Question

What is the role of FDG-PET-CT of PA-proven breast cancer?

Recommendation

FDG-PET-CT can replace conventional staging for primary breast cancer (skeletal scintigraphy, ultrasound of the liver, chest X-ray and/or CT).

 

FDG-PET-CT is recommended with stage III primary breast cancer.

 

FDG-PET-CT may be considered with stage II primary breast cancer within the framework of neoadjuvant treatment.

 

Aside from local conventional imaging, FDG-PET-CT may be considered as an additional procedure in the case of complaints that are suspicious for locoregional recurrence or distant metastases.

 

In patients with a positive axillary node on FDG-PET-CT as unexpected finding, the chance of lymph node metastasis is high and additional ultrasound examination with punction is indicated.

 

In relation to the large chance of false positive findings, the guideline development group is of the opinion that in case of small aspecific abnormalities on FDG-PET-CT these should be disregarded and treatment can remain curative in intent.

Conclusions

 

Level 3

The sensitivity of FDG-PET(-CT) is too low for detection of a primary breast cancer.

 

C          AHRQ 2001

 

Level 3

FDG-PET(-CT) does not play a decisive role in staging of clinically negative axilla and cannot replace the SN procedure.

 

C          Cooper 2011

 

Level 3

Omitting the SN procedure and performing a direct ALND in patients with a positive axillary node on FDG-PET-CT, in which the procedure was performed for another reason, can be considered.

 

C          Cooper 2011, Aukema 2009

 

Level 3

FDG-PET(-CT) may potentially replace conventional staging.

 

C          Fuster 2008, Mahner 2008, Koole 2011

 

Level 3

In the case of (suspicion of) local, regional or distant metastasis of an invasive breast cancer, FDG-PET(-CT) has greater diagnostic value than conventional staging, with impact on treatment.

 

C          Pennant 2010, Isasi 2005, Fueger 2005, Dirisamer 2010

Literature summary

In asymptomatic patients without locally advanced disease, staging is largely limited to clinical examination. In patients with stage III breast cancer, staging is performed with imaging. So far, these patients usually undergo skeletal scintigraphy, ultrasound of the liver and chest X-ray [Aukema, 2009]. A relatively new technique is positron emission tomography (PET) with the glucose analogue F-18-fluorodeoxyglucose (FDG), currently often used in combination with computer tomography (CT). FDG-PET is an accurate technique in oncological practice in staging and re-staging of recurrent disease, in the detection of occult tumours and the evaluation of residual laesion after therapy [Juweid, 2006]. It is a non-invasive examination of the entire body. By combining anatomical and functional information, integrated PET-CT systems have a better accuracy than FDG-PET only or FDG-PET in combination with a separate CT for the detection of malignant abnormalities [Antoch, 2004, Poeppel 2009]. FDG-PET is highly sensitive for the detection of lytic skeletal metastases, but sclerotic laesions may be missed with this technique.

The CT component contributes to a higher specificity, also in the case of skeletal abnormalities.

The diagnostic value of FDG-PET-CT is greater in the staging and re-staging of patients with breast cancer than the value of FDG-PET or CT only [Fueger, 2005; Czernin, 2010]. FDG-PET-CT has gained an increasing role in recent years in the different diagnostic aspects of breast cancer.

 

Detection of primary breast cancer

The sensitivity of FDG-PET for the detection of subcentimetre laesions is low, approximately 57% [Lavayssière, 2009]. Avril (2000) had an overall sensitivity of 80.3% with 144 patients. The detection of T1 tumours was decidedly lower than for T2 tumours, 68.2% and 91.9% respectively. Fuster (2008) studied 60 patients with tumours > 3 cm. FDG-PET-CT detected all laesions but FDG-PET-CT visualised only 14 of the 19 multicentric and/or multifocal tumours compared to MRI. The relatively limited spatial resolution of PET and the variable uptake of FDG in breast tumours play a role in this moderate result. Well-differentiated and slow growing tumours have a lower metabolic activity and , as a result, are more often false negative. FDG-PET therefore has a higher sensitivity for invasive ductal carcinoma than for invasive lobular carcinoma. Non-invasive tumours such as ductal and lobular carcinoma in situ (DCIS and LCIS) generally have a low uptake of FDG or are even negative. There is a correlation between uptake and aggressiveness of the tumour [Lavayssière, 2009]. In a group of 116 tumours, Kumar (2006) found that smaller tumours (≤ 1 cm) and low-grade were powerful independent predictors of false-negative examinations. In a systematic review of 13 studies (n=16-144/study), in which an FDG-PET was performed in patients with suspected breast cancer, FDG-PET had a (predicted) sensitivity of 89% and a (predicted) specificity of 80%. The (individual) risk of a false negative result was too great to omit a biopsy in patients with a negative FDG-PET [AHRQ, 2001]. The sensitivity of the examination is therefore too low for detection of a primary breast cancer in routine staging.

 

Staging lymph nodes

Accurate staging of axillary nodes is important to determine the prognosis and select the right patients for additional treatment. Studies that have shown that the value of FDG-PET(-CT) in determining the axillary node status show a wide range of sensitivity and specificity. In a systematic review of 26 studies (n=2,591), an average sensitivity of 63% (95%CI: 52-74%) was found and an average specificity of 94% (95%CI: 91-96%) for PET or PET-CT [Cooper, 2011]. The average sensitivity was 11% (5-22%) for micrometastases (≤ 2 mm; 5 studies; n=63) and 57% (47%-66%) for macrometastases (>2 mm; 4 studies; n=111). FDG-PET(-CT) has a lower sensitivity and specificity than the SN procedure. Replacement of the SN procedure by FDG-PET may spare patients the negative effects of the SN procedure but results in more false negatives with a greater recurrence rate. In short, FDG-PET(-CT) does not play a meaningful role as standard non-invasive procedure during staging of clinically negative axilla. However, specificity is very high. The seven FDG-PET-CT studies in this review (n=862) have an average specificity of 96% (95%CI: 90-99%). On this basis, omitting the SN procedure and performing a direct ALND in patients with a positive axillary node on FDG-PET-CT, in which the procedure was performed for another reason, can be considered [Cooper, 2011; Aukema, 2009].

Detection of extra-axillary lymph nodes is important for lymph node staging and any adjustment that may need to be made to the treatment plan. Aukema (2010) found PET-positive extra-axillary lymph nodes in 28% (17/60) of patients with stage II-III breast cancer, of which 7 could be evaluated using ultrasound and were pathologically proven. Radiotherapy was adjusted in 7 patients (12%).

 

Staging – detection of distant metastases with primary breast cancer

A complete diagnostic work-up for the detection of distant metastases consisting of chest X-ray or CT, skeletal scintigraphy and ultrasound of the liver is not indicated for most patients with primary breast cancer stage I and II but is in fact indicated for patients with stage III breast cancer [Puglisi, 2005]. In a prospective study, Hoeven (2004) researched the value of FDG-PET in 48 patients with locally advanced breast cancer and negative conventional work-up. Metastases was suspected in 10 patients. Further work-up confirmed 4 metastases. Fuster (2008) conducted a prospective study with 60 patients with large (>3 cm) primary breast cancer and compared FDG-PET with conventional imaging. FDG-PET had a sensitivity and specificity of 100% and 98% respectively for the detection of metastases and conventional imaging of 60% and 93%. In a larger retrospective study, Mahner (2008) studied 199 patients with locally advanced breast cancer (n=69) or suspected recurrence (n=50). FDG-PET detected distant metastases with a sensitivity, specificity and accuracy of 87%, 83% and 86% respectively. For conventional imaging (chest X-ray, ultrasound of the abdomen and skeletal scintigraphy) this was 43%, 98% and 74% and for CT this was 83%, 85% and 84%. The diagnostic accuracy of FDG-PET for the detection of distant metastases is better than that of conventional imaging but comparable to that of CT. The diagnostic information provided by FDG-PET and CT was also found to complement each other in this study. This data suggests that one FDG-PET(-CT) examination may potentially replace conventional imaging [Koole, 2011].

 

Re-staging – detection of locoregional recurrence and distant metastases

Patients with a locoregional recurrence of breast cancer can sometimes still be treated with curative intent using surgery. The presence of distant metastases determines the treatment plan and prognosis to a large degree. That is why adequate detection of distant metastases is crucial. Isasi (2005) reported, in a meta-analysis of 16 studies and 808 patients, a median sensitivity of 93% and a median specificity of 82% for FDG-PET in the detection of recurring breast cancer (local, regional and distant). The pooled sensitivity was 90% (95%CI: 87%-93%) and the pooled percentage of false positives was 11% (95%CI: 7%-15%), after excluding outliers.

In a systematic review of 28 studies, Pennant (2010) studied the value of FDG-PET(-CT) in the detection of recurring breast cancer (local, regional or distant). The size of the studies varied from 10 to 291 patients (median 45). FDG-PET had a significantly higher sensitivity and specificity for the detection of locoregional recurrence and distant metastases compared to conventional imaging, 89% and 93% versus 79% and 83% respectively. FDG-PET-CT had a significantly higher sensitivity compared to CT (95% versus 80%) but not a significantly higher specificity (89% versus 77%). FDG-PET-CT had a significantly higher sensitivity compared to FDG-PET (96% versus 85%) but the specificity was not significantly higher (89% versus 82%). FDG-PET and FDG-PET-CT (the latter on the basis of 1 study) showed no significant difference in sensitivity or specificity compared to different MRI techniques. The overall sensitivity, on a patient basis of FDG-PET-CT (n=5) and FDG-PET (n=25), was 96% (95%CI: 89%-99%) and 91% (95%CI: 86%-94%) and the overall specificity was 89% (95%CI: 75%-95%) and 86% (95%CI: 79%-91%). It should be noted that the evaluated studies were generally small and retrospective. In addition, subgroup analysis was conducted on all studies and not only on comparative studies.

This data suggests there is a higher diagnostic accuracy for the detection of locoregional recurrence and distant metastases when FDG-PET is added to conventional imaging.

 

FDG-PET-CT has added diagnostic value compared to FDG-PET and CT only, in the detection of recurring breast cancer. Change in the treatment plan varied in the different studies from 11% to 74% (median 27%). These changes include (not) starting hormonal therapy and chemotherapy. In three studies, change in the treatment plan was only scored if this change was a direct result of FDG-PET(-CT) examination. Estimations of the frequency in change varied in these studies from 11 to 25%.

 

It can be concluded from the review by Pennant (2010) that it is still too early to fully replace conventional staging by FDG-PET-CT. FDG-PET-CT already appears to be justified when metastatic disease is suspected after unclear findings on conventional imaging. FDG-PET-CT also appears to be valuable as an addition to current practice when a recurrence is suspected.

Dirisamer (2010) found a higher sensitivitiy (93%) for FDG-PET-CT compared to FDG-PET (84%) and CT (66%) only in 52 patients with a suspected recurrence (regional and distant). FDG-PET-CT was correct in 96% of patients, FDG-PET in 85% and CT in 73%. All missed laesions on CT concerned lymph nodes (< 10 mm).

 

In a study in the Netherlands, the impact of FDG-PET-CT on treatment was evaluated in 56 patients with proven locoregional recurrence [Aukema, 2010]. FDG-PET-CT detected additional tumour locations in 32 patients (57%). Distant metastases were detected in 11 patients using conventional imaging and in 23 patients with FDG-PET-CT (significant difference). FDG-PET-CT detected additional laesions in 25 patients (45%) that were not visible with conventional imaging. FDG-PET-CT had an impact on the treatment plan in 27 patients (48%) because more extensive locoregional disease or distant metastases were detected. Extensive surgery was prevented and a switch made to palliative treatment in 20 patients (36%). The sensitivity, specificity, accuracy, PPV and NPV of FDG-PET-CT were 97%, 92%, 95%, 94% and 96% respectively. Aukema concludes that FDG-PET-CT added to conventional imaging plays an important role in the staging of patients with locoregional recurrence.

Considerations

An increasing number of hospitals in the Netherlands are performing FDG-PET-CT. Due to collaboration agreements, the modality is available to all patients.

At almost all locations, this leads to replacement of conventional staging by FDG-PET-CT, both for stage III and IV breast cancer, for neoadjuvant therapy and if a (local, regional or distant) recurrence is diagnosed or suspected.

This has consequences for treatment of the patient, despite the fact that there is still no literature data on long-term results. Due to the high sensitivity and specificity of FDG-PET-CT for axillary lymph node metastases, the procedure also has consequences for recommendations for axillary node staging in the Netherlands. It is still too early to omit ultrasound and punction and immediately move across to axillary node dissection or for a binding recommendation for FDG-PET-CT. Aside from high sensitivity, many abnormalities are also found, which later do not appear to be due to metastases. A clear strategy has not yet been developed to deal with this, because a pathological diagnosis cannot always be obtained.

In relation to the large chance of false-positive findings in the case of small aspecific abnormalities on FDG-PET-CT, these should be disregarded and treatment can remain curative in intent.

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.