5. Recurrent or metastatic breast cancer – Breast Cancer
5.1 Definition and prognosis
5.1.1 Definition
Local or locoregional recurrences are: the recurrence of breast cancer in the ipsilateral breast, on the ipsilateral thoracic wall including the overlying skin, the regional lymph nodes of the axilla, the supra- and infraclavicular region and along the internal mammary vessels.
The local or locoregional recurrence can be isolated or in combination with distant metastases in other organ systems [926], [927].
Early detection of isolated local or locoregional recurrence has a positive influence on survival. Therefore, regular monitoring of local and axillary tumor freedom is an important task of aftercare. Accordingly, local/local-regional recurrences are mainly treated with curative (50-70%) and only about 30% with palliative targeting [928].
5.1.2 Incidence and prognosis
Local relapses after breast-conserving surgery and radiation occur with a frequency of 5-10% (after 10 years). The median 5-year survival rate is 65 (45-79)% [929]. Recurrences on the thoracic wall after mastectomy are observed in 4 (2-20)% and recurrences in the axilla in 1 (0.1-8)%. These patients show a 5-year survival of 50 (24-78)% and 55 (31-77)% respectively on [929]. Locoregional recurrences occurring simultaneously at different sites are observed with a frequency of 16 (8-19)% and are associated with a 5-year survival of 21 (18-23)% [930]. The course and biological behavior of the inbreast recurrence after BET and the local recurrence after MRM do not differ significantly [931], [932], [933], [934]. For both constellations the same prognostic factors for the clinical course are found without differences. In the event of a local recurrence, the primary prognostic factors continue to apply, differences exist only between "early" ( 2 years) local recurrences. The "early" recurrences can be cured to a lesser extent and are also correlated with a higher rate of secondary recurrence and distant metastasis [935], [936], [937], [938], [939].
Prognostic factors for the occurrence of local/local recurrence after MRM or BET:
- Number of lymph nodes affected
- Tumor size (maximum diameter)
- Grading
- Hormone receptor status
- Resection status (R0/R1/R2)
- Focality (unifocal > multifocal > inflammatory LR)
A local relapse or a locoregional relapse is treated locally. In operable cases, a complete excision of the recurrent tumor should be aimed for. Postoperative radiotherapy after extirpation may improve local tumor control [940]. If local tumor control is achieved with this therapy, long-term survival is possible [931]. In case of inoperability radiotherapy is the therapeutic procedure of choice [940]. Due to the high risk for a subsequent systemic progression a systemic therapy can be considered in addition to the local therapy of the recurrence (surgery and/or radiotherapy) [936]. The effect of systemic chemotherapy has not yet been proven by prospective randomized studies [936].
Prognostic factors for disease progression after local/local recurrence after MRM or BET:
- Resection status of the local relapse (R0, R1, R2)
- Tumor size of the local recurrence
- Localization (scars vs. far away from scars)
- Focus
- Grading
- Hormone receptor status
- Length of the disease-free interval
- primary lymph node status
5.2 Diagnostic for locale or locoregional recurrences
Mammography and breast ultrasound are to be used for the imaging clarification in case of suspected local/local recurrence - as in the diagnosis of primary breast carcinoma.
Breast MRI should be used if no sufficiently reliable diagnostic statement can be made with other methods with regard to the risk situation of the woman.
For the primary histological clarification of a locoregional recurrence, mammary sonography and minimally invasive biopsy methods are suitable.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2b
- Consensus
- Strong consensus
- References
- [28]
If distant metastases are suspected, they can be excluded by appropriate diagnostic measures.
In case of newly diagnosed breast cancer and the clinical suspicion of metastases, imaging staging should be performed.
As staging examinations, a contrast-enhanced CT (thorax, abdomen, pelvis) and a bone scintigram should be performed.
A PET-CT should only be used if there is a strong suspicion of remote metastasis in symptomatic patients using other methods and this metastasis cannot be reliably detected or ruled out.
Background 5.1 to 5.7
The goals of follow-up care are mentioned in Chapter 6. These include the diagnosis of curable local recurrence and locoregional recurrence.
Since there were different definitions of recurrence, an international consensus group was formed to define the different localizations of recurrence [945]:
- Local recurrence: Any epithelial invasive breast cancer and any DCIS in the ipsilateral breast or in the skin or subcutaneous tissue in the ipsilateral thorax
- Regional recurrence: Occurrence of the recurrence in the ipsilateral lymph nodes of the axilla and around the clavicle
- The locoregional recurrence summarizes the local recurrence and the regional recurrence.
In Germany the following constellations are called local or locoregional recurrences according to the previous S3 guidelines for early detection, diagnosis, therapy and aftercare of breast cancer:
The recurrence of breast cancer in the ipsilateral breast, on the ipsilateral thoracic wall including the overlying skin, the regional lymph nodes of the axilla, the supra- and infraclavicular region and/or along the internal mammary vessels.
In case of local and locoregional recurrence without distant metastasis there is usually a curative therapy chance. Factors for a good prognosis of patients with local and locoregional recurrence are age of the patient below 70 years, a finding as small as possible at diagnosis of the recurrence, a longer disease-free interval and the complete removal of the recurrence [946], [947], [948].
Early detection of these recurrences is therefore important. Patients in follow-up care after completion of locoregional primary therapy are therefore offered regular examinations to detect intramammary or locoregional recurrence as early as possible. At the same time the patient must be informed about the typical clinical signs of a local and locoregional recurrence [28], [31], [873].
After a mastectomy, a clinical and sonographic examination should be performed at least annually to monitor the ipsilateral thoracic wall and the regional lymph node stations. After breast-conserving therapy, regular mammography with supplementary mammary sonography is also recommended [28], [941], [949], [950].
Apparative diagnostics (mammography, sonography) to assess the ipsilateral and contralateral thoracic wall and axilla should be performed at least once a year.
Although in principle a stratification of the aftercare with regard to the imaging procedures used and the examination frequency according to individual risk constellation seems to be reasonable, there is no sufficient data available in the literature on this subject [951] Recommendations for the indication and implementation of the various diagnostic and interventional procedures for the primary diagnosis of breast cancer (see Chapter 4.2) can largely be transferred to the aftercare situation. There are differences, however, in that changes in the breast after surgery and radiotherapy can lead to limited assessability in mammography and sonography. If the differentiation between scarred and carcinomatous lesions cannot be made in mammography and sonography when a recurrence after BET is suspected, a magnetic resonance imaging (MRI) examination of the breast should be performed. As in the primary diagnosis of breast cancer, histological confirmation should be sought before determining the therapy in the case of recurrence - if technically feasible using percutaneous minimally invasive biopsy procedures.
If the recurrence is histologically confirmed, a mammography and sonography of the contralateral mamma should be performed as well as a re-staggering [28], [941]. This re-staggering comprises a contrast-enhanced computed tomography of the thorax and abdomen [234] and can be supplemented by a PET-CT if the suspicion of a distant metastasis cannot be confirmed or disproved by other diagnostic methods [234]. This re-staging is justified by the fact that before the start of therapy it must be assessed whether a curative or palliative therapy goal exists [952], [953].
5.3 Treatment of local/locoregional recurrence
5.3.1 Local (intramammary) recurrence
In case of a suspected diagnosis of a locoregional relapse, a histological backup with re-determination of ER, PR and HER2 and a complete re-staging should be performed first to exclude metastases and to enable the planning of an interdisciplinary therapy strategy.
- Consensus
- Strong consensus
In the case of intramammary recurrence (DCIS/invasive carcinoma), the secondary mastectomy provides the highest local tumor control.
- Consensus
- Strong consensus
If the initial situation is favourable, e.g. DCIS or invasive carcinoma with a long recurrence-free interval and no skin infestation, breast-conserving surgery can be performed again after careful clarification.
Before a new breast-conserving surgery, the possibility of re-irradiation (partial breast irradiation) should be examined, discussed in an interdisciplinary tumour conference and, if necessary, the patient should be introduced to a radiotherapist.
- Consensus
- Consent
In the case of breast-conserving surgery, the patient should be advised of an increased risk of a renewed intramammary recurrence.
- Consensus
- Strong consensus
Background 5.8 to 5.12
The therapy of intramammary local recurrence consists, if possible, in surgical intervention with the aim of R0 resection. The highest tumor control is achieved by mastectomy [932]. If organ preservation surgery is performed again, there is an increased risk of another intramammary recurrence. A renewed breast-conserving procedure can be performed if the initial position is favorable - DCIS or invasive carcinoma with a long recurrence-free interval or in the absence of skin infestation or a long distance from the primary tumor localization - [958]. The highest local control is achieved if the disease-free interval is over 5 years and if there are clearly negative resection margins during the renewed breast-conserving surgery [956], [959]. In the case of renewed breast-conserving surgery, local flap plasty, such as M. latissimusdorsi plasty, should be performed with restraint and after detailed explanation, since a survival disadvantage cannot be excluded and reduced cosmetic results are achieved. If the axilla is clinically unremarkable, a renewed axillary intervention after primary axillary dissection is not recommended. If no radiotherapy has been performed as part of the primary therapy, postoperative radiotherapy should be followed. After radiotherapy with initial breast-conserving procedure, in the recurrence situation with renewed local excision, repeated external radiation or local brachytherapy may be considered if necessary to reduce recurrence and avoid salvage mastectomy [954], [960], [961], [962].
Survival after local or locoregional relapse varies considerably. Proven independent and significant prognostic factors for survival with or without additional therapy are the disease-free interval and tumor mass of the relapse, multifocality, as well as the initial tumor stage and the time to metastasis [928], [963], [964], [965], [966], [967], [968]. Further prognostic factors are grading, resectability (R0 versus R1 versus R2), hormone receptor status and HER2 oncogene status of the recurrent tumor [928], [967], [969].
Patients should be informed and educated about the possibility of a renewed breast-conserving procedure under appropriate initial conditions. A local recurrence indicates the biology of the disease and the avoidance of salvage mastectomy does not necessarily mean a deterioration in overall survival.
5.3.2 Local recurrence after mastectomy
If possible, an isolated recurrence of the thoracic wall should be surgically removed completely (R0). If the ribs/intercostal muscles are affected, the decision on therapy should be made in interdisciplinary cooperation with thoracic surgery.
- Consensus
- Strong consensus
Background 5.13
The incidence of local/local recurrence after mastectomy depending on tumor biology is 9-20% [970], [971]. Among these, in about one third the recurrence is locally limited and - in decreasing frequency - manifested on the thoracic wall, in the supraclavicular region, in the axilla as well as in 10-30% multilocally [939], [964], [972], [973]. The complete excision of the tumor should be aspired. Small scar recurrences can be treated by wide excision in healthy individuals, larger thoracic wall recurrences by chest wall resections. In the case of larger chest wall excisions, covering the defect with skin flaps may be necessary. An interdisciplinary surgical procedure in cooperation with plastic surgery may be necessary. If an R0 resection is achieved, the 5-year survival rate is 40-60%.
If no irradiation has been carried out as part of the primary therapy, postoperative irradiation should be followed. In the presence of unfavorable risk factors, renewed small volume irradiation may also be indicated after recurrent surgery [974], [975].
In the presence of distant metastases, a renewed surgical intervention may be considered as palliative surgery of the local recurrence for pain, ulceration or for psychosocial reasons [976].
In case of symptomatic local recurrence (e.g. ulceration, pain), local therapy (surgical intervention, radiotherapy) can be considered even in the presence of distant metastases with the aim of reducing symptoms.
- Consensus
- Strong consensus
5.3.3 Axillary lymph node recurrence
In the case of an axillary lymph node recurrence, local control of the disease should be achieved by renewed surgical axillary intervention, if necessary with radiotherapy. Preoperatively, a CT thorax should be performed to extend the lymph node metastasis.
- Consensus
- Strong consensus
Background 5.15
Axillary recurrence occurs after axillary dissection or sentinel node biopsy in about 1%. The 5-year survival in axillary recurrence after axillary dissection is approximately 55% [929]. In case of recurrence after sentinel node biopsy the 5-year survival is significantly higher [977] with 93%.
For isolated locoregional recurrences, surgical rehabilitation is the method of first choice. If surgical treatment options for locoregional lymph node recurrences (in contrast to local recurrences) are limited or not curatively feasible, radiotherapy in combination with systemic therapy represents the most promising local therapy modality for tumor control, by which the chance of a cure can be maintained [978].
5.3.4 Pharmacological therapy
A systemic therapy after R0 resection of a locoregional recurrence should be considered for a prolonged disease-free interval as well as a prolonged overall survival.
- Consensus
- Strong consensus
Background 5.16
In principle, a locoregional recurrence like the primary disease is also to be considered a systemic disease and requires systemic therapy.
An additional systemic endocrine therapy after surgical therapy and R0 situation can extend the disease-free interval in patients with a hormone receptor-positive recurrence; however, the improvement of the survival rate is not proven [979], [980], [981], [982], [983], [984]. In case of hormone sensitive recurrences a postoperative endocrine therapy should be started or the current endocrine therapy should be changed. Possibly this will improve disease-free and overall survival.
The data on chemotherapy after isolated locoregional recurrence and surgical therapy is weak. However, the results of a prospective randomized study [985] are available. In the CALOR study patients with surgically free tumor margins after mastectomy or breast-conserving therapy and free margins were randomized to chemotherapy (n=85) or no chemotherapy (n=77) (1:1). The choice of chemotherapy was in the hands of the study centres, but should include at least two therapeutic agents and be carried out over 3-6 months. In case of positive estrogen receptors, adjuvant endocrine therapy was used. Radiation therapy was carried out on microscopically affected tumour margins. An anti-HER2 therapy was optionally available in case of positive HER2 receptor. The primary study objective was disease-free survival (DFS). Patients with metastases were excluded. After a median follow-up of 4.9 years, a 5-year DFS of 69% (95% CI 56-79) was observed in the group with chemotherapy and 57% (95% CI 44-67) without chemotherapy (HR 0.59, 95% CI 0.35-0.99), p=0.046). The benefit was significant with negative estrogen receptor and greater than with positive estrogen receptor of the local recurrence [ER negative: DFS 67% versus 35%, HR 0.32 (95% CI 0.14-0.73); ER positive: 70% versus 69%, HR 0.94 (95% CI 0.47-1.89)]. In terms of overall survival, the use of chemotherapy also showed a significant benefit for the overall collective. 5-year survival was 88% with chemotherapy versus 76% without chemotherapy [HR 0.41 (95% CI 0.19-0.89), p=0.024)], but there was no significant difference between the ER positive and negative subgroups. Even though the groups are small overall, the study shows a significant benefit from the use of systemic therapy after surgical rehabilitation. Thus, patients should be informed about the data situation, advantages and disadvantages should be weighed and the use of chemotherapy should be considered.
The data on chemotherapy after isolated locoregional recurrence and surgical therapy is clearly arranged. This is particularly true for patients with inadequate adjuvant primary therapy (e.g. trastuzumab-naive, HER2-positive patients, triple-negative patients). In case of a HER2-positive local recurrence a combination of chemotherapy and HER2-targeted therapy can be considered [985], [986].
If, in the course of a locoregional recurrence, R0 resection is unlikely and therefore the local findings are not operable, endocrine therapy should be initiated for endocrine responsive tumors (based on the immunohistochemistry of the local recurrence). In extensive thoracic wall recurrences, chemotherapy can improve local control. If necessary, surgical repair is possible afterwards. For HER2-overexpressing tumours, HER2-targeted therapy in combination with chemotherapy or anti-hormonal therapy (for Er+) should be considered (http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf Chapter Systemic treatment of recurrent or stage IV-breast cancer. BINV-17 version 3.2012).
5.3.5 Radiation therapy
Irradiation after recurrence surgery
Irradiation after recurrence surgery should be discussed and decided on on an interdisciplinary basis.
Postoperative radiotherapy should be performed if no previous radiotherapy had been performed or the local recurrence had not undergone radical surgery (R1-2).
- Consensus
- Strong consensus
Background 5.17
If no irradiation has been performed in the course of primary therapy, postoperative irradiation can be discussed. In the presence of additional unfavourable risk factors, small-volume irradiation may again be indicated even after adjuvant radiotherapy previously performed as part of primary therapy. In the case of inoperability, radiotherapy as well as systemic hormone and chemotherapy can be used as the sole measure or in combination. There is evidence that simultaneous chemotherapy or hyperthermia as radiation-sensitizing procedures can achieve higher response rates.
In the previously irradiated area, lower-dose re-irradiation with simultaneous surface hyperthermia can lead to better local tumor control than re-irradiation alone. The survival rates are not improved [987], [988].
In the case of an inoperable local recurrence, palliative radiotherapy, possibly in combination with chemotherapy, can be useful for symptom control.
- Consensus
- Strong consensus
In case of an intramammary or thoracic wall recurrence without prior radiation after breast-conserving surgery (R0) or after mastectomy (R0), the indication for adjuvant radiotherapy should be analogous to the recommendations in the primary situation.
- Consensus
- Strong consensus
In the case of intramammary recurrence after pre-radiation after breast-conserving surgery (R0), the indication for adjuvant radiotherapy should be discussed on an interdisciplinary basis and can be made by the 1st radiotherapy, especially in patients without serious late effects.
- Consensus
- Strong consensus
In case of a recurrence of the thoracic wall after pre-irradiation after mastectomy (R0), a new indication for local control should be discussed interdisciplinary.
- Consensus
- Strong consensus
In case of a chest wall recurrence after primary mastectomy with subsequent radiotherapy after resection of the recurrence (R0), the indication for a renewed adjuvant radiotherapy should be discussed interdisciplinary in the presence of risk factors (narrow resection, rpN+, G3, lymph vessel invasion). This can be done in patients without serious late effects from the 1st radiotherapy.
- Consensus
- Strong consensus
In case of a chest wall recurrence after primary mastectomy with subsequent radiotherapy after resection of the recurrence (R0), the indication for a renewed adjuvant radiotherapy should be discussed interdisciplinary in the presence of risk factors (narrow resection, rpN+, G3, lymph vessel invasion). This can be done in patients without serious late effects from the 1st radiotherapy.
- Consensus
- Strong consensus
For recurrences that are not in a previously irradiated area and have been R1/R2 resected - without the possibility of surgically creating an R0 situation with an acceptable risk - additional radiotherapy should be recommended in this situation.
- Consensus
- Strong consensus
In the presence of recurrences after R1/R2 resection and prior irradiation without the possibility of creating an R0 situation surgically with an acceptable risk, the indication for renewed radiotherapy should be discussed on an interdisciplinary basis.
This can be provided by the 1st radiotherapy in patients without serious late effects.
- Consensus
- Strong consensus
5.4 Distant metastases
5.4.1 Systemic therapy in pre- and perimenopausal patients and positive hormone receptor status and negative HER2 status.
In pre- and perimenopausal patients, endocrine therapy, possibly combined with targeted therapy, shall be offered if hormone receptor status is positive and HER2 status is negative.
Endocrine-only monotherapy is not indicated in patients with the need to achieve rapid remission to avert marked symptoms of the affected organ.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1b
- Consensus
- Strong consensus
- References
- [28] [989] [990] [991] [992] [993] [994]
Change note
Endocrine therapy +/- targeted therapy is the therapy of choice for positive hormone receptor status and negative HER2 status. Endocrine therapy is not indicated in patients where there is a need to achieve rapid remission in order to avert pronounced symptoms of the affected organ.Background 5.26
Endocrine therapy is less toxic than chemotherapy and should therefore always be used as first-line therapy. Especially those patients who have had a long disease-free interval, who have responded to previous anti-hormonal therapy measures, and who do not belong to the small group of patients in whom a very rapid onset of action is necessary (e.g., in cases of shortness of breath in diffuse lung metastasis or threatened liver failure in liver metastasis or possible ileus in peritoneal carcinomatosis), benefit from endocrine therapy. With a positive hormone receptor status, remission is expected in 60% of patients, with a negative hormone receptor status in less than 10%. Endocrine therapy should therefore only be used in exceptional cases of negative hormone receptor status. In rare cases with unknown hormone receptor status, however, the indication for endocrine therapy can be made dependent on the clinical course.
If a patient responds to endocrine therapy, it is continued until progression is achieved. In case of progression, the use of alternative endocrine substances is indicated and justified. Only after all endocrine treatment measures have been exhausted or in case of non-response to endocrine therapy should a switch to cytostatic therapy be made.
In the presence of HER2 overexpression, a worse response to endocrine therapy is to be expected. Studies combining endocrine therapy with HER2-targeted therapy could not show a survival benefit from additional HER2-targeted therapy. Therefore, chemotherapy in combination with HER2-targeted therapy is recommended for patients with hormone receptor-positive, HER2-positive tumours, see the section Distant Metastases - Chemotherapy [992], [995], [996], [997], [998], [999], [1000], [1001], [1002], [1003], [1004], [1005], [1006]
A combined chemo-endocrine therapy is not recommended. Although it can increase remission rates, it also leads to increased toxicity without extending the progression-free interval or overall survival.
In premenopausal patients, endocrine-based therapy should be with a CDK4/6 inhibitor with ovarian function abolished and in combination with an aromatase inhibitor or with fulvestrant (depending on prior therapy).
In premenopausal patients, ovarian function elimination (GnRH analogs, ovariectomy) may be performed in combination with tamoxifen if tamoxifen therapy was discontinued more than 12 months ago.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1b
- Consensus
- Strong consensus
- References
- [28] [992] [1018] [1019]
Change note
In premenopausal patients, elimination of ovarian function (GnRH analogues, ovarectomy) in combination with tamoxifen is the treatment of choice if tamoxifen therapy was not discontinued less than 12 months ago. Alternatively, the ovarian function can be eliminated in the same way as in postmenopausal patients and endocrine therapy can be combined with CDK4/6 inhibitors.For sequential endocrine therapies, the different endocrine agents should be selected depending on previous therapies, response, and tumor and patient characteristics.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- 5
2c (Oxford 2009)
- Consensus
- Strong consensus
- References
- [28] [1020] [1021]
Change note
Subsequently, in premenopause, ovarian suppression can be used in combination with an aromatase inhibitor or fulvestrant, for example, or in combination with palbociclib. The therapy can thus be carried out while maintaining ovarian suppression in analogy to the treatment of postmenopausal patients.Background 5.27.
In a meta-analysis of 26 trials involving 3,606 patients with advanced breast carcinoma, Fossati et al [1022] demonstrated that the combination of chemotherapy and endocrine therapy resulted in increased remission rates but not prolonged survival compared with chemotherapy alone. Under combined chemoendocrine therapy, adverse effects such as edema tendency and cardiovascular complications were significantly increased.
Background 5.28.
Data from AMNOG benefit assessments are available on therapy with CDK4/6 inhibitors in addition to endocrine therapy in pre- or perimenopausal patients for a total of three randomized controlled trials (MONARCH-2 [1009], PALOMA-3 [1012] and MONALEESA-7 [1015]) on three substances (abemaciclib, palbociclib and ribociclib) are available. These studies are randomized, controlled, blinded clinical trials (see guideline report for full study assessment details). PALOMA-3 and MONARCH-2 included patients with failure of a prior line of therapy regardless of menopausal status, while MONALEESA-7 included only pre- and perimenopausal patients. Stratification by menopausal status was performed post hoc for PALOMA-3 and MONARCH-3 to meet the requirements of the benefit assessment for the G-BA. The data on abemaciclib and palbociclib presented below are therefore results of subgroup analyses. With non-significant effect estimates, these do not have sufficient test strength to allow a statistically sound interpretation and should therefore be regarded as exploratory results.
The following results were taken from the corresponding benefit assessment procedures, in each case from modules 4 and/or the relevant publications. At the time of the amendment, the active substances abemaciclib and ribociclib are still in additional, ongoing benefit assessment procedures without decisions on the additional benefit by the G BA. The status of the procedure can be viewed on the pages of the G-BA (Abemaciclib: https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/535/; Ribociclib: https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/526/ und https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/527/).
Overall survival
Regarding overall survival, there were no consistent benefits of treatment with CDK4/6 inhibitors for the group of pre- or perimenopausal patients. There was no significant survival benefit with treatment with abemaciclib or palbociclib compared with placebo (abemaciclib HR: 0.69 [0.38; 1.25], palbociclib HR: 1.07 [0.61; 1.86]) [1009], [1012]. There was a significant survival benefit for premenopausal or perimenopausal patients when treated with ribociclib (HR: 0.71 [0.54; 0.95]), but there were also significant effect differences with respect to ethnicity, lineage of therapy, and age: patients with age <40 years: HR 0.79 [0.48; 1.30] vs. age ≥40 years: HR 0.68 [0.48; 0.98]. Asian female patients: HR 0.40 [0.22; 0.72]) vs. non-Asian female patients: HR 0.91 [0.64; 1.30]) [1015]. Stratified by line of therapy, the first-line HR was 0.68 [0.45; 1.00] and the second- and follow-up-line HR was 0.78 [0.50; 1.21] [1023].
Progression-free survival
In all three studies, there was a clear advantage under therapy with CDK4/6 inhibitors vs. placebo in terms of progression-free survival: HR 0.41 [0.25; 0.70] with abemaciclib (second- and subsequent-line) [1010], HR 0.44 [0.23; 0.83] with palbociclib (second- and subsequent-line) [1013], and HR 0.52 [0.38; 0.70] with ribociclib in the first-line and HR 0.62 [0.44; 0.89] in the second- and subsequent-line, respectively [1016]. No persistent effect modifications in subgroups emerged for any of the three agents
[1010], [1013], [1016], [1024], [1025], [1026], i.e., the advantage of CDK4/6 inhibitors was also evident in the subgroup strata studied.
Health-related quality of life
A generalizing statement on the effect of CDK4/6 inhibitors on health-related quality of life was made for all studies using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the Global Health Status scale. For this purpose, a minimum clinically relevant difference of 10 points was assumed [1027], [1028]. There was no significant, clinically relevant improvement (HR: 0.63 [0.33; 1.20]) for patients treated with abemaciclib [1011]. Under palbociclib, there were also no statistically significant differences compared with placebo (HR: 0.81 [0.47; 1.41]) [1014]. However, clinically relevant benefits with respect to global health status versus placebo were identified under second- and follow-up ribociclib (HR: 0.70 [0.53; 0.92] [1017]. Given the heterogeneous results for the CDK4/6 inhibitors evaluated, no robust evidence of improvement in quality of life can be derived for them.
Adverse events
Treatment with CDK4/6 inhibitors was generally associated with a significantly higher incidence of adverse events. Expressed as hazard ratios for the occurrence of adverse events with Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3, comparable effect estimates were obtained for all agents: HR 5.64 [2.54; 12.55] among abemaciclib, HR 5.90 [2.91; 11.95] among palbociclib, and HR 4.14 [3.28; 5.23] among ribociclib [1011], [1014], [1017]. Among all agents, patients discontinued treatment significantly more often than on placebo: RR 4.18 [0.22; 79.00] under abemaciclib, RR 3.60 [0.19; 67.81] under palbociclib, and HR 1.66 [0.82; 3.38] under ribociclib [1011], [1014], [1017].
Overall, the evidence particularly supports a benefit of treating pre- and perimenopausal patients in second- and subsequent-line therapy with CDK4/6 inhibitors in terms of significant effects on progression-free survival. Results on tolerability of CDK4/6 inhibitors were comparable for all patient populations analyzed and indicated significantly higher event rates compared with placebo. Adverse events can be minimized by careful management of therapy [1029].
Conclusion pre- and perimenopausal patients
CDK4/6 inhibitors in early benefit assessment
For palbociclib, ribociclib and abemaciclib, results of the early benefit assessment according to § 35a SGB are available at the time of guideline preparation (last review: February 2020). The Institute for Quality and Efficiency in Health Care (IQWiG) and the Federal Joint Committee (G-BA) concluded that for palbociclib, ribociclib, and abemaciclib there is no evidence of an added medical benefit compared with the respective appropriate comparator therapy for any therapy line or patient group [1030], [1031], [1032], [1033], [1034], [1035]. This conclusion was mainly based on the observed unfavorable side effect profile in the absence of evidence for benefits in overall survival or quality of life. Effects on progression-free survival (PFS) are only considered in the early benefit assessment if analyses are available that show PFS as a valid surrogate endpoint for overall survival. According to IQWiG, these were not available. Thus, the discrepancy between the results of the early benefit assessment and the guideline recommendation on overall survival data, which were not available at the time of the early benefit assessment, and the consideration of progression-free survival as a benefit parameter can be explained. For abemaciclib and riboclicib, however, further benefit dossiers are ongoing at the time of the admendment and their final assessments are still pending.
The adverse events shown were generally compared with the placebo or endocrine therapy alone as defined by the G-BA. In clinical practice, however, a comparison to chemotherapy associated with significantly more severe side effects is appropriate. CDK4/6 inhibitors are expected to show a significantly more tolerable side effect profile than placebo compared to available chemotherapeutic agents. In addition, side effects are very well managed with established supportive measures [1029]. A tabular overview in the form of evidence tables of the listed effect estimates can be found in the evidence report for this guideline.
Background 5.29 to 5.31.
Unless CDK4/6 inhibitors are given, the initial therapeutic step is ovarian function elimination (GnRH analogs, ovariectomy, or radiomenolysis) in combination with tamoxifen. If tumor progression occurs or tamoxifen is contraindicated, a third-generation aromatase inhibitor plus GnRH analog can be used, and fulvestrant plus GnRH analog may also be considered. Despite sparse data, therapy should be largely analogous to the treatment of postmenopausal patients while maintaining ovarian suppression [1018], [1021], [1036], [1037], [1038], [1039], [1040].
Thus, therapy can be performed while maintaining ovarian suppression in analogy to the treatment of postmenopausal patients. As options can be used in combination with a GNRH analogue depending on the previous therapy:
- aromatase inhibitors
- fulvestrant
- tamoxifen
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus
- References
- [997] [28] [989] [992] [1041] [1042] [1043] [1044]
Change note
As a first endocrine treatment step in metastasis, an aromatase inhibitor should be used in postmenopausal patients if adjuvant tamoxifen alone or no adjuvant therapy has been administered. A clear recommendation as to whether a steroidal or non-steroidal aromatase inhibitor should be used primarily cannot be given. Letrozole can be combined with a CDK4/6 inhibitor.5.4.2 Systemic therapy in postmenopausal patients and positive hormone receptor status and negative HER2 status.
In postmenopausal patients, endocrine therapy, possibly combined with targeted therapy, should be offered if hormone receptor status is positive and HER2 status is negative.
Endocrine therapy is not indicated in patients with the need to achieve rapid remission to avert marked symptoms of the affected organ.
Combined chemo-endocrine therapy is not recommended. Although it may increase remission rates, it also leads to increased toxicity without prolonging progression-free interval or overall survival.
Background 5.32 and 5.33
See background text to 5.26 and 5.27
5.4.2.1 First-line therapy
Combination therapies with an aromatase inhibitor or fulvestrant with CDK 4/6 inhibitors should be performed if this group of substances has not yet been used.
Treatment with fulvestrant should particularly follow pretreatment with an aromatase inhibitor, but can also be used as a first line of therapy, especially in patients who have not yet undergone endocrine pretreatment.
Background 5.34
First-line therapy of postmenopausal patients with CDK4/6 inhibitors
For postmenopausal patients, data are available on first-line therapy with CDK4/6 inhibitors in combination with endocrine therapy from a total of five randomized controlled trials of three compounds (abemaciclib: MONARCH-3; palbociclib: PALOMA-1 and PALOMA-2; ribociclib: MONALEESA-2 and MONALEESA-3). MONARCH-3, PALOMA-2, MONALEESA-2, and MONALEESA-3 were randomized, controlled, and blinded clinical trials, whereas PALOMA-1 was conducted as an open label study and thus subject to a higher potential for bias.
Gesamtüberleben
With regard to overall survival, there have been no significant advantages for postmenopausal patients in first-line therapy to date (see evidence tables in the guideline report - section 14.6).
Progressionsfreies Überleben
In contrast, treatment with CDK4/6 inhibitors showed significant advantages over placebo in terms of progression-free survival in all studies. With abemaciclib: HR 0.54 [0.42; 0.70], with palbociclib HR 0.49 [0.32; 0.75] (PALOMA-1), resp. HR : 0.58 [0.46; 0.72] (PALOMA-2) and under ribociclib HR 0.57 [0.43; 0.74] (MONALEESA-2) and HR 0.58 [0.42; 0.80] (MONALEESA-3), respectively) [1025], [1055], [1056], [1058].
Gesundheitsbezogene Lebensqualität
There is no evidence of an effect of treatment with CDK4/6 inhibitors on health-related quality of life in postmenopausal patients in terms of a clinically relevant difference in scores on the EORTC QLQ-C30 or FACT-B questionnaire (see guideline report).
Adverse events
Treatment with CDK4/6 inhibitors was also generally associated with a significantly higher incidence of adverse events for postmenopausal patients: Under abemaciclib, the effect for UE with CTCAE grade ≥3 was HR 3.14 [2.25; 4.39] (MONARCH-3), under palbociclib HR 5.47 [3.15; 9.51] (PALOMA-1) and 5.50 [4.14; 7.31] (PALOMA-2), respectively, and under ribociclib HR 4.21 [3.40; 5.21] [1054], [1055], [1056], [1059]. Patients discontinued treatment significantly more often under abemaciclib and ribociclib than under placebo. With abemaciclib, the hazard ratio was 6.04 [2.18; 16.70]; with ribociclib, first-line HR was 4.23 [2.31; 7.74]; and for any line of therapy, it was 2.73 [1.58; 4.74] [1011], [1014], [1054], [1056], [1059].
Conclusion postmenopausal patients in first-line therapy
Overall, the evidence in postmenopausal patients in first-line therapy with CDK4/6 inhibitors shows a treatment advantage over comparator therapy only for the endpoint progression-free survival. The results for tolerability of CDK4/6 inhibitors were comparable for all patient populations analyzed and indicated significantly higher event rates compared with comparator therapy. Comments on the benefit assessments by IQWiG and the decisions of the G-BA can be found in chapter 5.4.1. A tabular overview in the form of evidence tables of the listed effect estimates can be found in the evidence report for this guideline
5.4.2.2 Second and follow-up line therapy
After prior anti-hormonal therapy with a non-steroidal aromatase inhibitor as well as CDK4/6 inhibitors, follow-up therapy with exemestane and the mTOR inhibitor everolimus can be performed.
Further steps in the endocrine treatment sequence in postmenopausal patients represent, depending on the pretreatment, the use of alpelisib (if a corresponding PI3KA mutation is detected) or antiestrogens, estrogen receptor antagonists, switching the aromatase inhibitor from a steroidal to a nonsteroidal aromatase inhibitor, or vice versa.
- Consensus
- Strong consensus
Background text 5.36.
Second-line and follow-up therapy of postmenopausal patients with CDK4/6 inhibitors
For postmenopausal patients, data are available on second and subsequent line therapy with CDK4/6 inhibitors in combination with endocrine therapy from a total of three randomized controlled trials on three substances (abemaciclib: MONARCH-2, palbociclib: PALOMA-3; ribociclib: MONALEESA-3). These studies are randomized, controlled, blinded clinical trials. The population of postmenopausal patients in second-line and follow-up therapy was extracted for the MONARCH-2 and PALOMA-3 studies in the form of subgroups in order to be able to represent the patient group required by the G-BA. The data on abemaciclib and palbociclib presented below are therefore the results of subgroup analyses. With non-significant effect estimates, these do not have sufficient test strength to allow a statistically sound interpretation and should therefore be regarded as exploratory results.
Overall Survival
With regard to overall survival, there were advantages for the postmenopausal patients in the second- and follow-up-line therapy. There was a significant survival advantage over placebo here for abemaciclib (HR 0.77 [0.61; 0.98]) and palbociclib (HR 0.73 [0.57; 0.95]) [1009], [1012]. For ribociclib, the hazard ratio for overall survival was just below the significance threshold (HR 0.73 [0.53; 1.00]) [1057]. No subgroup analyses (e.g., with regard to age or ethnicity) are available for the group of postmenopausal patients in second-line or follow-up therapy.
Progression-free Survival
There were significant advantages of treatment with CDK4/6 inhibitors over placebo in terms of progression-free survival in all studies. With abemaciclib: HR 0.58 [0.46; 0.73], with palbociclib: HR 0.41 [0.30; 0.56], and with ribociclib HR 0.58 [0.42; 0.80] [1060], [1061], [1058].
Health-related quality of life
There is no evidence of an effect of treatment with CDK4/6 inhibitors on health-related quality of life in postmenopausal patients in terms of a clinically relevant difference in EORTC QLQ-C30 score (see guideline report).
Adverse events
Treatment with CDK4/6 inhibitors was also generally associated with a significantly higher incidence of adverse events for postmenopausal patients: For abemaciclib, the effect estimate for UE with CTCAE grade ≥3 under any line of therapy was HR 3.34 [2.43; 4.59], for palbociclib HR 4.54 [3.22; 6.41], and for ribociclib HR 4.46 [3.45; 5.77] [1011], [1014], [1059]. Patients discontinued treatment significantly more often with abemaciclib and ribociclib than with placebo. Under abemaciclib, the effect estimate was HR 2.32 [1.03; 5.23] and under ribociclib, HR 2.73 [1.58; 4.74] [1011], [1014], [1059].
Conclusion Second- and Follow-up-Line Therapy of Postmenopausal Patients with CDK4/6 Inhibitors
Overall, the evidence supports a benefit of treating postmenopausal patients in second- and subsequent-line therapy with CDK4/6 inhibitors in the form of significant effect estimates for both progression-free survival and overall survival that have not been achieved in the past. Results on tolerability of CDK4/6 inhibitors were comparable for all patient populations analyzed and indicated significantly higher event rates compared with placebo. Comments on the benefit assessments by IQWiG and the decisions of the G-BA can be found in chapter 5.4.1. A tabular overview in the form of evidence tables of the listed effect estimates can be found in the evidence report for this guideline.
Background 5.37. and 5.38.
First-line drugs are third-generation aromatase inhibitors. Subgroup analyses for three predominantly used aromatase inhibitors (anastrozole, exemestane, and letrozole) show similar survival benefits [1062].
After failure of a nonsteroidal aromatase inhibitor (anastrozole or letrozole), administration of everolimus in addition to exemestane has been shown to prolong progression-free survival. Thus, this approach represents another treatment option.
In case of tumor re-progression, antiestrogens, estrogen receptor antagonists, and finally high-dose progestogens or estrogens can be used [1063], [1064].
Aromatase inhibitor treatment is associated with a significant increase in side effects induced by hormone withdrawal [1065]. During aromatase inhibitor therapy, fewer hot flashes, thromboembolic events, and endometrial cancer occur as side effects compared with tamoxifen, but the rate of arthralgias and myalgias is increased. Furthermore, higher bone density loss and possibly a higher rate of osteoporotic fractures are to be expected. However, these aspects are often not of primary concern in the palliative treatment situation.
A combination of fulvestrant and aromatase inhibitors is not recommended due to controversial data [1066], [1067], [1068], [1069], [1070], [1071], [1072], [1073], [1074], [1075], [1076].
Summary conclusion on the use of CK4/6 inhibitors in patients with breast cancer
The clinical trial data presented here include results from populations defined a priori in the study protocol as well as results from post-hoc subgroups, some of which were prescribed by the G-BA. They were listed to ensure a complete reporting of the available evidence.
However, a final interpretation of the subgroup analyses presented is hampered by statistical limitations (multiple testing, insufficient test strength (power). Therefore, the recommendations formulated by the guideline group on the use of CK4/6 inhibitors are based on the analyses of the respective overall populations in the studies (see guideline report).
In these patients, advantages of the CDK4/6 inhibitors were shown with respect to prolonged overall survival, especially for abemaciclib as well as ribociclib [1009], [1015]. In addition, significant prolongation of progression-free survival was observed for all agents [1060], [1061], [1016], [1025], [1058].
These survival benefits outweigh any lack of effects with respect to health-related quality of life as well as the well-treatable side effects
5.4.3 Chemotherapy of metastatic breast cancer
Pre-chemotherapy criteria
Before chemotherapy is administered, the patient's general condition and comorbidity, previous therapies and compliance should be assessed.
- Consensus
- Strong consensus
Toxicity assessment
During the therapy, a regular toxicity assessment (subjective and objective) should be carried out. The dosage as well as the desired time intervals should be carried out according to generally accepted standard or currently published therapy regimes. After determination of a suitable and representative measurement parameter (symptoms, tumor markers, imaging) before the start of therapy, an evaluation of the therapeutic effect should be performed at least every 6-12 weeks in accordance with clinical requirements. In the course of time, the imaging intervals can be extended if the remission is persistent and the clinical and laboratory chemical assessment of the disease status is good.
- Consensus
- Strong consensus
Modification of chemotherapy
Therapy should be discontinued if clinically relevant progression or intolerable toxicity is observed.
A switch to another chemotherapy should not be made without proven progression or intolerable toxicity.
- Consensus
- Strong consensus
Polychemotherapy/combination therapy
The combination therapy of chemotherapy and bevacizumab in first-line therapy can improve progression-free survival, but with an increased rate of side effects and without impact on overall survival.
In the case of more severe symptoms and rapid growth or aggressive tumour behaviour, i.e. high remission pressure, polychemotherapy or chemotherapy + bevacizumab can be performed.
Background 5.34 to 5.39
Due to the heterogeneity of the metastases and the individual course of the disease, no uniform therapy strategy can be given. This applies in particular to the cytostatic treatment of metastasized breast carcinoma. Although monotherapy has lower remission rates than polychemotherapy, this does not have a significant negative impact on survival time. Monotherapies are better tolerated, so that monotherapy should be used whenever possible. Monotherapy should be used in cases of minor symptoms and slow tumour growth or ineffectiveness of endocrine therapy. Polychemotherapy is only indicated for severe symptoms, rapid tumour growth and aggressive tumour behaviour. Cytostatic therapy should be based on the therapeutic index in the case of incurable disease, whereby the effect (e.g. symptom control) and side effects of a therapy must be considered and weighed up. For the majority of patients, the use of subjectively less stressful monotherapies compared to a combination therapy is recommended. This is supported by a Cochrane meta-analysis published in 2015, which showed that there were no significant differences in overall survival and progression-free survival between combination therapy and sequential monochemotherapy when compared with sequential monochemotherapy (OS HR 1.04 95% CI 0.93-1.16; p=0.45 / PFS HR1.11 95% CI 0.99-1.25; p=0.08). In comparison, the response was significantly higher with combination chemotherapy. However, combination chemotherapy also showed a higher toxicity with regard to the rate of febrile neutropenia. Many mainly non-haematological side effects were not described in this meta-analysis. In the meta-analysis, two scenarios of sequential monochemotherapy were described, one change of monochemotherapy with progression or fixed change of monochemotherapy without progression after a few cycles. The results were similar for both scenarios, with the hazard ratios described referring to the total collective. The authors conclude that the results of this meta-analysis support the recommendations for sequential monotherapy compared to combination chemotherapy [1077], except for the cases with rapid tumor progression and high remission pressure.
If the patient has not yet received anthracyclines/taxanes in adjuvant therapy, they can be used primarily.
Before and during chemotherapy the patient's general condition must be assessed regularly. During therapy, the side effects of this treatment must also be evaluated regularly. An evaluation of the therapeutic effect by means of imaging should be performed every 6-12 weeks (interval depending on the spread of the disease, disease dynamics and clinical situation). In the course of time, the imaging intervals can be extended in case of remission and good clinical and laboratory chemical assessment of the disease status. In case of progress or pronounced toxicity, therapy should be discontinued. The therapeutic index (individual patient benefit versus therapy-related side effects) should be positive in the overall assessment of the therapy.
The dosage as well as the intended time intervals of the therapy should be adapted to general guidelines of the therapy, i.e. recognized published protocols. Dose-intensified and high-dose therapies have not yet led to any improvement in effectiveness. Their use is only acceptable in the context of studies (Conchrane: [800]).
A meta-analysis by Ghersi et al. showed that taxane-containing chemotherapies were associated with improved progression-free and overall survival as well as an increased tumor response. However, they also led to an increased risk of neuropathy and a lower risk of nausea and vomiting compared to non-taxan-containing regimens [1085].
5.4.3.1 Bevacizumab in metastatic breast cancer (first line)
The improved efficacy of first-line treatment with paclitaxel plus bevacizumab (P/Bev) compared to paclitaxel monotherapy was demonstrated in a randomized phase III study: In the E2100 study, the combined use of P/Bev doubled the objective response rate (36.9% vs. 21.2%; p<0.001), was in einer nachfolgenden unabhängigen Auswertung bestätigt wurde (48,9% vs. 22,2%; p<0,0001). Dieses Ergebnis wurde unabhängig vom Hormonrezeptor-Status der Tumore erzielt. Mit P/Bev wurde eine signifikante Verlängerung der progressionsfreien Zeit (PFS) von 11.4 vs. 5.8 Monaten (HR 0,42; 95% CI, 0,34 – 0,52; p<0.001) im Vergleich zur Monotherapie erzielt, die ebenfalls in der Kontrollauswertung bestätigt wurde (11.3 vs. 5.8 Monate; HR 0,48; 95% CI 0.385 - 0.607; p < 0,0001) [1079], [1080]. Ein Vorteil hinsichtlich des medianen Gesamtüberlebens (OS) konnte hingegen nicht belegt werden (26.7 vs. 25.2 Monate; HR 0.88; p=0.16). Blutdruckerhöhungen > Grade 3 (14.8% vs. 0.0%, p < 0.001), Proteinurie (3.6% vs. 0.0%, p < 0.001), Kopfschmerzen (2.2% vs. 0.0%, p = 0.008) und cerebrovasculäre Ischämien (1.9% vs. 0.0%, p = 0.02) traten dabei deutlich häufiger beim Einsatz von P/Bev im Vergleich zur Monotherapie mit Paclitaxel auf [1079].
The efficacy of first-line combination therapy of capecitabine with bevacizumab (cap/ev) has also been demonstrated in several Phase III studies. These studies showed a median PFS for this taxane-free combination of 9.2 (RIBBON-1), 8.8 (CARIN) and 8.1 months (TURANDOT) [1081], [1082], [1083].
In the phase III study TURANDOT, which directly compared P/Bev with Cap/Bev, P/Bev was found to be superior to Cap/Bev with regard to ORR (44% vs. 27%; p grade 3), in particular neutropenia (18%) and peripheral polyneuropathy (14%), while in the Cap/Bev arm hand-foot syndrome (16%), elevated blood pressure (6%) and diarrhoea (5%) were prominent [1083].
In summary, the additional therapy with bevacizumab showed increased remission rates and an improvement of PFS (but without survival advantage, which makes a combination therapy especially suitable in case of higher "remission pressure" and in the absence of a risk constellation regarding side effects (no uncontrolled arterial hypertension, no cerebrovascular ischemia and no deep vein thrombosis in the history).
5.4.3.2 Regimens
Adriamycin 60 / cyclophosphamide 600
|
Day |
Substance |
Dosage |
|
1 |
Adriamycin |
60 mg/m² |
|
1 |
Cyclophosphamide |
600 mg/m² |
Cycle duration 21 days
Reference: [1086]
Adriamycin liposomal 75 / cyclophosphamide 600
|
Day |
Substance |
Dosage |
|
1 |
adriamycin liposoma |
75 mg/m² |
|
1 |
Cyclophosphamide |
600 mg/m² |
Cycle duration 21 days
Reference: [1087]
Adriamycin 50 / docetaxel 75
|
Day |
Substance |
Dosage |
|
1 |
Adriamycin |
50 mg/m² |
|
1 |
Docetacxel |
75 mg/m² |
Cycle duration 21 days
Reference: [1086]
Capecitabine 2000 / Bevacizumab 15
|
Day |
Substance |
Dosage |
Procedure |
|
1-14 |
Capecitabine |
1000 mg/m² KOF |
1-0-1 |
|
1 |
Bevacizumab |
15 mg/kg bw |
Cycle duration 21 days
Reference: [1083]
Capecitabine 2000 / Paclitaxel 175
|
Day |
Substance |
Dosage |
Procedure |
|
1-14 |
Capecitabine |
1000 mg/m² KOF |
1-0-1 |
|
1 |
Paclitaxel |
175 mg/m² KOF |
Cycle duration 28 days
Reference: [1088]
Cisplatin 75 / Gemcitabine 1250
|
Day |
Substance |
Dosage |
Carrier solution |
Appl. |
Inf. duration |
Procedure |
|
1 |
Cisplatin |
75 mg/m² KOF |
NaCl 0.9% 500 ml |
intravenously |
60 min |
Order |
|
1,8 |
Gemcitabine |
1250 mg/m² KOF |
NaCl 0.9% 250 ml |
intravenously |
30 minutes |
Order |
Cycle duration 21 days
Reference: [1089]
Cyclophosphamide 600 / non-pegylated liposomal doxorubicin 75
|
Day |
Substance |
Dosage |
|
1 |
Cyclophosphamide |
600 mg/m² KOF |
|
1 |
liposomal doxorubicin |
75 mg/m² KOF |
Cycle duration 21 days
Reference: [1087]
docetaxel
|
Day |
Substance |
Dosage |
|
1 |
docetaxel |
100 mg/m² KOF |
Cycle duration 21 days
Docetaxel 35, breast cancer
|
Day |
Substance |
Dosage |
|
1, 8, 15 |
docetaxel |
35 mg/m² KOF |
Cycle duration 28 days
Reference: [1092]
Doxorubicin 50 / docetaxel 75, breast cancer
|
Day |
Substance |
Dosage |
|
1 |
Doxorubicin |
50 mg/m² KOF |
|
1 |
docetaxel |
75 mg/m² KOF |
Cycle duration 21 days
Doxorubicin 60 / cyclophosphamide 600
|
Day |
Substance |
Dosage |
|
1 |
Doxorubicin |
60 mg/m² KOF |
|
1 |
Cyclophosphamide |
600 mg/m² KOF |
Cycle duration 21 days
Reference: [1086]
Epirubicin 60 / cyclophosphamide 600
|
Day |
Substance |
Dosage |
|
1 |
Epirubicin |
60 mg/m² |
|
1 |
Cyclophosphamide |
600 mg/m² |
Cycle duration 21 days
Reference: [1094]
Epirubicin 75 / cyclophosphamide 600
|
Day |
Substance |
Dosage |
|
1 |
Epirubicin |
75 mg/m² KOF |
|
1 |
Cyclophosphamide |
600 mg/m² KOF |
Cycle duration 21 days
Reference: [1094]
Epirubicin 75 / docetaxel 75
|
Day |
Substance |
Dosage |
|
1 |
Epirubicin |
75 mg/m² KOF |
|
1 |
docetaxel |
75 mg/m² KOF |
Cycle duration 21 days
Reference: [1093]
Epirubicin 60 / Paclitaxel 175
|
Day |
Substance |
Dosage |
|
1 |
Epirubicin |
60 mg/m² |
|
1 |
Paclitaxel |
175 mg/m² |
Cycle duration 21 days
Reference: [1094]
Epirubicin 60 / Paclitaxel 175
|
Day |
Substance |
Dosage |
|
1 |
Epirubicin |
60 mg/m² |
|
1 |
Paclitaxel |
175 mg/m² |
Cycle duration 21 days
Reference: [1094]
eribulin 1,23
|
Day |
Substance |
Dosage |
|
1, 8 |
Eribulin |
1, 23 mg/m² KOF |
Cycle duration 21 days
everolimus 10 / exemplestan 25, postmenopausal
|
Day |
Substance |
Dosage |
|
1-28 |
Everolimus |
10 mg |
|
1-28 |
Copy |
25 mg |
Cycle duration 28 days
Fulvestrant 500, postmenopausal
|
Day |
Substance |
Dosage |
|
1 |
Fulvestrant |
500 mg |
Cycle duration 28 days
Gemcitabine 1000 / Carboplatinum 4
|
Day |
Substance |
Dosage |
|
1, 8 |
Gemcitabine |
1000 mg/m² KOF |
|
1 |
Carboplatinum |
4 AUC |
Cycle duration 21 days
Reference: [1101]
Lapatinib 1250 / Capecitabine 2000
|
Day |
substance |
Dosage |
Procedure |
|
1-21 |
Lapatinib |
1250 mg |
1-0-0 |
|
1-14 |
Capecitabine |
1000 mg/m² KOF |
1-0-1 |
Cycle duration 21 days
Reference: [1102]
NabPaclitaxel 125 / carboplatinum
|
Day |
Substance |
Dosage |
|
1, 8 |
NabPaclitaxel |
125 mg/m² |
|
1, 8 |
Carboplatinum |
AUC 2 |
Cycle duration 21 days
Reference: [1103]
Nab-paclitaxel 100 / carboplatin 2 / bevacizumab 10, (triple negative)
|
Day |
Substance |
Dosage |
|
1, 8, 15 |
Nab paclitaxel |
100 mg/m² KOF |
|
1, 8, 15 |
Carboplatinum |
AUC 2 |
|
1, 15 |
Bevacizumab |
10 mg/kg bw |
Cycle duration 28 days
Reference: [1104]
Nab-paclitaxel 125 / Trastuzumab (4/2)
|
Day |
Substance |
Dosage |
|
1, 8, 15 |
Nab paclitaxel |
125 mg/m² KOF |
|
1 |
Trastuzumab |
4 mg/kg bw |
|
8, 15, 22 |
Trastuzumab |
2 mg/kg bw |
Cycle duration 28 days
Reference: [1105]
Nab-paclitaxel 125 weekly
|
Day |
Substance |
Dosage |
|
1, 8, 15 |
Nab paclitaxel |
125 mg/m² KOF |
Cycle duration 28 days
Paclitaxel 90 / Bevacizumab 10
|
Day |
Substance |
Dosage |
|
1, 8, 15 |
Paclitaxel |
90 mg/m² KOF |
|
1, 15 |
Bevacizumab |
10 mg/kg bw |
Cycle duration 28 days
Reference: [1079], [1080], [1083], [1107], [1108]
Paclitaxel 175 / Capecitabine 2000
|
Day |
Substance |
Dosage |
|
1 |
Paclitaxel |
175 mg/m² |
|
1-14 |
Capecitabine |
2000 mg/m² |
Cycle duration 21 days
Reference: [1088]
paclitaxel 175 / gemcitabine 1250
|
Day |
Substance |
Dosage |
|
1 |
Paclitaxel |
175 mg/m² KOF |
|
1-14 |
Gemcitabine |
1250 mg/m² KOF |
Cycle duration 21 days
Palbociclib 125 / Fulvestrant 500
|
Day |
Substance |
Dosage |
|
1-21 |
Palbociclib |
125 mg (every 4 weeks) |
|
1, 15, 29 |
Fulvestrant |
500 mg (only in 1st cycle, from 2nd cycle every 4 weeks) |
Cycle duration 28 days
Reference: [1110][1111], [1112]
Pertuzumab 840 / Trastuzumab 8 / Docetaxel 75, (HER2+) cycle 1
|
Day |
Substance |
Dosage |
|
1 |
Pertuzumab |
840 mg |
|
1 |
Trastuzumab |
8 mg/kg bw |
|
1 |
docetaxel |
75 mg/m² KOF |
Cycle duration 21 days
Pertuzumab 420 / Trastuzumab 6 / Docetaxel 75, (HER2+) cycle 2+
|
Day |
Substance |
Dosage |
|
1 |
Pertuzumab |
420 mg |
|
1 |
Trastuzumab |
6 mg/kg bw |
|
1 |
docetaxel |
75 mg/m² KOF |
Cycle duration 21 days
Reference: [1113]
Trastuzumab (8) 6 / Docetaxel 100, (HER2+)
|
Day |
Substance |
Dosage |
|
1 |
Trastuzumab |
(8) 6 mg/kg bw |
|
1 |
docetaxel |
100 mg/m² KOF |
Cycle duration 21 days
Reference: [1114]
Trastuzumab 6 / letrozole 2.5, HER2+/HR+
|
Day |
Substance |
Dosage |
|
1 |
Trastuzumab |
6 mg/kg bw |
|
1-21 |
Letrozole |
2.5 mg |
Cycle duration 21 days
Reference: [1115]
Trastuzumab (8) 6 / vinorelbine 30, breast carcinoma (HER2+)
|
Day |
Substance |
Dosage |
|
1 |
Trastuzumab |
(8) 6 mg/kg bw |
|
1, 8 |
Vinorelbine |
30 mg/m² KOF |
Cycle duration 21 days
Reference: [1114]
Trastuzumab Emtansin 3,6, (HER2+)
|
Day |
Substance |
Dosage |
|
1 |
trastuzumab emtansin |
3,6 mg/kg bw |
Cycle duration 21 days
trofosfamide 150
|
Day |
Substance |
Dosage |
Procedure |
|
1-10 |
Trofosfamide |
150 mg |
1-1-1 |
Cycle duration 28 days
Reference: [1118]
trofosfamide 50
|
Day |
Substance |
Dosage |
Procedure |
|
1-28 |
Trofosfamide |
50 mg |
1-1-1 |
Cycle duration 28 days
Reference: [1118]
vinorelbine 30
|
Day |
Substance |
Dosage |
|
1-28 |
Vinorelbine |
30 mg/m² KOF |
Cycle duration 21 days
Reference: [1119], [1120], [1121]
vinorelbine 70 oral
|
Day |
Substance |
Dosage |
|
1, 3, 5, 8, 10, 12, 15, 17, 19 |
Vinorelbine |
23.3 mg/m² KOF |
Cycle duration 28 days
Reference: [1122]
The following substances, for example, can be used as monotherapy: alkylanciens, anthraquinones, anthracyclines (also in liposomal form), eribulin, fluoropyrimidines, platinum complexes, taxanes and vinorelbine. In polychemotherapy, these substances can be combined with each other or with other substances. However, only combinations that have been verified in studies should be used.
- Consensus
- Strong consensus
Background 5.40
Due to the heterogeneity of the metastases and the individual courses of disease, no uniform therapy strategy can be specified. This applies in particular to the cytostatic treatment of metastasized breast carcinoma. Although monotherapy has lower remission rates than polychemotherapy, this does not have a significant negative impact on survival time. Monotherapies are better tolerated, so that monotherapy should be used whenever possible. Polychemotherapy is only indicated for severe symptoms, rapid tumor growth and aggressive tumor behavior.
If the patient has not yet received anthracyclines/taxanes in the adjuvant therapy, these can be used primarily.
Cytostatic therapy should be based on the therapeutic index in cases of incurable disease, whereby the effect (e.g. symptom control) and side effects of a therapy must be considered and weighed up. The use of subjectively less stressful monotherapies or combination therapies is recommended. This is supported by a Cochrane meta-analysis published in 2015, which showed that there were no significant differences in progression-free survival and overall survival between combination therapy and sequential monochemotherapy when compared with sequential monochemotherapy. The response was significantly higher with combination chemotherapy compared to sequential monochemotherapy. However, combination chemotherapy also showed a higher toxicity with regard to the rate of febrile neutropenia. Many mainly non-haematological side effects were not described in this meta-analysis. In the meta-analysis, two scenarios of sequential monochemotherapy were described, one change of monochemotherapy with progression or fixed change of monochemotherapy without progression after a few cycles. The results were similar for both scenarios, with the described results referring to the first scenario [1077].
Before and during chemotherapy, the patient's general condition must be assessed regularly. During therapy, the side effects of this treatment must also be evaluated regularly. An evaluation of the therapeutic effect by means of imaging should be performed every 6-12 weeks (interval depending on the spread of the disease, disease dynamics and clinical situation). In the course of time, the imaging intervals can be extended in case of remission and good clinical and laboratory chemical assessment of the disease status. In case of progress or pronounced toxicity, therapy should be discontinued. The duration of therapy depends on the therapeutic index, whereby tumor response and therapy-related side effects should be included in the overall assessment and therapy should only be continued if the assessment is positive.
The dosage as well as the intended time intervals of the therapy should be adapted to general guidelines of the therapy, i.e. recognized published protocols. Dose-intensified and high-dose therapies have not yet led to any improvement in effectiveness. Their use is only acceptable in the context of studies (Cochrane: [800]).
5.4.4 Metastatic HER2-positive breast cancer
Metastatic HER2-positive breast carcinomas should be treated with anti-HER2 therapy, provided that there are no cardiac contraindications.
In the case of a metastasized HER2-positive breast carcinoma, a dual blockade with trastuzumab / pertuzumab and a taxane should be used in first-line therapy.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1b
- Consensus
- Consent
- References
- [1123]
In the case of a metastasized HER2-positive breast carcinoma, therapy with T-DM1 should be used in second-line therapy.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1b
- Consensus
- Consent
- References
- [1123]
5.4.5 Specific metastatic localization
5.4.5.1 Basic management of distance metastases
The indication for surgical or local ablative therapy of distant metastases should be determined individually and in an interdisciplinary consultation.
- Consensus
- Strong consensus
Background 5.44
In individual cases, patients with oligometastasis (staging), good performance status and a long interval between initial therapy can benefit from local therapy [1125]. However, the prognostic relevance compared to an adequate systemic therapy is unclear, since only retrospective studies with strictly preselected patients are available.
In the following chapter, recommendations of the S3 guideline Supportive Therapy of Oncology Patients (Version 1, 2016) are listed at several points. The guideline group is of the opinion that these recommendations can be applied directly to patients with breast cancer. A renewed consensus on the recommendations by the breast cancer guideline group was not reached.
Caution: If this recommendation in the S3 guideline Supportive Therapy of Oncological Patients (current version at http://leitlinienprogramm-onkologie.de/Supportive-Therapie.95.0.html) is changed, for example in the context of an update, these recommendations also lose their validity at this point.
5.4.5.2 Specific management of bone metastases
For the diagnosis and therapy of skeletal metastases, please refer to the S3 guideline Supportive Therapy in Oncology Patients (http://leitlinienprogramm-onkologie.de/Supportive-Therapie.95.0.html).
Osseous metastases occur very frequently (> 50%) in patients with breast cancer. Associated skeletal complications / skeletal related events (SREs) such as pathological fractures, pain with increased analgesic consumption, spinal compression syndromes or hypercalcemia require effective and often interdisciplinary therapy. In symptomatic tumor patients, a bone scintigraphy is suitable for diagnosis to assess the spread of osseous involvement. If there is a risk of fractures in particular, an x-ray-based procedure (native x-ray / CT) should be performed. An MRI should be performed if soft tissue is involved or in the case of neurological deficits, especially myelocompression. In case of detection of a newly occurring osseous manifestation, a new spread diagnosis is necessary. These different imaging techniques have different sensitivities and specificities in the diagnosis of bone metastases [1126].
Depending on the urgency and the aim of the therapy, the proposal of a therapy should be determined on an interdisciplinary basis by the surgeon, radio-oncologist, nuclear medicine specialist, internal oncologist, oncology specialist, pain therapist and, if necessary, representatives of other specialist disciplines.
The following treatment options are available for patients with osseous manifestations:
- Medicated pain therapy
- Local irradiation
- Surgical intervention
- Systemic tumour therapy
- Cytostatic drugs, hormone therapy, targeted substances, immunomodulating therapy, etc.
- Radionuclides
- Bisphosphonates or RANK ligand antibodies
In the case of painful bone metastases, the first priority is consistent medicinal analgesia. For stable osseous manifestations including stable vertebral body manifestations without evidence of myelon compression, conservative therapy (e.g. systemic tumor therapy, radiotherapy, radionuclide therapy, bisphosphonates/RANK ligand antibodies) is indicated. For patients with myelon compression and neurological symptoms, surgery followed by radiotherapy or radiotherapy alone is available. Therapy recommendations should be made on an interdisciplinary basis, with special consideration of the underlying disease, operability and the chances of neurological recovery. In the combined therapy (surgery + radiotherapy), the surgical intervention should be performed first. Surgery and radiotherapy are available for patients with a risk of stability in case of osseous manifestation (with or without fracture already occurred). Surgery is to be preferred if it is feasible and a positive effect on quality of life and/or lifetime can be expected.
5.4.5.2.1 Indications for radiation therapy
from Supportive Guideline (Version 1, 2016)
Indications for local percutaneous radiotherapy for bone metastases are
- local pain symptoms,
- Restricted movement,
- Reduction of stability (risk of fracture),
- Condition after surgical stabilization,
- threatening or existing neurological symptoms (e.g. spinal cord compression).
- Consensus
- Strong consensus
Background 5.45
For the reasons for this recommendation, see S3 guideline Supportive therapy in oncological patients (http://leitlinienprogramm-onkologie.de/Supportive-Therapie.95.0.html).
The indication should always be interdisciplinary, especially in consideration of a potential surgical intervention.
For pain therapy of uncomplicated bone metastases (without already occurred spinal cord compression or fracture), a single time irradiation with 1 x 8 Gy achieves an equally good reduction as fractional irradiation series (5 x 4 Gy or 10 x 3 Gy). After fractionated irradiation, however, re-irradiation is less frequently necessary [1127]. The overall prognosis of the patient should be taken into account when selecting the radiation scheme for bone metastases. Fractionated irradiation concepts (e.g. 5 x 4 Gy or 10 x 3 Gy) should be preferred in patients with a more favorable prognosis. Recalcification of an osteolytic metastasis is expected at the earliest about 3 months after radiation therapy [1127]. With modern irradiation techniques a renewed palliative irradiation of skeletal metastases can usually be performed after pre-irradiation and achieves a good pain response in about half of the cases [1128]. Radiation therapy of osseous metastases can be performed in parallel to therapy with antiresorptive substances (bisphophonates, RANK ligand antibodies) [1129]. Radionuclide therapy with Samarium-153 can be performed in patients with multifocal osseous metastases of solid tumors to reduce pain symptoms [1130].
In patients with acutely occurred, functionally relevant spinal cord injury (e.g. leg paresis, bladder and rectum dysfunction) in good general condition and sufficient survival prognosis an emergency decompression should be performed to minimize permanent neurological deficits [1131] Surgical decompression should be followed by postoperative fractional radiotherapy. After surgical decompression in myelon compression, radiotherapy should be started within 14 days in dry wound conditions. After intralesional and marginal surgical procedures on osseous manifestations, local radiation therapy should be performed. Postoperative radiotherapy after stabilising procedures should be carried out after completion of wound healing. No preoperative radiotherapy should be performed on the extremities or the spinal column in the surgical area.
5.4.5.2.2 Indications for surgical tretment
from supportive guideline (Version 1, 2016)
Indications for surgical therapy of osseous manifestations may be:
- Myelon compression with neurological symptoms,
- pathological fracture,
- imminent fracture (fracture risk e.g. via Mirel Score, Spinal Instability Neoplastic Scale (SINS)),
- solitary late metastasis,
- radiation-resistant osteolysis,
- therapy-resistant pain.
- Consensus
- Strong consensus
Background 5.46
For the justification of this recommendation, see S3 guideline Supportive therapy in oncological patients (http://leitlinienprogramm-onkologie.de/Supportive-Therapie.95.0.html).
A biopsy under established conditions [1132] is to be performed in cases of osseous manifestations:
- First-time imaging evidence of possible (also multiple) skeletal metastasis in a long-past primary tumour
- Isolated bone lesion with potential curative therapy approach without further metastases
- Radiological and/or clinical findings are not consistent with the diagnosis of bone metastasis (differential diagnoses must be considered)
The indication for a surgical intervention should be interdisciplinary, in particular in consideration of a potential radiotherapeutic intervention.
Pathological fractures that have already occurred or are imminent represent the main indication for surgical therapy in the area of the extremities. In the presence of a pathological fracture of the lower extremities of a previously mobile patient, there is an indication for surgical therapy. When choosing the appropriate surgical procedure for osseous manifestations in the extremities, the patient's prognosis must be taken into account in addition to the entity and radiation sensitivity of the tumor.
In stable vertebral body metastases or manifestations without evidence of myelon compression, conservative therapy (systemic tumor therapy, radiotherapy, radionuclide therapy, bisphosphonate / RANK ligand antibodies) is preferable to surgery.
In the case of therapy-refractory pain with imminent or actual compression fracture of one or more vertebral bodies in the thoracic spinal canal and lumbar spine without invasion of the tumor into the spinal canal, rapid pain reduction can be achieved by percutaneous cement augmentation with vertebroplasty or kyphoplasty [1133], [1134]. Patients with acutely occurred, functionally relevant compression-related spinal cord injury (e.g. proximal leg paresis, bladder and rectum dysfunction) in good general condition and sufficient survival prognosis should undergo emergency decompression to minimize permanent neurological deficits. Surgical decompression should be followed by postoperative radiotherapy with 10 x 3 Gy. After surgical decompression in myelon compression, radiotherapy should be started within 14 days in dry wound conditions [1131].
5.4.5.2.3 Bone protective therapy
from Supportive Guideline (Version 1, 2016)
To prevent complications in osseous manifestations, an osteoprotective therapy with bisphosphonates/denosumab should be performed.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus
- References
- [871]
Background 5.47
For the reasons for this recommendation see S3 guideline Supportive Therapy in Oncological Patients (http://leitlinienprogramm-onkologie.de/Supportive-Therapie.95.0.html).
Therapy with bisophosphonates/RANK ligand antibodies in osseous manifestations can delay or prevent the occurrence of skeletal-related events (SREs) [1135], [1136]. To prevent complications in osseous manifestations an osteoprotective therapy with bisphosphonates/denosumab should be performed. In patients with osseous metastases in breast cancer and after one year of zoledronate therapy in 4-weekly intervals the subsequent administration of zoledronate should be every 12 weeks [1137].
In patients with osseous metastases of breast cancer, the administration of denosumab compared to zoledronate leads to a numerically small, statistically significant reduction of SREs [1138]. For other outcome parameters (e.g. pain, QoL, spinal compression, mortality, AE maxillary osteonecrosis) there is no evidence for a difference. Data on the comparison of Denosumab versus the other bisphosphonates are not available. In order to prevent osteonecrosis of the jaw, a dental examination and any necessary dental rehabilitation should be carried out before the administration of bisphosphonates or Denosumab, and the patient should be instructed and motivated to maintain above-average (careful and regular) oral hygiene. In addition, regular risk-adapted dental examinations should be performed [1139].
5.4.5.3 Treatment of brain metastases
Singular or solitary brain metastases should be resected with a favourable prognostic constellation if the metastasis localisation is accessible for resection and the risk of postoperative neurological deficits is low. Subsequently, local fractionated radiation or radiosurgery of the tumor bed should be performed.
For patients with single metastases, radiosurgery is an alternative to resection if the metastases are not larger than 3 cm and there is no midline shift in the sense of space-consuming cerebral pressure symptoms.
Infratentorial metastases should be primarily resected if occlusive hydrocephalus is imminent.
In the presence of a limited number of brain metastases (in the order of 2 - 4), which do not exceed a total irradiatable volume, initial radiosurgery should be preferred due to the lower negative effects on neurocognition compared to whole brain irradiation, the shorter treatment duration and the higher control rate. Should surgery or radiosurgery not be considered due to other, negative prognostic criteria, sole whole brain irradiation should be used. For patients with multiple brain metastases, sole whole brain irradiation should be used.
The combination of resection or radiosurgery with whole-brain radiation improves brain-specific progression-free survival compared to surgery or radiosurgery alone, but not overall survival. It can be considered in individual cases.
Background 5.48 to 5.53
Drug therapy: Drug therapy of tumors plays an increasingly important role in the treatment of brain metastases. It can be used in primary therapy in addition to radiotherapy or radiosurgery or as the sole therapy modality [1150]. The blood-brain barrier, which under physiological circumstances prevents the penetration of cytostatic drugs into the brain, is often permeable in cerebral metastases, so that cytostatic drugs can reach cerebral therapeutic levels [1151]. The response rate in the sole drug therapy of brain metastases can reach the response rate in other organ metastases and is up to 50% in breast cancer. The vast majority of brain metastases in breast cancer are parenchymatous metastases. 11-20% of brain metastases are leptomeningeal metastases. Diagnostics should include a cranial MRI in addition to clinical examination. A cytological detection of malignant cells in the CSF puncture is the gold standard for the diagnosis of a leptomeningeal metastasis. In the case of a negative CSF puncture if leptomeningeal metastasis is still suspected, the CSF puncture should be repeated [1152]. In general, the treatment of patients with solid brain metastases [1153] and leptomeningeal metastases [1152] is based on the premise that the systemic therapy should be based on the primary tumor and its molecular characteristics. In a systematic review of the therapy of leptomenin-geal metastases in breast cancer Scott et al. could show in 36 studies with a total of 851 patients with meningeosis carcinomatosa that 87% had been treated with intrathecal chemotherapy and the median overall survival was 15 weeks [1154]. In addition to 18 retrospective studies and 13 case collections, 5 prospective randomized studies were included in this current review. In the only prospective randomized study that exclusively included breast cancer patients, 35 patients with breast cancer and meningeosis carcinomatosa were randomized to systemic therapy + radiotherapy with and without additional intrathecal chemotherapy (ITC) [1155]. The systemic therapy was based on hormone receptor status, previous therapies and general condition. Radiotherapy was performed as whole brain irradiation if clinically indicated. Systemic therapy and radiotherapy were well balanced between both therapy arms. ITC was performed with methotrexate and applied via an ommaya reservoir. Neurological stabilisation or improvement was described in 59% (ITC) vs. 67% (no ITC). Median time to progression 23 (ITC) vs. 24 (no ITC) weeks. Overall survival was 18.3 weeks vs. 30.3 weeks (no ITC) (p=0.32) for those patients who were additionally treated with ITC. Therapy related neurological complications were found in 47% (ITC) vs. 6% (no ITC) (p=0.0072). The authors concluded that intrathecal chemotherapy in addition to adequate systemic therapy and possibly radiotherapy in breast cancer patients with meningeosis carcinomatosa does not prolong survival but leads to an increased risk of therapy-related neurological complications.
In breast cancer, more than a third of patients with HER2-positive tumours develop brain metastases when treated with targeted therapies. One reason could be that these tumours preferentially metastasise to the brain, where they are protected from the action of antibodies by the blood-brain barrier. Antibody-based therapy is also effective for existing brain metastases in HER2-positive patients, and trastuzumab has been shown to penetrate brain metastases. The EGFR/HER2 inhibitor lapatinib is also effective in the treatment of brain metastases, but cannot prevent the occurrence of brain metastases. In monotherapy the substance has an objective response rate of only 6% [1156]. In combination with capecitabine the response rates are up to 38% [1157], [1158], [1159]. Even higher response rates of more than 60% were reported in non-irradiated patients treated with lapatinib and capecitabine [1160]. The occurrence of brain metastases as the first progression event in metastatic HER2-positive breast cancer was comparable between lapatinib / capecitabine vs. trastuzumab / capecitabine (3% vs. 5%) - while progression-free survival (HR 1.30) was prolonged under trastuzumab / capecitabine [1161]. In a retrospective analysis of the EMILIA study, the cerebral progression rate between trastuzumab emtansine (T-DM1) vs. capecitabine / lapatinib was comparable (without cerebral metastases at baseline 2% vs. 0.7%; with previously known cerebral metastases 22.2% vs. 16.0%). Overall survival in patients with cerebral metastases at baseline was significantly extended by T-DM1 compared to capecitabine / lapatinib (HR 0.38; 26.8 vs. 12.9 months) [1162].
Overall, it must be emphasized that even after the occurrence of brain metastases, a continuation of the HER2 blockade may be useful to keep systemic metastases under control [1163], [1164].
Breast carcinoma is the second most common cause of CNS metastases (after lung carcinomas). Data on the actual incidence vary in the literature between 15-20%; in autopsy collectives up to 40% [1151], [1165]. In recent years an increasing incidence of brain metastasis in patients with breast cancer has been observed. The increasing incidence is attributed to longer survival due to better control of the underlying disease and extracranial metastases as well as improved diagnostic measures (MRI) and their greater use. Patients with triple-negative histology and HER2-positive status were identified as risk factors in subgroup analyses [1166]. A single metastasis in the brain with simultaneously detectable metastases in other organs is described as singular, while singular cerebral metastasis is described as the only (detected) metastasis in the organism.
The overall prognosis is limited with a median survival time of 2 to 25 months. However, individual patients survive several years without relapse. Particularly in the case of isolated brain metastases occurring late in the course of the disease, intensified therapy seems justified. By means of a recursive partition analysis of the Radiation Therapy Oncology Group (RTOG) on a collective with brain metastases (predominantly from lung cancer) in the USA, 3 prognosis classes (RPA Class I - III) based on whole brain irradiation were defined as therapeutic measures according to simple prognostic criteria (age 70, systemic disease controlled). With the help of these three classes, the median survival between less than 2 or longer than 7 months can be estimated [1167]. Based on more recent data, a new score, the so-called Graded Prognostic Assessment (GPA), was proposed in 2012 [1168], again based on whole brain irradiation, which was supplemented by primary tumor-specific indices specifically for breast cancer. Using the breast carcinoma-specific score (allocation of points for Karnofsky index, histological subtype, age), the median survival times for GPA 0-1: 3.4 months, for GPA 1.5-2: 7.7 months, for GPA 3: 15 months and for GPA 3.5-4: 25.3 months.
In addition to the above-mentioned prognosis factors, the therapy strategy depends on the number, location and size of the brain metastases. The main therapy modalities include resection, radiosurgery, fractional radiotherapy, e.g. as stereotactically guided, localized radiotherapy or as whole brain radiation, and drug therapy of tumors. When assessing the effect of local therapies in clinical trials, it should be noted that median survival time is not only influenced by the effectiveness of the treatment of brain metastases, but also by the consequences of systemic tumor progression.
Surgery: Surgery has a safe value in the therapy of brain metastases [1140]. The median survival improves by 6-9 months compared to whole brain irradiation alone when resecting single metastases and subsequent whole brain irradiation. In symptomatic large metastases the palliative effect of the resection is important. Two of 3 randomized studies concluded that resection of single or solitary metastases followed by whole brain irradiation is superior to sole whole brain irradiation [1141], [1142], [1143]. A third study did not prove the value of surgery [1169]. However, this discrepancy can be explained by later surgery in the radiotherapy arm and an overall prognostically unfavorable patient population. Numerous retrospective analyses also speak in favor of resection of single or solitary metastases [1170]. However, the local recurrence rates after sole resection are relatively high at 60% [1148]. Local as well as distant recurrences are reduced if whole-brain radiation is followed by surgery [1143], [1148]. Whether whole-brain irradiation can be replaced by a hypofractionated, circumscribed postoperative follow-up irradiation of the postoperative tumor bed to avoid the negative effects of whole-brain irradiation is the subject of ongoing studies. In all the studies cited, the group of breast cancer patients represented a relevant subgroup; data exclusively on the therapy of brain metastases in breast cancer do not exist.
Radiosurgery: The percutaneous stereotactic application of single high radiation doses (radiosurgery) is a standard therapy in the treatment of brain metastases. The high radiation dose often leads to good tumor control, while the surrounding healthy tissue is well protected by the steep dose drop to the periphery. Radiosurgery thus represents an alternative to neurosurgical resection. At present, radiosurgery is mostly used as primary treatment of single or multiple lesions with a diameter of up to 30 mm (or 15 ml) or as recurrence treatment in patients who show a recurrence in a previously conventionally irradiated region. Local control rates range from 73-94%. Retrospective cohort studies indicate an equivalence of radiosurgery and neurosurgical resection. Comparative studies have not yet been published. However, it must be emphasized that local control seems to be better after radiosurgery. In EORTC study 22952-26001 the cumulative incidence of local progression was 59% after resection compared to 31% after radiosurgery [1148].
The decision depends on clinical circumstances (per surgery: histological backup, mass effect, per radiosurgery: applicability in any localization, even in functionally non-resectable lesions such as brainstem).
Radiation therapy for limited (1-4 brain metastases) and multiple metastases, significance of whole brain radiation: On the question of the combination of radiosurgery alone or with additional whole-brain radiation, there are now data from 6 randomized studies [1144], [1145], [1146], [1147], [1148], [1149]. Here, too, the size of the randomized breast cancer patients was almost 20%, in addition to patients with lung cancer as the largest group. The first two studies unanimously showed an increased local metastasis control and "in-brain-control" (prevention of new intracranial metastases) in combination with radiosurgery and whole brain irradiation [1144], [1145]. In the three subsequent studies [1146], [1147], [1148], higher control rates were also shown due to the resulting dose escalation through the combination of radiosurgery and whole-brain irradiation, but this was not accompanied by a survival advantage of the whole collective and the neurocognitive endpoints showed a substantial deterioration through the addition of whole-brain irradiation. In two more recent studies, neurocognitive endpoints were placed in the foreground of the evaluation [1147], [1149]. Due to the deterioration of neurocognition with simultaneous lack of survival advantage, current recommendations of the American professional societies are to initially withhold or postpone whole brain irradiation in favor of radiosurgery, despite the improved tumor control proven in all studies (using regular follow-up MRIs). Since modern radiosurgical techniques are now available to perform this also in the case of multiple brain metastases (up to 10), the side effects of whole-brain radiation are increasingly questioned even in the case of multiple metastases [1171]. In this respect, initial radiosurgery may be preferred in the case of more than 4 lesions (taking into account the pattern of infection and localization) in order to avoid the negative effects of whole-brain radiation on neurocognition or to provide whole-brain radiation as a salvage option.
Which patients will benefit from additional whole brain irradiation in the future due to prognosis or infestation pattern, also with the help of the technically possible hippocampal sparing in order to avoid negative effects on neurocognition, is the subject of currently ongoing studies.
Whole brain irradiation: The sole fractionated whole brain irradiation (usually fractionated with 10 x 3 Gy) remains the therapy of choice for patients with multiple brain metastases, limited prognosis group and reduced general condition, in addition to the alternative of refraining from therapy (best supportive care). In this clinical constellation, whole brain irradiation improves the median survival time from 2 months with purely supportive therapy to 3-6 months. It leads to an improvement in tumour-related neurological symptoms and quality of life. If favourable prognostic factors are present, treatment should be performed normo-fractionated with 5 fractions per week, 2 Gy per fraction up to a total dose of 36-44 Gy in order to avoid neurotoxic late effects of radiation therapy and to achieve an extension of the neurological remission time. Since the hippocampus is considered a sensitive region with regard to the occurrence of neurocognitive late effects, it is currently being investigated whether modern radiation techniques (intensity-modulated radiotherapy, IMRT) allow bilateral sparing of the hippocampus ("hippocampal sparing") without compromising cerebral tumor control.
In the case of cerebral metastases, systemic therapy (chemotherapy / endocrine therapy / anti-HER2 therapy) should be used in addition to local therapy (surgery / radiotherapy).
- Consensus
- Strong consensus
5.4.5.4 Treatment of liver metastases
If liver metastases are present, in individual cases a resection or possibly another local therapy (RFA, TACE, SBRT, SIRT) may be indicated:
- no disseminated metastases
- controlled extrahepatic metastasis
Background 5.55
If a limited number, especially isolated liver metastases occur in the liver, a metastasis resection can be performed. Alternatively, radiofrequency ablation, transarterial chemoembolization (TACE) [1184] or stereotactic radiation (SBRT) may be considered, although even less data are available. Factors that positively influence the decision to resect are Time interval after primary treatment > 12 months, good response to systemic therapy and estrogen-receptor-positive disease. Systemic therapy should be followed after surgical therapy. A prerequisite for local liver metastasis therapy is usually the exclusion of extrahepatic metastases as well as a local/local/regional recurrence and secondary carcinomas. As a locoregional therapy method, the Yttrium-90-Radioembolization (SIRT) [1185] can be considered for hepatic metastases that exceed the possibilities of local procedures in terms of number and size. All in all, the data required for SIRT are lacking to prove a patient-relevant benefit.
In individual cases, liver resection or interventional liver therapy may be indicated within the framework of the overall oncological concept even in the case of multiple or bilateral liver metastases or also in the case of limited but stable extrahepatic tumors [1186], [1187], [1188], [1189]. Even if a curative approach cannot always be pursued with the mentioned procedures, a progression-free time may be achieved under certain circumstances.
For the symptomatic treatment of upper abdominal pain, nausea and other complaints of the patient until the expected effect of a metastasis-specific therapy has set in, in the absence of this effect or if the patient refuses tumour therapy, reference is made to the S3 guideline "Palliative medicine for patients with incurable cancer" (AWMF register number 128/001OL).
5.4.5.5 Treatment of lungmetastases
In the presence of pulmonary metastases, in individual cases a resection or possibly another local therapy (RFA, stereotactic radiotherapy) may be indicated:
- No disseminated metastases,
- controlled extrapulmonary metastasis.
Background 5.56
A metastasis resection is only indicated in the presence of a very limited, particularly solitary pulmonary metastasis after exclusion of extrapulmonary metastases. Factors that positively influence the decision to resect are: longer time interval after primary treatment > 24-36 months, good response to systemic therapy, solitary metastasis and estrogen-receptor-positive disease. Systemic therapy should be followed after surgical therapy. A prerequisite for lung metastasis resection is the exclusion of local/local recurrence, secondary carcinoma and, as a rule, extrapulmonary metastasis. For curative resection of pulmonary metastases a 5-year survival rate of 40 to 80% is given.
5.4.5.5.1 Malign pleural effusion
If a pleural carcinosis with symptomatic effusion formation occurs, the patient should be offered a pleurodesis.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus
- References
- [1195]
Hintergrund 5.57
Wenn maligne Pleuraergüsse symptomatisch sind und sonstige Manifestationen nicht im Vordergrund stehen, ist eine Pleurodese indiziert (Talkum, Tetrazyklin oder Bleomycin oder/und Einlage einer Thorax-Verweil-Drainage). Diese wird bevorzugt thorakoskopisch durchgeführt.
Zur symptomatischen Therapie von Dyspnoe, Schmerzen u. a. Beschwerden der Patientin bis zum Einsetzen der erwarteten Wirkung einer metastasenspezifischen Therapie, bei Ausbleiben dieser Wirkung oder wenn die Patientin eine Tumortherapie ablehnt, wird auf die S3-Leitlinie „Palliativmedizin für Patienten mit einer nicht heilbaren Krebserkrankung" (AWMF-Registernummer 128/001OL) verwiesen.
5.4.5.6 Cutaneous and soft tissue metastases
If skin and soft tissue metastases occur, surgical excision or other local therapy (e.g. radiotherapy) may be considered.
- Consensus
- Strong consensus
Background 5.58
Circumscribed skin metastases and metastases of soft tissue can be excised in healthy individuals or locally irradiated percutaneously. If the findings are not very extensive, topical procedures can be discussed [1196], [1197], [1198]. If necessary, electrochemotherapy can also be used [1199], [1200], [1201].
Exulcerative tumor growth / Cancer en Cuirasse:
Breast carcinoma is the malignant tumor which most frequently develops skin metastases, which already in curable stages of the disease lead to considerable symptom burden with impairment of the patient's quality of life [1202] Cancer en Cuirasse is a distinct, aggressive, nodular plate-like, partly exulcerated manifestation with consecutive lymphedema. It is often accompanied by pain, itching, bleeding and foetal odor. Due to the thick fibrotic manifestation with reduced vascularization of the carapace-like skin metastases, the causal therapy options are limited. As a rule, exudative skin metastases or Cancer en Cuirasse are non-curative stages of the disease. Patients are severely affected by the physical disfigurement, limited movement, pain, weeping of the wound and the sometimes very unpleasant odour. Palliative care aims to relieve all these symptoms. This requires complex interventions (wound care plus psychosocial support) [1198], [1202], [1203], [1204], [1205].
5.5 Palliative medicine
In the palliative situation, all necessary measures should be geared to the patient's individual therapy and life goals.
- Consensus
- Strong consensus
The right time to supplement regular care with palliative care depends primarily on the patient's needs and individual disease-related requirements.
- Consensus
- Strong consensus
Palliative care is characterised by a multi-professional and interdisciplinary approach.
- Consensus
- Strong consensus
The following principles should be applied in the palliative care of patients with an incurable breast cancer disease:
- consideration of and response to the patient's needs in all four dimensions (physical, psychological, social, spiritual)
- the consideration of patients' preferences
- the determination of realistic therapy goals
- Knowledge of the organizational forms of palliative care
- the creation of conditions that respect the intimacy of the patient
- Consensus
- Strong consensus
Palliative care includes medical symptom control, palliative care and psychosocial support until death. It is provided as general or specialised palliative care according to need.
- Consensus
- Strong consensus
Background 5.59 to 5.63
Palliative medicine/palliative care (synonym: palliative care) pursues the goal of improving the quality of life of patients with a life-threatening disease and their relatives. This is achieved by prevention and alleviation of suffering, by early recognition and treatment of physical, psychological, social and spiritual problems [1206], [1207], [1208], [1209], [1210], [1211], [1212], [1213], [1214], [1215], [1216], [1217], [1218], [1219], [1220]. This is done by preventing and alleviating suffering, by early recognition, careful assessment and treatment of pain and other distressing symptoms of a physical, psychosocial and spiritual nature [1206], [1207], [1208], [1209], [1210], [1211], [1212], [1213], [1214], [1215], [1216], [1217], [1218], [1219], [1220], [1221].
The recommendation is based on the consensus of the technical experts involved. Otherwise, the guideline group refers to the overarching interdisciplinary S3 cross-sectional guidelines "Palliative Care for Patients with Non-Curable Cancer" (AWMF Registry Number 128/001OL), the guideline "Supportive Therapy for Oncological Patients" (AWMF Registry Number 032/054OL) and the guideline "Psycho-oncological Diagnosis, Counselling and Treatment of Cancer Patients" (AWMF Registry Number 032/051OL) as well as the corresponding chapters in this guideline.
Palliative care
Palliative care includes medical symptom control, palliative care and psychosocial support until death [1207], [1208], [1209], [1210], [1211], [1212], [1213], [1214], [1215], [1216], [1217], [1218], [1219], [1220], [1222]. In the palliative situation, all necessary measures are oriented towards the individual therapy and life goals of the patient [1207], [1214]. Graduated palliative care is the necessary prerequisite for varying the intensity of treatment according to the symptom burden and at the same time ensuring continuity of palliative support [1223], [1224]. Symptom control, palliative care and psychosocial support stand for three dimensions of palliative treatment which must be included in every qualified palliative care offer, regardless of the level of specialization of the offer [1208]. Palliative care is provided in addition to (a) disease-modifying therapies with the primary therapeutic goal of prolonging life (palliative therapy), (b) prophylaxis or treatment of side effects associated with the disease or with these therapies (supportive therapy) [1206], [1214], [1216], [1220], [1225], [1226], [1227], [1228] and (c) the needs-based psychosocial and psycho-oncological care. Specialised co-treatment is advisable for patients in whom a high level of physical, psychosocial or spiritual stress persists despite general palliative medical measures. This is characterised by the fact that a team (a) with specialised training (e.g. palliative care nursing training or additional medical designation palliative medicine), (b) which (b) is mainly and primarily entrusted with palliative care, (c) is involved in the treatment of the patient in addition to routine care (S3 guideline AWMF register number 128/001OL). Routine integration of specialized palliative care into local therapy standards is aimed at in accordance with current international guideline recommendations [1207], [1214], [1229] in the sense that palliative care is integrated into treatment and no longer whether this should be done. In Germany, Gärtner et al. have developed disease-specific indicators for palliative medical counselling and, if necessary, co-care. These include (1.) metastasized and inoperable breast cancer, (2.) locally advanced and inoperable breast cancer, or (3.) recurrent disease situations in which intravenous chemotherapy is administered [1230].
For further information on the question of care structures, reference is made to the S3 guideline on oncological palliative care in the Oncology guideline program (AWMF register number 128/001OL).
5.5.1 Patients' needs
The highest therapeutic goal in palliative care - the individual quality of life - can only be evaluated and defined by the patient herself [1231], [1232]. The therapy goal must be measured against the patient's ideas, priorities and wishes [1233]. The patient's physical, psychosocial, spiritual and existential burdens can be [1207], [1208], [1209], [1210], [1211], [1212], [1213], [1214], [1215], [1216], [1217], [1218], [1219], [1220]. Patients with breast cancer have a high need for medical information and psychological support [1234], [1235], [1236]. It should be noted that the interindividual needs may be the same, but priorities may be weighted differently. In order to identify unconsidered needs, a short assessment is routinely performed when palliative care is called in, which includes the multidimensional needs of the patients according to their self-assessment [1237]. A validated single-item questionnaire is the "NCCN Distress Thermometer", while the "Palliative Outcome Scale (POS)" asks for special stresses and needs in more detail [1238], [1239], [1240]. A structured recording of the physical symptoms (e.g. Edmonton Symptom Assessments Scale (ESAS)) may also be helpful [1241]. For all three assessment instruments there are validated versions for Germany [1242], [1243], [1244]. Recording the patient load improves the need orientation in the care of patients [1245].
A prerequisite for the treatment of patients and a component of palliative basic values is the high appreciation of patient autonomy and participation [1211], [1215], which, in addition to the above-mentioned routine recording of the patient's self-assessment of quality of life and symptom burden, also includes the active inclusion and comprehensive/adequate information/education of the patient in the decisions for certain therapy options [1207], [1214]. In principle, the patient has the possibility to include close relatives in the discussions according to her wishes. In order to enable the patient to have her confidants be able to represent the presumed will of the patient as well as possible in the case of possible disturbances of consciousness in the course of the disease, there is the offer of consultation for writing a "power of attorney for medical matters" [1233]. Regarding further aspects of palliative care independent of the underlying diagnosis, reference is made to the S3 guideline "Palliative Care for Patients with Non-Curable Cancer" of the Oncology Guidelines Program (AWMF Register Number 128/001OL). It discusses questions of symptom control, palliative care, psychosocial support and care structures in detail and across all organs.
5.5.2 Family carers' needs
A central point of palliative care is the involvement of those close to the patient. In addition to family members, this means above all those persons who are important for the patient in the current situation, regardless of the degree of kinship. In principle, the patient has the possibility to include the persons she wishes in the discussions. However, the wishes and fears of the close relatives themselves as well as their needs, for example for information, also play an important role. With regard to further aspects of care for close relatives, reference is made to the S3 guideline "Palliative care for patients with incurable cancer" of the Oncology Guidelines Programme (AWMF register number 128-001OL).
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