Question

What is the contribution of chemotherapy to (disease-free) survival advantage in breast cancer patients?

Recommendation

The contribution of chemotherapy to (disease-free) survival advantage is limited in elderly patients with an ER+/low-stage breast cancer, especially if a second generation chemotherapy schedule is not possible due to comorbidity. With such dilemmas, Adjuvant Online may help in recommending only hormonal therapy for this category of patients.

 

Specific recommendations about:

Introduction

Adjuvant systemic chemotherapy and/or endocrine therapy is administered as a supplement to primary locoregional treatment, with the aim of eliminating any distant metastases (occult metastases) that may be present but cannot be detected yet. Many large randomised studies and a few important meta-analyses have shown that this form of treatment provides a clear contribution to the chance of curation of women with an early stage breast cancer [EBCTCG, 2005(1)]. The axillary lymph node status, the tumour size and grade, the age of the patient, and presence of HER2 overexpression are important for determining the risk of metastases. Aside from these classic prognostic factors, much research has been done in recent years on promising new prognostic factors that use the genetic profile of the tumour, enabling better characterisation of biological behaviour.

 

Each patient with primary operable breast cancer can, in principle, benefit from treatment with adjuvant systemic therapy. However, the chance of occult metastases is not the same for each patient. Risk profiling is necessary to distinguish patients with a good prognosis from patients with a poor(er) prognosis, with the aim of tailoring adjuvant therapy recommendations to the estimated prognosis.

Literature summary

In the past, treatment with adjuvant systemic therapy was recommended with an expected absolute ten-year survival advantage of at least 5%. The threshold for using adjuvant treatment was then placed at a ten-year chance of mortality of 20% or more, because the meta-analysis of the EBCTCG globally showed a 25% relative risk reduction in death with the adjuvant systemic therapies that were available at the time.

 

However, the effectiveness of current chemotherapy and hormonal therapy is greater. It appears from data from the meta-analysis of 2000 (published 2005(1)) that the 15-year relative risk reduction in death by anthracycline-containing chemotherapy, tamoxifen or the combination of both modalities is 20-57% (see below table).

 

Adjuvant systemic therapy is recommended if the absolute risk of a ten-year mortality is 15% or more. With the above mentioned relative reductions in the chance of death, the absolute chance of death is subsequently reduced by 4-5% for most categories of patients. For the chance of recurrence, the minimum condition is an absolute reduction of 10%. With current adjuvant treatments, this is almost always achieved at a chance of recurrence of 25% or higher.

 

There are various guidelines that may help with the treatment decision: St. Gallen, NCCN, and ASCO guidelines. The drawback is that none of these guidelines gives a quantitative impression of the (disease-free) survival advantage that can be expected for the treatment selected. In the programme Adjuvant!, an estimation is made of the prognosis and the effect of different treatment possibilities using patient and tumour-related characteristics [Ravdin, 2001(2)]. The program is validated in different large datasets, which  can be found at (www.adjuvantonline.com) [Olivotto, 2005(3)]. The basis  of this database is formed by SEER (Surveillance, Epidemiology and End Results) data with cancer-specific survival and recurrence curves based on data from the United States. The relative advantage through reduction in the risk of recurrence and death is derived from meta-analysis of the EBCTCG and has been processed in these curves, in order to arrive at age and tumour characteristic-dependant risk estimations.

 

The programme distinguishes three categories of chemotherapy schedules:

  • First generation schedules are 6 courses of CMF and 4 courses AC
  • Second generation schedules are 6 courses CAF, 6 courses FE100C/CE120F, 4 courses AC followed by 4 courses paclitaxel, and 4 courses TC (docetaxel, cyclophosphamide)
  • Third generation schedules are 6 courses TAC, 3 courses FE100C followed by 3 courses docetaxel, 4 courses AC followed by 4 courses docetaxel or 12 courses paclitaxel weekly and dose-dense (q 2 weeks) 4 courses AC followed by 4 courses paclitaxel

The second and especially third generation schedules have largely been studied with N+ patients.

 From the  hormonal interventions, tamoxifen or the combination of tamoxifen with ovarian ablation have been considered as equally effective in the premenopausal patient. For the postmenopausal patient, tamoxifen is considered as the first generation endocrine therapy and treatment with an aromatase inhibitor or the sequential treatment of tamoxifen followed by an aromatase inhibitor or an aromatase inhibitor followed by tamoxifen for a period of 5 years is considered as the second generation endocrine therapy.

 

The risk of death for HER2 overexpression and survival advantage for treatment with trastuzumab have not yet been included in Adjuvant!. In this guideline, the choice whether or not to undergo adjuvant treatment is based on the tables associated with this program, and for a large part corresponds with the 2011 St. Gallen criteria.

 

Eligible for treatment are:

  • all patients with N+ tumours, or
  • an unfavourable N0 tumour:
    • age < 35 years except a grade I tumour ≤ 1cm
    • age ≥ 35 years with a tumour of 1,1-2 cm and ≥ grade II or with a tumour > 2 cm
    • if there is HER2 overexpression in a tumour ≥ 0.5 cm independent of other characteristics, systemic therapy may also be considered

 

So far, most studies have been conducted in the general breast cancer population, in which the molecular heterogeneity of the disease has not been taken into account. On the basis of retrospective studies, hormone receptor status has been used as a guide for hormonal therapy since 2000. Developments are underway to develop tests using molecular techniques that may lead to a more personalised  treatment. A good example of this is determining HER2 overexpression in order to identify the group of patients who would benefit from the addition of trastuzumab to chemotherapy. In the future, tests might  become available indicating who will benefit from anthracyclins and who will benefit from taxanes.

References

  1. 1 - EBCTCG, (Early Breast Cancer Trialists’ Collaborative Group) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365(9472):1687-1717.
  2. 2 - Ravdin PM, Siminoff LA, Davis GJ, Mercer MB, Hewlett J, Gerson N, et al. Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. JCO 2001;19(4):980-991.
  3. 3 - Olivotto IA, Bajdik CD, Ravdin PM, Speers CH, Coldman AJ, Norris BD, et al. Population-based validation of the prognostic model ADJUVANT! for early breast cancer. JCO 2005;23(12):2716-2725.
  4. 4 - Bertelsen L, Bernstein L, Olsen J et al. Effect of systemic adjuvant treatment on risk for contralateral breast cancer in the Women's Environment, Cancer and Radiation Epidemiology Study. J Natl Cancer Inst 2008;100:32-40.
  5. 5 - Sideras K, Ingle JN, Ames MM, Loprinzi CL, Mrazek DP, Black JL, Weinshilboum RM, Hawse JR, Spelsberg TC, Goetz MP Coprescription of tamoxifen and medications that Inhibit CYP2D6. JCO 2010;28(16):2768-2776.

Considerations

The studies mentioned on the effects of adjuvant hormonal therapy (including chemotherapy-induced loss of ovarian function) found that such treatment lead to a significant reduction in the chance of contralateral hormone-positive breast cancer (relative reduction in the chance of 30 to 70 %) [EBCTCG, 2005(1); Bertelsen, 2008(4)].

 

In premenopausal patients with a hormone-sensitive breast cancer, inactivation of the ovarian function in combination with tamoxifen is an acceptable alternative if treatment with chemotherapy is not desirable (on medical grounds) or if the patient declines chemotherapy.
There is insufficient data indicating that variants in the CYP2D6 genotype influence the action of tamoxifen. It is therefore not recommended that the CYP2D6 genotype is determined outside of a research context.

 

Strong CYP2D6 inhibitors should be avoided in the use of tamoxifen. If an antidepressant is still desired, a drug should be chosen with as little inhibitory effect on CYP2D6 as possible. For selective serotonin reuptake inhibitors this concerns venlafaxine, escilatropam and mirtazapine [Sideras, 2010(5)].

 

The physician informs the patient about the possibilities regarding the choice of hormonal adjuvant treatment, taking the risk profile, types of hormonal treatments (upfront aromatase inhibitor versus sequential), side effects and the possibility of preventing osteoporosis into account. The physician and patient make a choice together.

 

The advantage of chemotherapy is especially limited in older patients with a (small) N0 tumour. If a second generation schedule is not possible due to comorbidity, Adjuvant! (AOL) may help in the decision to recommend hormonal therapy only in this category of patients.

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.