Cover of Evidence reviews for breast radiotherapy

Evidence reviews for breast radiotherapy

Early and locally advanced breast cancer: diagnosis and management

Evidence review H

NICE Guideline, No. 101

Authors

.

London: National Institute for Health and Care Excellence (NICE); .
ISBN-13: 978-1-4731-3008-1
Copyright © NICE 2018.

Breast radiotherapy

This evidence report contains information on 4 reviews relating to breast radiotherapy.

  • Review question 8.1 What radiotherapy techniques are effective for excluding the heart from the radiation field without compromising coverage of the whole breast target volume for people with early or locally advanced breast cancer?
  • Review question 8.2 Is there a subgroup of people with early invasive breast cancer who do not need breast radiotherapy after breast-conserving surgery?
  • Review question 8.3 Is there a subgroup of women with early invasive breast cancer for whom partial breast radiotherapy is an equally effective alternative to whole breast radiotherapy after breast-conserving surgery?
  • Review question 8.4 What are the indications for radiotherapy to internal mammary nodes?

Review question 8.1. What radiotherapy techniques are effective for excluding the heart from the radiation field without compromising coverage of the whole breast target volume for people with early or locally advanced breast cancer?

Introduction

The number of early breast cancer survivors is increasing. This is the result of a combination of increased incidence of the disease, widespread availability of breast screening and the development of more effective treatment strategies. As a consequence, more women cured of breast cancer will live with the late effects of their treatment.

Breast radiotherapy is associated with a 1–2% excess of non-breast cancer mortality, the majority of which is attributable to cardiac disease. There is a linear, no-threshold relationship between mean heart dose and the risk of subsequent major coronary events. Excluding the heart from the radiotherapy field reduces mean heart dose and therefore the risk of longer term cardiac side effects

The objective of this review is to determine which heart-sparing breast radiotherapy techniques are effective without compromising the treatment of the whole breast volume, and to identify which techniques should be offered to spare the heart during radiotherapy.

PICO table

See Table 1 for a summary of the population, intervention, comparison and outcome (PICO) characteristics of this review.

Table 1. Summary of the protocol (PICO table).

Table 1

Summary of the protocol (PICO table).

For full details see review protocol in appendix A.

Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual; see the methods chapter for further information.

Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy.

Clinical evidence

Included studies

Four observational studies (number of participants, N=236) and 1 randomized cross over study (N=28) were included in the review (Barlett 2017; Barlett 2015; Chi 2015; Czeremszynska 2017; Eldredge Hindy 2015). All 5 studies reported on the mean heart dose. One study (Eldredge Hindy 2015) reported on the target coverage. No studies reported data on local recurrence rate, treatment related morbidity or mortality.

There was no evidence available for shielding and proton beam radiotherapy.

See also the study selection flow chart in appendix C, forest plots in appendix E and study evidence tables in appendix D.

Excluded studies

Studies not included in this review with reasons for their exclusions are provided in appendix K.

Summary of clinical studies included in the evidence review

Table 2 provides a brief summary of the included studies

Table 2. Summary of included studies.

Table 2

Summary of included studies.

See appendix D for full evidence tables.

Quality assessment of clinical studies included in the evidence review

The clinical evidence profile for this review question (heart sparing radiotherapy) is presented in Table 3 and Table 4. The evidence was very low quality because of the observational nature of the included studies and small sample size.

Table 3. Summary clinical evidence profile: Comparison 1. Deep inspiration breathhold versus free breathing.

Table 3

Summary clinical evidence profile: Comparison 1. Deep inspiration breathhold versus free breathing.

Table 4. Summary clinical evidence profile: Comparison 2. Deep inspiration breathhold versus prone radiotherapy.

Table 4

Summary clinical evidence profile: Comparison 2. Deep inspiration breathhold versus prone radiotherapy.

See appendix F for full GRADE tables.

Economic evidence

A systematic review of the economic literature was conducted but no relevant studies were identified which were applicable to this review question. Economic modelling was not undertaken for this question because other topics were agreed as higher priorities for economic evaluation.

Evidence statements

Comparison 1. Deep inspiration breath-hold versus free breathing
Critical outcomes
Mean heart dose
  • There is very low quality evidence from four prospective cohort studies (N=236) that deep inhalation breath hold produces clinically meaningful reduction in mean heart dose compared with free breathing at radiotherapy for people with invasive breast cancer and/or ductal carcinoma in situ (DCIS) receiving whole breast radiotherapy.
Target coverage
  • There is very low quality evidence from one prospective cohort study (N=81) that deep inspiration breath-hold does not produce clinically meaningful change in target coverage compared to free breathing at radiotherapy for people with invasive breast cancer and/or DCIS receiving whole breast radiotherapy.
Important Outcomes
Local recurrence rate
  • No evidence was found for this outcome.
Treatment-related morbidity
  • No evidence was found for this outcome.
Treatment-related mortality
  • No evidence was found for this outcome.
Comparison 2. Deep inspiration breath-hold versus prone radiotherapy
Critical outcomes
Mean heart dose
  • There is low quality evidence from one randomized cross over study (N=28) that deep inhalation breath hold produces clinically meaningful reduction in mean heart dose compared with prone radiotherapy for people with invasive breast cancer and/or DCIS receiving whole breast radiotherapy.
Target coverage
  • No evidence was found for this outcome.
Important Outcomes
Local recurrence rate
  • No evidence was found for this outcome.
Treatment-related morbidity
  • No evidence was found for this outcome.
Treatment-related mortality
  • No evidence was found for this outcome.
Other interventions
  • There was no evidence available on shielding or on proton beam radiotherapy

The committee’s discussion of the evidence

Interpreting the evidence
The outcomes that matter most

As this review question is considering a heart sparing radiotherapy technique, mean heart dose and target coverage were selected as critical outcomes by the committee. The inclusion of treatment-related morbidities and treatment-related mortality as important outcomes was to allow a balance of the benefits and harms of treatments to be made. Local recurrence rate was identified as other important outcome.

No evidence was available for treatment-related morbidities, treatment-related mortality and local recurrence rate.

The quality of the evidence

The quality of the evidence for this review was assessed using GRADE. For comparison of mean heart dose using deep inspiratory breath-hold technique compared to free breathing, the evidence was of a very low quality, and was downgraded due to observational study design and imprecision due to small sample size. For target coverage, the evidence was of very low quality due to observational study design and small sample size.

The quality of evidence for mean heart dose using deep inspiratory breath-hold technique compared to prone radiotherapy was low quality. The evidence quality was downgraded mainly due to uncertainty around the estimate due to small sample size and indirectness due to the inclusion of only women with large breasts.

Benefits and harms

The use of deep inspiratory breath-hold technique during whole breast radiotherapy leads to reduction in mean heart dose without compromising the target coverage. Specifically, it leads to a reduction in mean heart dose by 1.29 Gy, which is almost a 50% reduction in the mean heart dose. The committee discussed that this may potentially lead to reduction in late cardiovascular morbidity/mortality and will be particularly beneficial for people with cardiovascular risk factors. The committee were aware of estimates that a decrease in 1 Gy led to a 7% reduction in cardiovascular morbidity (Darby 2013). The committee noted that reduction in cardiovascular morbidity may also lead to cost reduction to the NHS. The committee also discussed that heart sparing radiotherapy techniques may reduce treatment related anxiety for people undergoing radiotherapy and improve quality of life due to decreased cardiovascular effects.

There was no evidence available regarding treatment related morbidity or mortality and local recurrence rate for deep inspiratory breath hold technique. Based on their experience and expertise, the committee discussed that deep inspiratory breath hold technique only requires a change in position during radiotherapy and is not known to be associated with serious harms. However, the committee discussed that deep inspiratory breath-hold technique may be more demanding for people who may struggle to do this exercise. The committee also discussed that people with disabilities, particularly respiratory compromise, may be unable to perform the breathing exercises required and therefore unable to access the technique.

The committee agreed that although many centres were already offering the breath-hold technique, some centres did not use it routinely and therefore this recommendation would reduce variation in practice across the country.

Cost effectiveness and resource use

A systematic review of the economic literature was conducted but no relevant studies were identified which were applicable to this review question.

The committee discussed that the use of deep inspiratory breath-hold technique will require increased resource use within some radiotherapy departments. This will include a coaching session of up to 45 minutes to train the person to use the technique, an extension to the radiotherapy treatment time of approximately 10 to 15 minutes (as the treatment is paused between breath-holds), and possibly some initial training time for the radiotherapy team to implement the use of routine breath-hold technique. The extended treatment time will also impact on the utilisation of equipment, which may already be used to capacity.

However, these costs may be offset in the longer term by the expected reduction in cardiac events and therefore a reduction in the costs to the NHS of managing these events. Therefore, it is likely that the technique would be cost-effective in cost per QALY terms.

While there may be resource implications for those centres not currently using the technique, the overall resource impact of implementing the recommendation across the NHS was not thought to be significant because the technique is already being used in many centres.

Other factors the committee took into account

The committee noted that deep inspiratory breath-hold technique may also benefit people with right sided breast cancer, particularly when the target volume extends over the midline, but had not looked at evidence for this so were unable to make a specific recommendation for this group of people.

References

  • Bartlett 2015

    Bartlett, F. R., Colgan, R. M., Donovan, E. M., McNair, H. A., Carr, K., Evans, P. M., Griffin, C., Locke, I., Haviland, J. S., Yarnold, J. R., Kirby, A. M. (2015) The UK HeartSpare Study (Stage IB): Randomised comparison of a voluntary breath-hold technique and prone radiotherapy after breast conserving surgery. Radiotherapy and Oncology, 114, 66–72. [PubMed: 25739317]

  • Bartlett 2017

    Bartlett, F. R., Donovan, E. M., McNair, H. A., Corsini, L. A., Colgan, R. M., Evans, P. M., Maynard, L., Griffin, C., Haviland, J. S., Yarnold, J. R., Kirby, A. M. (2017) The UK HeartSpare Study (Stage II): Multicentre Evaluation of a Voluntary Breath-hold Technique in Patients Receiving Breast Radiotherapy. Clinical Oncology, 29, e51–e56. [PubMed: 27890346]

  • Chi 2015

    Chi, F., Wu, S., Zhou, J., Li, F., Sun, J., Lin, Q., Lin, H., Guan, X., He, Z. (2015) Dosimetric comparison of moderate deep inspiration breath-hold and free-breathing intensity-modulated radiotherapy for left-sided breast cancer. Cancer/Radiotherapie, 19, 180–186. [PubMed: 25921618]

  • Czeremszynska 2017

    Czeremszynska, B., Drozda, S., Gorzynski, M., Kepka, L. (2017) Selection of patients with left breast cancer for deep-inspiration breath-hold radiotherapy technique: Results of a prospective study. Reports of Practical Oncology and Radiotherapy, 22, 341–348. [PMC free article: PMC5496478] [PubMed: 28701900]

  • Darby 2013

    Darby, S.C., Ewertz M., McGale, P, Bennet A.M., Blom-Goldman, U., Bronnum, D., Correa, C., Cutter, D., Gagliardi, G., Gigante, B., Jensen, M.B., Nisbet, A., Peto, R., Rahimi, K., Taylor, C., Hall, P.(2013) Risk of ischemic heart disease in women after radiotherapy for breast cancer. New England Journal of Medicine, 368(11),987–98. [PubMed: 23484825]

  • Eldredge-Hindy 2015

    Eldredge-Hindy, H., Lockamy, V., Crawford, A., Nettleton, V., Werner-Wasik, M., Siglin, J., Simone, N. L., Sidhu, K., Anne, P. R. (2015) Active Breathing Coordinator reduces radiation dose to the heart and preserves local control in patients with left breast cancer: Report of a prospective trial. Practical Radiation Oncology, 5, 4–10. [PMC free article: PMC4289538] [PubMed: 25567159]

Review question 8.2. Is there a subgroup of people with early invasive breast cancer who do not need breast radiotherapy after breast-conserving surgery?

Introduction

Adjuvant whole breast radiotherapy is the current standard treatment option for most people with stage 1 and 2 breast cancer after breast-conserving surgery (BCS). Multiple retrospective studies and an overview of randomized trials have established the equivalence of this treatment approach compared with mastectomy in terms of both disease-free and overall survival. Whole breast radiotherapy halves the risk of local recurrence. However, local recurrence rates have fallen dramatically over the last 30 years, so that the absolute benefit of radiotherapy for some individuals may not outweigh the potential risks (for example, normal tissue toxicity, cardiac morbidity, second cancers). For many women, increasingly diagnosed with small screen-detected cancers, it is the late complications of radiotherapy, rather than the risk of local recurrence, that is their predominant concern.

Whilst the proportional benefit of radiotherapy is similar across all subgroups of women with breast cancer, the absolute benefit for women with good prognosis tumours is small. The aim of this review is to determine if specific groups of women can be identified in whom breast radiotherapy does not have a favourable risk/benefit ratio and so can be omitted.

PICO table

See Table 5 for a summary of the population, intervention, comparison and outcome (PICO) characteristics of this review.

Table 5. Summary of the protocol (PICO table).

Table 5

Summary of the protocol (PICO table).

For full details see review protocol in appendix A.

Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual; see the methods chapter for further information.

Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy.

Clinical evidence

Included studies

Six studies (N=3977) were included in the review (Blamey 1990; Holli 2009; Hughes 2013; Kunkler 2013; Wickberg 2014; Williams 2011). These studies report data from 6 trials: British Association of Surgical Oncologists (BASO) II trial (number of publications, k=1), Cancer and Leukemia Group B (CALGB) 9434 trial (k=1), Holli 2009 (k=1), Postoperative Radiotherapy in Minimum-Risk Elderly (PRIME; k=1), PRIME II (k=1), and Uppsala/Orebro trial (k=1). The BASO II, CALGB, and PRIME II trials compared BCS and endocrine therapy with or without whole breast radiotherapy, Holli 2009 and Uppsala/Orebro trial compared BCS and dissection of the axilla with or without whole breast radiotherapy, and the PRIME trial compared BCS alone with or without whole breast radiotherapy.

All studies reported data for subgroups of interest: T stage 1, (k=2), N stage 0 (k=5), age ≥65 years (k=3), no adjuvant systemic therapy received (k=1), and negative surgical margins (k=5).

The clinical studies included in this evidence review are summarised in Table 6 and evidence from these are summarised in the clinical GRADE evidence profile below (Table 7). See also the study selection flow chart in appendix C, forest plots in appendix E and study evidence tables in appendix D.

This review updates a question from the previous guideline CG80 (NICE 2009). Therefore, studies for this topic identified by the previous guideline are incorporated into forest plots, GRADE evidence profiles, and evidence statements. However, studies are not incorporated where there is more recent data available from the same trial, unless different outcomes are reported, or where a change in protocol from the previous guideline means that studies no longer meet inclusion criteria. Therefore, 21 articles included in the previous guideline were not incorporated into the current results for the following reasons: did not meet current inclusion criteria outlined in review protocol (k=16), more recent data available (k=2), insufficient presentation of results in original article to include in analysis (k=2), does not report data for any subgroups of interest so cannot inform current question (k=1). This resulted in only one article (Whelan 2000) from CG80 being added to the current evidence.

Excluded studies

Studies not included in this review with reasons for their exclusions are provided in appendix K.

Summary of clinical studies included in the evidence review

Table 6. Summary of included studies.

Table 6

Summary of included studies.

See appendix D for full evidence tables.

Quality assessment of clinical studies included in the evidence review

The clinical evidence profile for this review question (breast radiotherapy after breast-conserving surgery) is presented in Table 7. The majority of the evidence is moderate or low quality. This is primarily due to small number of events of interest occurring.

Table 7. Summary clinical evidence profile: Comparison 1. No whole breast radiotherapy versus whole breast radiotherapy.

Table 7

Summary clinical evidence profile: Comparison 1. No whole breast radiotherapy versus whole breast radiotherapy.

See appendix F for full GRADE tables.

Economic evidence

A systematic review of the economic literature was conducted but no relevant studies were identified which were applicable to this review question. Economic modelling was not undertaken for this question because other topics were agreed as higher priorities for economic evaluation.

Evidence statements

Comparison 1. No whole breast radiotherapy versus whole breast radiotherapy
Critical outcomes
Local recurrence rate
  • There is moderate quality evidence from 2 RCTs (N=1378) that whole breast radiotherapy produces clinically meaningful reductions in local recurrence at 10 to 12 year follow-up compared with no whole breast radiotherapy for women with T stage 1 invasive breast cancer.
  • There is moderate quality evidence from 4 RCTs (N=3340) that whole breast radiotherapy produces clinically meaningful reductions in local recurrence at 5 to 12 year follow-up compared with no whole breast radiotherapy for women with N stage 0 invasive breast cancer.
  • There is moderate quality evidence from 4 RCTs (N=3340) that whole breast radiotherapy produces clinically meaningful reductions in local recurrence at 5 to 12 year follow-up compared with no whole breast radiotherapy for women with invasive breast cancer and negative surgical margins following breast-conserving surgery.
  • There is low quality evidence from 2 RCTs (N=1962) that whole breast radiotherapy produces clinically meaningful reductions in local recurrence at 5 to 10 year follow-up compared with no whole breast radiotherapy for women with invasive breast cancer aged 65 years and over.
Treatment-related morbidity
  • There is low quality evidence from 1 RCT (N=171) that whole breast radiotherapy reduces fractures (cause unspecified) at 5 year follow-up compared with no whole breast radiotherapy for women aged 65 years and over with N stage 0 invasive breast cancer and negative surgical margins following breast-conserving surgery. However, this was not statistically or clinically significant.
  • There is moderate quality evidence from 1 RCT (N=171) that there is no effect of whole breast radiotherapy on congestive cardiac failure at 5 year follow-up for women aged 65 years and over with N stage 0 invasive breast cancer and negative surgical margins following breast-conserving surgery.
  • There is low quality evidence from 1 RCT (N=171) that there was no effect of whole breast radiotherapy following breast-conserving surgery on myocardial infarction at 5 year follow-up for women aged 65 years and over with N stage 0 invasive breast cancer and negative surgical margins.
  • There is low quality evidence from 2 RCTs (N=1497) that there was no effect of whole breast radiotherapy following breast-conserving surgery on secondary cancer (cause unspecified) at 5 year follow-up for women aged 65 years and over with N stage 0 invasive breast cancer and negative surgical margins.
Health-realted quality of life
  • There is low quality evidence from 1 RCT (N=206) that whole breast radiotherapy produces clinically significant reductions in depression at 5 year follow-up compared with no whole breast radiotherapy for women aged 65 years and over with N stage 0 invasive breast cancer and negative surgical margins following breast-conserving surgery. However, this was not statistically significant.
  • There is low quality evidence from 1 RCT (N=206) that whole breast radiotherapy produces clinically significant reductions in anxiety at 5 year follow-up compared with no whole breast radiotherapy for women aged 65 years and over with N stage 0 invasive breast cancer and negative surgical margins following breast-conserving surgery. However, this was not statistically significant.
  • There is low quality evidence from 1 RCT (N=168) that there is no effect of radiation on HRQoL, as measured by EQ5D at 5 year follow-up, for women aged 65 years and over with N stage 0 invasive breast cancer and negative surgical margins following breast-conserving surgery.
  • There is evidence from 1 RCT (N=720) that that whole breast radiotherapy produces clinically significant improvements in HRQoL, as measured by Breast Cancer Chemotherapy Questionnaire at 2 month follow-up, compared with no whole breast radiotherapy in women with N stage 0 invasive breast cancer and negative surgical margins following breast-conserving surgery. It was not possible to judge the overall quality of this evidence as it was included from the previous NICE guideline (CG80).
Important outcomes
Overall survival
  • There is moderate quality evidence from 1 RCT (N=263) that whole breast radiotherapy produces clinically meaningful increases in overall survival at 12 year follow-up compared with no whole breast radiotherapy for women with T stage 1 invasive breast cancer.
  • There is moderate quality evidence from 3 RCTs (N=1154) that whole breast radiotherapy produces clinically meaningful increases in overall survival at 5 to 12 year follow-up compared with no whole breast radiotherapy for women with N stage 0 invasive breast cancer.
  • There is moderate quality evidence from 3 RCTs (N=1154) that whole breast radiotherapy produces clinically meaningful increases in overall survival at 5 to 12 year follow-up compared with no whole breast radiotherapy for women with invasive breast cancer and negative surgical margins following breast-conserving surgery.
  • There is high quality evidence from 2 RCTs (N=891) that there was no effect of whole breast radiotherapy following breast-conserving surgery on overall survival at 5 to 10 year follow-up for women with invasive breast cancer aged 65 years and over.
  • There is moderate quality evidence from 1 RCT (N=381) that there was no effect of whole breast radiotherapy on overall survival at 20 year follow-up for women with invasive breast cancer not receiving adjuvant systemic therapy.
Disease-free survival
  • No evidence was found for this outcome.
Treatment-related mortality
  • No evidence was found for this outcome.

The committee’s discussion of the evidence

Interpreting the evidence
The outcomes that matter most

As the purpose of this review was to determine if the use of radiotherapy could lead to a clinically meaningful reduction in recurrence of breast cancer after surgery in low risk people, and the risks and benefits of this approach were thought to be finely balanced, the committee prioritised local recurrence rate, treatment-related morbidity and health related quality of life as critical outcomes. Overall survival, disease-free survival and treatment-related mortality were selected as important outcomes.

There was no evidence available for disease-free survival and treatment-related mortality. There was also no evidence available for several of the subgroups of interest, specifically positive margins, oestrogen receptor (ER) status, human epidermal growth factor receptor 2 (HER2) status, grade, younger age, women who received adjuvant systemic therapy, T stage 2 and above and N stage 1 and above.

The quality of the evidence

The quality of the evidence for this review was assessed using GRADE. The evidence for local recurrence rate ranged from moderate to high across the different subgroups. The evidence for treatment-related morbidity and HRQoL was low quality. The evidence for overall survival across the different subgroups of interest ranged from moderate to high quality (with most of it being moderate quality).

The committee noted that there were high rates of performance bias in the studies due to the inability to blind for whole breast radiotherapy. However they considered this was unlikely to have a significant impact due to the objective nature of the outcomes. There were also high rates of imprecision due to small number of events of interest and small sample sizes.

The evidence showed that whole breast radiotherapy produces clinically meaningful reductions in local recurrence compared with no breast radiotherapy for people with T1 breast cancer, N0 breast cancer, people with invasive breast cancer and negative surgical margins following breast-conserving surgery, and people with invasive breast cancer aged 65 years and over. The committee noted that radiotherapy reduces recurrence rates for all women, but it was important to discuss the benefits and risks with individual patients. Some patients may be very anxious about recurrence, and want everything possible to reduce risk. However, some patients interpret risk more rationally and would rather avoid potential side effects when the risk of recurrence is small.

The evidence showed that whole breast radiotherapy produces clinically significant reductions in anxiety and depression compared with no whole breast radiotherapy for individuals aged 65 years and over with N stage 0 invasive breast cancer and negative surgical margins following breast-conserving surgery. However these data had low event rates and the symptoms of anxiety and depression were only measured at a single time point, not over a period of time. Therefore the Committee were uncertain about the actual effect size for this outcome.

The evidence showed that whole breast radiotherapy produces clinically meaningful increases in overall survival compared with no whole breast radiotherapy for individuals with T stage 1 invasive breast cancer, N stage 0 invasive breast cancer, and in individuals with invasive breast cancer and negative surgical margins following breast-conserving surgery. No clinically meaningful differences in overall survival were found in people aged 65 and over and individuals not receiving adjuvant systemic therapy

Benefits and harms

Given that the evidence showed clinically meaningful reductions in local recurrence, anxiety and depression and increases in overall survival with whole breast radiotherapy for people with invasive breast cancer who have had breast conserving surgery with clear margins, the Committee agreed to offer this treatment to this group.

The absolute risk of local recurrence at 5 years is very low, based on the evidence. There are harms associated with the use of radiotherapy and the benefits on overall survival are only realised in the longer term (5 and 10 year survival is the same with or without radiotherapy). Therefore the benefits of giving radiotherapy to those with a very low absolute risk of recurrence are less certain, particularly if they are willing to take endocrine therapy. Consequently the committee recommended there should be a discussion about the benefits and harms of whole breast radiotherapy with this group of people so that they can make an informed choice about their treatment. Important factors to include in the discussion are the local recurrence rates with and without radiotherapy, that overall survival is the same and that there is no increase in serious late effects with radiotherapy.

Cost effectiveness and resource use

A systematic review of the economic literature was conducted but no relevant studies were identified which were applicable to this review question.

The committee discussed the potential costs and savings of recommendations and agreed that an increase in resources would not be required as the use of whole breast radiotherapy after breast-conserving surgery is already standard practice. Therefore it is possible that the recommendations could lead to cost savings if radiotherapy is omitted in low risk patients (following a discussion with the patient).

References

  • Blamey 2013

    Blamey, R.W., Bates, T., Chetty, U., Duffy, S.W., Ellis, I.O., George, D., Mallon, E., Mitchell, M.J., Monypenny, I., Morgan, D.A., Macmillan, R.D., Patnick, J., Pinder, S.E., (2013) Radiotherapy or tamoxifen after conserving surgery for breast cancers of excellent prognosis: British Association of Surgical Oncology (BASO) II trial. European journal of cancer, 49, 2294–302. [PubMed: 23523089]

  • Holli 2009

    Holli, K., Hietanen, P., Saaristo, R., Huhtala, H., Hakama, M., Joensuu, H., (2009) Radiotherapy after segmental resection of breast cancer with favorable prognostic features: 12-year follow-up results of a randomized trial. Journal of Clinical Oncology, 27, 927–32. [PubMed: 19114687]

  • Hughes 2013

    Hughes, K.S., Schnaper, L.A., Bellon, J.R., Cirrincione, C.T., Berry, D.A., McCormick, B., Muss, H.B., Smith, B.L., Hudis, C.A., Winer, E.P., Wood, W.C., (2013) Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. Journal of Clinical Oncology, 31, 2382–7. [PMC free article: PMC3691356] [PubMed: 23690420]

  • Kunkler 2015

    Kunkler, I.H., Williams, L.J., Jack, W.J., Cameron, D.A., Dixon, J.M., (2015) Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. The Lancet. Oncology, 16, 266–73. [PubMed: 25637340]

  • NICE 2009

    National Institute for Health and Clinical Excellence. (2009) Early and locally advanced breast cancer: diagnosis and treatment. NICE guideline (CG80). [PubMed: 19167201]

  • Whelan 2000

    Whelan, T. J., Levine, M., Julian, J., Kirkbride, P., Skingley, P. (2000). The effects of radiation therapy on quality of life of women with breast carcinoma: Results of a randomized trial. Cancer, 88, 2260–2266. [PubMed: 10820347]

  • Wickberg 2014

    Wickberg, A., Holmberg, L., Adami, H.O., Magnuson, A., Villman, K., Liljegren, G., (2014) Sector resection with or without postoperative radiotherapy for stage I breast cancer: 20-year results of a randomized trial. Journal of Clinical Oncology, 32, 791–7. [PubMed: 24493730]

  • Williams 2011

    Williams, L.J., Kunkler, I.H., King, C.C., Jack, W., Pol, M., (2011) A randomised controlled trial of post-operative radiotherapy following breast-conserving surgery in a minimum-risk population. Quality of life at 5 years in the PRIME trial. Health technology assessment (Winchester, England), 15, i–xi, 1–57. [PubMed: 21366974]

Review question 8.3. Is there a subgroup of women with early invasive breast cancer for whom partial breast radiotherapy is an equally effective alternative to whole breast radiotherapy after breast-conserving surgery?

Introduction

Whole breast radiotherapy (WBRT) is the current standard adjuvant treatment option for most women with early invasive breast cancer after breast conserving surgery (BCS). Multiple retrospective studies and an overview of randomized trials have established the equivalence of this treatment approach compared with mastectomy in terms of both disease-free and overall survival.

WBRT halves the risk of local recurrence. However, local recurrence rates have fallen dramatically over the last 30 years, so that the absolute benefit of WBRT for some women may not outweigh the potential risks (normal tissue toxicity, cardiac morbidity, second cancers). For many women, increasingly diagnosed with small screen-detected cancers, it is the late complications of radiotherapy (RT), rather than the risk of local recurrence, that is their predominant concern. Whilst the proportional benefit of radiotherapy is similar across all subgroups of women with breast cancer, the absolute benefit for women with good prognosis tumours is small. The risk of true local recurrence is highest in the area of the breast close to the site of the original tumour raising the possibility that there are women at low risk of local recurrence for whom treatment of the whole breast volume and surrounding tissue is not necessary.

The aim of this review is to determine if there is a group of women in whom partial breast radiotherapy (PBR) would offer a better risk-benefit approach than whole breast radiotherapy.

PICO table

See Table 8 for a summary of the population, intervention, comparison and outcome (PICO) characteristics of this review.

Table 8. Summary of the protocol (PICO table).

Table 8

Summary of the protocol (PICO table).

For full details see review protocol in appendix A.

Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual; see the methods chapter for further information.

Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy.

Clinical evidence

Included studies

Six randomised trials (N=6215), reported on in 12 publications (The Groupe Européen de Curiethérapie and the European SocieTy for Radiotherapy & Oncology [GEC-ESTRO; Ott 2016; Polgar 2017; Strnad 2016]; Intensity Modulated and Partial Organ Radiotherapy [IMPORT-LOW; Coles 2017] Livi 2015 [Livi 2010; Livi 2015]; Polgár 2007 [Lovey 2007; Polgar 2007; Polgar 2013]; Randomized Trial of Accelerated Partial Breast Irradiation [RAPID; Olivotto 2013]; Rodriguez 2013 [Rodriguez 2013]), and 1 systematic review (Hickey 2016) were included in the review.

Evidence from these are summarised in Table 9 and the clinical GRADE evidence profile in Table 10.

See also the study selection flow chart in appendix C, forest plots in appendix E and study evidence tables in appendix D.

Excluded studies

Studies not included in this review with reasons for their exclusions are provided in appendix K.

Summary of clinical studies included in the evidence review

Table 9. Summary of included studies.

Table 9

Summary of included studies.

See appendix D for full evidence tables.

Quality assessment of clinical studies included in the evidence review

The clinical evidence profile for this review question (partial-breast radiotherapy versus whole-breast radiotherapy after breast-conserving surgery) is presented in Table 10. The majority of the evidence is moderate or low quality. This is primarily due to small number of events of interest occurring.

Table 10. Summary clinical evidence profile: Comparison 1. Partial-breast radiotherapy versus whole-breast radiotherapy after breast-conserving surgery.

Table 10

Summary clinical evidence profile: Comparison 1. Partial-breast radiotherapy versus whole-breast radiotherapy after breast-conserving surgery.

See appendix F for full GRADE tables.

Economic evidence

Included studies

One relevant study was identified in a literature review of published cost-effectiveness analyses on this topic; Shah 2013 (see appendix H and appendix I for summary and full evidence tables). The study considered the cost-effectiveness of accelerated partial breast radiotherapy (APBRT) techniques in comparison to whole beam radiotherapy (WBRT) techniques. The analysis was a cost-utility analysis measuring effectiveness in terms of quality adjusted life years (QALYs).

Excluded studies

See supplement 1: Health economics for the list of excluded studies.

Summary of studies included in the economic evidence review

The base case results of Shah 2013 showed that all APBRT techniques were cost-effective and indeed dominant in comparison to whole beam intensity modulated radiotherapy (IMRT) techniques (i.e. less costly and more effective). In comparison to WBRT with 3D conformal radiotherapy (CRT), APBRT techniques with IMRT or 3DCRT were again found to be dominant. However, other forms of APBRT were found to be more costly and more effective with ICERs of $12,514, $67,329 and $557 per QALY for single lumen, multi lumen and interstitial APBRT techniques, respectively.

The analysis was deemed to be only partially applicable to the decision problem in the UK setting as it was conducted from the perspective of the US health care system. Furthermore, serious limitations were identified in the analysis. Most notably, uncertainty around the base case estimates was not assessed as no deterministic or probabilistic sensitivity analyses were conducted.

Overall, the analysis appears to suggest that accelerated partial breast radiotherapy may be cost-effective in comparison to whole beam radiotherapy. However, further research would be required before drawing decisive conclusions around the cost-effectiveness of accelerated partial breast radiotherapy in the UK context.

Evidence statements

Comparison 1. Partial breast radiotherapy versus whole breast radiotherapy
Critical outcomes
Local recurrence
  • There is low quality evidence from 5 RCTs (N=3407) that there is no effect of a difference on local recurrence free survival at 5 to 10 years follow-up for women with invasive breast cancer when comparing partial breast radiotherapy with whole breast radiotherapy.
Treatment-related morbidity
  • There is very low quality evidence from 6 RCTs (N=3764) that there is no clinically important difference in physician-reported cosmesis at 5 years follow-up between women with invasive breast cancer who received partial breast radiotherapy compared with those who received whole breast radiotherapy.
  • There is very low quality evidence from 4 RCTs (N=1966) that there is no clinically important difference in patient-reported cosmesis at 5 years follow-up between women with invasive breast cancer who received partial breast radiotherapy compared with those who received whole breast radiotherapy.
  • There is low quality evidence from 1 RCT (N=335) that partial breast radiotherapy produces clinically meaningful reductions in nurse-reported cosmesis at 5 years follow-up compared with whole breast radiotherapy for women with invasive breast cancer.
  • There is low quality evidence from 3 RCTs (N=1790) that partial breast radiotherapy produces clinically meaningful reductions in acute radiotherapy skin toxicity at 0 to 90 days follow-up compared with whole breast radiotherapy for women with invasive breast cancer.
  • There is very low quality evidence from 5 RCTs (N=3175) that there is no clinically important difference in late radiotherapy skin toxicity at 3 to 5 years follow-up for women with invasive breast cancer when comparing partial breast radiotherapy with whole breast radiotherapy.
  • There is very low quality evidence from 3 RCTs (N=2475) that there is no clinically important difference in breast pain at 3 to 5 years follow-up for women with invasive breast cancer when comparing partial breast radiotherapy with whole breast radiotherapy.
  • There is low quality evidence from 3 RCTs (N=1899) that there is no clinically important difference in fat necrosis at 3 to 5 years follow-up for women with invasive breast cancer when comparing partial breast radiotherapy with whole breast radiotherapy.
Health-realted quality of life
  • There is low quality evidence from 1 RCT (N=205) that that partial breast radiotherapy produces clinically important improvements in HRQoL, as measured using EORTC QLQC30 and BR23 module at 2 year follow-up, compared with whole breast radiotherapy for women with invasive breast cancer.
Important outcomes
Overall survival
  • There is moderate quality evidence from 3 RCTs (N=3047) that there is no clinically important difference in overall survival at 5 years follow-up for women with invasive breast cancer when comparing partial breast radiotherapy with whole breast radiotherapy.
Disease-free survival
  • There is moderate quality evidence from 4 RCTs (N=3305) that there is no clinically important difference in disease-free survival at 5 years follow-up for women with invasive breast cancer when comparing partial breast radiotherapy with whole breast radiotherapy.
  • There is moderate quality evidence from 4 RCTs (N=3305) that there is no clinically important difference in distant metastasis-free survival at 5 years follow-up for women with invasive breast cancer when comparing partial breast radiotherapy with whole breast radiotherapy.
Treatment-related mortality
  • There is moderate quality evidence from 1 RCT (N=1184) of no clinically important difference in treatment-related mortality at 5 year follow-up for women with invasive breast cancer, but no treatment related deaths were observed in this study.
Economic evidence statement
  • Evidence from one cost-utility analysis) showed that all APBRT techniques were dominant in comparison to WBRT with IMRT. APBRT using IMRT or 3DCRT were found to be dominant in comparison to WBRT with CRT while other APBRT techniques were found to be more costly and more effective with ICERs of $12,514, $67,329 and $557 per QALY for single lumen, multi lumen and interstitial APBRT techniques, respectively. The analysis was partially applicable with serious limitations.

The committee’s discussion of the evidence

Interpreting the evidence
The outcomes that matter most

The critical outcomes were local recurrence, treatment-related morbidity and health related quality of life. This is because breast radiotherapy following surgery is done to reduce the risk of local recurrence and by irradiating less of the breast there is a potential impact on treatment-related morbidity and health related quality of life. Overall survival, disease-free survival and treatment related mortality were considered important outcomes, because the group offered partial breast radiotherapy are typically at low risk of disease recurrence and even lower risk of death from breast cancer.

The quality of the evidence

The evidence came from randomised trials and ranged from very low to high quality. The major issue was heterogeneity in treatment-related morbidity with some trials favouring partial breast RT but others favouring whole breast RT. This was most likely due to the different surgical and partial breast radiotherapy techniques used in the trials, for example the use of accelerated partial breast radiotherapy. For this reason the committee based their recommendations on the trials with surgical techniques, radiotherapy regimens and adjuvant endocrine therapy most applicable to the UK.

The evidence review aimed to identify a group with a particularly low absolute risk of local recurrence who would be best suited to partial breast radiotherapy. The inclusion criteria of the trials meant that only low risk patients were included and there were too few cases of local recurrence to define such a group. For this reason the committee used the trial entry criteria of the most relevant trial (IMPORT-LOW) in their recommendation: women aged 50 and over with tumours that are less than or equal to 3 cm, N0, oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative and grade 1 to 2.

The committee acknowledged that follow-up in the trial most relevant to the UK setting had not yet reached 10 years and that differences in local recurrence may become evident with longer follow-up. For this reason they did not make a strong recommendation in favour of partial breast radiotherapy

Benefits and harms

The benefits of partial breast radiotherapy accrue from irradiating less tissue. This results in fewer acute adverse effects like skin toxicity and potentially fewer late adverse effects involving the heart and lungs. The potential harm of partial breast radiotherapy, as opposed to whole breast radiotherapy, is there may be an increased rate of local recurrence requiring further treatment. The evidence, however, suggests the absolute rates of local recurrence are very low in this selected patient group and are equivalent between partial breast and whole breast radiotherapy, at least up to five years.

The committee were also aware of the Royal College of Radiologists 2016 consensus statement on partial breast radiotherapy after breast-conserving surgery which recommended its use in women aged 50 and over with tumours that are less than or equal to 3 cm, N0, ER-positive, HER2-negative and grade 1 to 2.

Cost effectiveness and resource use

The committee considered the results of the cost-utility study (Shah 2013) identified in the literature review conducted for this topic. The analysis was thought to have demonstrated the potential cost-effectivenes of accelerated partial breast radiotherapy in comparison to whole beam therapy. However, as the analysis was not directly applicable to the UK context, it was not thought to give a reliable estimate of cost-effectiveness in the UK context.

In terms of the potential resource impact, the committee considered there would be a potential reduction in costs of treating late effects if partial breast radiotherapy were used but there may also be increased costs in treating local recurrence beyond five years, the balance of these is as yet unknown. The use of partial breast radiotherapy delivered as external beam radiotherapy would not have any implications on planning time, delivery time or patient counselling time, and is already used in most centres in the UK.

Other factors the committee took into account

The committee excluded those people with lobular carcinoma from the recommendation for partial breast radiotherapy due to the increased risk of multicentricity and therefore local recurrence in this group.

The committee were aware that NICE were in the process of developing separate guidance on the use of the intrabeam radiotherapy system in early breast cancer and so intrabeam radiotherapy was not considered in this review.

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Review question 8.4. What are the indications for radiotherapy to internal mammary nodes?

Introduction

Targeting clinically negative internal mammary nodes (IMN) with radiotherapy as part of the post-operative treatment of breast cancer is not commonly recommended in the UK. Notwithstanding the high rates of subclinical IMN involvement and a prior meta-analysis which demonstrated that regional node irradiation in conjunction with chest wall radiotherapy improved outcomes, there remains uncertainty about the benefits of this approach as isolated parasternal relapses are rare. Furthermore, until recently it has proven difficult to encompass the IMN using the available radiotherapy technologies whilst respecting safe dose limits to the heart and lungs.

The previous guideline CG80 (NICE 2009) recommended that radiotherapy to the IMN chain should not be offered after breast surgery. Recent randomised controlled trials (RCTs) and 1 large case controlled study have led to a reappraisal of this approach, and this review aims to revisit the potential indications for the inclusion of IMN in the radiation treatment volume

PICO table

See Table 11 for a summary of the population, intervention, comparison and outcome (PICO) characteristics of this review.

Table 11. Summary of the protocol (PICO table).

Table 11

Summary of the protocol (PICO table).

For full details see review protocol in appendix A.

Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual; see the methods chapter for further information.

Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy.

Clinical evidence

Included studies

Six studies (n=10,981) were included in the review (Choi 2016; Hennequin 2013; Matzinger 2010; Poortmans 2015; Thorsen 2016; Whelan 2015), which report data from 5 trials: Danish Breast Cancer Group – Internal Mammary Node (DBCG-IMN) trial (k=1), European Organisation for Research and Treatment of Cancer (EORTC) trial 22922/10925 (k=2), Hennequin, Bossard 2013 (k=1), Korean Radiation Oncology Group (KROG) 08-06 trial (k=1), MA.20 trial (k=1).

The DBCG-IMN trial compared radiotherapy to the breast/chest wall, scar, and the supraclavicular, infraclavicular and axially lymph nodes with or without internal mammary (IM) lymph nodes, the EORTC trial 22922/10925 compared radiotherapy to the IM and medial supraclavicular (MS) lymph nodes with no radiation to the IM and MS lymph nodes, Hennequin 2013 compared radiotherapy to the chest wall, supraclavicular nodes, and apical axillary nodes (for pN+ cases) with or without radiotherapy to the IM lymph nodes, KROG-08-06 trial compared radiotherapy to the breast, IM and supraclavicular lymph nodes with radiotherapy to the breast and supraclavicular lymph nodes only, and MA.20 compared whole breast radiation with or without radiation to the IM, supraclavicular and axillary lymph nodes.

Only 2 studies (Poortmans 2015; Whelan 2015) reported data for critical outcomes by subgroups of interest: 0 lymph node metastases (k=2), 1–3 lymph node metastases (k=2), 4+ lymph node metastases (k=2), T stage 1 (k=1), T stage 2 (k=1), T stage 3 (k=1), medial tumour position (k=1), and lateral tumour position (k=1).

The clinical studies included in this evidence review are summarised in Table 12 and evidence from these are summarised in the clinical GRADE evidence profile below (Table 13). See also the study selection flow chart in appendix C, forest plots in appendix E, and study evidence tables in appendix D.

Excluded studies

Studies not included in this review with reasons for their exclusions are provided in appendix K.

Summary of clinical studies included in the evidence review

Table 12. Summary of included studies.

Table 12

Summary of included studies.

Quality assessment of clinical studies included in the evidence review

The clinical evidence profile for this review is presented in Table 13. The majority of the evidence is moderate or low quality. This is primarily due to imprecision around the estimates due to a small number of events of interest and wide confidence intervals.

Table 13. Summary clinical evidence profile: Comparison 1. Radiotherapy to the internal mammary nodes versus no radiotherapy to the internal mammary nodes.

Table 13

Summary clinical evidence profile: Comparison 1. Radiotherapy to the internal mammary nodes versus no radiotherapy to the internal mammary nodes.

See appendix F for full GRADE tables.

Economic evidence

A systematic review of the economic literature was conducted but no relevant studies were identified which were applicable to this review question. Economic modelling was not undertaken for this question because other topics were agreed as higher priorities for economic evaluation.

Evidence statements

Comparison 1. Radiotherapy to the internal mammary nodes versus no radiotherapy to the internal mammary nodes
Critical outcomes
Locoregional recurrence rate
  • There is moderate quality evidence from 1 RCT (N=1832) that radiotherapy to the internal mammary nodes produces clinically meaningful reductions in locoregional recurrence following surgery for early invasive breast cancer compared with no radiotherapy to the internal mammary nodes at 10 year follow-up.
Disease-free survival
  • There is moderate quality evidence from 3 RCTs (N=7170) that radiotherapy to the internal mammary nodes produces clinically meaningful increases in disease-free survival following surgery for early invasive breast cancer compared with no radiotherapy to the internal mammary nodes at 10 year follow-up.
  • There is high quality evidence from 2 RCTs (N=1955) that radiotherapy to the internal mammary nodes produces clinically meaningful increases in disease-free survival following surgery for individuals with 0 positive lymph nodes compared with no radiotherapy to the internal mammary nodes at 10 year follow-up.
  • There is high quality evidence from 2 RCTs (N=3283) that radiotherapy to the internal mammary nodes produces clinically meaningful increases in disease-free survival following surgery for individuals with 1–3 positive lymph nodes compared with no radiotherapy to the internal mammary nodes at 10 year follow-up.
  • There is moderate quality evidence from 2 RCTs (N=596) that there is no clinically important effect of radiotherapy to the internal mammary nodes on disease-free survival at 10 year follow-up for individuals with 4 or more positive lymph nodes.
  • There is high quality evidence from 1 RCT (N=2408) that there is no clinically important effect of radiotherapy to the internal mammary nodes on disease-free survival at 10 year follow-up for individuals with T stage 1 invasive breast cancer.
  • There is high quality evidence from 1 RCT (N=1430) that radiotherapy to the internal mammary nodes produces clinically significant increases in disease-free survival following surgery for individuals with T stage 2 invasive breast cancer compared with no radiotherapy to the internal mammary nodes at 10 year follow-up.
  • There is low quality evidence from 1 RCT (N=141) that there is no clinically important effect of radiotherapy to the internal mammary nodes on disease-free survival at 10 year follow-up for individuals with T stage 3 invasive breast cancer.
  • There is low quality evidence from 1 RCT (N=261) that there is no clinically important effect of radiotherapy to the internal mammary nodes on disease-free survival at 10 year follow-up for individuals with medially located invasive breast cancer.
  • There is moderate quality evidence from 1 RCT (N=1142) that there is no clinically important effect of radiotherapy to the internal mammary nodes on disease-free survival at 10 year follow-up for individuals with laterally located invasive breast cancer.
Treatment-related morbidity
  • There is moderate quality evidence from 2 RCTs (N=2542) that radiotherapy to the internal mammary nodes produces clinically meaningful increases in acute radiation pneumonitis (within 3 to 6 months of completing radiotherapy) for individuals with invasive breast cancer compared with no radiotherapy to the internal mammary nodes. However, this was not statistically significant.
  • There is high quality evidence from 2 RCTs (N=5686) that there is no effect of radiotherapy to the internal mammary nodes on secondary cancer (potentially radiation-induced) at 10 year follow-up for individuals with invasive breast cancer.
  • There is low quality evidence from 1 RCT (N=3866) that radiotherapy to the internal mammary nodes produces clinically meaningful reductions in arm/shoulder function impairment at 3 year follow-up for individuals with invasive breast cancer compared with no radiotherapy to the internal mammary nodes. However, this was not statistically significant.
  • There is moderate quality evidence from 2 RCTs (N=5686) that there is no effect of radiotherapy to the internal mammary nodes on fatigue at 3 month to 3 year follow-up for individuals with invasive breast cancer.
  • There is low quality evidence from 1 RCT (N=1820) that radiotherapy to the internal mammary nodes produces clinically meaningful increases in grade 2+ acute pain (site not specified; within 3 months of completing radiotherapy) for individuals with invasive breast cancer compared with no radiotherapy to the internal mammary nodes. However, this was not statistically significant.
  • There is high quality evidence from 2 RCTs (N=5686) that there is no effect of radiotherapy to the internal mammary nodes on skin toxicity at 3 month to 3 year follow-up for individuals with invasive breast cancer.
  • There is moderate quality evidence from 2 RCTs (N=5686) that radiotherapy to the internal mammary nodes produces clinically meaningful increases in lung toxicity at 3 to 10 year follow-up for individuals with invasive breast cancer compared with no radiotherapy to the internal mammary nodes.
  • There is low quality evidence from 3 RCTs (N=7020) that there is no effect of radiotherapy to the internal mammary nodes on cardiac toxicity at 10 year follow-up for individuals with invasive breast cancer.
  • There is moderate quality evidence from 1 RCT (N=1820) that radiotherapy to the internal mammary nodes produces clinically meaningful increases in grade 2+ lymphoedema at 10 year follow-up for individuals with invasive breast cancer compared with no radiotherapy to the internal mammary nodes.
  • There is low quality evidence from 1 RCT (N=1334) that radiotherapy to the internal mammary nodes produces clinically meaningful increases in grade 3+ morbidity as measured by the SOMA-LENT scale at 10 year follow-up for individuals with invasive breast cancer compared with no radiotherapy to the internal mammary nodes. However, this was not statistically significant.
  • There is moderate quality evidence from 1 RCT (N=3866) that there is no effect of radiotherapy to the internal mammary nodes on mastitis at 3 year follow-up for individuals with invasive breast cancer.
  • There is moderate quality evidence from 1 RCT (N=3866) that radiotherapy to the internal mammary nodes produces clinically meaningful reductions in breast infection at 3 year follow-up for individuals with invasive breast cancer compared with no radiotherapy to the internal mammary nodes. However, this was not statistically significant.
  • There is moderate quality evidence from 1 RCT (N=3866) that radiotherapy to the internal mammary nodes produces clinically meaningful reductions in radionecrosis at 3 year follow-up for individuals with invasive breast cancer compared with no radiotherapy to the internal mammary nodes. However, this was not statistically significant.
  • There is low quality evidence from 1 RCT (N=3866) that there is no effect of radiotherapy to the internal mammary nodes on osteonecrosis at 3 year follow-up for individuals with invasive breast cancer.
  • There is moderate quality evidence from 1 RCT (N=3866) that there is no effect of radiotherapy to the internal mammary nodes on oedema at 3 year follow-up for individuals with invasive breast cancer.
  • There is low quality evidence from 1 RCT (N=3866) that radiotherapy to the internal mammary nodes produces clinically meaningful reductions in breast/chest wall pain at 3 year follow-up for individuals with invasive breast cancer compared with no radiotherapy to the internal mammary nodes. However, this was not statistically significant.
  • There is moderate quality evidence from 1 RCT (N=3866) that radiotherapy to the internal mammary nodes produces clinically meaningful increases in retrosternal pain at 3 year follow-up for individuals with invasive breast cancer compared with no radiotherapy to the internal mammary nodes. However, this was not statistically significant.
  • There is moderate quality evidence from 1 RCT (N=3866) that radiotherapy to the internal mammary nodes produces clinically meaningful increases in dysphagia at 3 year follow-up for individuals with invasive breast cancer compared with no radiotherapy to the internal mammary nodes. However, this was not statistically significant.
Important outcomes
Overall survival
  • There is high quality evidence from 4 RCTs (N=10,259) that radiotherapy to the internal mammary nodes produces clinically meaningful increases in overall survival following surgery for individuals with invasive breast cancer compared with no radiotherapy to the internal mammary nodes at 10 year follow-up.
Health-related quality of life
  • No evidence was found for this outcome.

The committee’s discussion of the evidence

Interpreting the evidence
The outcomes that matter most

The committee prioritised locoregional recurrence rate, disease-free survival and treatment-related morbidity as critical outcomes. Locoregional recurrence and disease-free survival were prioritised ahead of overall survival as the time taken for overall survival events to occur means there is less data available and it is less commonly examined by trials. Overall survival and health-related quality of life were selected as important outcomes.

There was no evidence available for health-related quality of life.

The quality of the evidence

The quality of the evidence for this review was assessed using GRADE. The evidence for locoregional recurrence was moderate quality. For disease-free survival the evidence was moderate quality for the sample as a whole, but the data for different subgroups ranged from low to high quality (with most of it being either moderate or high). The evidence for treatment related morbidity ranged from low to high quality with most of it being either low or moderate quality. Overall survival evidence was high quality.

It was noted that there were high rates of performance bias due to no blinding in studies. However it was agreed that this was unlikely to have a significant impact on the results due to the objective nature of the outcomes for which there was evidence available. It was also noted that there were high rates of imprecision for locoregional recurrence and treatment-related morbidities due to small number of events of interest and wide confidence intervals.

The committee noted that only two studies (Poortmans 2015; Whelan 2015) reported data for critical outcomes by the subgroups of interest. There was also no subgroup data based on laterality which could impact on toxicity.

The committee also noted that most of the studies had used internal mammary chain radiotherapy in conjunction with radiotherapy to the supraclavicular fossa. As a result it was difficult to determine the relative benefit of treatment solely to the internal mammary chain from these studies. Therefore the committee based their recommendations on the evidence from the one study that only irradiated the internal mammary nodes (rather than also irradiating the supraclavicular fossa). As this study reported overall survival, which was an important, not a critical outcome, the committee made a weaker recommendation.

Only one study included node negative patients and this gave radiotherapy to both trial arms. Therefore the committee agreed not to make any recommendations based on these data or for this group of people. The committee also noted the data on disease free survival for different T-stage had very wide confidence intervals and agreed not to make any recommendations based on this.

Benefits and harms

The evidence showed clinically meaningful reductions in locoregional recurrence and clinically meaningful increases in disease-free survival and overall survival with radiotherapy to the internal mammary nodes. The evidence also showed clinically meaningful increases in disease free survival for people with 0 and 1–3 positive lymph nodes. Whilst no clinically meaningful effect was found on this outcome for people with 4 or more positive nodes, the committee noted that the sample size was small and the magnitude of the effect was similar. They therefore agreed to recommend radiotherapy to the internal mammary chain for all node positive patients.

The committee noted that the evidence showed there was clinically meaningful increases in lung toxicity associated with radiotherapy to the internal mammary nodes. Therefore, based on their knowledge and experience, they recommended that a radiotherapy technique should be used that minimises the dose to the lung. Although the evidence review here did not demonstrate increased cardiac toxicity the committee were aware that radiotherapy to avoid cardiac toxicity was a separate question and that a heart-sparing technique should be used.

The committee noted that the potential benefits of giving radiotherapy to the internal mammary chain were likely to be reductions in locoregional recurrence and improvements in overall survival and disease-free survival. The potential harms would be increased treatment-related morbidity, but the committee noted that the evidence had not shown a clinically meaningful effect for anything except lung toxicity and grade 2+ lymphoedema. For lung toxicity a recommendation had been made to minimise the potential harm, but the risk of lymphoedema could not, unfortunately, be minimised.

Cost effectiveness and resource use

A systematic review of the economic literature was conducted but no relevant studies were identified which were applicable to this review question.

The committee carefully considered the economic implications in this topic area as they were aware that including the internal mammary chain in the radiotherapy field may increase costs as it would increase planning time. It should be noted however that these potential cost increases cannot be captured when employing standard costing methodology for radiotherapy using NHS reference costs. This reflects the manner in which radiotherapy costs are estimated in NHS Reference costs whereby radiotherapy planning and delivery costs are stratified according to the type of radiotherapy delivered (and this category would not change when including the internal mammary chain). There is also no change in the overall dosage or number of fractions when including the internal mammary chain and so again there is no change in costs according to NHS Reference cost methodology.

While it is not possible to estimate the cost impact, the committee agreed that any increased cost would be minor as including the internal mammary chain does not impact delivery time or the number of sessions required. Further, any expenditure was considered to be worthwhile because of a decrease in locoregional recurrence and improved disease-free survival.

Other factors the committee took into account

The committee discussed the fact that including the internal mammary chain within the nodal radiotherapy target and using a radiotherapy technique that minimises the dose to the lung and heart is not currently standard practice and will require additional training, technique development and implementation. There will be an increase to both the planning, dosimetry and treatment times to deliver this, and this will need to be done on a centre basis to ensure tolerance doses can be achieved, with respect to each centres specific equipment, set-up and imaging protocols.

With regard to nodal voluming, current guidelines recommend that if nodal volumes are to be treated, then these sites should be volumed to assist in field placement. If looking purely at the time it takes to volume the IMC, then the estimated additional time is approximately an extra 30 minutes per patient. Delineating the supraclavicular fossa (SCF) target volume may add a further 20–30 minutes. A number of patients may also require axillary radiotherapy as a treatment alternative to surgical clearance and this will have further voluming time increases of about 30 minutes.

References

  • Choi 2016

    Choi, J., Kim, Y. B., Shin, K. H., Ahn, S. J., Lee, H. S., Park, W., Kim, S. S., Kim, J. H., Lee, K. C., Kim, D. W., Suh, H. S., Park, K. R., Shin, H. S., Suh, C. O., (2016) Radiation Pneumonitis in Association with Internal Mammary Node Irradiation in Breast Cancer Patients: An Ancillary Result from the KROG 08-06 Study. Journal of Breast Cancer, 19, 275–282. [PMC free article: PMC5053312] [PubMed: 27721877]

  • Hennequin 2013

    Hennequin, C., Bossard, N., Servagi-Vernat, S., Maingon, P., Dubois, J. B., Datchary, J., Carrie, C., Roullet, B., Suchaud, J. P., Teissier, E., Lucardi, A., Gerard, J. P., Belot, A., Iwaz, J., Ecochard, R., Romestaing, P., (2013) Ten-year survival results of a randomized trial of irradiation of internal mammary nodes after mastectomy. [Erratum appears in Int J Radiat Oncol Biol Phys. 2014 Aug 1;89(5):1145]. International journal of radiation oncology, biology, physics, 86, 860–6. [PubMed: 23664327]

  • Matzinger 2010

    Matzinger, O., Heimsoth, I., Poortmans, P., Collette, L., Struikmans, H., Van den Bogaert, W., Fourquet, A., Bartelink, H., Ataman, F., Gulyban, A., Pierart, M., Van Tienhoven, G., EORTC Radiation Oncology & Breast Cancer Groups (2010) Toxicity at three years with and without irradiation of the internal mammary and medial supraclavicular lymph node chain in stage I to III breast cancer (EORTC trial 22922/10925). Acta oncologica, 49, 24–34. [PubMed: 20100142]

  • NICE 2009

    National Institute for Health and Clinical Excellence. (2009). Early and locally advanced breast cancer: diagnosis and treatment. NICE guideline (CG80). [PubMed: 19167201]

  • Poortmans 2015

    Poortmans, P. M., Collette, S., Kirkove, C., Van Limbergen, E., Budach, V., Struikmans, H., Collette, L., Fourquet, A., Maingon, P., Valli, M., De Winter, K., Marnitz, S., Barillot, I., Scandolaro, L., Vonk, E., Rodenhuis, C., Marsiglia, H., Weidner, N., van Tienhoven, G., Glanzmann, C., Kuten, A., Arriagada, R., Bartelink, H., Van den Bogaert, W., EORTC Radiation Oncology & Breast Cancer Groups (2015) Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer. New England Journal of Medicine, 373, 317–27. [PubMed: 26200978]

  • Thorsen 2016

    Thorsen, L. B., Offersen, B. V., Dano, H., Berg, M., Jensen, I., Pedersen, A. N., Zimmermann, S. J., Brodersen, H. J., Overgaard, M., Overgaard, J., (2016) DBCG-IMN: A Population-Based Cohort Study on the Effect of Internal Mammary Node Irradiation in Early Node-Positive Breast Cancer. Journal of Clinical Oncology, 34, 314–20. [PubMed: 26598752]

  • Whelan 2015

    Whelan, T. J., Olivotto, I. A., Parulekar, W. R., Ackerman, I., Chua, B. H., Nabid, A., Vallis, K. A., White, J. R., Rousseau, P., Fortin, A., Pierce, L. J., Manchul, L., Chafe, S., Nolan, M. C., Craighead, P., Bowen, J., McCready, D. R., Pritchard, K. I., Gelmon, K., Murray, Y., Chapman, J. A., Chen, B. E., Levine, M. N., M. A. Study Investigators (2015) Regional Nodal Irradiation in Early-Stage Breast Cancer. New England Journal of Medicine, 373, 307–16. [PMC free article: PMC4556358] [PubMed: 26200977]

Appendices

Appendix B. Literature search strategies

Literature search strategies for 8.1. What radiotherapy techniques are effective for excluding the heart from the radiation field without compromising coverage of the whole breast target volume for people with early or locally advanced breast cancer?

Database: Medline & Embase (Multifile)

Last searched on Embase 1974 to 2017 July 10, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to Present.

Date of last search: 11 July 2017

Database: Cochrane Library via Wiley Online

Date of last search: 11 July 2017

Literature search strategies for 8.2. Is there a subgroup of people with early invasive breast cancer who do not need breast radiotherapy after breast-conserving surgery?

Database: Medline

Database: Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present.

Date of last search: 18 November 2016

Database: Embase

Database: Embase Classic+Embase 1947 to 2016 Week 45.

Date of last search: 18 November 2016

Database: Cochrane Library via Wiley Online

Date of last search: 18 November 2016

Literature search strategies for 8.3. Is there a subgroup of women with early invasive breast cancer for whom partial breast radiotherapy is an equally effective alternative to whole breast radiotherapy after breast-conserving surgery?

Database: Medline & Embase (Multifile)

Database: Last searched on Embase 1974 to 2017 August 03, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to Present

Date of last search: 4 August 2017

Database: Cochrane Library via Wiley Online

Date of last search: 4 August 2017

Literature search strategies for 8.4. What are the indications for radiotherapy to internal mammary nodes?

Database: Medline

Last searched on Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to Present.

Date of last search: 5 January 2017

Database: Embase

Last searched on Embase Classic+Embase 1947 to 2017 January 04.

Date of last search: 5 January 2017

Database: Cochrane Library via Wiley Online

Date of last search: 5 January 2017

Appendix C. Clinical evidence study selection

Clinical evidence study selection for 8.1. What radiotherapy techniques are effective for excluding the heart from the radiation field without compromising coverage of the whole breast target volume for people with early or locally advanced breast cancer?

Figure 1. Flow diagram of clinical article selection for heart sparing radiotherapy review

Clinical evidence study selection for 8.2. Is there a subgroup of people with early invasive breast cancer who do not need breast radiotherapy after breast-conserving surgery?

Figure 2. Flow diagram of clinical article selection for breast radiotherapy after breast-conserving surgery

Clinical evidence study selection for 8.3. Is there a subgroup of women with early invasive breast cancer for whom partial breast radiotherapy is an equally effective alternative to whole breast radiotherapy after breast-conserving surgery?

Figure 3. Flow diagram of clinical article selection for partial-breast radiotherapy versus whole-breast radiotherapy after breast-conserving surgery

Clinical evidence study selection for 8.4. What are the indications for radiotherapy to internal mammary nodes?

Figure 4. Flow diagram of clinical article selection for radiotherapy to the internal mammary nodes

Appendix D. Clinical evidence tables

Clinical evidence tables for 8.1. What radiotherapy techniques are effective for excluding the heart from the radiation field without compromising coverage of the whole breast target volume for people with early or locally advanced breast cancer?

Table 14. Studies included in the evidence review for heart sparing radiotherapy (PDF, 349K)

Clinical evidence tables for 8.2. Is there a subgroup of people with early invasive breast cancer who do not need breast radiotherapy after breast-conserving surgery?

Table 15. studies included in the evidence review for breast radiotherapy after breast-conserving surgery (PDF, 458K)

Clinical evidence tables for 8.3. Is there a subgroup of women with early invasive breast cancer for whom partial breast radiotherapy is an equally effective alternative to whole breast radiotherapy after breast-conserving surgery?

Table 16. Studies included in the evidence review for partial breast radiotherapy (PDF, 673K)

Clinical evidence tables for 8.4. What are the indications for radiotherapy to internal mammary nodes?

Table 17. Studies included in the evidence review for radiotherapy to the internal mammary nodes (PDF, 457K)

Appendix E. Forest plots

Forest plots for 8.1. What radiotherapy techniques are effective for excluding the heart from the radiation field without compromising coverage of the whole breast target volume for people with early or locally advanced breast cancer?

Comparison 1. Deep inspiration breat-hold versus free breathing

Figure 5. Mean heart dose

Figure 6. Target coverage

Comparison 2. Deep inspiration breath-hold versus prone radiotherapy

Figure 7. Mean heart dose

Forest plots for 8.4. What are the indications for radiotherapy to internal mammary nodes?

Comparison 1. Radiotherapy to the internal mammary nodes versus no radiotherapy to the internal mammary nodes

Figure 31. Locoregional recurrence at 10 year follow-up

Figure 32. Disease-free survival at 10 year follow-up

Figure 33. Treatment related morbidity: secondary cancer (potentially radiation-induced) at 10 year follow-up

Figure 34. Treatment related morbidity: lung toxicity at 3 to 10 year follow-up

Figure 35. Treatment related morbidity: cardiac toxicity at 10 year follow-up

Figure 36. Treatment related morbidity: Grade 2+ lymphoedema at 10 year follow-up

Figure 37. Treatment-related morbidity: arm/shoulder function impairment at 3 year follow-up

Figure 38. Treatment-related morbidity: fatigue at 3 month to 3 year follow-up

Figure 39. Treatment related morbidity: skin toxicity at 3 month to 3 year follow-up

Figure 40. Treatment related morbidity: mastitis at 3 year follow-up

Figure 41. Treatment related morbidity: breast infection at 3 year follow-up

Figure 42. Treatment related morbidity: radionecrosis at 3 year follow-up

Figure 43. Treatment related morbidity: oedema at 3 year follow-up

Figure 44. Treatment related morbidity: breast/chest wall pain at 3 year follow-up

Figure 45. Treatment related morbidity: retrosternal pain at 3 year follow-up

Figure 46. Treatment related morbidity: dysphagia at 3 year follow-up

Figure 47. Treatment related morbidity: osteonecrosis

Figure 48. Treatment related morbidity: Grade 2+ acute (within 3 months of the completion of treatment) pain (site not specified)

Figure 49. Treatment related morbidity: acute (within 3 to 6 months of the completion of treatment) radiation pneumonitis

Figure 50. Treatment related morbidity: Grade 3+ morbidity on SOMA-LENT scale at 10 year follow-up

Figure 51. Overall survival at 8 to 10 year follow-up

Appendix F. GRADE tables

GRADE tables for 8.1. What radiotherapy techniques are effective for excluding the heart from the radiation field without compromising coverage of the whole breast target volume for people with early or locally advanced breast cancer?

Table 5. Clinical evidence profile: Comparison 1. Deep inspiration breath-hold versus free breathing (PDF, 260K)

Table 6. Clinical evidence profile: Comparison 2. Deep inspiration breath-hold versus prone radiotherapy (PDF, 237K)

GRADE tables for 8.2. Is there a subgroup of people with early invasive breast cancer who do not need breast radiotherapy after breast-conserving surgery?

Table 18. Clinical evidence profile: Comparison 1. No whole breast radiotherapy versus whole breast radiotherapy (PDF, 384K)

GRADE tables for 8.3. Is there a subgroup of women with early invasive breast cancer for whom partial breast radiotherapy is an equally effective alternative to whole breast radiotherapy after breast-conserving surgery?

Table 19. Clinical evidence profile: Comparison 1. Partial-breast radiotherapy versus whole-breast radiotherapy after breast-conserving surgery (PDF, 404K)

GRADE tables for 8.4. What are the indications for radiotherapy to internal mammary nodes?

Table 20. Clinical evidence profile: Comparison 1. Radiotherapy to the internal mammary nodes versus no radiotherapy to the internal mammary nodes (PDF, 472K)

Appendix G. Economic evidence study selection

Economic evidence study selection for 8.1. What radiotherapy techniques are effective for excluding the heart from the radiation field without compromising coverage of the whole breast target volume for people with early or locally advanced breast cancer?

See Supplement 1: Health economics literature review for details of economic study selection.

Economic evidence study selection for 8.2. Is there a subgroup of people with early invasive breast cancer who do not need breast radiotherapy after breast-conserving surgery?

See Supplement 1: Health economics literature review for details of economic study selection.

Economic evidence study selection for 8.3. Is there a subgroup of women with early invasive breast cancer for whom partial breast radiotherapy is an equally effective alternative to whole breast radiotherapy after breast-conserving surgery?

See Supplement 1: Health economics literature review for details of economic study selection.

Economic evidence study selection for 8.4. What are the indications for radiotherapy to internal mammary nodes?

See Supplement 1: Health economics literature review for details of economic study selection.

Appendix H. Economic evidence tables

Economic evidence tables for 8.1. What radiotherapy techniques are effective for excluding the heart from the radiation field without compromising coverage of the whole breast target volume for people with early or locally advanced breast cancer?

No economic evidence was identified for this review question.

Economic evidence tables for 8.2. Is there a subgroup of people with early invasive breast cancer who do not need breast radiotherapy after breast-conserving surgery?

No economic evidence was identified for this review question.

Economic evidence tables for 8.3. Is there a subgroup of women with early invasive breast cancer for whom partial breast radiotherapy is an equally effective alternative to whole breast radiotherapy after breast-conserving surgery?

Table 21. Economic evidence table showing the included health economic evidence for the optimal duration of adjuvant endocrine therapy for people with oestrogen-receptor positive breast cancer (PDF, 352K)

Economic evidence tables for 8.4. What are the indications for radiotherapy to internal mammary nodes?

No economic evidence was identified for this review question.

Appendix I. Health economic evidence profiles

Health economic evidence profiles for 8.1. What radiotherapy techniques are effective for excluding the heart from the radiation field without compromising coverage of the whole breast target volume for people with early or locally advanced breast cancer?

No economic evidence was identified for this review question.

Health economic evidence profiles for 8.2. Is there a subgroup of people with early invasive breast cancer who do not need breast radiotherapy after breast-conserving surgery?

No economic evidence was identified for this review question.

Health economic evidence profiles for 8.3. Is there a subgroup of women with early invasive breast cancer for whom partial breast radiotherapy is an equally effective alternative to whole breast radiotherapy after breast-conserving surgery?

Table 22. Summary table showing the included health economic evidence for the cost-effectiveness of partial breast radiotherapy after breast-conserving surgery

Health economic evidence profiles for 8.4. What are the indications for radiotherapy to internal mammary nodes?

No economic evidence was identified for this review question.

Appendix J. Health economic analysis

Health economic analysis for 8.1. What radiotherapy techniques are effective for excluding the heart from the radiation field without compromising coverage of the whole breast target volume for people with early or locally advanced breast cancer?

No health economic analysis was conducted for this review question.

Health economic analysis for 8.2. Is there a subgroup of people with early invasive breast cancer who do not need breast radiotherapy after breast-conserving surgery?

No health economic analysis was conducted for this review question.

Health economic analysis for 8.3. Is there a subgroup of women with early invasive breast cancer for whom partial breast radiotherapy is an equally effective alternative to whole breast radiotherapy after breast-conserving surgery?

No health economic analysis was conducted for this review question.

Health economic analysis for 8.4. What are the indications for radiotherapy to internal mammary nodes?

No health economic analysis was conducted for this review question

Appendix K. Excluded studies

Excluded studies for 8.1. What radiotherapy techniques are effective for excluding the heart from the radiation field without compromising coverage of the whole breast target volume for people with early or locally advanced breast cancer?

Clinical studies

Download PDF (257K)

Economic studies

See Supplement 1: Health economics literature review for list of excluded economic studies.

Excluded studies for 8.2. Is there a subgroup of people with early invasive breast cancer who do not need breast radiotherapy after breast-conserving surgery?

Clinical studies

Download PDF (242K)

Economic studies

See Supplement 1: Health economics literature review for list of excluded economic studies.

Excluded studies for 8.3. Is there a subgroup of women with early invasive breast cancer for whom partial breast radiotherapy is an equally effective alternative to whole breast radiotherapy after breast-conserving surgery?

Clinical studies

Download PDF (443K)

Economic studies

See Supplement 1: Health economics literature review for list of excluded economic studies.

Excluded studies for 8.4. What are the indications for radiotherapy to internal mammary nodes?

Clinical studies

Download PDF (282K)

Economic studies

See Supplement 1: Health economics literature review for list of excluded economic studies.

Appendix L. Research recommendations

Research recommendations for 8.1. What radiotherapy techniques are effective for excluding the heart from the radiation field without compromising coverage of the whole breast target volume for people with early or locally advanced breast cancer?

No research recommendations were made for this review question.

Research recommendations for 8.2. Is there a subgroup of people with early invasive breast cancer who do not need breast radiotherapy after breast-conserving surgery?

No research recommendations were made for this review question.

Research recommendations for 8.3. Is there a subgroup of women with early invasive breast cancer for whom partial breast radiotherapy is an equally effective alternative to whole breast radiotherapy after breast-conserving surgery?

No research recommendations were made for this review question.

Research recommendations for 8.4. What are the indications for radiotherapy to internal mammary nodes?

No research recommendations were made for this review question.