This document is an excerpt of an outdated breast-cancer guideline (2002).

Chapter 3

[ Locally advanced breast cancer]

[ Introduction]

In the past, locally advanced breast cancer was synonymous with unresectable breast cancer. During the 1950s, criteria for unresectability were formulated by Haagensen et al.1 In particular, signs of unresectability included the presence of oedema of the skin (peau d’orange), ulceration, satellite skin nodules, inflammatory breast cancer (T4), palpable axillary lymph nodes fixed to one another or to the chest wall (N2), palpable infraclavicular, supraclavicular or internal mammary lymph nodes (N3) or lymphoedema of the arm (caused by tumour growth). Patients with this stage of disease underwent radical mastectomy and had a poor prognosis with a high risk of locoregional recurrence.

In addition, Haagensen carried out the triple biopsy in patients with clinically operable disease which consisted of taking lower axilla, infraclavicular and internal mammary biopsies.2 If the internal mammary or infraclavicular biopsy was tumour-positive, the prognosis was as poor as that of clinically inoperable patients, and these cases were therefore also considered to be inoperable. The infraclavicular biopsy was applied as an operability criterion up until the 1990s in some parts of the Netherlands, and was also found to predict a negative prognosis comparable with that of clinically inoperable disease.3-5

Initially, the main aim of treatment for locally advanced breast cancer was to control the local disease with minimal mutilation, and patients were therefore treated solely with radiotherapy. During the 1970s and 1980s, it was hoped that adjuvant systemic therapy might improve the prognosis, and so the treatment became more intensive. Neoadjuvant systemic therapy and surgery were also added to the treatment options to improve the disappointing locoregional control achieved.6 With the increasing intensity of treatment (chemotherapy, surgery, radiotherapy, hormone therapy) for both locoregionally advanced tumours and those with more than four involved nodes and which had been operated on, the role of the infraclavicular biopsy generally lost its value as a staging tool.

Neoadjuvant chemotherapy reduced the size of some initially unresectable tumours, making them suitable for breast-conserving surgery. Nowadays, large local tumours (> 5 cm; T3) with no further clinical signs of unresectability are also included in the category of locally advanced breast cancer, and treated with neoadjuvant chemotherapy, surgery, radiotherapy and hormone treatment (if hormone receptor-positive).6-8

A supraclavicular palpable node metastasis was previously considered to be a distant metastasis (M1) by the UICC TNM classification.9 However, according to the new classification system (2002, appendix 1 ) it is considered to represent regionally advanced disease (N3c). This reflects the fact that patients in this stage of the disease usually receive the same treatment as other patients with locoregionally advanced disease, providing there are no synchronous distant metastases. This is so as to achieve optimal locoregional control.

 

Definition

Locoregionally advanced breast cancer is used to describe breast cancer which is unresectable on the basis of the classic unresectability criteria: oedema of the skin (peau d’orange), ulceration, satellite skin nodules, inflammatory carcinoma, infiltration of the chest wall (T4), lymph nodes fixed to one another and/or to deeper structures (N2), or palpable internal mammary, parasternal, infraclavicular and/or supraclavicular lymph nodes (N3) In addition, large primary tumours (> 5 cm; T3) are also included in this category (T3, T4 all N classes, M0; all T classes, N2 or 3, M0).

 


[3.1 Diagnostic procedures]

The diagnostic work-up for locoregionally advanced breast cancer does not, in principle, differ from that of earlier stages of breast cancer. The tumour is usually clinically palpable and accessible for radiographic diagnostic investigations and fine-needle aspiration cytology (FNAC). Since the treatment of choice is usually neoadjuvant chemotherapy, and since it may not be possible to collect live tumour tissue after chemotherapy, it is advisable to establish a histological diagnosis by means of a core biopsy, where the hormone receptor status and other prognostic characteristics can also be analysed . It is also advisable to confirm the presence of lymph node metastases with (possibly ultrasound-guided) FNAC.

For locoregionally advanced disease, the risk of synchronous distant metastasis is greater than for an earlier stage of breast cancer. 10-12 In the presence of synchronous distant metastases, the nature and intensity of the multidisciplinary treatment may vary. The treatment choices depend on the nature and prognostic significance of the locoregional situation and the distant metastases, and should be made on an individual basis within a multidisciplinary setting. Therefore, a staging investigation consisting of a chest X-ray, skeletal scintigraphy and ultrasound of the liver to rule out synchronous distant metastases, is recommended.

 

[3.2 Treatment]

Locoregionally advanced breast cancer is a perfect example of a disease in which multidisciplinary treatment is indicated. The prognosis of a patient with locoregionally advanced disease is poorer than that of a patient with early disease. The five-year survival rate is 40-60%, and the 10-year survival rate is around 25%, depending on the tumour load. The possibility of curing the disease is not excluded, and treatment is with curative intent. Inflammatory breast cancer, characterised by diffuse redness, peau d’orange and possibly swelling of the entire (or at least more than a third of the) breast (TNM classification T4d), represents a separate category. This form of breast cancer has a five-year survival rate of 20-25%. Current treatment of locoregionally advanced breast cancer consists of neoadjuvant chemotherapy, followed by some degree of surgery and locoregional radiotherapy. If the tumour is hormone-receptor positive, subsequent adjuvant hormone therapy is advised.

The development of the current treatment recommendations for locoregionally advanced breast cancer must be considered within the context of the historical development outlined above. During the first half of the twentieth century, radical mastectomy was the standard treatment for breast cancer, in addition to relatively inadequate radiotherapy. Haagensen’s criteria for unresectability were introduced because it had been found that patients who fulfilled these criteria had a very poor prognosis in terms of survival, as well as poor locoregional control following mutilating (Halsted’s) mastectomy. More or less intensive locoregional surgery (even with internal mammary and/or supraclavicular lymphadenectomies) made no difference in this respect.2,13,14 For that reason, radiotherapy alone was chosen with the aim of controlling the locoregional disease until death, with minimal mutilation. Radiotherapy alone achieved five-year survival rates of 30-40%, clinically complete response rates of 70-90% and a permanent locoregional control rate of 50-80%.5,15-18 The development of chemotherapy during the 1970s gave rise to the hope of improving survival with (neo)adjuvant chemotherapy.

 

3.3 [ Systemic treatment]

The five randomised clinical trials which investigated the value of adjuvant and/or neoadjuvant treatment compared with locoregional treatment alone for unresectable locoregionally advanced breast cancer, could find no survival benefit,19-23 not even in the long-term.24,25 EORTC trial 10972 only found a long-term survival benefit for adjuvant hormonal treatment, but not for chemotherapy.25 The Danish Breast Cancer Cooperative Group(DBCG) trial 77B should also be discussed here. This trial examined the addition of CMF chemotherapy to mastectomy and radiotherapy in high risk patients (T3 and/or N+). Although these were stringently selected patients with resectable disease, a large proportion would fall into the locoregionally advanced category according to the current criteria (refer to the above definition). In this trial, a survival benefit was found with chemotherapy, which nevertheless decreased as the disease became more advanced.26 Another (far smaller) trial randomised patients with inoperable breast cancer to hormonal and chemotherapeutic adjuvant treatment, and found no difference in five-year disease-free survival. 27 One trial compared neoadjuvant hormonal and chemotherapeutic treatment. Apart from a higher response rate with chemotherapy, no differences were found.28 Two trials investigated the addition of hormonal treatment to a combination of chemotherapy, radiotherapy and surgery. These studies found no improvement in survival, but the follow-up periods were relatively short.29,30 Two trials comparing different chemotherapy regimens also failed to detect any differences.31,32 Nor has any benefit been found in randomised trials that compared high-dose chemotherapy and stem cell reinfusion with conventional (neo)adjuvant chemotherapy.33,34

One advantage of adding chemotherapy to locoregional treatment was that initial or neoadjuvant chemotherapy brought about good tumour regression, after which better locoregional control could be achieved with a combination of surgery and radiotherapy compared with just radiotherapy alone.6-8,35-44 In these studies, response rates with chemotherapy of between 40-85% were reported, with pathologically complete response rates of 15-25%, and five-year survival rates of 30-65%. The majority of the studies are retrospective studies from a single institute or prospective phase II studies. Three randomised trials compared neoadjuvant treatment with adjuvant chemotherapy before and after chemotherapy, respectively, and radiotherapy.45-48 These studies found that neoadjuvant treatment could increase the number of breast-conserving procedures, and improve locoregional control. Most of the studies used anthracycline-containing regimens, and these regimens appear to yield the best response rates compared with other regimens.34,38,40-44

In terms of the optimal number of courses of chemotherapy, many different regimens appear to be in use: ranging from a total of four to 27 courses (median 7), two to nine of which are neoadjuvant (median 4).19,30-32,39-41,43-51 In three studies, neoadjuvant chemotherapy was given until a maximum response was achieved. 39,41,51 Schwartz et al. required a median of seven courses of CMF (range 3-14) to achieve maximum response,39 while Pierce et al. required a median of five courses of CAMFTE (range 4-11), 51 and Morrell et al. used a median of four courses of MVAC (range 3-5) in a study where they had decided at the outset not administer more than five courses.41 From these observations, it seems reasonable to deduce that four courses is insufficient to achieve maximum regression in the majority of patients. Six courses of neoadjuvant anthracycline-containing chemotherapy seems to be a sound recommendation, although in the absence of further regression between two and four courses, continuation with the fifth and sixth courses does not appear advisable.

Inter-study differences in patient selection make it difficult to interpret and compare both randomised studies and phase II studies, and retrospective studies. Some studies involve patients classed as inoperable according to the criteria defined by Haagensen. 8,16,17,22,23,32,35-37,40,41 Other studies, on the other hand, include patients from the same category and those with a tumour-positive infraclavicular biopsy.5,19,20,25,28,34 A number of studies comprise inoperable patients and those with a T3 tumour,6,24,38,39,42-44 or even operable high-risk patients (with T3 tumours and/or tumour-involved axillary nodes). 24,25,46-48,52 In addition to the differences in survival between these groups, there is also considerable variation in prognosis within the patient groups themselves. Furthermore, nowadays women appear to present for treatment with less advanced forms of cancer. In addition, in a number of the above-mentioned studies only the responders to neoadjuvant chemotherapy were analysed, which has resulted in a bias when comparing locoregional treatment studies. This relates to the high-dose chemotherapy trials, amongst others.33,34 These and other factors make it difficult to compare patient series from different periods. Nevertheless, it can be concluded that neoadjuvant chemotherapy increases the possibility of breast-conserving treatment compared with locoregional treatment alone. Adjuvant hormone therapy has been found to yield a survival benefit for both resectable and unresectable locoregionally advanced breast cancer.25 There is insufficient evidence of a survival benefit with neoadjuvant chemotherapy for unresectable disease, but for operable high-risk breast cancer a survival benefit does seem to exist.26

 

[ Conclusions]

 

 

Grade 1

 

[ Neoadjuvant chemotherapy increases the possibility of breast-conserving treatment for locoregionally advanced breast cancer], and [improves locoregional control ].

 

 

[A2 Powles,47 Mauriac48,52 ]

 

Grade 1

 

[There is insufficient evidence of a survival benefit with (neo)adjuvant chemotherapy for unresectable breast cancer ].

 

 

[A2 Schaake-Koning,19 Koning,24 Derman,21 Rubens,20 Bartelink25]

 

 

Grade 3

 

[ Anthracycline-containing chemotherapy results in higher response rates than other forms of chemotherapy] .

 

 

[C Kuerer44]

 

 

Grade 3

 

[ Adjuvant hormone therapy for locally advanced breast cancer results in improved survival in the long-term ].

 

 

[A2 Bartelink25]

 

 

 

3.4 [ Locoregional treatment]

As for neoadjuvant chemotherapy, sufficient evidence regarding the optimum [ locoregional therapy] for locoregionally advanced disease does not exist. Haagensen’s unresectability criteria were developed because surgery alone (even when very extensive) was not sufficient to achieve an acceptable survival rate or locoregional control, and radiotherapy alone also resulted in inadequate locoregional control, particularly with a high tumour load.5,13,14 Therefore, in addition to neoadjuvant chemotherapy, [ a combination of surgery and radiotherapy] is usually chosen. Two randomised trials have been carried out in which surgery was compared with radiotherapy following neoadjuvant chemotherapy.49,53 In these trials no difference in (disease-free) survival was found between the two locoregional forms of treatment. Two other trials randomised patients to additional radiotherapy or no radiotherapy after (neo)adjuvant chemotherapy and surgery.50,54 These studies also found an improvement in locoregional control but no difference in survival between the two treatment arms. In fact, there was a trend towards poorer metastasis-free survival in the radiotherapy arm. It is appropriate to discuss the Danish and Canadian trials in this context, where patients were randomised to radiotherapy or no radiotherapy after surgery and chemotherapy in (operable) high-risk patients (T3 and/or N+).55-57 These trials revealed a benefit in terms of locoregional control and survival in the radiotherapy arm. The recent meta-analysis of radiotherapy trials also found a three-fold reduction in the risk of locoregional recurrence.58 This improvement in locoregional control also leads to a better breast cancer-related survival, which appears to be partially negated by the increased long-term cardiovascular mortality. Since breast cancer-related mortality is more important in the case of locoregionally advanced disease than, for example, cardiovascular mortality (particularly in the long term), the benefit of radiotherapy in this group of patients may be relatively greater.

There is no level A evidence for the importance of surgery in locoregional control or (disease-free) survival of locoregionally advanced disease. There are, however, strong indications that locoregional control after radiotherapy increases as the tumour load decreases.5,15-17 This can be achieved by neoadjuvant chemotherapy and removal of the residual tumour or mastectomy. Although some recommend treating residual tumours up to 10 cm in size with radiotherapy alone, most authors do advise removing the residual tumour surgically prior to radiotherapy.51,59-62 Precisely how radical the surgery should be is unknown. Although axillary node dissection can still yield prognostic information after neoadjuvant chemotherapy, it is unclear whether it will be of any therapeutic relevance.63,64 In an NSABP trial where patients were randomised to radical mastectomy or total mastectomy with or without regional radiotherapy, no difference in survival or disease-free survival could be found in either patients with clinically negative axillae or those with clinically suspect axillae.65 In a French study of 250 patients (including 110 with clinically palpable axillary nodes) who were treated solely with neoadjuvant chemotherapy and radiotherapy, only six axillary recurrences developed.66 This suggests that axillary radiotherapy, particularly if the axilla is clinically negative, can achieve sufficient axillary control. It is known that combining complete axillary node dissection with radiotherapy increases the toxicity of the treatment.67,68 It therefore seems reasonable to recommend exercising restraint with regard to axillary surgery in the case of a clinically negative axilla.

Inflammatory breast cancer (T4d) represents a separate problem. In view of the diffuse invasion of the lymph system beneath the skin in this form of breast cancer, it is by definition unresectable. Although the redness and peau d’orange often decrease rapidly after chemotherapy, the chance of non-radical resection remains high even after radical mastectomy. Some authors therefore recommend just chemotherapy and radiotherapy for this group of patients.69 Other studies have reported a benefit with the addition of surgery following neoadjuvant chemotherapy and radiotherapy.70-72 Yet others have found that the benefit in local control exists solely in patients who respond well to chemotherapy.73-75

The difficulty in interpreting these types of studies is that there is always some degree of selection bias.

There is therefore insufficient evidence to recommend the standard addition of a mastectomy to the chemotherapy and radiotherapy regimens.

 

[ Conclusions]

 

 

Grade 1

 

[For resectable locally advanced breast cancer, radiotherapy following chemotherapy and surgery can reduce the risk of locoregional recurrence by a factor of three ], [and can thereby improve the disease-related survival ] .

 

 

[A1 EBCTCG58]

[A2 Overgaard,55,57 Ragaz56 ]

 

 

Grade 3

 

[For classic unresectable locoregionally advanced breast cancer, radiotherapy has been found to bring about an improvement in locoregional control], [but no survival benefit ].

 

 

[A2 Papaioannou54]

 

 

Grade 2

 

[There is no randomised evidence to indicate a beneficial effect when adding surgery to neoadjuvant chemotherapy and radiotherapy ]. In view of the poorer locoregional control after radiotherapy alone as the tumour load increases, [ resection of the macroscopic residual tumour following neoadjuvant chemotherapy would appear to give better locoregional control ] .

 

 

[B Thomas,17 Pierce,51 Fisher65 ]

 

 

Grade 3

 

[In the case of inflammatory breast cancer (T4d), there is insufficient evidence to support the standard addition of surgery to chemotherapy and radiotherapy].

 

 

[C de Boer,69 Perez,71 Fleming72 ]

 

 

 

Other considerations

As mentioned above, during the last decades of the twentieth century, the general attitude towards treatment of locoregionally advanced disease changed from a defeatist attitude (‘ensure that these patients with a poor prognosis suffer from their disease as little as possible until their death, with as little as possible/non-mutilating treatment’) to an optimistic approach (‘try everything to achieve a maximum chance of cure and/or progression-free survival’). As outlined above, the present, more aggressive, approach has not yet been supported in terms of a survival benefit. Although wanting to try everything and to investigate new options in prospective studies is certainly justifiable, a [ less aggressive approach] is not, by definition, wrong. Strictly speaking, there is no age limit for neoadjuvant chemotherapy, but in patients with comorbidity or those who are elderly and vulnerable or who do not wish chemotherapy, a [combination of hormone therapy and locoregional treatment] is perfectly justifiable. Two randomised trials have been carried out which investigated the sequence of locoregional treatment and hormone therapy. Both trials found no difference in survival.76,77

Any tumour with clinical invasion of the skin requires multidisciplinary treatment comprising surgery, radiotherapy, chemotherapy and (for positive hormone receptors) hormone therapy. For small, operable tumours which have invaded the skin, in individual cases the sequence of the different treatment modalities can be changed from that described above.

 

[ Recommendations]

Patients with locoregionally advanced breast cancer should receive multidisciplinary treatment with [ curative intent]. [ The treatment should comprise the following components ]:

·             [Neoadjuvant chemotherapy, preferably ] [six courses containing anthracycline].

·             Surgery [to reduce the tumour load]. [It is unclear whether limited or radical surgery is better ]. [In case of a clinically negative axilla, omission of axillary node dissection appears justifiable].*

·             [Locoregional radiotherapy ].

·             [Hormonal adjuvant treatment, if the hormone receptors are positive].

 

*[ For inflammatory breast cancer, the role of surgery in addition to neoadjuvant chemotherapy and radiotherapy is unclear].

 

[Since there is no evidence to suggest that the above-mentioned intensive multidisciplinary treatment yields a better survival than less intensive treatment], [less intensive alternatives can be offered to the patient in the presence of concomitant circumstances which may form a relative contraindication to (parts of) the multidisciplinary approach] .

 

Supportive care, provision of information

As with early stage breast cancer, receiving the diagnosis of locoregionally advanced disease is an important and emotional event. The prognosis is poorer than for early stage breast cancer. An additional staging investigation is recommended and should be explained. Various issues need to be discussed over the course of a number of meetings, preferably in the presence of a partner or a trusted person. The patient should be given the opportunity to ask additional questions and the assistance of a breast care nurse can be extremely helpful in this respect. The team of carers should bear in mind that the patient may require psychological support during, but particularly after the treatment when the patient is required to carry on alone after a prolonged period of daily medical care. The patient should be aware of that she can contact fellow breast cancer sufferers through workgroups of the Dutch Association of Comprehensive Cancer Centres and the Dutch Breast Cancer Association, and she should also be informed of the possibility of obtaining leaflets and written information.

The following aspects should be included in the information provided to patients:

·             The treatment is of curative intent and although there is a risk of the disease recurring after treatment, there is also a good chance of prolonged remission and even cure.

·             The treatment is intensive to minimise the risk of local recurrence of the tumour .

The side-effects of the treatment modalities should be discussed. In the case of multidisciplinary treatment, special attention should be paid to those side-effects which are more likely to occur as the result of combining treatment modalities, such as the possibility of more severe skin reactions to radiotherapy following anthracycline-containing chemotherapy and the increased risk of lymphoedema and shoulder problems in the longer term after combining axillary radiotherapy and surgery.

 

Communication

 

With the patient

Given the multidisciplinary nature of the treatment and that the patient therefore has to deal with various specialists, it is highly important that there is good collaboration within the team to ensure the patient does not receive contradictory information. It is preferable that the specialists from the various disciplines are acquainted with the patient before treatment starts, to make the patient feel more comfortable. Coordination of the treatment by one specialist is desirable. The breast care nurse can play an important role here by coordinating the communication between the various doctors and the patient.

 

In-hospital

As for all oncology patients, it is preferable that the cases of patients with locoregionally advanced breast cancer are discussed during a multidisciplinary meeting. As a minimum, the team should comprise a surgical oncologist, a radiation oncologist and a medical oncologist, and preferably also a pathologist, a diagnostic radiologist and a breast care nurse.

 

Transmural

The general practitioner should be informed of the complex treatment of locally advanced breast cancer and of its curative intent.

 

Continuity of care

The multidisciplinary treatment of locoregionally advanced breast cancer is very time-consuming. Once the treatment has ended, there is a risk of the patient becoming depressed, when she realises the full impact of the disease and feels abandoned. As a first step, it is therefore advisable to make an appointment very soon after the last treatment visit, and to be watchful for these signs. Since radiotherapy is usually the last treatment step, the first appointments can also be used to assess the acute (skin) toxicity of the radiotherapy. Thereafter, the follow-up does not differ to that of operable disease, with the understanding that the risk of recurrence and metastasis is higher (refer to chapter 4 ).

 

Distribution and centralisation of care, infrastructure

As outlined above, the treatment of locoregionally advanced breast cancer requires good multidisciplinary collaboration. No specific infrastructure is necessary, but good communication between those making the diagnoses and those treating the patient in the various disciplines is required, preferably in the form of structured weekly discussions.

 

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