Question

How should local neoadjuvant treatment be performed?

Recommendation

Follow-up to neoadjuvant treatment should be discussed within the framework of multidisciplinary consultation.

 

Breast surgery

  • Omitting breast surgery is advised against, even with clinical complete remission
  • cT4 if operable after systemic treatment (also mastitis carcinomatosa, cT4D)

 

Contraindications for BCT:

  • Suspected microcalcifications in multiple quadrants
  • A non-radical resection that is more than focal
  • The wishes of the patient regarding mastectomy

 

Axillary node dissection:

  • Non-identified SN in the case of stage II (cT2-3N0);
  • Clinically positive nodes in the case of stage II (cT1-2N1);
  • With downstaging of stage III (cN2-3) to yN1.

 

Locoregional radiotherapy (breast, chest wall, axillary and periclavicular)

  • Always locoregional with (still) inoperable local disease
  • cN2-3 on initial diagnosis, or pN2-3 at the time of ALND (> 3 positive nodes)
  • Stage III (cT3N1 or cT0-2N2-3 or cT4) on initial diagnose, or ypT3N+, ypT4 at the time of surgery (possibly omitting irradiation of the lateral axillary)

 

Locoregional radiotherapy (breast, chest wall, periclavicular, with or without lateral axillary)

  • Always locoregional with (still) inoperable local disease
  • Stage III (cT3N1 or cT0-2N2-3 or cT4) on initial diagnosis, or ypT3N+, ypT4 at the time of surgery
  • In total (SN and ALND) > 3 positive nodes

 

Local radiotherapy (breast or chest wall):

  • Always in the case of BCT
  • A tumour positive resection surface of the primary tumor, irradicality
  • ypT3 and one or more of the following risk factors: angioinvasive growth, grade III, age ≤ 40 years
  • ypT2 if cT3, and one or more of the following risk factors: angioinvasive growth, grade III, age ≤ 40 years
  • Consider if ypN1, and one or more of the following risk factors: angioinvasive growth, grade III, age ≤ 40 years

 

Parasternal radiotherapy may be considered in the case of:

  • Parasternal metastases demonstrated by means of SN
  • Parasternale FDG uptake with anatomical substrate on FDG-PET-CT scan
  • Stage III without further knowledge about possible parasternal drainage

Conclusions

 

Level 1

In stage II breast cancer, neoadjuvant chemotherapy leads to an increase in the number of breast-conserving treatments.

 

A1        Mauri 2005, Mieog 2007

 

Level 1

In studies in which local surgery was not performed following a good response to neoadjuvant chemotherapy, the risk of locoregional recurrences was higher than when local surgery was performed.

 

A1        Mauri 2005, Mieog 2007

 

Level 3

After neoadjuvant chemotherapy for breast cancer with locoregional metastasis, surgical removal of the residual tumour (if possible) leads to better local control.

 

C          Pierce 1992, Mauri 2005, Mieog 2007, Daveau 2010, Abrous-Anane 2010

 

Level 2

After neoadjuvant chemotherapy and if BCT is chosen, patients with two or more of the following factors have an increased risk of locoregional recurrence:

  •   cN2-3 classification before starting chemotherapy
  •   a multifocal residual tumour  
  •   a residual tumour > 2 cm on pathology analysis
  •   lymphangio-invasion in biopsy or in the postoperative specimen

 

B          Chen 2005, Huang 2006

 

Level 1

Radiotherapy, added to chemotherapy and   surgery, reduces the chance of a locoregional recurrence by a factor of three in the case of a resectable breast cancer with local metastasis, and as a result improves the long-term (15-year) survival.

 

A1        EBCTCG 2000

A2        Overgaard 1999, Ragaz 2005

 

Level 1

An improvement in locoregional control using radiotherapy has been demonstrated for classic irresectable breast cancer with locoregional metastasis, but no survival advantage.

 

A2        Papaioannou 1983, Olson 1997

 

Level 2

After neoadjuvant chemotherapy, both the initial clinical disease stage and postoperative stage are independent predictors of the risk of locoregional recurrence. Even if a pathological complete remission has been achieved.

 

B          Buchholz 2008, Garg 2004, Huang 2004, McGuire 2007

 

Level 2

Locoregional control, disease-free survival and disease-specific survival appear to be improved by postoperative radiotherapy after neoadjuvant chemotherapy in patients with multiple risk factors (cT3-4, cN2-3, pN+).

 

B          Huang 2004, McGuire 2007

Literature summary

Treatment consists of surgery and radiotherapy. While local and regional treatment cannot always be separated, the local treatment of breast and regional lymph node stations are discussed separately in the below sections. While mastectomy or lumpectomy were always conducted together with axillary node dissection in the past, local and regional treatment are considered more as separate entities these days. This certainly applies after neoadjuvant systemic therapy, because in this situation the diagnostic aspect of the ALND no longer applies, because the initial axillary status (prior to neoadjuvant systemic therapy) is already known.

Surgery

Neoadjuvant chemotherapy is commenced with irresectable stage III breast cancer with the aim of making surgery possible by reducing the tumour load prior to the intervention. There are strong indications that reducing the tumour load improves the locoregional effect of radiotherapy [Yang, 2006]. Most authors recommend surgical removal of the residual tumour prior to irradiation [Machiavelli, 1998; Recht, 2000; Daveau, 2010]. A French series of 232 patients also showed the addition of surgery provides an advantage with inflammatory breast cancer (T4D) [Abrous Anane, 2011]. It is possible with inoperable stage III breast cancer that the disease has not responded sufficiently to the neoadjuvant treatment and is still irresectable. Fortunately this is rare. In that case, the addition of surgery after radiotherapy is an option, but there is no evidence or consensus on this.

 

Breast-conserving surgery after neoadjuvant therapy (instead of mastectomy)

With larger operable tumours, an important reason to initiate neoadjuvant chemotherapy is to make BCT possible where this initially did not appear possible. An important question is whether clear indications can be formulated on when (not) to perform breast-conserving surgery. In the NSABP-B27 study, 87% had a clinical objective response and 26.1% a pCR (including 7.2% DCIS) to AC-docetaxel neoadjuvant chemotherapy [Bear, 2006]. In the meta-analyses of neoadjuvant versus postoperative adjuvant chemotherapy, a significant reduction in the number of mastectomies was seen with the use of neoadjuvant chemotherapy (absolute reduction 16.6%; 95%CI 15.1-18.1%) [Mieog, 2007].

It is the question as to what extent the choice for BCT in this category of patients has a negative influence on local control. An increased risk of locoregional recurrences was found in the meta-analyses with the use of neoadjuvant chemotherapy (RR 1.22; 95%CI 1.04-1.43). This risk was only elevated in three studies, in which patients with a clinical complete remission [Mauriac, 1999] did not undergo breast surgery [Broët, 1999; Gazet, 2001; Scholl, 1994]. The relative risk in these three studies was 1.53 (95%CI 1.17-2.00). In the remaining studies together, in which breast surgery was performed, no significant elevation in risk was seen (RR 1.10; 95%CI 0.87-1.38). The poorer local control after neoadjuvant chemotherapy therefore appears to be explained by the fact that the macroscopic residual tumour or even the amount of tumour remaining in a clinical complete remission is too much for the radiotherapy alone to get under control. In a French series of 165 patients with a cCT following neoadjuvant chemotherapy, 100 patients who were treated exclusively with radiotherapy showed a trend of poorer locoregional control than the 65 patients with cCR who received a lumpectomy and radiotherapy [Daveau, 2010]. A combination of surgery and radiotherapy is therefore necessary as locoregional treatment even with a clinical complete remission [Mauri, 2005; Mieog, 2007; Daveau, 2010]. A possible additional explanation for the poorer local control after neoadjuvant chemotherapy is the postponement of locoregional treatment [Huang, 2003].

The same considerations apply in the choice of breast-conserving surgery as with primary surgical treatment. Diffuse microcalcifications throughout the breast form a contraindication, because calcifications will not disappear with neoadjuvant therapy [Buchholz, 2003; Buchholz, 2008]. Multicentric tumours also make the choice for BCT less logical unless with a good response, all the marked original tumour-containing areas can be radically excised. If a resection that is more than focal is irradical, the risk of recurrence is elevated and re-excision is recommended.

Researchers of the MDACC developed a prognostic index based on a prognostic study with 340 patients who underwent a BCT after neoadjuvant therapy, [Chen, 2005]. According to this index, patients with two or three of the following factors should have an unacceptably high risk of recurrence (12% and 18% after 5 years respectively) if they receive breast-conserving treatment after neoadjuvant chemotherapy: cN2 or cN3, residual pathological tumour > 2cm, lymphangio-invasion or a multifocal pattern of the residual tumour. There are also a few negative points associated with this study, the subgroup of patients with multiple factors was small. Positive excision margins were very limited in this study so that this factor could not be analysed. Patients in this study had a remission of all skin abnormalities, had no macroscopic residual tumour and no residual abnormalities on the mammogram. It therefore involved a selected group [Chen, 2005].

 

The prognostic index was validated using another dataset, namely 815 patients who after neoadjuvant chemotherapy had undergone surgery (BCT or mastectomy with ALND) and radiotherapy [Huang, 2006]. At a score of 0/1, the ten-year locoregional recurrences were low for mastectomy with ALND as well as BCT. At a score of 2 however, there were lower locoregional recurrence percentages for mastectomy with ALND versus BCT (12% versus 28%). For patients with a score of 3 or 4, recurrence percentages of 19% were even found after ten years following mastectomy with ALND versus 61% after BCT. BCT therefore appears safe, subject to good selection based on the abovementioned factors.

 

Radiotherapy of the breast or chest wall

In principle, the same indications apply after neoadjuvant chemotherapy for postoperative radiotherapy as with patients who have not undergone neoadjuvant chemotherapy. Postoperative locoregional radiotherapy reduces the risk of locoregional recurrence and long-term survival with large tumours (≥ T3) and tumours with more than 3 positive nodes (≥ pN2) [EBCTCG, 2000]. Possibly also with 1-3 positive nodes (pN1) [Overgaard, 1999; Ragaz, 2005]. However, there are a few uncertainties. The indications for radiotherapy after BCT or mastectomy with ALND and the regional node areas are traditionally partially based on postoperative pathological criteria. This pathological data is unreliable after neoadjuvant therapy.

 

A study of 150 patients after neoadjuvant chemotherapy and mastectomy with ALND without radiotherapy showed that both the initial clinical stage and the eventual pathological metastasis of the disease are independent predictors for the locoregional recurrence [Buchholz, 2003]. The locoregional recurrence percentage correlated with the T stage (T3-4), clinical stage (stage IIIB, IV), pathological residual disease (> 2 cm) and positive nodes after chemotherapy [Buchholz, 2003]. In a follow-up study [Huang, 2004], 542 patients from 6 prospective studies that had received neoadjuvant chemotherapy, mastectomy with ALND and postoperative radiotherapy, were compared with 134 patients from the same 6 studies who had not been irradiated. While radiotherapy was not a randomised variable, this study found that radiotherapy improved locoregional control for patients with clinical T3 and T4 tumours, stage > IIB (T2N1, T3N0) and pathological residual disease > 2 cm. This study also found that radiotherapy improved the disease-specific survival in stage > IIIB, cT4 and with 4-10 positive nodes. It was also found that patients with stage III who had a pCR, still had a high risk of locoregional recurrence. The study by McGuire (2007) researched 226 patients who had a pCR after neoadjuvant chemotherapy. Radiotherapy did not give an improvement in the locoregional control for patients with stage I and II disease, but the ten-year local control for stage III patients was significantly improved with radiotherapy (7.3% vs 33%; p=0.004). Postoperative radiotherapy was also associated with an improvement in the disease-free and total survival (total survival 77% vs 33%; p=0.002).

 

A prospective study on 132 stage I and II patients who received neoadjuvant chemotherapy followed by mastectomy with ALND without radiotherapy showed that patients with stage cT3 or ypT3 tumours or ypN2-3 had a high risk of locoregional recurrence. Patients with stage I and II tumours with 1-3 positive nodes after chemotherapy had a limited risk of locoregional recurrence [Garg, 2004]. Patient age under 40 years was also found to be a risk factor for locoregional recurrence in this series. Downstaging through neoadjuvant chemotherapy therefore does not appear to lead to a better local control [Bucholz, 2003, Huang 2004]. It therefore seems justified to recommend postoperative radiotherapy for patients who have a pN1 classification (1-3 positive axillary nodes) after neoadjuvant chemotherapy.

 

Regional treatment

The location and extent of treatment of the regional node areas after neoadjuvant systemic therapy is even less clear than with operated primary breast cancer. Whether or not regional metastases are present is of prognostic importance. As downstaging may occur after neoadjuvant systemic treatment, it is recommended to document the regional node status using cytological punction of clinically suspect nodes or those that appear suspect on an ultrasound and/or SN procedure prior to starting neoadjuvant treatment. Similar to primary operated disease, the number of regional recurrences after neoadjuvant treatment is noticeably small. In a review and retrospective analysis of more than 4,000 patients from the MDAH, an axillary recurrence percentage of 1% was found, and literature was cited with axillary recurrence percentages between 1.0 and 2.1% after surgery and between 0.8 and 3.1% after radiotherapy. [Newman, 2000]. In a French study of 250 patients (including 100 with clinically palpable axillary nodes) who were exclusively treated with neoadjuvant chemotherapy and radiotherapy, there were only 6 axillary node recurrences (2.4%) [Jacquillat, 1990]. There are no randomised trials that have researched the optimal treatment of regional node areas after neoadjuvant systemic therapy. The guideline development group is therefore of the opinion that standard treatment (as if no neoadjuvant treatment was administered) must be followed.

 

The standard for primary operable disease (stage I, II: cT1-2N0-1 or cT3N0) is:

  • no regional treatment in the case of negative axillary/SN
  • ALND or radiotherapy in the case of a positive SN
  • ALND in the case of non-identified SN or primary positive nodes (cN1)

Postoperative locoregional radiotherapy is indicated if more than 3 tumour-positive nodes are found during ALND.

 

Locoregional radiotherapy was the standard treatment for breast cancer with locoregional metastasis (stage III, (cT3N1; cT4N0-1; cT1-4N2-3) in the 60’s, because (modified) radical mastectomy gave extremely poor results in the area of survival and locoregional control [Haagensen, 1963;Dahl Iversen, 1963; Kaae, 1963]. While mastectomy with ALND was performed in many phase II studies on neoadjuvant chemotherapy in order to determine the pathological CR rate, there is no evidence on the therapeutic value of doing so. An ALND is of course unable to provide a useful benefit to treatment of demonstrated node metastases in the periclavicular node area of the parasternal node chain (N3). Axillary nodes fixed together or to the chest wall may be treated with an ALND but postoperative radiotherapy is almost certainly indicated in such a situation because it usually involves more than three tumour-positive nodes. The disadvantage of ALND plus postoperative regional radiotherapy is that this combination increases arm and shoulder morbidity [Larson, 1986; Ryttov, 1988].

 

Remaining considerations:

An ALND may be considered in the case of downstaging N2 disease to yN1, in order to reduce the tumour load prior to radiotherapy. With this treatment plan, Kuerer found only 3 axillary recurrences in a series of 191 patients with initially node-positive stage III breast cancer [Kuerer 1998, 1999]. He suggested that a choice could be made between ALND or radiotherapy in the case of an axillary that has become clinically negative.

 

It seems sensible to only treat the parasternal node chain if a parasternal node metastasis has been demonstrated using a pathologically proven SN metastasis or has been shown to be probable on the basis of an increased uptake of an FDG-PET-CT.

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.