, German and Dutch. Excluded trials will be recorded in the 'Characteristics of excluded studies' table with reasons for their exclusion.
Data extraction and management
Two authors (IK and CW) will perform data extraction independently, and we will resolve disagreements by discussion. We will record data on data extraction forms. Forms will be developed and piloted independently by the same two authors. We will request further information from the authors of the original studies if the data extracted are limited. For those studies with more than one publication, we will extract data from all publications, but consider the final or updated version of each study as the primary reference.
We will extract the following information from the included primary studies to data extraction forms:
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Publication details: i.e. year, country, authors.
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Methods: presence of analysis for local recurrences, variables in the analysis, length of follow‐up, type of data analysis.
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Participants: inclusion and exclusion criteria, population data (i.e. number of patients, age of analysed patients, time of diagnosis, tumour stage, receptor status, menstrual status, other adjuvant treatments), withdrawals.
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Interventions: i.e. doses, regimen, scheme, length, type of radiotherapy.
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Outcome measures.
Data will be entered into Review Manager software (RevMan).
Assessment of risk of bias in included studies
Two authors (IK and CW) will independently assess the risk of bias of the included studies. Any disagreement will be resolved by a third review author (TD). We will use The Cochrane Collaboration's 'Risk of bias' tool which contains domain‐based judgements (Higgins 2011). A judgement of 'low risk' will indicate a low risk of bias, 'high risk' will indicate a high risk of bias and 'unclear' will indicate an uncertain risk of bias, according to the specific criteria for each domain. These domains address:
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Sequence generation: was the allocation sequence adequately generated? We will rate this domain as 'low risk' if the investigators describe a random component in the sequence generation process such as: referring to a random‐number table, using a computer random‐number generator, coin tossing, shuffling cards or envelopes, throwing dice, drawing of lots or minimisation.
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Allocation concealment: was allocation adequately concealed? We will rate this domain as 'low risk' if participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal the allocation: central allocation or sequentially‐numbered, opaque, sealed envelopes.
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Blinding of participants and personnel, and outcome assessors: was knowledge of the allocated interventions adequately prevented during the study? We will rate this domain as 'low risk' if there is no blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by the lack of blinding; if blinding of participants, key study personnel and outcome assessment is ensured, and it is unlikely that the blinding could have been broken.
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Incomplete outcome data: were outcome data adequately assessed and accounted for? We will rate this domain as 'low risk' if there are no missing outcome data; if the reasons for missing outcome data are unlikely to be related to the true outcome; if missing outcome data are balanced in numbers across intervention groups with similar reasons for missing data across groups; if for dichotomous data, the proportion of missing outcomes compared with observed event risk is not enough to have a clinically‐relevant impact on the intervention effect estimate; if for continuous outcome data, the plausible effect size among missing outcomes is not enough to have a clinically‐relevant impact on the observed effect size; or if missing data have been imputed using appropriate methods.
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Selective outcome reporting: are reports of the study free of suggestion of selective outcome reporting? We will rate this domain as 'low risk' if the study protocol is available and all of the study's pre‐specified outcomes that are of interest in the review have been reported in the pre‐specified way; or when the study protocol in not available, if it is clear that the published reports include all expected outcomes, including those that were pre‐specified.
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Other potential threats to validity: was the study apparently free from other problems that could put it at risk of bias? We will rate this domain as 'low risk' if the study appears to be free of other sources of bias.
Measures of treatment effect
We will present dichotomous outcomes (i.e. acute and late toxicity, cosmetic assessments) as odds ratios (ORs) with 95% confidence intervals (CIs). An OR equal to 1 indicates no difference in the incidence between the experimental group and the control group, an OR greater than 1 indicates that the incidence in the experimental group is higher than that in the control group, and an OR less than 1 indicates that the incidence in the experimental group is lower than that in the control group.
We will summarise continuous outcomes (i.e. quality of life and treatment costs) using the standardised mean difference (SMD). When an SMD is greater than 0, it will indicate that the level in the experimental group is higher than in the control group, and when an SMD is less than 0, this will indicate that the level in the experimental group is lower than in the control group.
We will express time‐to‐event outcomes (i.e. local recurrence, overall survival, disease‐free survival) as hazard ratios (HRs) with 95% CIs. If we cannot obtain the HR and associated variances directly from the trial publication or from the authors, we will obtain these data indirectly using the methods described by Parmar et al, by employing the other available summary statistics or data extracted from published Kaplan‐Meier curves (Parmar 1998).
Unit of analysis issues
The unit of analysis will be the individual patient.
Dealing with missing data
Missing trial‐level information
In the case of missing or unavailable trial‐level information, as specified under Data extraction and management we will contact trial authors by email with a request for this information.
Missing patient‐level data in published studies
If studies report results obtained based on different analysis sets, the result of the most appropriate set will be selected (e.g. intention‐to‐treat rather than per protocol). If studies only report results based on an inappropriate analysis set (e.g. per protocol where there is a difference in protocol violations between both treatment groups), this will be considered in the studies’ 'Risk of bias' assessment and in sensitivity analysis.
If studies report results obtained using different methods for dealing with missing patient information, the result of the most appropriate approach will be selected (e.g. results based on a multiple imputation approach rather than complete‐case analysis or single imputation). If the included studies only report results obtained with inappropriate methods for handling missing data (e.g. last observation carried forward), this will be considered in the studies’ 'Risk of bias' assessment and in sensitivity analysis.
Assessment of heterogeneity
We will use the I² statistic to assess the percentage of total variation across studies due to heterogeneity rather than chance, where a value greater than 50% will be considered to indicate substantial heterogeneity (Higgins 2011). We will also perform visual inspection of the forest plots. Further assessment of heterogeneity using meta‐regression will be conducted if we include at least 10 trials. A random‐effects model will be used for data synthesis if the combined assessment indicates important heterogeneity between studies and if the number of trials is sufficiently large.
Assessment of reporting biases
The reporting biases include publication, time‐lag, multiple publication, location, citation and language biases. We will contact trial authors about the reasons for the non‐reporting of data of some outcomes. Reporting bias will be assessed using funnel plot and statistics when at least 10 studies are included. The funnel plot is a simple scatter plot of the intervention effect estimates from individual studies. We will also keep in mind that asymmetry in funnel plots is not necessarily caused by publication bias and some effect estimates can produce spurious asymmetry.
Data synthesis
We will perform meta‐analyses based on summary information from published papers for all outcome variables for which at least two studies provide comparable data. For all outcome types, we will use the random‐effects model if substantial heterogeneity is suggested and if the number of trials is sufficiently large (more than 10). In the case of homogeneity or a small number of trials, we will use a fixed‐effect model.
Study results for dichotomous outcomes will be combined using the generic inverse‐variance method (DerSimonian 1986). To combine studies with dichotomous outcome data with studies using time‐to‐event analyses we will use Peto's method (Yusuf 1985).
Meta‐analyses will be conducted using Review Manager (RevMan) software. The quality of the evidence for local recurrence‐free survival and overall survival at 5 and 10 years as well as quality of life and acute and late toxicity will be summarised using a 'Summary of findings' table.
Subgroup analysis and investigation of heterogeneity
To correct for differences in dosage per fraction and overall treatment time, we will use the BED to compare different radiation fractionation schemes.
Furthermore, if there is a sufficient number of eligible RCTs, and data are available, we will perform a subgroup analysis according to:
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margin status (negative or close/positive);
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age (< 40 or ≥ 40 years old).
Sensitivity analysis
We will perform sensitivity analyses on the different levels of risk of bias. We will perform the analysis both with and without trials of low quality (high risk of bias) in order to assess the effect of quality on the results.
