Question

How to treat patients with micrometastases or isolated tumour cells in the sentinel lymph node and/or axillary nodes?

Recommendation

Specific recommendations about axillary treatment can be found in a different module.

 

Specific recommendations about adjuvant systemic therapy in the case of (sub)micrometastases can be found in a different module.

Conclusions

 

Level 2

There are indications that omitting an axillary node dissection in at least a proportion of patients with SN micrometastases does not lead to a reduction in survival or an increase in the number of axillary recurrences. It is difficult to see from the current literature which patients this involves.

 

B          Bilimoria 2009, Cox 2008, Pernas 2010, Wasif 2010, Giuliano 2010

 

Level 2

It is plausible that omitting an axillary node dissection in patients with isolated tumour cells in the SN does not lead to an increase in the number of axillary recurrences.

 

B          Pugliese 2010, Cox 2008, Calhoun 2005, Jakub 2002, Jeruss 2005, Giobuin 2009, Schulze   2006

Literature summary

Quite a lot of observational studies show the prognostic importance of the presence of micrometastases and isolated tumour cells in the axillary nodes and/or sentinel lymph node (SN). A recent meta-analysis of cohort studies showed that the presence of axillary node metastases of 2 mm or smaller is accompanied with a poorer survival than the absence of such metastases (pooled HR for death: 1.44; 95%CI 1.29-1.62) [de Boer 2010]. In another meta-analysis of the same group, a risk of 12.3% of non-SN metastasis was found in the presence of isolated tumour cells in the SN (total pooled risk: 12.3%; 95%CI 9.5-15.7) [van Deurzen, 2008; Straver, 2010]. In a systematic review by Cserni (2004), percentages of 10-15% additional axillary metastases were seen for the group of patients with a micrometastasis or isolated tumour cells. For the first 2,000 patients participating in the AMAROS study, it appeared the percentage of additional axillary metastases was 18%, both with micrometastases and isolated tumour cells [Straver 2010]. A number of different centres developed a nomogram to help predict the risk of non-SN metastases in the presence of axillary node micrometastases or isolated tumour cells, in which those of the Memorial Sloan-Kettering Cancer Centre and the Tenon score seem to be the most reliable for this specific group of patients [Coutant, 2009]. From a recent study in the Netherlands it appears that the nomogram of the Memorial Sloan-Kettering Cancer Centre, applied to 168 women with a positive sentinel node who underwent an axillary node dissection, is of insufficient predictive value in order to determine the treatment plan in individual cases [van den Hoven, 2010].

 

Given patients with micrometastases or isolated tumour cells in the SN form a separate prognostic population, it raises the question if they should be treated in the same manner as patients with axillary node macrometastases. In some of the cases there was displacement of epithelial cells [Bleiweiss, 2006; van Deurzen, 2009 (1); van Deurzen, 2009 (2)]. It is not clear here if marginal sinus metastases have the biological properties to be or become tumour forming.

The results must be seen in the light of the chance of metastasis in the non-sentinel nodes in an axillary lymph node dissection if no tumour is found in the SN biopsy itself. This chance is generally about 7%. In the study by Krag (2007), the percentage of false-negative SN biopsies was even 9.8%. In a pooled meta-analysis of 14,959 patients [van der Ploeg, 2008] there is an acceptable axillary node recurrence percentage of 0.3% after a median follow-up of 34 months in patients with an SN negative status. This is 0.7% after 95 months follow-up in the NSABP B-32 trial [Krag, 2010].

 

Axillary node dissection

Randomised studies that have researched the benefit of a complete axillary lymph node dissection (ALND) in patients with micrometastases or isolated tumour cells in the axillary nodes and/or SN have not been published yet. Ten comparative observational studies researched the benefit of ALND in patients with micrometastases in the axillary node [Pernas, 2010; Wasif, 2010; Bilimoria, 2009; Bulte, 2009; Cox, 2008; Haid, 2006; Schulze, 2006; Fan, 2005; Jeruss, 2005; Liang, 2001], while seven comparative observational studies were found for patients with isolated tumour cells in the axillary node [Pugliese, 2010; Giobuin, 2009; Cox, 2008; Schulze, 2006; Calhoun, 2005; Jeruss, 2005; Jakub, 2002].

 

The largest retrospective cohort study compared 3,674 patients with axillary node micrometastases who only underwent an SN biopsy with 6,585 patients who, in addition, also underwent an ALND [Bilimoria, 2009]. No differences were found in the 5-year survival (corrected HR: 0.95; 95%CI 0.70-1.27; p=0.75) and axillary recurrence percentage (0.4% after SN biopsy vs. 0.2% after SN biopsy and ALND, p=0.18). The hazard ratio was corrected for age, T classification and tumour grade (amongst other things). It is necessary to mention a few important side notes for this study. It concerns a cancer registry database, in which it can be presumed there was an underregistration of (axillary) recurrences. In addition, there was no multivariate correction for the use of systemic therapy. Another large retrospective cohort study was also based on cancer registry data [Wasif 2010]. This study was aimed at understanding to what extent ASCO guidelines are followed, especially the recommendation to perform a routine ALND in patients with micrometastases in the SN. Of the 5,353 enrolled patients with micrometastases in the SN, 2,160 (40.4%) underwent no additional ALND. No difference in total survival was found between patients who did or did not undergo an additional ALND (89% after SN biopsy vs. 90% after SN biopsy and ALND, p=0.98). However, these results were not corrected for primary tumour characteristics or the use of systemic therapy. Data on (axillary) recurrence was not reported by the authors.

Similar findings for survival [Cox, 2008] and recurrence [Bulte, 2009; Cox, 2008; Fan, 2005; Haid, 2006; Jeruss; 2005; Liang; 2001, Pernas; 2010; Schulze, 2006] were found in smaller cohort studies. Cox (2008) compared the outcomes of 2,108 patients with a negative SN with those of 151 patients with isolated tumour cells (see below) and 122 patients with micrometastases in the SN. General and disease-free survival were not significantly worse in the group with micrometastases. Within the group with micrometastases, no difference was found in general survival between patients treated with or without additional ALND. After a (short) median follow-up of 1.7 years, axillary recurrences were also not found in the group who were only treated with an SN biopsy. In a small prospective study, Pernas (2010) compared the outcomes of 14 patients with micrometastases in the SN and treated with an additional ALND with that of 45 patients who only underwent an SN biopsy. One patient in the group treated with additional ALND developed an infraclavicular recurrence. After a median follow-up of 60.4 months, the group who were only treated with an SN biopsy were recurrence-free. The number of patients with micrometastases in the SN in the other studies varied from 9 to 45 [Bulte, 2009; Fan, 2005; Haid, 2006; Liang, 2001; Schulze, 2006]. After a follow-up varying between 13.5 and 47 months, these patients remained free of axillary recurrence, independent of treatment with ALND. Only Fan (2005) reported a recurrence in the group who were only treated with an SN biopsy, but without clarifying where. None of these studies corrected for primary tumour characteristics or the use of systemic therapy.

Incidentally, non-comparative studies also found low axillary recurrence percentages (0-3%) in patients who only underwent an SN biopsy [Fournier, 2004; Langer, 2009; Yegiyants, 2010].

 

In a retrospective analysis of a prospective database, Pugliese (2010) compared 76 patients with isolated tumour cells in the axillary node who had only undergone an SN biopsy with 95 patients who also underwent an ALND. After a median follow-up of 6.4 years, no axillary node recurrences were found, 3 local recurrences and 6 distant recurrences. Eight of the 9 recurrences were determined in patients treated with SN biopsy and ALND. The five-year recurrence-free survival of the total cohort was 97% (95%CI 92.1 - 98.6). Other authors also found low axillary recurrence percentages of 0% [Calhoun, 2005; Jakub, 2002; Jeruss, 2005; Giobuin, 2009; Schulze, 2006] to 2.3% [Cox, 2008] of patients with isolated tumour cells in the axillary node who only underwent an SN biopsy. Only one comparative study reported survival figures for patients with isolated tumour cells [Cox, 2008]. In this study, 44 patients underwent only an SN biopsy and 107 patients an SN biopsy and ALND. While the authors do not report any figures, the Kaplan-Meier curve shows a significantly worse survival in the group who only underwent an SN biopsy (p=0.02).

None of these studies corrected for primary tumour characteristics or the use of systemic therapy.

 

Finally, a large study was conducted by the Memorial Sloan-Kettering Cancer Centre in which 6 of the 287 patients (2%) with a positive SN who only underwent an SN biopsy developed an axillary recurrence in comparison with 6 of the 1,673 patients (0.4%) who also underwent an axillary node dissection (p=0.004) [Park, 2007]. In patients with an H&E-positive SN (predominantly micrometastases), the axillary recurrence percentage without ALND was 5% after 23 months. This study also did not correct for primary tumour characteristics or the use of systemic therapy.

 

Axillary irradiation

None of the studies specifically compared the effect of irradiation or non-irradiation in patients with micrometastases or isolated tumour cells in the SN.

Considerations

Four randomised studies have been published so far with and without ALND in patients with a negative SN [Veronesi, 2010; Zavagno, 2008; Canavese, 2009; Krag, 2010]. Omitting ALND is considered safe in the case of a negative SN. In this study, patients with isolated tumour cells were considered node positive, and therefore underwent an ALND as a standard. The limited data that has been published so far in relation to axillary management if isolated tumour cells in the SN are found has been derived from observational series, and show a low recurrence percentage. Another retrospective analysis of 6,838 patients treated between 1998 and 2004 also shows little influence on the breast cancer-specific survival of an axillary node dissection in patients with micrometastases [Yi, 2010]. In an analysis in the Netherlands (the MIRROR study), the regional recurrence percentage in patients with SN isolated tumour cells who did not undergo ALND also appeared acceptable (2% after 5 years of follow-up). In the ASCO guideline, ALND is not recommended as a standard with SN-isolated tumour cells.

In the pre-SN era, no difference was found in the NSABP B04 trial in clinically node-negative patients in relation to survival between an ALND, regional irradiation or omitting both [Fisher, 1985]. Reed (2009) suggests that the extremely low axillary recurrence percentage generally described in literature after breast-sparing treatment could be linked to radiotherapy of a proportion of level I and II of the axilla in mantle-fields. In the EORTC study 10981/22023 (the AMAROS study), closed in April 2010 with almost 4,800 patients, in which all patients with a positive SN received axillary treatment, randomised between surgery or radiotherapy of the axillary and periclavicular region, the total number of axillary recurrences strongly fell behind expectations (personal communication). While it has not been unequivocally proven yet, the guideline development group deems it likely on the basis of available literature and experience from the AMAROS study that axillary irradiation could be an alternative to an axillary node dissection in patients with metastasis/metastases in the SN for whom treatment of the axillary is considered necessary.

For the time being, ASCO does standard recommend an ALND in patients with SN micro/metastases. The series reported so far do show a low regional recurrence percentage, but these series are partly biased due to patient selection, small patient numbers, short follow-up duration, or underreporting of recurrences during follow-up (cancer registration databases) [Pepels 2011].

 

The ACOSOG (American College of Surgeons) Z-11 study was recently published [Giuliano, 2010; Giuliano, 2011]. This concerned a prospective study in which patients with a positive SN (≥ 3 SN+ excluded) were randomised between ALND or no further axillary treatment in patients who underwent BCT. In this study, 891 patients were evaluated with a median follow-up of 6.3 years; no significant difference was found in local or regional recurrence (0.5% after ALND, 0.9% after SN procedure). Adjuvant systemic therapy was administered in 97% of cases. The authors concluded that it is justified to omit an ALND in patients who undergo a BCT, receive adjuvant systemic therapy and with a positive SN.

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.