Question

Which choices do we have in neoadjuvant systemic therapy?

Recommendation

Neoadjuvant chemotherapy

  • The choice of chemotherapy depends on tumour characteristics, age and performance, in accordance with adjuvant chemotherapy
  • Neoadjuvant therapy consists of 6, to a maximum of 8 courses, in accordance with adjuvant schedules
  • Response evaluation should not take place earlier than after 3-4 courses, except if progression is evident at an earlier stage
  • The treatment plan with stable disease is to continue chemotherapy, because a pathological response may still occur
  • With evident progression during sequential anthracycline-taxane treatment (RECIST increase > 20% in largest diameter), an earlier switch must be made to a taxane
  • Locoregional therapy is indicated if there is evident progression while the patient is on a taxane-containing combination

 

Neoadjuvant hormonal therapy

  • Neoadjuvant hormonal therapy is an alternative to chemotherapy in elderly and fragile patients with hormone receptor-positive tumours.
  • If neoadjuvant hormonal therapy is chosen, aromatase inhibitors are preferable to tamoxifen for postmenopausal patients.
  • Locoregional therapy must generally be started after 3-6 months, no later than with a maximum response.

 

Neoadjuvant trastuzumab

  • The addition of trastuzumab to neoadjuvant chemotherapy must be considered for patients with HER-2-overexpression who are eligible for neoadjuvant chemotherapy

 

Additional adjuvant therapy (after locoregional treatment)

  • Continuing trastuzumab until one year after commencement
  • Continuing hormonal treatment until at least 5 years after commencement

Conclusions

Level 1

The neoadjuvant administration of first, second or third generation chemotherapy in patients with a primary operable or locally metastatic breast cancer (cT1c-4 and cN0-2) provides a disease-free and total survival that is comparable to postoperative administration of the same therapy.

 

A1        Mauri 2005, Mieog 2007

A2        Bear 2006

 

Level 3

There are no randomised studies available comparing neoadjuvant hormonal therapy with the same hormonal treatment postoperative.

 

Similar to chemotherapy, neoadjuvant hormonal therapy appears to make downstaging possible for hormone receptor-positive tumours, with an improved chance of radical surgery in stage III or BCT where mastectomy initially seemed necessary.

 

Comparison of the response percentage between neoadjuvant tamoxifen and aromatase inhibitor is in favour of the aromatase inhibitor for postmenopausal patients.

 

B          Eierman 2001, Smith 2005, Cataliotti 2006, Semiglazov 2007

C          Ellis 2001, Mlineritsch 2008, Takei 2008

  

Level 2

The addition of trastuzumab to neoadjuvant chemotherapy improves the pathological complete response percentage.

 

B          Buzdar 2005, Buzdar 2007, Gianni 2010

Literature summary

Neoadjuvant systemic therapy

Chemotherapy

In the overview by the Early Breast Cancer Trialists Collaborative Group [EBCTCG, 2005], it is demonstrated that adjuvant chemotherapy provides a clear survival advantage for stage II breast cancer. This has not been separately studied for tumours with locoregional metastasis (stage III), but systemic chemotherapy is generally accepted for this stage of disease. An essential question is whether neoadjuvant chemotherapy is at least as effective as adjuvant chemotherapy. Nine phase III studies were identified in a meta-analysis, in which a total of approximately 4,000 patients were randomised for the same chemotherapy, neoadjuvant versus postoperative adjuvant [Mauri, 2005]. However, most of these studies used first or at the most second generation chemotherapy schedules, sometimes in combination with endocrine therapy. Almost all studies included patients with a clinical stage T1-4N0-2. This meta-analysis did not find a difference in the survival rate (RR 1.0; 95%CI 0.90-11.2), or disease progression (RR 0.99; 95%CI 0.91-1.07).

Treatment plan if there is no response to neoadjuvant chemotherapy

The response rate after neoadjuvant chemotherapy is 80-90% and the risk of progression less than 5-10% [Kaufmann, 2006]. There is no clear treatment plan if there is progression (RECIST > 20% increase in diameter) during chemotherapy. The choice could be made to switch to local treatment earlier or to switch to an alternative, non-cross-resistant chemotherapy.

 

In the Gepartrio pilot study, patients with a clinical response after two courses of TAC neoadjuvant chemotherapy were treated with another four courses of TAC. Patients who had no clinical response after two courses were randomised between another 4 courses of TAC or switching to vinorelbine/capecitabine [von Minckwitz, 2005]. The patients with a clinical response after two courses had a pCR in 23% of cases. In 7.3% of cases, the clinical non-responders had a pCR when continuing with TAC, versus 3.1% in patients who already switched early to a non-cross-resistant schedule. Vinorelbine/capecitabine was found to be less effective than continuing with TAC in patients with stable disease. It therefore does not seem desirable to already determine after two courses that there is insufficient response to chemotherapy.

 

The Aberdeen study still achieved a 55% clinical response with non-responders (stable disease or progression) on second generation anthracycline-containing neoadjuvant chemotherapy when therapy was switched to docetaxel. The patients with a clinical response to anthracycline neoadjuvant chemotherapy also had a doubling in the pCR percentage (from 15% to 31%) and an increase in the five-year survival from 78% to 93% after switching chemotherapy to docetaxel. In the subgroup without clinical response to AC chemotherapy in the larger NSABP-B27 study, there was no advantage provided by the addition of docetaxel, while patients who did have a clinical response to the disease-free survival did improve significantly (HR 0.71) [Bear, 2006]. In an MD Anderson Cancer Centre (MDACC) study, 106 patients with insufficient response (residual tumour following surgery of more than 1 cm3) were randomised for postoperative continuation of the anthracycline-containing neoadjuvant schedule or switching to an alternative non-cross-resistance schedule (vinorelbine, methotrexate and 5-FU). The trend was better survival of patients treated with the alternative [Thomas, 2004].

Neoadjuvant hormonal therapy

Adjuvant hormonal therapy improves survival in both stage II and stage III breast cancer, as long as the tumour contains a positive oestrogen receptor and/or progesterone receptor [EBCTCG, 2005]. There is less known about the value of hormonal therapy in the neoadjuvant setting. No studies have been performed that compare preoperative and postoperative hormonal therapy. In relation to responders, it must be noted here that in contrast to chemotherapy, neoadjuvant hormonal therapy is added to standard adjuvant hormonal therapy.

 

A number of studies have been performed with neoadjuvant hormonal therapy, especially in postmenopausal patients. In a few phase II studies, clinical response percentages between 35 and 60% were found, but low pathological complete response percentages [Ellis, 2001; Mlineritsch 2008; Takei, 2008]. One phase II study randomised 180 patients between neoadjuvant exemestane, neoadjuvant anastrozole and neoadjuvant chemotherapy and found no difference in the chance of objective response (64%), chance of pathological response (3 vs 6%) and the possibility of breast-conserving surgery between hormonal therapy and chemotherapy [Semiglazov, 2007]. A few studies randomised between tamoxifen and an aromatase inhibitor. In the randomised IMPACT study, no significant difference was seen in the response rate between tamoxifen and aromatase inhibitor [Smith, 2005]. In two other randomised studies, the Letrozole P024 study and the much larger PROACT study, an aromatase inhibitor was found to give a somewhat better response percentage than tamoxifen [Eierman, 2001; Cataliotti, 2006]. In the last study, in which 451 patients participated, simultaneous administration of chemotherapy was permitted and administered to 44% of patients. The response percentages were comparable for patients who had only received hormonal therapy, or combined therapy. Similar to neoadjuvant chemotherapy, all studies mention resectability where this did not appear possible initially and/or breast-conserving surgery while a mastectomy had previously been planned.

 

Neoadjuvant trastuzumab

A few studies have been published in which the role of neoadjuvant trastuzumab has been researched [Buzdar, 2005; Kaufman, 2006; Chang, 2010]. A randomised study of the MDACC was closed after 42 patients because the aim had been achieved, namely improvement in the pCR percentage from 26.3% to 65.2%. The three-year recurrence-free survival increased from 85% to 100% (p=0,041) [Buzdar, 2005; Buzdar, 2007]. The Noah trial randomised 228 patients with locoregional metastatic (stage III) HER-2-positive breast cancer for neoadjuvant chemotherapy with or without trastuzumab [Gianni 2010]. The clinical response percentage improved from 71 to 87% and the pCR percentage from 19 to 38%. With a median follow-up of 3.2 years, the primary endpoint improved: an increase in the three-year disease-free survival from 56 to 71% (HR 0.59; 95%CI 0.38-0.90; p=0.013). In a series of 109 patients with demonstrated axillary node metastases prior to treatment, the axillary pCR percentage was found to be 74% after neoadjuvant chemotherapy with trastuzumab [Dominici, 2010].

Considerations

In many patients with an indication for adjuvant hormonal therapy, there is also an indication for chemotherapy. If a neoadjuvant setting is chosen due to irresectability of the locoregional disease or for the purposes of downstaging to better provide breast-conserving treatment, it seems logical to choose the therapy with the best response percentages. Chemotherapy appears to lead to better pathological response percentages than neoadjuvant hormonal therapy. While comparable response percentages in the randomised phase two trial of Semiglazov (2007) within this framework are intriguing, and although some suggest that the response percentages of hormone receptor positive, HER-2-negative tumours after chemotherapy would be worse than after hormonal therapy, there is insufficient evidence to date to make a positive choice for neoadjuvant hormonal therapy [Iwata, 2010]. Neoadjuvant hormonal therapy seems a good possibility in older and vulnerable patients. The optimal duration of neoadjuvant hormonal therapy is unclear (most studies report 3 to 6 months or more). Disease regression occurs slowly. One should strive for maximum regression and in any case not wait until the tumour is progressive again.

 

With a doubling of the pCR percentage, neoadjuvant treatment with trastuzumab has shown encouraging results compared to no trastuzumab. No studies have been performed to see whether neoadjuvant chemotherapy with trastuzumab is better than or equivalent to postoperative adjuvant chemotherapy with trastuzumab. It is therefore attractive to add trastuzumab neoadjuvant to chemotherapy in patients with HER-2-overexpression and indication for systemic therapy, in order to be able to perform breast-conserving surgery more often.

In the study by Buzdar (2007), trastuzumab was administered for a duration of 24 weeks. Local therapy (surgery/radiotherapy) was postponed until 24 weeks after diagnosis. Now that the standard total treatment duration is one year, it is unclear what the best timing of locoregional treatment should be after neoadjuvant treatment with trastuzumab. A delay in locoregional therapy until one year after diagnosis hardly seems attractive. In general, it is therefore recommended to commence local therapy after completing chemotherapy and to continue trastuzumab postoperatively as adjuvant treatment. The choice of neoadjuvant chemotherapy with HER-2 inhibition is in accordance with the adjuvant setting.

In a series of 142 patients with a pCR percentage of 50%, the HER-2 was determined again.In 8 of the 25 patients, in which it could still be measured, HER-2-overexpression could no longer be detected [Mittendorf 2009]. For the time being, it is still unclear whether and how determining the HER-2 status again in the definitive surgical sample should influence postoperative treatment. Given it does not have therapeutic consequences for the time being, renewed determination of the HER-2 status can be left out.

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.