Question

How should patients with an isolated locoregional recurrence of breast cancer be treated?

Recommendation

Patients with an isolated locoregional recurrence of breast cancer are treated with curative intent as follows:

 

  • a recurrence in the spared breast: salvage mastectomy
  • a local recurrence after mastectomy and/or an isolated regional recurrence after mastectomy or BCT, in a previously non-irradiated area: high-dose radiotherapy, where possible preceded by surgical removal of the tumour
  • a chest wall recurrence in a previously irradiated area: re-irradiation, with hyperthermia, after surgical removal where possible.
  • if the hormone receptors are positive: secondary adjuvant hormonal treatment

 

After salvage mastectomy with R1 resection or lymphangitis cutis, additional re-irradiation and hyperthermia may be considered

 

Secondary adjuvant chemotherapy may be considered in a few situations.

  • invasive recurrence with poor tumour characteristics after DCIS
  • breast recurrence with poor tumour characteristics, after BCT, where adjuvant chemotherapy was not originally administered
  • axillary recurrence after tumour excision, SN procedure and radiotherapy, where adjuvant chemotherapy was not originally administered

Conclusions

 

Level 3

The best salvage treatment of an isolated local recurrence after mastectomy in a previously non-irradiated area, appears to be high-dose radiotherapy after surgical removal of the tumour.

 

The best salvage treatment of an isolated regional recurrence after mastectomy or BCT in a previously non-irradiated area, appears to be high-dose radiotherapy after surgical removal of the tumour.

 

C           Mendenhall 1988, Schwaibold 1991, Jager 1998, Mora 1996, Kamby 1997, Willner 1997,   Nielsen 2006, Van der Sangen 2003

 

Level 3

Salvage mastectomy provides the best local control for an isolated breast recurrence after BCT.

 

C           Kurtz 1989, Fourquet 1989, Osborne 1994, Haffty 1991, Fowble 1990, Abner 1993, Dalberg 1998,   Galper 2005

 

Level 2

In the case of a locoregional recurrence of breast cancer after mastectomy in a previously irradiated area, low-dose re-irradiation with hyperthermia leads to a better local control than re-irradiation only.

 

A2        Jones 2005

B          Vernon 1996, Zagar 2010

 

Level 3

There are indications that cytoreductive surgery prior to hyperthermia with irradiation provides a better local control of a local recurrence in an irradiated area.

 

C          Hehr 2001, Kapp 1992, van der Zee 1999, Oldenborg 2010

 

 

Level 3

Secondary adjuvant hormonal therapy improves   disease-free survival when treating a locoregional recurrence.

 

A2        Borner 1994

 


 Level 3

There is insufficient evidence for the benefit of secondary adjuvant chemotherapy in the treatment of a locoregional recurrence.

 

C          Rauschecker 2001, Danoff 1983, Haylock 2000

Literature summary

The choice of treatment of an isolated locoregional recurrence (without synchronous distant metastases) depends on a large number of factors, such as primary treatment (BCT/mastectomy, whether radiotherapy, chemotherapy and/or hormonal therapy has/has not been administered), the interval between the primary treatment and recurrence, size/extent of metastasis of the recurrence and resectability.

 

In general, locoregional treatment with curative intent is chosen. The most important prognostic factors for survival after salvage treatment of a locoregional recurrence after mastectomy are the interval between the original treatment and the size or extent of metastasis [van Tienhoven, 1999; Aberizk, 1986; Mendenhall, 1988; Schwaibold, 1991; Jager, 1998; van der Sangen, 2003]. Unfavourable factors during the original treatment such as positive axillary nodes [van Tienhoven, 1999; Jager, 1998] and the location of the recurrence (local or regional or both) are also mentioned as prognostic factors [van der Sangen, 2003]. The interval is also the most important prognostic factor after BCT for the effect of salvage treatment, aside from the size of the recurrence, the original node status and localisation of the recurrence (local or regional) [Aberizk, 1986; Osborne, 1994; Voogd, 2005; Elkhuizen, 2001; Kurtz, 1989; Fourquet, 1989; van Tienhoven, 1999; Haffty, 1991]. A separate subgroup of recurrences can be distinguished after BCT, which may be second primary tumours [Recht, 1988; Kurtz, 1990; Kurtz, 1989; Osborne, 1994]. These are recurrences that occur late, after approximately 7 years, and/or at a different location in the breast than around the original scar. These recurrences have a much better prognosis than the recurrences localised early and/or around the original scar.

 

Interpretation and comparison of treatment results from different studies is difficult because the patients with a locoregional recurrence form an extremely heterogenous group and because the articles describe different subgroups. Only the isolated locoregional recurrences are assessed in the failure analysis of the EORTC and DBCG trials [van Tienhoven, 1999]. Some studies only involve local (breast) recurrences, or even only operable breast recurrences [Fourquet, 1989; Fowble 1990; Abner, 1993].

 

The general tendency is to choose an intensive locoregional treatment with curative intent. Depending on the prognostic factors mentioned, a five-year locoregional control of 60-70% and five-year survival of 40-65% appear feasible for such treatment of isolated locoregional recurrences [Clemons, 2001; van Tienhoven; 1999, Voogd, 2005].

Local treatment of the local recurrence after mastectomy

While some authors only administer high dose radiotherapy in the case of a local recurrence after mastectomy [Aberizk, 1986; Jager, 1998; Deutsch, 1986; His, 1998], some form of surgery preceded radiotherapy in most series [Voogd, 2001; van Tienhoven, 1999; Mendenhall, 1988; Schwaibold, 1991; van der Sangen, 2003; Mora, 1996; Kamby, 1997; Willner, 1997; Nielsen, 2006]. This enables better local control to be achieved [Schwaibold, 1991; Kurtz, 1989; Nielsen, 2006]. Differences in outcomes of these retrospective studies must be interpreted carefully, due to differences in patient populations, in the therapy administered and therapy techniques. In addition, the local recurrence is irresectable in 20-40% of cases [Voogd, 2001; van Tienhoven, 1999; Schwaibold, 1991]. The best treatment results seem to be gained by as early as possible detection of the local recurrence, complete surgical removal where possible and high-dose radiotherapy in the entire mastectomy area. The following is meant with high-dose radiotherapy: in case of microscopic complete excision (R0), a dosis equivalent to 50 Gy in 5 weeks; followed by a boost in the case of incomplete (R1 or R2) or no excision.

 

If an isolated local recurrence occurs in the scar or regionally in an area previously irradiated, then high-dose radiotherapy is not possible. In that case, low-dose re-irradiation with hyperthermia is the treatment of choice [Vernon, 1996; Jones, 2005; Kapp, 1992; van der Zee, 1999; Hehr, 2001; Zagar, 2010]. This lead to a significantly better local control in five randomised trials than with re-irradiation alone [Vernon, 1996]. A later randomised trial for superficial tumours confirmed this [Jones 2005]. The amount of tumour is again an important prognostic factor here. There are indications that a better local control is also possible in this situation if the recurrence is first surgically removed [Kapp, 1992; van der Zee, 1999; Hehr, 2001; Oldenborg, 2010].

Local treatment of the local recurrence after BCT

Most literature on local recurrences after BCT concern recurrences in the breast [Fisher, 1991; Whelan, 1994; Elkhuizen, 2001; van der Sangen, 2006; Kurtz, 1989; Fourquet, 1989; Osborne, 1994; Haffty, 1991; Fowble, 1990; Abner, 1993; Dalberg, 1998; Galper, 2005; Osteen, 1994; Salvadori, 1999]. Most authors recommend salvage mastectomy as the treatment of choice, although some also deem local re-excision possible in a select group, or even re-irradiation [Osteen, 1994; Salvadori, 1999; Mullen, 1997]. In a series of 341 patients with a breast recurrence, Galper (2005) found a significantly poorer disease-free and overall survival for the 27 patients whose recurrence was again treated with lumpectomy and radiotherapy. It also applies here that most series select patients, which makes it difficult to compare results. Some (18-27%) of the local recurrences are also not operable after BCT [van Tienhoven, 1999; Salvadori, 1999; Mullen, 1997]. Re-irradiation with hyperthermia is recommended in these cases, unless high-dose radiotherapy (50 Gy of the entire breast with boost) is possible.

If the salvage mastectomy is non-radical, or there are other high risk characteristics such as lymphangitis cutis, additional re-irradiation plus hyperthermia may be considered [Kapp, 1992; van der Zee, 1999; Hehr, 2001; Oldenborg, 2010].

Local treatment of regional recurrences

Regional recurrences after mastectomy or BCT form a separate, heterogenous category. In principle, a regional recurrence after mastectomy is no different to a regional recurrence after BCT. This includes (in decreasing frequency), supraclavicular, axillary, infraclavicular and parasternal recurrences. There is not much literature available with recommendations for treatment, and where it is available it concerns series in which local and regional recurrences are described together as a group [van Tienhoven, 1999; Aberizk, 1986; Mendenhall, 1988; Schwaibold, 1991; Voogd, 2005; Perre, 1996; Jager, 1998; His, 1998; Mora, 1996; Kamby, 1997; Willner, 1997; Nielsen, 2006; Salvadori, 1999]. In a series of 42 isolated supraclavicular recurrences, radiotherapy showed an advantage above systemic treatment [Van der Sangen, 2003]. The treatment plan for regional recurrences in this series is in fact no different than for local recurrences, bearing in mind that it is generally less common for regional recurrences to be resectable.

In general, the same recommendations therefore apply as those formulated for local recurrences after mastectomy. For recurrences in a non-irradiated area: high-dose radiotherapy, where possible preceded by surgical removal of the recurrence. For recurrences in a previously irradiated area: re-irradiation with hyperthermia, also after surgical removal where possible.

 

Systemic treatment of a locoregional recurrence

The positive results of adjuvant systemic treatment after primary locoregional treatment of stage I and II breast cancer and the often slow growth rate of the breast cancer, so that the recurrence often does not manifest for several years, lead to the question if delayed or secondary adjuvant systemic treatment could also lead to a survival advantage. In a Cochrane systematic review, three completed and published studies were found with four randomised comparisons [Rauschecker, 2001]. One of these randomised comparisons was never reported on and the patient number in two were too small and were negative. Only the trial of the Swiss Group for Clinical Cancer Research (SAKK) randomised tamoxifen versus nothing in 178 patients. This trial showed an improvement in the 5-year disease-free survival of 36% versus 54%, but no survival advantage [Borner, 1994]. There were three trials underway at the time of the review (2001), which have been unsuccessful in the meantime due to insufficient accrual. A few studies retrospectively researched the role of additional chemotherapy, but found no or little significant difference [Danoff, 1983; Haylock, 2000]. Secondary adjuvant hormonal therapy may be recommended on the basis of the SAKK trial [Borner, 1994].

 

It is possible that locoregional control of non-resectable locoregional recurrences may be improved using secondary neoadjuvant chemotherapy, in analogy to primary locoregional metastatic disease (see chapter 7), but there is no evidence in the literature to this effect.

 

Supportive care, information

Discovering there is a locoregional recurrence is an emotionally loaded event for patients. It should be explained to the patient, preferably in the presence of a partner or trusted person, that the prognosis has therefore worsened and that additional research is required to exclude metastasis. The assistance of a specialised nurse is essential.

 

Continuity of care

After treating the locoregional recurrence, the treatment provider should be alert for questions from the patient and problems in relation to processing the setback. The chance of a recurrence or metastasis is quite high, especially in the first few years. A new follow-up period is therefore desirable for both these reasons.

 

Metastasis and concentration, infrastructure

Hyperthermia is only possible at a few locations in the Netherlands (Amsterdam, Rotterdam, Tilburg). You can find more information about this at www.hyperthermie.nl.

Considerations

There are a few situations one can imagine secondary adjuvant chemotherapy being considered for, despite the lack of evidence. In general, examples are situations in which an indication for adjuvant chemotherapy was originally lacking, and in which the tumour stage at the time of the recurrence is such that there is an indication for it now.

  • invasive recurrence with poor tumour characteristics after original treatment of a DCIS.
  • breast recurrence with poor tumour characteristics, after BCT for a relatively favourable tumour, for which adjuvant chemotherapy was not originally administered. There seems to be a second primary tumour with poorer characteristics
  • axillary recurrence after tumour excision, SN procedure and radiotherapy, where adjuvant chemotherapy was not originally administered

 

In case of locoregional recurrences that occur simultaneously with or after distant metastases, the relative importance of systemic and locoregional treatment must be considered on the basis of risk estimation. Locoregional surgery appears to improve the prognosis of primary metastatic breast cancer, it is not known if this also applies to a simultaneous locoregional and distant recurrence of breast cancer [Ruiterkamp, 2010]. In any case it must be kept in mind that an uncontrolled locoregional recurrence is associated with a large morbidity and that locoregional treatment has a better chance of preventing this than systemic treatment alone.

Authorization date and validity

Last review : 13-02-2012

Last authorization : 13-02-2012

The national Breast Cancer guideline 2012 is a living guideline, in other words there is no standard term of revision. NABON continually watches at new developments and clinical problems in the areas of screening, diagnostics, treatment and aftercare, and whether this requires an update.

Initiative and authorization

Initiative : Nationaal Borstkanker Overleg Nederland

Authorized by:
  • Nederlandse Internisten Vereniging
  • Nederlandse Vereniging voor Heelkunde
  • Nederlandse Vereniging voor Psychiatrie
  • Nederlandse Vereniging voor Radiologie
  • Nederlandse Vereniging voor Radiotherapie en Oncologie

General details

Approximately 14,000 women (and 100 men) are diagnosed with invasive breast cancer each year in the Netherlands, and about 1,900 have an in situ carcinoma. A woman's risk of having breast cancer over the course of her life is 12-13%. This means that breast cancer is the most common form of cancer in women in the Netherlands. Early detection, particularly via national breast cancer screening, combined with adjuvant therapy followed by locoregional treatment, improves the prognosis in women with breast cancer

The guideline on Breast Cancer Screening and Diagnostics, published in 2000, was updated in 2007. In 2002, the first multidisciplinary National Breast Cancer Guideline was published, it was revised in 2004, 2005 and 2006. In 2008 both guidelines were combined to Breast Cancer Guideline, which 2012 revision is now effected.

Scope and target group

This guideline is written for all the members of the professional groups that have contributed to its development.

 

This guideline is a document with recommendations and instructions to support daily practice. The guideline is based on the results of scientific research and expert opinion, with the aim of establishing good medical practice. It specifies the best general care for women with (suspected) breast cancer and for those who are eligible for screening. The guideline aims to serve as a guide for the daily practice of breast cancer screening, diagnostics, treatment and aftercare. This guideline is also used in the creation of informational materials for patients, in cooperation with the KWF (Dutch Cancer Society).

Member of workgroup

A core group consisting of a radiologist, surgeon, pathologist, medical oncologist and radiation therapist began preparing for the revision of the breast cancer practice guidelines in 2009. A multidisciplinary guideline development group was formed in early 2010 to implement the revision. This group consisted of mandated representatives from all of the relevant specialisations concerned with breast cancer, plus two delegates from the BVN (Dutch Breast Cancer Society) (see list of guideline development group members). The benefits of such a multidisciplinary approach are obvious: not only does it best reflect the care, but it offers the greatest possible expertise for the guideline. In composing the development group, geographic distribution of the members, balanced representation of the various organisations and agencies concerned, and a fair distribution in academic background were taken into account as much as possible.

 

The guideline development group received procedural and administrative support from IKNL (Comprehensive Cancer Centre for the Netherlands) and support on methodology from Bureau ME-TA. Partial funding was obtained from SKMS (Quality Funds Foundation of Dutch Medical Specialists). This subsidy would not have been possible without the extensive assistance provided by the NVvR (Radiological Society of the Netherlands).

Declaration of interest

Partial funding for the guideline revision was obtained from the Society of Dutch Medical Specialists in the framework of the SKMS. IKNL sponsored some of the cost. On two occasions, as well as at the beginning and end of the process, all of the members of the guideline development group were asked to fill out a statement of potential conflicts of interest, in which they stated their relationship with the pharmaceutical industry. A list of these statements of interest can be found in the appendices.

Patient involvement

In developing this guideline, four clinical questions were formulated. These questions emerge from an inventory of clinical problems collected in the field from professionals, patients and patient representatives.

 

Also, A multidisciplinary guideline development group was formed in early 2010 to create and implement the revision. This group consisted of mandated representatives from all of the relevant specialisations concerned with breast cancer, plus two delegates from the BVN (Dutch Breast Cancer Society).

 

Method of development

Evidence based

Implementation

Feasibility has been taken into account in developing the guideline. This included attention to factors that could promote or hinder putting the advice into practice. Examples include the implementation of an analysis of problems, the multidisciplinary composition of the guideline development group, and making active use of support from the guideline development group members. Presenting the draft guideline to the field and communicating what, if anything, is being done with the responses, also promotes implementation. In this manner, a guideline has been developed that answers current questions in the field.

The guideline is distributed widely and is available in digital form on the Dutch Guideline Database. The guideline may also be brought to the attention of a wider audience in other periodicals or continuing education sessions, for example. To promote use of the guideline, we recommend that the regional tumour working groups and group practices, as well as scientific and professional organisations, repeatedly bring the guideline to the attention of their members. Any problems that may arise in using the guidelines can then be discussed and, when appropriate, submitted to the national guideline development group, as it is a "living" guideline. If desirable, parts of the guideline can be made more explicit by formulating regional additions or translation to the local situation in departmental and/or hospital protocols.

In principle, indicators are determined during development of the guideline that can be used to monitor implementation of the recommendations. Via a documentation project, these indicators can then be used to determine the extent of compliance with the guideline. The information from the documentation project becomes input for the revision of the guideline.

Methods and proces

This module has been evidence-based revised in 2008 and consensus based updated in 2012.

 

A revision of an existing guideline consists of revised and updated text. Revised text is new text based on an evidence-based review of the medical literature; updated text is the old guideline text which has been edited by the experts without performing a review of medical literature. Each section of the guideline states what type of revision has taken place. Each chapter of the guideline is structured according to a set format, given below. The purpose of this is to make the guideline transparent, so that each user can see on what literature and considerations the recommendations are based on.

 

Description of the literature

To the greatest extent possible, the answers to the fundamental questions (and therefore the recommendations in this guideline) were based on published scientific research. The articles selected were evaluated by an expert in methodology for their research quality, and graded in proportion to evidence using the following classification system:

 

Classification of research results based on level of evidence

A1

Research   on the effects of diagnostics on clinical outcomes in a prospectively   monitored, well-defined patient group, with a predefined policy based on the   test outcomes to be investigated, or decision analysis research into the   effects of diagnostics on clinical outcomes based on results of a study of   A2-level and sufficient consideration is given to the interdependency of   diagnostic tests.

A2

Research   relative to a reference test, where criteria for the test to be investigated   and for a reference test are predefined, with a good description of the test   and the clinical population to be investigated; this must involve a large   enough series of consecutive patients; predefined upper limits must be used,   and the results of the test and the "gold standard" must be   assessed independently. Interdependence is normally a feature of situations   involving multiple diagnostic tests, and their analysis must be adjusted   accordingly, for example using logistic regression.

B

Comparison   with a reference test, description of the test and population researched, but   without the other features mentioned in level A.

C

Non-comparative   trials

D

Opinions   of experts, such as guideline development group members

 

Conclusions

Based on the medical literature, one or more relevant conclusions are made for each section. The most important literature is listed according to the level of evidential strength, allowing conclusions to be drawn based on the level of
evidence. All the medical literature included in the conclusion is described in the bibliography.

 

Classification of conclusions based on literature analysis

1

Based   on 1 systematic review (A1) or at least 2 independent A2 reviews.

2

Based   on at least 2 independent B reviews

3

Based   on 1 level A2 of B research, or any level C research

4

Opinions   of experts, such as guideline development group members

 

Other considerations

Based on the conclusion(s), recommendations are made. However, there are other considerations that contribute to formulation of the recommendation besides literature evidence, such as safety, the patients' preferences, professional expertise, cost-effectiveness, organisational aspects and social consequences. The other considerations are mentioned separately. In this manner, it is clear how the guideline development group arrived at a particular recommendation.

 

Recommendations

The final wording of the recommendation is the result of the scientific conclusion, taking into account the other considerations. The purpose of following this procedure and drawing up the guidelines  in this format is to increase transparency.

 

References

An alphabetical list of literature references can be found at the end of the guideline.

 

All draft texts have been discussed by the guideline development group.

Search strategy

Searches are available upon request. Please contact the Richtlijnendatabase.