6. Treatment, support and continuing care – Breast Cancer
6.1 General concept
The chapters in Section 6 - Treatment, Care, Accompaniment of our patients - have been redefined and restructured due to the significant development of diagnostic and therapeutic options in recent years. For example, the start of aftercare has so far referred to the completion of primary treatment (if necessary, no later than 6 months after surgery). The definition of this period has changed with the introduction of neoadjuvant therapies, adjuvant long-term therapies with antibodies and (anti-)hormones and the modified forms of radiation therapy. Consequently, the content and timing of the term "aftercare" must be adapted. In addition, there are overlaps between the various subject areas that exist at different points in time in the care chain for patients with breast cancer.
The chapter "Treatment, care and support" covers the psychosocial aspects and psycho-oncology and supportive therapies. Both chapters deal thematically with treatment situations that begin in the context of primary treatment, but which also seamlessly move on to long-term support. The chapter on rehabilitation covers the period following the completion of primary local therapy. This point in time is usually the end of primary treatment by means of surgery (also after previous neoadjuvant chemotherapy) or radiotherapy (also after previously carried out adjuvant chemotherapy).
Following the completion of the primary local therapy, in particular the completed radiotherapy, the newly defined aftercare will then follow, focusing on the earliest possible detection of locoregional or intramammary recurrences, contralateral breast carcinoma, the targeted search for metastases in the event of symptoms or justified suspicion, as well as the diagnosis and therapy of side effects and late effects of the primary and long-term therapies.
The final sections in this restructured chapter are palliative care, which will be discussed due to its increasing importance, and the not unimportant complementary medicine.
The tasks of the treating physicians have changed due to the increasing complexity of the diagnosis and therapy options or the time periods. Although data from prospective randomised trials with regard to individual aspects such as adverse effects, long-term toxicity or the use of supportive measures are available, the definition of the investigations, both in terms of the interval and the type of investigations, is defined on a study-specific basis. Summarising overall data from prospective randomised studies for the corresponding evidence-based recommendations for action within the framework of this changed range of tasks are not available. A generalisation for everyday clinical practice can therefore only be made after an evaluation of the study data and the combination of individual aspects. It must also be taken into account that since 2004, no new prospective randomized studies have been published to test new methods or time intervals for the diagnosis of locoregional recurrence or distant metastases. Short-term, almost annual variations in therapy recommendations therefore make it impossible to change the recommendations on intervals and the type of diagnosis. Prospective randomized studies to test this have been initiated, so that the data situation may improve in the near future.
6.2 Psycho-oncological aspects
6.2.1 Basic principles of psycho-oncological care
Today, psycho-oncology is a separate discipline whose task is to scientifically research the various psychosocial aspects in the development, treatment and course of cancer in children, adolescents and adults and to apply the relevant findings to the care and treatment of patients [29], [1246], [1247], [1248]. Psycho-oncology is an integral part of the care of patients with breast cancer. In Germany, further education and training curricula are offered by corresponding professional associations to ensure professional qualification. The addressees of these further training courses are doctors, psychologists and social pedagogues, who are referred to in the following as psycho-oncology specialists. An additional psycho-oncological qualification is a prerequisite for recognition as a psycho-oncological specialist [1249]. The psycho-oncological care of breast cancer patients should be implemented in an interdisciplinary manner between all professional groups involved in the treatment. This implies that a psycho-oncological specialist is integrated into the treatment team in the respective care setting (inpatient and outpatient treatment, inpatient rehabilitation, outpatient aftercare) and is in regular contact with the medical staff. This exchange should be regulated and structured in the form of case discussions or ward conferences [1250], [1251], [1252] Detailed aspects of psycho-oncological care can be found in the S3 guideline for psycho-oncological diagnostics, counselling and treatment of cancer patients [29].
Psycho-oncological support
All patients and their relatives should be informed early on about the possibilities of psycho-oncological support.
- Consensus
- Strong consensus
6.2.2 Psycho-oncological care strategies and interventions
Psycho-oncological care of patients with breast cancer includes patient-oriented information and counselling [37], [1254], [1255], [1256], [1257], [1258], [1259], a qualified psychological diagnosis and determination of needs [29], [1260], [1261], [1262] as well as a targeted psycho-oncological treatment to support the management of the disease and treatment consequences [1263]. The relatives must be included in the psycho-oncological care [1264], [1265].
All patients should receive screening for psychosocial stress. Psycho-oncological screening should be carried out as early as possible, at appropriate intervals if clinically indicated, or repeatedly as the disease progresses if the patient's condition changes (e.g. recurrence or progression of the disease).
- Consensus
- Strong consensus
- References
- [1266]
Background 6.3
The diversity and complexity of possible psychological impairments in breast cancer in different disease and treatment phases require that the need for psychosocial treatment be determined individually and that a psycho-oncological specialist be involved as needed, as well as a reference to the support services offered by self-help. This is the only way to adequately address the different problems and burdens of breast cancer patients.
Target areas of psycho-oncological interventions in breast cancer are:
- Anxiety, depression, stress experience [1267], [1268] [873]
- Disease processing, disease settings [1265], [1269], [1270], [1271]
- Health-related quality of life and functional status [1253], [1272]
- Body image and self-concept [1273], [1274], [1275] [873]
- social relations, communication [1276], [1277], [1278]
- Sexuality [873], [1255], [1273], [1274], [1275]
- Fatigue [873], [1239], [1279], [1280], [1281], [1282], [1283]
- Pain [1284], [1285]
- neuropsychological impairments (attention, memory, concentration) [873], [1286]; see also Chapter 6.5 Rehabilitation.
Within the framework of a systematic literature review the following psycho-oncological interventions for breast cancer patients could be identified as evidence-based [1266]:
- Individual psychotherapeutic interventions [1255], [1259], [1266], [1287], [1288]
- psychoeducative individual or group intervention as well as supportive expressive group therapy [1249], [1289], [1290], [1291], [1292]
- Relaxation method [1293], [1294], [1295], [1296], [1297]
- Couple Counselling or Couple Therapy [1274], [1298], [1299], [1300], [1301]
The publication [1266] summarizes the results for all diagnosis groups. Since studies with breast cancer patients accounted for about 50% of all included publications, a subanalysis was conducted for the target group of breast cancer patients, which yielded an identical evaluation of the evidence base.
Without systematic research, randomised studies, in some cases meta-analyses, are available for the following interventions:
- Neurocognitive Training [300], [1286], [1302], [1303] ; see also Chapter 6.5 Rehabilitation
- artistic therapy methods (art, music and dance therapy) [1304], [1305], [1306], [1307], [1308]
A systematic literature search has shown that relaxation techniques, psychoeducational interventions, individual psychotherapeutic interventions and psychotherapeutic group interventions show significant improvements with regard to the target variables anxiety, depression, psychological well-being and quality of life. In some studies, only significant effects on depressiveness could be achieved for the couple interventions, while no effects could be demonstrated for the other target parameters.
Psycho-oncological interventions
The psycho-oncological interventions listed below should be offered to patients after the individual needs have been determined using validated measuring instruments:
- Relaxation method
- psychoeducational interventions
- individual psychotherapeutic interventions
- psychotherapeutic group interventions
- psychotherapeutic couple interventions
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus
- References
- [1266]
Background 6.4
In addition to the clinical picture, validated measuring instruments such as the psycho-oncological basic documentation (PO BaDo), the German version of the Hospital Anxiety and Depression Scale (HADS), the Hornheider questionnaire or the distress thermometer [1309] can be helpful for individual assessment of needs.
In order to ensure continuity of psycho-oncological care after inpatient treatment, patients should be informed about further outpatient and aftercare offers by professional helpers and self-help.
- Consensus
- Strong consensus
Background 6.5
It has proven to be helpful to include quality of life in addition to the classical parameters for the assessment and planning of diagnostics and therapeutic measures. For the assessment of quality of life, structured and standardized questionnaires (such as the EORTC QlQ C30 or FACT G) [1310], [1311], [1312], [1313] can be used in addition to the medical consultation. These questionnaires can be used to evaluate the patients' well-being in somatic (intensity and frequency of physical symptoms, functional limitations), psychological (anxiety, depression, cognitive limitations) and social (family life, work, sexuality) areas [1314]. They have been tested in elaborate studies with regard to their measurement quality (reliability, validity and sensitivity) [1263]. Randomized studies on the use of quality of life instruments in routine care are available [1315], [1316].
The patient's quality of life should be assessed using validated methods (e.g. EORTC QlQ C30) at appropriate intervals when clinically indicated or when there are changes in the disease status.
- Consensus
- Consent
Background 6.6
For a sufficient supply, the validated recording of the quality of life is necessary for the identification of previously unrecognized secondary problems such as fatigue or insufficiently adjusted pain. In the case of identification of quality of life problems, appropriate measures for their treatment or alleviation must be initiated.
Necessary for adequate therapy is the establishment of a regional network of all health care professions in the inpatient and outpatient sector and specific treatment according to agreed recommendations for each area of intervention.
The evaluation of validated questionnaires and the visualisation of existing deficits (e.g. by means of a profile showing inroads in the above options) is a prerequisite for individual therapy and a helpful instrument for improved communication between doctor and patient [1317]. The EORTC QlQ C30 [1318], for example, is a suitable questionnaire for recording quality of life. The distress thermometer [1319] can also be considered with the additional questions as an instrument for recording general stress.
6.3 Supportive therapy
This chapter with the respective marked statements and background texts is partly based on the S3 guideline "Supportive therapy in oncological patients" [871].
The following sections with background texts are partly taken literally from the S3 guideline "Supportive therapy in oncological patients":
- Definition
- Drug-induced nausea and vomiting
- Radiotherapy induced nausea and vomiting
- Neutropenia, febrile neutropenia (FN), infections
- Anemia
- Neurotoxicity
Some of the background texts have been significantly shortened and focused on relevant content for the care of patients with breast cancer. For more detailed information on the background and data, please refer to the S3 guideline "Supportive Therapy for Oncological Patients" [871].
The remaining sections were updated by the chapter authors based on the previous version.
6.3.1 Definition
Supportive therapy is understood to be supportive measures that optimize the safety and tolerability of cytostatic therapies and other drug treatments, surgical interventions or radiotherapy for the treatment of the underlying malignant disease. Supportive measures are an indispensable part of the oncological treatment concept, the prevention and treatment of complications and side effects of cancer therapy. A major goal of supportive therapy is to maintain or improve the patient's quality of life and to be able to implement modern therapy strategies without abortion, dose reduction or extension of intervals.
Supportive therapy includes all supporting measures to avoid or treat side effects of the cancer disease or therapy. These can relate to the management of physical, psychological symptoms or to side effects throughout the entire treatment process and course of disease, starting with diagnosis, through tumor therapy, to aftercare (from S3 guideline "Supportive therapy in oncological patients" as defined by the international supportive organization MASCC; www.mascc.org/about-mascc, accessed 02-10-2016). Supportive therapy and palliative medicine or palliative care are not synonymous. Whether "side effects of cancer" are part of supportive or palliative medical therapy is disputed (from AWMF S3 guideline Palliative Medicine for Patients with Non-Curable Cancer; [1320]).
6.3.2 Significance and qualification of side effects
In the case of concomitant symptoms of cytostatic therapies, a distinction must be made between objectively measurable side effects or damage on the one hand and subjectively perceived impairment on the other. These effects are often evaluated differently by doctors and patients - for example, nausea and alopecia are experienced by the patient as very stressful, while the doctor's attention is directed more towards objectively measurable organ toxicities (e.g. myelosuppression) that may be life-threatening.
For better understanding and documentation, it is recommended to indicate the severity of adverse effects according to a generally accepted classification, e.g. according to the Common Terminology Criteria for Adverse Events of the American National Cancer Institute - currently version 4.03 (NCI-CTCAE) [1321] - or the toxicity scales of the WHO.
6.3.3 Principle of supportive therapy
Supportive therapy in oncology or senology comprises an interdisciplinary spectrum of measures that serve to improve the conditions for the feasibility of a therapy, reduce side effects, achieve treatment results that meet the objectives and maintain or improve the patient's quality of life.
In principle, foreseeable toxicities should be anticipated and, if possible, primarily avoided. The individual situation and comorbidities of the patients must always be taken into account when selecting and dosing e.g. drug-based cancer therapy. If side effects cannot be avoided, prophylaxis is generally more advantageous than treatment of the already manifest toxicity. In everyday clinical practice, therefore, concomitant diseases and risk factors for side effects should be systematically recorded before the start of cytostatic treatment and the therapy protocol should be adapted accordingly.
The patient should be informed early and in detail about expected side effects, general measures to avoid them and treatment options. Preventive medication should be prescribed. The drug prophylaxis of nausea and vomiting as well as the avoidance of neutropenia in certain chemotherapies are oncological standards which must be adhered to according to the current guidelines listed below.
In the course of therapy, undesirable effects must be specifically and promptly queried and documented in order to be able to react accordingly with modifications of the treatment protocol (e.g. dose reduction) as well as indicated measures for the treatment of any toxicities that have occurred. This includes among others
- Detection and treatment of infections,
- Detection and treatment of symptomatic anaemia,
- Detection and treatment of skin toxicities,
- Detection and treatment of lymphedema.
Physical activity
The patient should be advised to be physically active during oncological therapy, as this has a positive effect on the physical fitness of the patient and thus facilitates the performance of daily activities (ADL).
6.3.4 Medication-induced nausea and vomiting
Nausea and vomiting induced by chemotherapy and/or targeted therapy are among the most stressful side effects of drug treatment, whereby vomiting can be effectively prevented in the vast majority of cases with adequate antiemetic prophylaxis. More problematic is the nausea, which is often still subjectively impairing.
Avoiding nausea and vomiting, which can be caused by chemotherapy or other oncological preparations, is an essential supportive measure in oncology and thus for the doctors in charge.
The symptom complex includes nausea, gagging and vomiting. The intensity of nausea and vomiting is classified internationally according to the Common Terminology Criteria for Adverse Events (CTCAE) into 4 degrees of severity [1321].
Table 6: Common Terminology Critera for Adverse Events (CTCAE, Version 4.03)
|
Criterion |
Grade 0 |
Grade 1 |
Grade 2 |
Grade 3 |
Grade 4 |
|
Nausea |
No nausea |
Something, food intake not restricted |
Moderate, food intake restricted |
Strong, no food intake |
|
|
Vomiting |
No vomiting |
1-2x/day |
3-5x/day |
≥ 6x/day |
Life-threatening |
Nausea and vomiting are divided into 3 forms according to the time of symptomatology in accordance with the S3 guideline "Supportive therapy in oncological patients":
- Acute: Occurs within 24 hours after the start of tumour therapy,
- delayed: Occurs later than 24 hours after the start of tumour therapy and lasts up to 5 days,
- anticipatory: consequence of a classical conditioning triggered by external factors such as smell, taste and visual impressions, by psychological factors such as fear and tension or characterized by nausea and vomiting during a previous tumor therapy
6.3.4.1 Diagnostics
The general occurrence, frequency and intensity are recorded in a conversation before and after each therapy cycle, before the start of a new therapy cycle and at regular intervals in the case of long-term therapy. It is also possible to use patient diaries to document the occurrence between two cycles.
In addition, numerous other causes of nausea and vomiting are possible in oncological patients, which should be considered and clarified by differential diagnosis, especially if there is no temporal connection between the occurrence and application of the tumour therapy or a new occurrence during ongoing therapy. These are described in detail in the S3 guideline "Supportive therapy in oncological patients" [871].
6.3.4.2 Prophylactic pharmacotherapy
In principle, antiemetic prophylaxis is based on the emetogenic potential of the drugs (see Table 10). Table 10 shows the substances which are of importance for patients with breast cancer. An overview of all antineoplastic substances can be found in the current S3 guideline "Supportive Therapy in Oncological Patients" [871].
With regard to the emetogenic risk of drug therapy, the following factors play an essential role according to the S3 guideline "Supportive Therapy in Oncological Patients":
- Type of therapy: higher for cytostatic drugs than for anti-hormonal therapy and targeted therapies (e.g. antibodies or kinase inhibitors),
- Dosage: higher with increasing dosages,
- Therapy regimen: higher for dose-dense therapy regimens,
- Combination: higher in combination with other emetogenic drugs and in combination with radiotherapy.
The cytostatic drug with the highest emetogenic potential determines the classification in the group "high, moderate, low or minimal". Here, the emetic risk in the absence of antiemetic prophylaxis is considered. For oral therapies the emetogenic potential is given for a complete therapy cycle. No additive effect on the emetogenic potential is to be expected from other cytostatic drugs, e.g. in combination chemotherapy. An exception is the anthracycline/cyclophosphamide-based chemotherapy for patients with breast cancer [1323], [1324], [1325].
Table 7: Emetogenes Potenzial der beim Mammakarzinom verwendeten einzelnen Zytostatika, aktualisiert 5/2012
|
High: Risk of vomiting without antiemetic prophylaxis > 90 % |
|
|
Anthracycline in combination with cyclophosphamide |
Cyclophosphamide (> 1500 mg/m2) |
|
Cisplatin |
|
|
Moderate: risk of vomiting without antiemetic prophylaxis 30-90 % |
|
|
Carboplatin*\footnote {* Cave: Carboplatin is a special group; see recommendations below.} |
Doxorubicin |
|
Cyclophosphamide ( |
Epirubicin |
|
Cyclophosphamide, per os |
Mitoxantrone (> 12 mg/m2) |
|
Low: risk of vomiting without antiemetic prophylaxis 10-30 %. |
|
|
Capecitabine |
Methotrexate |
|
docetaxel |
Mitoxantrone ( |
|
Eribulin |
Nab paclitaxel |
|
everolimus |
Paclitaxel |
|
5-fluorouracil |
Pertuzumab |
|
Gemcitabine |
|
|
Ixabepilon |
Topotecan |
|
Lapatinib |
Trastuzumab emtansin |
|
liposomal doxorubicin |
|
|
Minimal: risk of vomiting without antiemetic prophylaxis |
|
|
Anastrozole |
Letrozole |
|
Bevacizumab |
Methotrexate, per os |
|
Bleomycin |
Tamoxifen |
|
Copy |
Trastuzumab |
|
Fulvestrant |
Vinorelbine |
|
GnRH Analogues |
|
According to the S3 guideline "Supportive Therapy in Oncological Patients" [871] belongs to the patient-specific risk factors:
- Gender: higher for women,
- Age: higher in younger patients,
- Travel sickness / morning sickness: higher in patients with this condition,
- History of nausea and vomiting: higher in patients with previous exposure to chemotherapy,
- Alcohol consumption: lower in patients with chronic heavy alcohol consumption,
- Anxiety: higher in anxious patients,
- and the negative expectation
If necessary, the antiemetic prophylaxis should be adjusted if patient-specific risk factors are present.
Other factors may include the time of day of treatment, the environment/ environment and other emetogenic drugs, e.g. opiates.
In order to keep the side effects of the therapy low, to reduce the strain on the patient and to optimise the feasibility and acceptance of the therapy, antiemesis must always be carried out as prophylaxis during tumour treatment. Before each new therapy cycle, the effectiveness of the previous prophylaxis must be evaluated and adjusted if necessary. For the planning and implementation of supportive antiemetic therapy, the following aspects must be considered:
- antiemetic prophylaxis before the start of therapy according to the cytostatic drug protocol,
- detailed knowledge of the emetogenic risk of the respective therapy,
- Knowledge of individual patient risk,
- Reserve medication for the case of need,
- Education of the patient before therapy about prophylaxis and emergency medication,
- Radiation of peace and security,
- regular airing of the room,
- sufficient hydrogenation,
- Provide for distraction/relaxation.
The administration of antiemetics must always be carried out as a prophylaxis before the start of chemotherapy application. The oral administration of antiemetics is equivalent to the i.v. administration. Prophylaxis must be taken on the 1st day of chemotherapy application (acute phase) and on days 2 to 3 or 4 (delayed phase). In the case of chemotherapy lasting several days, prophylaxis for the acute phase should be repeated every day and prophylaxis for the delayed phase should be continued for two subsequent days.
The American Society of Clinical Oncology (ASCO) and the Multinational Association of Supportive Care in Cancer (MASCC) have developed guidelines for the prevention and control of nausea and vomiting which, together with the current data situation, form the basis of the recommendations of the S3 guideline "Supportive Therapy in Oncology Patients", which are presented in the following [1324] [1325] Background and detailed information on the data and literature of the individual drugs as well as dosages can be found in the current S3 guideline "Supportive Therapy in Oncology Patients" [871].
6.3.4.3 Highly emetic cancer chemotherapy
The following statement was taken from the S3 guideline "Supportive therapy in oncological patients":
Acute phase:
In the case of a one-day drug therapy with a risk of vomiting > 90%, prophylaxis with 5-HT3-RA, NK1-RA and dexamethasone should be administered before the drug therapy.
Delayed phase:
In a one-day drug therapy with a risk of emesis > 90%, prophylaxis with dexamethasone should be continued for another 2-4 days after the end of the highly emetogenic therapy.
If the NK1- RA aprepitant was part of the primary prophylaxis, it is to be administered for 2 further days with 80 mg daily. Fosaprepitant or netupitant/palonosetron is only administered on day 1 of the drug therapy.
Abbreviation: 5-HT3-RA - 5-hydroxytryptamin3-receptor antagonist, NK1- RA - neurokinin-1-receptor antagonist
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus
- References
- [871]
6.3.4.4 Anthracycline/Cyclophosphamide (AC)-based chemotherapy specifically for patients with breast cancer
In all international guidelines as well as in the S3 guideline "Supportive Therapy in Oncological Patients" AC-based chemotherapy is now classified as highly emetogenic [1323], [1324], [1325]. In analogy to the approval studies of highly emetogenic chemotherapy, aprepitant was applied for 3 days in the so-called Warr study of AC-based chemotherapy, but the combination with ondansetron and dexamethasone was only given on day 1. Patients in the control arm received ondansetron and dexamethasone on day 1 and ondansetron for 2 additional days. The primary endpoint was also the complete response. In this study, the additional administration of aprepitant in the overall phase of AC-based chemotherapy resulted in a 9% higher CR (p = 0.015) [1327]. In contrast to the highly emetogenic chemotherapy no significant effect of aprepitant in the delayed phase (day 2-5) of vomiting could be achieved. It is worth mentioning that the response rate in the delayed phase of 55% (control arm 49%) was significantly lower than in phase III studies with cisplatin-containing chemotherapy (complete response 75-76%), so that a reclassification of AC-based chemotherapy as highly emetogenic chemotherapy is logical.
In another large phase III study (n = 1449) in AC-containing chemotherapy, the efficacy of NEPA (netupitant/palonosetron) and dexamethasone day 1 versus palonosetron and dexamethasone day 1 was tested [1328]. No further antiemetic prophylaxis was given beyond day 1. The complete response on days 1-5 was 66.6% in the control arm and 74.3% in the experimental arm (p = 0.001).
6.3.4.5 Moderately emetic cancer chemotherapy
The following statement was taken from the S3 guideline "Supportive therapy in oncological patients":
Also recommendation level B and 0
Acute phase:
In the case of drug therapy of tumours with an emesis risk > 30-90% (except carboplatin, see next recommendation), prophylaxis with 5-HT3- RA and dexamethasone should be carried out before chemotherapy. (recommendation grade A)
Delayed phase:
In the case of a drug therapy with known emetogenic potential in the delayed phase (oxaliplatin, doxorubicin, cyclophosphamide and bendamustin (for bendamustin: EC recommendation)), dexamethasone should be administered on days 2 to 3. (recommendation level B)
Other drug therapies with a moderate risk of vomiting do not require antiemetic prophylaxis on days 2-3. (recommendation grade 0)
Abbreviation: 5-HT3-RA - 5-hydroxytryptamine3 receptor antagonist
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1a
5 - Consensus
- Strong consensus
- References
- [871]
Background 6.9
Since the use of carboplatin is increasing in patients with breast cancer, especially in triple-negative carcinomas in neoadjuvant and BRCA mutation-associated metastatic carcinomas, the corresponding recommendation from the S3 guideline "Supportive Therapy in Oncological Patients" is presented below
Also recommendation level B and 0
Acute phase:
In the case of carboplatin-containing chemotherapy (from AUC ≥ 4), prophylaxis with a 5-HT3 receptor antagonist and dexamethasone should be carried out before application. (recommendation level A)
In addition, an NK1-RA can be administered. (recommendation level 0)
Delayed phase:
In the case of carboplatin-containing chemotherapy (from AUC ≥ 4), antiemetic prophylaxis with dexamethasone should be administered on days 2-3. (recommendation grade B)
If the NK1- RA aprepitant was part of the primary prophylaxis, it should be administered for another 2 days with 80 mg daily. Fosaprepitant or netupitant/palonosetron is administered only on day 1 of carboplatin therapy. (recommendation level A)
Abbreviation: 5-HT3-RA - 5-hydroxytryptamin3 receptor antagonist, NK1- RA - neurokinin-1 receptor antagonist
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus
- References
- [871]
6.3.4.6 Low emetic cancer chemotherapy
The following statement was taken from the S3 guideline "Supportive therapy in oncological patients" [871]:
Acute phase:
In the case of drug therapy of tumours with a risk of vomiting 10-30%, antiemetic prophylaxis can be omitted or carried out with dexamethasone, 5-HT3- RA or metoclopramide. (recommendation grade 0)
Delayed phase:
In case of tumor therapy with a risk of vomiting 10-30%, no primary antiemetic prophylaxis should be taken on days 2-3. (recommendation grade A)
- Consensus
- Strong consensus
6.3.4.7 Minimally emetic cancer chemotherapy
In accordance with the S3 guideline "Supportive Therapy in Oncological Patients", no prophylaxis is recommended for minimal risk, analogous to MASCC/ESMO and ASCO LL in first-line therapy [1324], [1325]. Randomized studies do not exist in this setting. In case of nausea and vomiting prophylaxis is indicated from the next therapy course on.
6.3.4.8 Anticipatory nausea ad vomiting
Anticipatory ("learned") vomiting is triggered by classical conditioning after nausea and vomiting during previous therapies, as a consequence of patient-specific and therapy-related factors and fear and negative expectations, and is difficult to control with classical antiemetics [1329]. In cases of anticipatory nausea and vomiting a behavioral therapy including desensitization and hypnosis and benzodiazepines can be used.
6.3.4.9 Nausea and vomiting despite optimal prophylaxis
The emetic risk of the therapy is to be re-evaluated, as well as disease status, concomitant diseases and medication. Differential diagnoses of nausea and vomiting should be excluded. It should be ensured that the optimal regime is used. According to the S3 guideline "Supportive Therapy in Oncological Patients" [871], an alternative antiemetic regimen should be applied in the follow-up cycle. There should be no dose increase of 5HT3-RA/NK1-RA beyond the recommended daily dose. Furthermore, the administration of an antiemetic of the same substance class should not be performed.
In cases of nausea and/or vomiting despite optimal antiemesis, the following drugs can be used as rescue antiemesis with a strong consensus of the S3 guideline "Supportive therapy in oncological patients":
- Neuroleptics and other dopamine receptor antagonists:
- Olanzapine, initial 1 x 5 mg p.o.,
- Haloperidol, initial 1-3 x 1 milligrams p. o,
- ...metoclopramide, 3 x 10 mg p. o. (maximum daily dose 0.5 mg/kg bw to a maximum of 30 mg) over 5 days,
- Levomepromazine, initial 3 x 1-5 mg p.o. Alizapride, initial 3 x 50 mg.
- benzodiazepines:
- Lorazepam, initially 1 x 1-2 mg p.o,
- Alprazolam, initial 1 x 0.25-1.0 mg p.o.,
- H1 blocker:
- Dimenhydrinate, initially 3 x 50-100 mg p.o. or 1-2 x 150 mg rectally.
The antiemetic effect of neuroleptics (e.g. haloperidol) is much less pronounced than with metoclopramide. As with benzodiazepines, the desired psychological distancing is more important. Phenothia-zines, the so-called low-potency neuroleptics (e.g. levopromazine) have a stronger sedative effect than butyrophenones (high-potency neuroleptics: haloperidol). On the other hand, the extrapyramidal side effects (parkinsonoid) of phenothiazines are much less pronounced than those of butyrophenones.
Olanzapine should be preferred to metoclopramide as a rescue antiemesis. This is an off-label use. In addition, the sedating component [1330] should be considered.
In exceptional cases cannabinoids may be considered.
6.3.4.10 Nonpharmacological treatment options
Non-drug interventions for the treatment of chemotherapy-induced nausea and vomiting are recommended in the guideline of the Oncology Nursing Society in combination with pharmaceutical measures [1331]. Various procedures such as acupuncture and acupressure, relaxation techniques and massages can be used as an accompanying measure and in individual cases support drug therapy options.
In anticipatory vomiting as a cognitive process, primarily psychological interventions are discussed, such as progressive muscle relaxation, systemic desensitization, hypnosis and cognitive distraction [1332].
Acupuncture or acupressure are also used for the prophylaxis of nausea and vomiting under drug therapy of tumors. In the published studies, acupuncture was investigated in combination with drug prophylaxis. Some positive results have been described, but so far no statistically significant improvements in adults have been reported in randomised trials.
6.3.5 Radiotherapy-induced nausea and vomiting
Nausea and vomiting are among the most stressful side effects of radiotherapy in terms of localization. Intensity and duration of the symptoms depend, among other things, on the type of radiotherapy used, the dose, the irradiated area (volume) and the combination with chemotherapy [1333].
The emetogenic potential of radiotherapy of the breast is estimated to be minimal [1323], [1326]. General routine antiemetic prophylaxis is therefore not recommended.
Dopamine receptor antagonists or 5-HT3-serotonin receptor antagonists can be used as rescue medication. The potentiating effect of dexamethasone has been proven [1334].
In the case of radiation of osseous metastasis, cerebral metastasis or soft tissue metastasis the emetic risk should be assessed according to the localization and prophylaxis should be initiated, if reasonable, according to the criteria mentioned below.
In contrast to the more aggressive chemotherapies, vomiting under radiotherapy is relatively less pronounced in incidence and intensity. However, the emetic episodes can become subjectively just as stressful due to the usually several weeks of treatment. Observational studies suggest an incidence of emesis under radiotherapy of about 7-28%. The rate of nausea is much higher at about 40%. The incidence of nausea in patients with upper abdominal radiation is even given as 66% [1333], [1335].
The dominant risk factor for the occurrence of nausea and vomiting is the radiotherapy itself. In addition, patient-specific risk factors increase the risk of vomiting (see also tumour therapy related nausea and vomiting).
The intensity of these side effects is influenced by several factors, which are summarized in Table 11.
Table 8: Strahlentherapiespezifische Faktoren des emetogenen Risikos
|
Localization of the radiotherapy |
|
Radiotherapy volume |
|
Single and total radiation therapy Dose/fractionation |
|
Radiotherapy Technology |
Table 9: Zusammenfassung der antiemetischen Prophylaxe
|
Emesis risk |
Irradiated body region |
Antiemetic prophylaxis |
|
High |
Full body irradiation |
5-HT3-RA and dexamethasone |
|
Moderate |
Upper abdomen, BWS/LWS , neuro axis depending on the technique |
5-HT3-RA and dexamethasone can be used for dexamethasone |
|
Low |
Pelvis, cranium, ENT |
5-HT3-RA or rescue therapy |
|
Minimal |
Extremities, chest |
No routine prophylaxis |
In the case of combined radiochemotherapy, antiemetic prophylaxis is based on the highest achieved risk class of radiotherapy or chemotherapy. For example, in the case of combined radiochemotherapy with cisplatin, the emetogenic potency of cisplatin is decisive for antiemetic prophylaxis. In this case prophylaxis with a 5-HT3-RA, dexamethasone and NK1-RA is recommended [1336], [1337].
6.3.6 Neutropenia, febrile neutropenia (FN), infections
Febrile neutropenia (FN) and neutropenia-associated infections are a significant factor in morbidity and mortality after cytotoxic therapy. In addition, they can lead to a dose reduction of chemotherapy and/or cycle delays [1338]. Granulocyte colony stimulating factors (G-CSF) are approved for the reduction of the incidence of febrile neutropenia and duration of neutropenia in malignant diseases with cytotoxic chemotherapy.
The sole presence of afebrile neutropenia after tumor therapy does not justify the administration of G-CSF.
- Consensus
- Strong consensus
The prophylactic administration of G-CSF depends on the risk of developing febrile neutropenia according to the individual risk factors and the cytotoxic therapy used.
- Level of evidence
- 1b
- Consensus
- Strong consensus
- References
- [871]
Patient-specific risk factors should be evaluated before the start of each chemotherapy cycle to estimate the overall risk of febrile neutropenia.
- Consensus
- Strong consensus
Patient specific risk factors for an increased incidence of febrile neutropenia
No individual risk factor can be clearly identified. The following factors, especially when they occur in combination, are likely to increase the risk of febrile neutropenia:
- Age > 65 years
- Low performance status (low Karnofsky Index, high ECOG)
- Comorbidities (COPD, heart failure NYHA III-IV, HIV disease, autoimmune disease, significantly impaired kidney function)
- Very advanced, symptomatic tumor disease
- Past history of chemotherapy...
- Laboratory parameters (anemia, lymphocytopenia
Other study endpoints such as infection-related mortality were also included in the evaluation.
- Consensus
- Strong consensus
Based on the risk of developing febrile neutropenia under the respective tumor therapy protocol, the classification is made into 5 categories:
- Risk ≥ 40% for one FN
- Risk ≥ 20% and
- Risk
- < 20 % und ≥ 10 % für eine FN
- < 10 % für eine FN
- Consensus
- Strong consensus
Recommendation for G-CSF prophylaxis depending on the febrile neutropenia risk
Patients with solid tumors who receive tumor therapy with a febrile neutropenia risk ≥ 40% should be given prophylactic G-CSF.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus
- References
- [871]
In patients with solid tumors who have undergone tumor therapy with a febrile neutropenia risk ≥ 20% and
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus
- References
- [871]
In patients with solid tumors who have a febrile neutropenia risk of <20% and > 10% and have individual risk factors, prophylactic G-CSF sould be administered.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus
- References
- [871]
In patients with solid tumors who have a febrile neutropenia risk of < 20% und ≥ 10% without individual risk factors, no prophylactic G-CSF should be administered.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus
- References
- [871]
Patients with solid tumors who have a febrile neutropenia risk < 10% should not receive prophylactic G-CSF administration.
- Consensus
- Strong consensus
Prophylactic administration of G-CSF should take place no earlier than 24 hours and no later than 3 days after completion of chemotherapy, unless otherwise specified in the protocol.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus
- References
- [871]
Patients receiving pegfilgrastim should be administered 24 hours after completion of chemotherapy unless otherwise specified in the protocol.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1b
- Consensus
- Strong consensus
- References
- [871]
In therapy situations where dose-dense (increased frequency) or dose-intensified (increased dose) tumor therapies show a survival benefit, the prophylactic administration of G-CSF should be carried out according to the established therapy protocol.
- Consensus
- Strong consensus
In case of febrile neutropenia after tumor therapy, G-CSF should not be administered routinely.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus
- References
- [871]
6.3.6.1 Infections in neutropenia
Fever in chemotherapy-associated neutropenia is due to infection in over 95% of cases. Nevertheless, no pathogen can be detected in 50 - 70% of patients. The immediate use of broad-spectrum antibiotics is therefore necessary in order to prevent further development into a potentially life-threatening infection or to treat [1339], [1340], [1341], [1342] immediately and effectively. Infections are the most frequent therapy-related causes of death in cancer patients. The risk of febrile neutropenia or life-threatening infections correlates with the severity and duration of neutropenia [1343]. The mortality due to infections in chemotherapy-induced neutropenia is 2.8% and early mortality is 5.7% [1344]. Documented infections in neutropenia have a significantly worse prognosis than febrile neutropenia [1339], [1344], [1345]. Multivariate analysis revealed the following risk factors for a fatal course of FN: gram-negative sepsis (relative risk: 4.92), invasive aspergillosis 3.48, invasive candidiasis 2.55, lung disease 3.94, cerebrovascular disease 3.26, kidney disease 3.16, liver disease 2.89, pneumonia 2,23, gram-positive sepsis 2.29, hyptension 2.12, pulmonary artery embolism 1.94, heart disease 1.58, leukemia 1.48, lung cancer 1.18, age > 65 years 1.12 [1344].
The diagnosis and therapy of infections in neutropenia are presented in a differentiated manner in special recommendations and guidelines, which are explicitly referred to here.
- German Society for Hematology and Medical Oncology (DGHO), Onkopedia Guidelines, https://www.onkopedia.com/de/onkopedia/guidelines/infektionen-bei-haematologischen-und-onkologischen-patienten-uebersicht/@@view/html/index.html
- European Society of Medical Oncology (ESMO): http://www.esmo.org/Guidelines/Supportive-Care/Management-of-Febrile-Neutropaenia
- National Comprehensive Cancer Network (NCCN) https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf
6.3.7 Cancer therapy-induced anemia
Patients with a tumor disease often suffer from anemia that can cause clinical symptoms. The cause can be the tumor disease itself as well as chemotherapy or radiotherapy/radiochemotherapy.
Chemotherapy can trigger or intensify anemia. When treating anaemia, it is therefore necessary to consider the possible causes, including multiple causes. Depending on the clinical constellation, blood transfusions, erythropoiesis-stimulating agents (ESA) or, in the case of functional iron deficiency, the substitution of intravenous iron, also in combination with ESA, can be considered. In these cases, an accurate and individual risk-benefit assessment is necessary.
In this S3 guideline, the forms of anaemia are defined as follows:
Tumour anaemia (anaemia in chronic disease): This form of anaemia results from the activation of the immune system (by tumour, infection, autoimmune disease) with complex effects on haematopoiesis, iron metabolism and its regulation.
Tumor therapy induced anemia: Anemia caused by chemotherapy (including "new substances") and/or radiotherapy and/or radiochemotherapy.
Chemotherapy-induced anaemia: anaemia caused by chemotherapy
6.3.7.1 Definition of anemia
Anaemia is a reduction in the number of erythrocytes, characterized by a decrease in hemoglobin concentration (Hb) and/or hematocrit in peripheral blood.
The lower reference value of haemoglobin is defined (WHO) as 12 g/dl (7.45 mmol/l) in central European adults, depending on age, in non-pregnant women and 13 g/dl (8.07 mmol/l) in men.
6.3.7.2 Anemia in cancer, anemia of chronic disease (ACD)
Symptomatic anemia is frequent in cancer patients and, depending on the type and stage of tumor, amounts to approx. 31-50% already at diagnosis of solid tumors without therapy. The prevalence is even higher in hematological neoplasias [1346], [1347].
Anemia in cancer without therapeutic influence is caused by the activated immune system. This form of anaemia is called anaemia of chronic disease (ACD) [1348]. In the foreground are disorders mediated by inflammatory cytokines (tumor necrosis factor-α, interleukin-1-α and -ß, interleukin-6, interferon-γ). They concern homeostasis of iron metabolism, inhibited proliferation of erythroid precursor cells, insufficient synthesis of and reduced response to erythropoietin (EPO) in relation to anemia, and a shortening of erythrocyte survival [1348], [1349], [1350].
Hepcidin, a type II acute phase peptide produced in the liver, inhibits intestinal iron absorption, iron release from enterocytes, iron mobilization from the reticulohistiocyte system (RHS) and iron uptake into the erythropoietic progenitor cells [1351]. Hepcidin binds to the single cellular iron exporter ferroportin and causes its degradation. There is a reduced haemoglobin synthesis in the case of iron overload of the organism. Despite increased storage iron, haematopoiesis results in insufficient iron being available, corresponding to a functional iron deficiency.
With increased erythropoietic activity, the precursor cells of erythropoiesis in the bone marrow, the proerythroblasts, form the molecule erythroferrone, which inhibits the formation of hepcidin in the liver and thereby promotes the absorption and distribution of iron from the storage cells [1352]. In reduced or suppressed hematopoiesis, erythroferrone production is therefore reduced and hepcidin production is increased.
6.3.7.3 Incidence of cancer therapy-induced anemia
Under tumor therapy anemia occurs in about 75% of all patients, most frequently in gynecological tumors (81-88%) and in patients with lung cancer (77-83%) [1347].
With radiotherapy alone, anemia is reported in about 38% of patients, with rates of 51% in patients with lung cancer, 35% in patients with breast cancer, 49% in tumors of the gastrointestinal tract, 54% in gynecological tumors and 42% in malignant lymphomas [1347], [1353]. In prostate carcinoma the anemia rate is about 32% [1346].
In combined radio- and chemotherapy the overall anemia rate is about 62% [1347].
6.3.7.4 Diagnostics
6.3.7.4.1 Laboratory parameters
The following values may be elevated in chronic anemia: Ferritin, free transferrin-iron binding capacity (transferrin saturation decreased), BSG, fibrinogen, CRP and haptoglobin, zinc protoporphyrin (ZPP), soluble transferrin receptor in serum, erythropoietin in serum (but not sufficient, i.e. inadequately increased).
Table 10: Anemia workup
|
Diagnostics for anaemia |
|
|
exclusion of additional causes of anaemia, clinical examination |
|
|
absolute and functional iron deficiency Bleeding Vitamin B12 (cobalamin) and folic acid deficiency Hemolysis |
Renal dysfunction haematological systemic disease other internal diseases (infection, chronic inflammatory disease) |
|
Laboratory Diagnostics |
|
|
Basic diagnostics |
additional laboratory diagnostics |
|
Blood count with Hb, Hk, MCV, MCH quantitative reticulocyte count Differential blood count |
Erythropoietin levels hypochromic erythrocytes
|
|
Iron status: ferritin, transferrin Transferrin saturation |
Reticulocyte hemoglobin (CHr) Zinc protoporphyrin (ZPP), soluble transferrin receptor (sTfR) |
|
Holo-trans-cobalamin (vitamin B12), folic acid |
Hemolysis parameters: LDH, haptoglobin, Coombs test |
|
Routine laboratory with liver and kidney function parameters: bilirubin, transaminases, albumin, creatinine |
Bleeding diagnosis: thromboplastin time (Quick, INR), stool on blood, urine status |
6.3.7.4.2 Therapy options in cancer therapy-induced anemia
Anemia therapy is indicated for clinical complaints (see above). The tolerance of anemia varies greatly from individual to individual. The lowered Hb value alone is not sufficient to establish an indication.
Depending on the severity of the anemia, there are several options for the treatment of tumor therapy induced anemia. The listed therapeutic approaches are erythropoiesis-stimulating agents, iron replacement and transfusions with different degrees of recommendation.
6.3.7.4.3 Erythropoiesis-stimulating agents (ESA) in chemotherapy-induced anemia
The use of ESA in oncology is subject to a strict indication. The recommendations in this chapter therefore only refer to chemotherapy-induced anaemia.
Currently, ESAs with an Hb value ≤ 10 g/dl (6.2 mmol/l) are approved for the treatment of symptomatic, chemotherapy-induced anaemia in tumour patients to increase the haemoglobin value to a maximum of 12 g/dl (7.5 mmol/l).
The de novo research of the Cochrane Haematological Malignancies Group was based on the fundamental work of Tonia et al. [1354] and the subsequently published RCTs in the sense of an update research [1355], [1356], [1357], [1358].
Erythropoiesis-stimulating agent administration can be considered for the therapy of chemotherapy-induced anaemia.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- ⊕⊕⊝⊝
- Consensus
- Consent
- References
- [871]
When considering the use of erythropoiesis-stimulating agents, patients should be informed about the benefits (potential increase in quality of life and reduction in transfusion frequency) and risks (thromboembolic complications and hypertension).
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- ⊕⊝⊝⊝
- Consensus
- Strong consensus
- References
- [871]
6.3.7.4.4 Iron substitution
The chapter on iron replacement also only refers to patients with chemotherapy-induced anaemia.
6.3.7.4.5 Differential diagnosis and diagnostic workup
An iron deficiency often occurs in tumor patients on [1359]. Depending on the severity, 3 stages are distinguished: storage iron deficiency, iron deficient erythropoiesis and iron deficiency anaemia (Table 14). Thus, a negative iron balance initially leads to iron deficiency without affecting erythropoiesis. In the stage of iron-deficient erythropoiesis (functional iron deficiency, FID) the supply of the erythropoietic precursors in the bone marrow is insufficient, but the hemoglobin is still normal [1360]. Only when the hemoglobin level falls below the hemoglobin level is iron deficiency anemia (absolute iron deficiency, AID) present.
When making a diagnosis, it should be borne in mind that ferritin can show false normal or elevated values in inflammatory and malignant diseases and thus mask an existing iron deficiency. On the other hand, transferrin saturation can be lower in chronic diseases despite normal iron stores. Here, the determination of the soluble transferrin receptor (sTfR), zinc proto-porphyrin (ZPP), hypochromic erythrocytes or reticulocyte hemoglobin can be helpful.
Table 11: Stages and diagnostic workup of iron deficiency
|
Stages and diagnostics of iron deficiency |
|
1. lack of storage iron |
|
Ferritin for men in females |
|
2. iron deficiency erythropoiesis, corresponds to functional iron deficiency or Functional Iron Deficiency (FID) |
|
Transferrin saturation (TSAT) Ferritin > 30-800 ng/ml + If necessary, sTfR (transferrin receptor) or ZPP (zinc protoporphyrin) or hypochromic erythrocytes or reticulocyte hemoglobin |
|
3. iron deficiency anemia, corresponds to absolute iron deficiency or Absolute Iron Deficiency (AID) |
|
Hb Transferrin saturation (TSAT) For patients with tumor disease: serum ferritin value (With otherwise healthy people: Serum ferritin value |
In the case of a therapy with erythropoiesis-stimulating agents, if there is a functional iron deficiency, in order to achieve an increase in Hb, the accompanying therapy can be carried out with i.v. iron. Analyses of overall survival have not been performed in the respective studies.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- 1b
- Consensus
- Strong consensus
- References
- [871]
The available evidence from the RCTs is not sufficient to make a recommendation for or against i.v. iron therapy alone due to methodological deficiencies.
- Level of evidence
- 1b
- Consensus
- Strong consensus
- References
- [871]
6.3.7.4.6 Transfusion of packed erythrocytes
Evidence-based recommendations on the indication can be found in greater detail in the guidelines of the AABB (formerly "American Association of Blood Banks"), last published in 2012 [1361], especially for the intensive care sector also from Great Britain [1362], and in detail in the "Cross-sectional guidelines (BÄK) for therapy with blood components and plasma derivatives", (last 4th edition, updated 2014, [1363]).
According to the cross-sectional guideline of the BÄK, transfusion is not indicated in chronically anaemic patients without cardiovascular diseases, even at haemoglobin concentrations of up to 8.0-7.0 g/dl (HK 24-21 % = 5.0-4.3 mmol/l), as long as no symptoms attributable to the anaemia occur. Exceptions allow even deeper triggers, on the one hand if the symptom burden is low or tolerable, on the other hand in special therapeutic situations.
Aspects of quality of life must be weighed against the risks of transfusions (especially iron overload), which are usually necessary in chronic anaemia.
In addition to the BÄK cross-sectional guidelines, it should be mentioned that in the presence of cardiovascular risk factors only triggers of 8 g/dl versus 10 g/dl have been randomly compared to [1364], without finding disadvantages for the restrictive strategy. Patients with infarcts within the last 30 days were not included. Due to the occasional coincidence of neoplastic and cardiovascular diseases at an older age, it should be taken into account that randomized studies on the range of < 7g/dl as a possible trigger.
In a variety of clinical contexts, a restrictive indication for transfusion is not associated with clinical disadvantages for patients with acute anemia. By analogy, a similar situation can also be assumed in the absence of data on tumour therapy-induced anaemia.
- Consensus
- Strong consensus
In addition to the clinical condition and the severity of the anaemia symptoms, the decision to transfuse is based on the Hb value (or haematocrit), the acute nature of the blood loss and the patient's compensation options and risk factors.
- Consensus
- Strong consensus
Table 12: Recommendations for RBC transfusion in acuute anemia as pre cross-sectional guidelines (BÄK) for therapy with blood components 2014
|
For the indication of an erythrocyte transfusion, individual consideration of the criteria Hb concentration, compensatory capacity and risk factors of the patient is recommended: |
|||
|
Hb area |
Compensability/risk factors |
Transfusion |
Evaluation *** |
|
< 6 g/dl (<3,7 mmol/l) |
/ |
yes * |
1 C+ |
|
> 6-8 g/dl (> 3.7 - 5.0 mmol/l) |
Adequate compensation, no risk factors |
no |
1 C+ |
|
Compensation limited, risk factors present (e.g. CHD, heart failure, cerebrovascular insufficiency) |
yes |
1 C+ |
|
|
Indications of anemic hypoxia (physiological transfusion triggers: e.g. tachycardia, hypotension, ECG ischemia, lactic acidosis) |
yes |
1 C+ |
|
|
8-10 g/dl (5.0 - 6.2 mmol/l) |
Indications of anemic hypoxia (physiological transfusion triggers: e.g. tachycardia, hypotension, ECG ischemia, lactic acidosis) |
yes |
2 C |
|
> 10 g/dl (> 6.2 mmol/l) |
/ |
no ** |
1 A |
|
Notice! Haemoglobin concentration alone is not an adequate measure of O2 supply. In hypovolaemia, the hematocrit does not correctly reflect erythrocyte deficiency. Individual factors may require indications that deviate from the recommendations. |
|||
|
* In individual cases, with adequate compensation and without risk factors, lower Hb values can be tolerated without transfusion. ** In individual cases a transfusion to Hb values > 10 g/dl may be indicated. *** Assessment level of the BÄK 1A: Strong recommendation that applies to most patients, based on randomized controlled trials without significant methodological limitations 1C +: Strong recommendation that applies to most patients, no randomized controlled trials, but clear data 2C: Very weak recommendation, depending on the individual case, a different procedure may be indicated; based on observational studies, case descriptions |
|||
In patients with long-term tumour therapy-induced anaemia, a transfusion is recommended if the Hk is below 24 - 21% or the haemoglobin concentration is less than 8 - 7 g/dl (< 5,0 – 4,3 mmol/l), after considering and weighing the overall situation.
- Consensus
- Strong consensus
In hospitalized patients with chronic anemia, whose clinical condition and laboratory parameters are closely monitored, only one red cell concentrate should be administered if the trigger is slightly undershot.
- Consensus
- Strong consensus
Background 6.32 and 6.33
The recommendation to always give only one red cell concentrate and only in exceptional cases two preparations, because more transfusions would not be beneficial for the patient, comes from a setting with intensive monitoring of patients and daily controls of the blood count [1365], [1366], The strategy is not evaluated in terms of safety for a setting with longer control intervals.
The reduction of the transfusion frequency is part of the North American initiative "Choosing wisely" to optimize the medical measures [1367]. There the recommendation was chosen to "transfuse the minimum number of units necessary to relieve the symptoms of anemia or to bring the patient into a safe Hb range (7-8 g/dL in stable, non-cardiological inpatients)". The background text also recommends avoiding transfusion of two units where one unit would be sufficient. On the other hand, in order to improve the quality of life (reduced fatigue, better mobility in everyday life and sports, reduction in the frequency of visits to the doctor), it may be useful, for example in outpatients, to transfuse two red cell concentrates even at Hb values around 8 g/dl, depending on the planned interval until follow-up. The aspects of transfusion medical care (blood supply time and logistics) must also be taken into account.
6.3.8 Neurotoxicity
The neurotoxicity associated with the treatment of the patient with a breast cancer is usually chemotherapy-induced peripheral neuropathy (CIPN). This is a peripheral neuropathy which can be motor or sensory. The symptoms are manifold. Often it is limited to mild paresthesia, hypaesthesia and hyperaesthesia, mostly affecting hands and feet, sometimes a superficial, burning or stabbing neuropathic pain may occur. An impairment of the sensation of vibration and the sense of position (depth sensitivity) can also occur. Furthermore, the neuropathic pain can significantly impair the patient's quality of life. Motor neuropathy of the proximal muscle group is rarely seen.
After completion of the therapy, symptoms usually disappear within a few months.
Risk factors include an existing neuropathy (e.g. diabetic, alcohol toxic, renal insufficiency), increased age, combination therapies with platinum derivatives (e.g. cisplatin > 300 mg/m², grade I-II 14-63%, grade III-IV 7-21%), eribulin (grade I-IV up to 35%, grade III-IV up to 8%) and the taxanes, which are of fixed importance in the therapy of breast cancer [1368]. With regard to the taxanes docetaxel, paclitaxel and nab-paclitaxel are used. Thus, the supportive therapy of neurotoxicity is particularly relevant for breast cancer patients.
6.3.8.1 Taxane-associated neuropathy
Typically, neuropathy is more frequent under paclitaxel than under docetaxel (sensory neuropathy grade III/ IV: 2-33% versus 1-9%; motor neuropathy grade III/ IV: 0-14% versus 1-9%) [1369]. It occurs less frequently under the weekly administration of paclitaxel than under the three-weekly administration (grade III/ IV: 19% versus 12%, p=0.001) [1370]. Sensory neuropathy occurs more frequently under nab-paclitaxel than under standard paclitaxel. In a study by Gradishar et al. a third degree sensory neuropathy was observed significantly more frequently with 10% than under paclitaxel with 2% (p<0,001) [1371]. Es zeigte sich jedoch auch eine rasche Erholung der Neuropathie auf Grad I oder II mit einem Median von 22 Tagen. Nach 28 Tagen war die Anzahl der Patientin mit einer sensorischen Neuropathie dritten Grades in beiden Armen identisch. Motorische Neuropathien und sensorische Neuropathien vierten Grades wurden nicht beobachtet. In Bezug auf das Auftreten der sensorischen Neuropathie ist auch die hö-here Dosierung des nab-Paclitaxels im Vergleich zum konventionellen Palcitaxel zu berücksichtigen. In einer Phase-II-Studie wurde die Dosierung von 175 m/m² nab-Paclitaxel bei 43 Patientinnen mit einem metastasierten Mammakarzinom untersucht [1372]. Es trat keine Neuropathie Grad III oder IV auf. In Bezug auf die wöchentliche Therapie mit nab-Paclitaxel untersuchten Gradishar und Kollegen 302 nicht vorbehandelte Patientinnen mit einem metastasierten Mammakarzinom mit Docetaxel 100 mg/m², q21d, nab-Paclitaxel 300 mg/m², q21d, oder nab-Paclitaxel 150 mg/m² oder 100 mg/m², q7d [1373]. Die Inzidenz der sensorischen Neuropathie zeigte sich zwischen Docetaxel und allen drei nab-Paclitaxel-Armen gleich (p > 0.1). Within the nab-paclitaxel arms, the rate of sensory neuropathy was higher at the dosages of 300 mg/m², q21d, and 150 mg/m², q7d. Sensory neuropathy recovered more rapidly under nab-paclitaxel than under docetaxel. The time to recovery on ≤ 2nd degree was 22, 22 and 19 days for the doses 300 mg/m², 100 mg/m² and 150 mg/m². In the docetaxel arm this took 37 days. In the publication of the study with the final analysis of overall survival no significant difference in the incidence of neuropathies was observed between the four arms (p=0.83) [1374]. Recovery time to grade II and below was 20-22 days for nab-paclitaxel and 41 days for docetaxel. In further studies, patients with progression under taxane therapy in the metastatic situation or metastasis within 12 months after adjuvant taxane therapy were treated with 100 mg/m² (n=106) or 125 mg/m² nab-paclitaxel, d1, 8, 15, q28d, [1106]. The median number of cycles was 5.3 and 4.7. In the cohort with 100 mg/m², 9 patients (8%) developed a grade III sensory neuropathy, whereas three patients already had a pre-existing grade I neuropathy. Under the 125 mg/m² dose, 19% (n=14) of the patients showed a grade III sensory neuropathy, with three patients also having a grade I neuropathy before the start of therapy. Of the 23 patients with a grade III neuropathy, 15 patients were able to continue the therapy with a reduced dosage after a 1-2 week therapy break. The study did not show any grade IV neuropathy, while 17% (n=18) developed grade II neuropathy under the 100 mg/m² dose and 32% (n=24) under the 125 mg/m² dose.
6.3.8.2 Diagnostics
According to the S3 guideline "Supportive Therapy for Oncological Patients" [871], CIPN is diagnosed on the basis of the patient's medical history and clinical findings. In case of special questions electrophysiological examinations may be necessary. It is essential that these are carried out before the start of therapy and before each cycle. To prevent a higher degree of chemotherapy-induced polyneuropathy, its early detection is crucial. In order to ensure an early diagnosis of CIPN, patients need to be instructed in the documentation of neurotoxic symptoms and reliable methods of CIPN recording, which are presented in detail in the S3 guideline "Supportive therapy in oncological patients" [871]. The world's leading scale for quantitative assessment of peripheral neurotoxicity is based on the National Cancer Institute-Common Toxicity Criteria (NCI-CTC).
The following statement was taken from the S3 guideline "Supportive therapy in oncological patients":
An examination of the neurological status should be carried out before initiating a potentially neurotoxic tumour therapy to determine the initial findings and identify patients at risk.
Before each cycle, a detailed anamnesis should be taken with special consideration of possible neurotoxicities, including a repetition of the neuro status if necessary.
- Consensus
- Strong consensus
6.3.8.3 Patient education
It is essential to inform the patient in detail about the background of neurotoxicity, the risks and behavioural measures before therapy. As a result of possible sensory-motor failures, there is a risk of burns and frostbite (e.g. use thermometers when bathing and rinsing), falls and injuries with subsequent wound infections and in some cases limited fitness to drive. Patients should have regular examinations for pressure points and injuries, good skin care on hands and feet and regular gripping exercises with hands and feet.
6.3.8.4 Prophylaxis of CIPN
There is currently insufficient data from RCTs for the prophylaxis of function loss through CIPN using non-drug methods. Nevertheless, the expert consensus of the S3-guideline "Supportive Therapy in Oncological Patients" recommends regular exercise training, especially of finger and toe functions, because in the context of CIPN-related sensory limitations, consecutive additional motor disorders are to be expected.
With regard to drug therapy, there is no effective prophylaxis of chemotherapy-induced polyneuropathy. Standardized prophylactic measures or causal therapy approaches are not yet available for CIPN according to the S3 guideline "Supportive Therapy in Oncological Patients" [871]. Therefore, prevention and early detection of CIPN have the highest priority [1375]. According to the S3 guideline "Supportive Therapy in Oncological Patients", prophylaxis of chemotherapy-induced polyneuropathy with the following substances is not recommended:
- Alpha lipoic acid (recommendation level A, level of evidence 1b),
- Amifostine (recommendation grade B, level of evidence 1a),
- Calcium and magnesium (recommendation grade B, level of evidence 1a),
- Carbamazepine (recommendation level B, level of evidence 1b),
- diethyldithiocarbamate (DDTC),
- Glutathione (recommendation level A, level of evidence 1a),
- and vitamin E (recommendation level B, level of evidence 1a).
6.3.8.5 Therapy of CIPN
In principle, a dose reduction can be considered in patients with known diabetic or alcohol-induced neuropathy or in patients with the development of severe neuropathy, but this must be weighed against the potential loss of efficacy of oncological therapy.
The data available on the treatment of CIPN with non-drug interventions are limited to date. The effectiveness of non-drug interventions has been evaluated in a review by Streckmann et al. [1376]. In this review 18 studies on "exercise interventions for neuropathic patients" were analysed. The review described a positive effect for exercise therapy to treat PNP of different etiologies. Training methods such as endurance training, balance training, vibration training, Tai Chi, walking and standing training, also using weights, were used. Basically, this review results in an advantage for balance training regardless of the underlying genesis. For CIPN, a combination of endurance, strength and sensorimotor training has been found to be effective, which led to the following statement in the S3 guideline "Supportive Therapy in Oncological Patients":
In manifest chemotherapy-induced polyneuropathy, exercise therapy should be used to improve functionality:
This may include:
- Balance exercises
- sensomotoric training
- Coordination training
- Vibration training
- Fine Motor Training
- Consensus
- Strong consensus
Background 6.35
With regard to the initiation of symptomatic drug therapy, the decision and selection of drugs should be made on the basis of a risk-benefit analysis. The latter includes, in particular, sedative effects that often occur at the beginning of the therapy when the dosage is administered, and which require special consideration also for impairment of driving ability.
In general, CINP shows a poor response to pain therapy drugs. There is a choice of selective serotonin-noradrenalin-reuptake inhibitors (SSNRI), e.g. venlafaxine, duloxetine, tricyclic antidepressants, e.g. amitriptilin, clomipramine, imipramine or doxepin, for shooting pain carbamazepine, gabapentin, pregabalin.
According to the S3 guideline "Supportive Therapy in Oncological Patients" [871], the following drug therapies can be considered in the case of chemotherapy-induced polyneuropathy:
- SSNRI venlafaxine (expert consensus),
- Amitriptyline (recommendation level 0, level of evidence 1b),
- Gabapentin (recommendation level 0, level of evidence 1b),
- Pregabalin (expert consensus).
In case of pain in chemotherapy-induced polyneuropathy, therapy with duloxetine should be considered (recommendation level B, level of evidence 1b) [1377]. This is an off-label use. The effect is greater in platinum-induced neuropathy than in taxane-induced neuropathy. The recommendation is consistent with the ASCO guidelines [1375]. In the case of neuropathic pain, opioids are also available as effective drugs (expert consensus). However, data on opioid therapy in CIPN and neuropathic pain are still limited [897], [1378]. In addition, side effects and tolerance development can limit the application. Non-opioid analgesics (NSAID, paracetamol and metamizole) have only a low effectiveness in neuropathic pain and are to be viewed very critically due to the potential side effects (e.g. gastrointestinal ulcers, renal insufficiency, cardiovascular side effects, very rarely agranulocytosis in metamizole) in accordance with the S3 guideline "Supportive therapy in oncological patients".
6.3.8.6 Other toxicities
Other toxicities associated with different systemic therapies of the patients and with different frequencies depending on the therapy are diarrhoea, mucositis and stomatitis and skin toxicities. Since these can significantly reduce the quality of life of a patient with a therapy for breast cancer, prophylactic as well as therapeutic measures are essential if they occur. Extensive supportive therapies are available for these side effects which, together with the handling of extravasations, are reflected in the S3 guideline "Supportive Therapy in Oncological Patients" [871].
6.4 Follow-up and long-term care
6.4.1 Objectives
Aftercare in the narrower sense includes structured examinations of locoregional or intramammary recurrence and contralateral breast carcinoma, examinations for distant metastases and the monitoring of long-term therapies with diagnosis and therapy of consequences and side effects. It begins due to the variation of the therapy regimen following the completion of the primary locoregional therapy [1379].
Patients with a completely different starting position are treated within the scope of aftercare. These include, for example, patients after neoadjuvant or adjuvant chemotherapy, targeted therapy, endocrine system therapy or complementary and alternative therapy procedures (CAM). They also include patients who have been treated within the framework of studies. Patients who have received radiation therapy must be regularly and specifically examined for radiogenic late effects.
An individualized risk-adapted aftercare would be necessary. While therapy decisions are made according to risk classifications (TNM stage, steroid hormone receptors, growth factor receptors, age, etc.), there are no larger valid studies that have investigated individualized risk-adapted follow-up. Survival comparisons of the different tumour stages show that survival rates are stage-dependent, so that stage-adapted risk stratification could be carried out. There are no criteria for modifying the structured aftercare established to date. Thus, patients with a high risk of locoregional recurrence and a risk of distant metastasis are accompanied and treated in the same way in structured follow-up as those with a low risk of recurrence.
At the same time, it is also apparent that a time limit of 5 years for aftercare is not sufficient given the different risk constellations of the patients. Thus, even without direct study funding, the time frame for follow-up care has been extended from currently 5 years to a period of 10 years [1380]. It should be noted that therapy monitoring should be continued for at least 10 years.
There are no new prospective randomised studies that take into account different risk constellations, adapted aftercare schedules or integration of newer diagnostic methods. The currently practiced aftercare concept supported by prospective randomized studies is to be seen as an orientation, although it should be adapted to the individual situation of the affected woman due to the symptoms.
Aftercare for patients with breast cancer begins with the completion of locoregional primary treatment. It consists of an anamnesis, physical examination, medical consultation, care and support as well as imaging diagnostics to detect local and locoregional recurrence and contralateral breast carcinoma.
In case of abnormal findings, the follow-up care should be designed in a symptom-oriented manner.
Background 6.36
In contrast to the situation in metastatic breast carcinoma patients with an intramammary or locoregional recurrence have a curative therapy chance.
For the early detection of distant metastases and their treatment there are no large prospective randomized studies available that have shown a significant survival benefit. A further distinction must be made here between patients who are undergoing long-term therapy and those who have metastasized after a therapy-free interval [1384], [1386].
The basis of the aftercare is the attention and the conversation. Central concerns are the reduction of anxiety and the improvement of the patient's quality of life. This is supplemented by a physical examination, which includes in particular the local findings and the contralateral mamma. The invitation to participate in the recommended early cancer detection examinations, especially in the genital area, should be made [1379].
If necessary, the individual follow-up care of breast cancer patients should include oncologically experienced specialists and other professional groups, for example psycho-oncologists, physiotherapists, lymphologists, oncological nurses, breast care nurses, etc. Depending on individual needs, the patient should be provided with information about the possibilities of further counselling and care, including offers of self-help.
6.4.2 Examinations to detect locoregional and in-breast recurrences or contralateral breast cancer
A local/local recurrence after mastectomy and/or axilla dissection can usually be diagnosed by clinical examination. Palpation of the thoracic wall and the lymph drainage areas is therefore a central part of the follow-up examinations [1390]. Local/locoregional or intramammary recurrences in patients with breast-conserving surgery are in most cases curatively treatable. They should therefore be diagnosed as early as possible. Aftercare should therefore include a mammography at least once a year and, if possible, a complementary mammary sonography of the affected breast.
Imaging diagnostics for the detection of local and locoregional recurrences and contralateral carcinomas should include annual mammography and quality-assured sonography.
Background 6.38
The time of the start of mammography in the context of follow-up care must also depend, among other things, on the type of radiation (e.g. intraoperative radiation, postoperative brachytherapy, etc.) and the local findings of the breast.
Since the scar region frequently changes postoperatively and the differential diagnosis between scarring changes and recurrence is difficult, mammography and sonography of the affected side may be necessary at shorter intervals during the first 3 years after surgery [929]. If the findings are difficult to assess (scar, DD recurrence) an MRI is necessary for further diagnosis [1393], [1394]. The patient with breast carcinoma should therefore not be integrated into the mammography screening with a 2-year examination interval.
A previous breast carcinoma is a strong risk factor for contralateral breast carcinoma. The contralateral breast and axilla must be palpated at every follow-up examination and sonographic checks must be performed. Mammography controls and sonography are to be performed [1395].
MRI examinations can provide additional information for high-risk patients [1293][1395], [1396].
The established quality-assured ultrasound examination in follow-up care, the recall and biopsy rates increase. Most commonly, patients report (82%) that they derive positive psychological aspects from the increased attentiveness and the associated safety; rarely, some (< 6%) feel a psychological burden due to insecurity and anxiety. Imaging diagnostics should therefore only be performed to supplement mammography
Background 6.39
The question of the significance of ultrasound in aftercare was addressed in the context of the S3 guidelines (see evidence report SF 4.6-1 Ultrasound Aftercare). A total of 54 publications were identified for the period 2005 to 2016. According to methodological inclusion and exclusion criteria, only 2 studies could be included in the evaluation. According to the study by Riebe et al. 2007 (LoE 3a), the clinical examination and mammography alone show a sensitivity of 81.8% and a PPV of 37.5%. The addition of the ultrasound examination (thoracic wall + axilla bds.) increased the sensitivity to 100% and the PPV to 41%. In the prospective cohort study by Wojcinski et al. 2011 (LoE 2c) with n = 735 patients, the addition of ultrasound (according to DEGUM Level I) showed a significantly increased local recurrence detection rate from 3.7% (95%CI: 2.3-5.0) to 4.5% (95%CI: 3.0-6.0) p=0.041, accompanied by an increase in the recruitment rate from 3.3% to 5.9% (p<0.0001) und der Biopsierate von 9.0% auf 11.8% (p<0.0001). Alle Patientinnen mit Lokalrezidiv wiesen keine Fernmetastasierung auf. Die Patientinnen bewerteten die psychischen Aspekte der zusätzlichen Untersuchungen in 82% (95%CI: 79.3-84.8) positiv als „sicherer und aufmerksam kontrolliert“, psychisch belastet als „verunsichert und ängstlich“ nur 5.9% (95% CI: 4.2-7.6).
6.4.3 Men with breast cancer
Men with breast cancer, like women, should receive annual imaging diagnostics, especially since there is a higher risk of contralateral carcinoma.
- Consensus
- Consent
Background 6.40
Men with breast cancer have a higher risk than women with breast cancer for contralateral breast cancer. A study with data from the Surveillance, Epidemiology, and End Results database with follow-up of n=1,788 patients showed a 30-fold increased risk for contralateral breast cancer (SIR [standardized incidence ratio] 29.64, 95% CI: 15-52) compared to the general male population, while women with breast cancer have only a 2-4-fold increased risk [1397].
6.4.4 Examination for metastases
The 3 most frequent metastasis sites in patients with breast cancer are the lung, liver and bones. Within the framework of the primary therapy, a stage-dependent diagnosis of the spread of the disease is carried out. The currently available prospective randomized studies have shown that an intensified follow-up at fixed intervals with lung x-ray, bone scintigraphy, upper abdomen sonography, tumor marker or CT diagnostics in symptom-free patients does not result in a survival advantage [1384], [1386], but rather shortens recurrence-free survival. However, the studies in question were conducted so long ago that it is currently impossible to assess, against the background of new therapeutic procedures, whether a corresponding survival advantage can be achieved today. Prospective randomized studies with risk adaptation of a diagnostic aftercare program or the integration of procedures such as PET, SPECT/CT, short-term tumor marker controls, examination for circulating tumor cells, risk determination according to gene chips or tissue micro arrays, etc. are currently not available. In addition, it is possible that metastases in patients with breast cancer may be detected between the intervals of follow-up visits due to their symptoms. Therefore, it is all the more important to inform the affected person about the self-observation of persistent symptoms or the self-examination of the operated region.
An intensified apparatus and laboratory diagnostics with x-ray thorax, bone scintigraphy, CT, PET or MRT as well as blood count, serum biochemistry or tumor marker determination are part of metastasis diagnostics, not of standard aftercare, and are only indicated in case of clinical abnormalities.
6.4.5 Diagnostic workup and treatment of side effects and sequelae of primary and long-term treatments
Among other things, the examinations in the context of aftercare are intended to check and document the success of the primary therapy. The overriding principle is to help patients overcome their fear of a recurrence of the disease. With a favourable tumour constellation (pT1 N0 M0), the 10-year survival probability is over 90%.
Therapy consequences and toxicities of local therapies such as surgery and radiation and of systemic therapies such as chemotherapy, targeted therapy, endocrine therapy, osteooncological therapy or complementary and alternative methods (CAM) can be recognized and treated if necessary. Since more and more breast cancer patients are being treated curatively, but the necessary therapies are carried out over a longer period of time, the support of long-term therapies and the treatment of concomitant symptoms or late effects are becoming increasingly important. It is important to distinguish between early and late effects, between local and systemic side effects and between long-term side effects of already completed therapies or acute side effects of current therapies.
The patient should be informed about therapy-specific short and long-term side effects and late effects. Targeted diagnostic and therapeutic measures should be recommended to her if necessary, or these should be performed on her.
Local therapy side effects are edema, sensitivity disorders, pain in the chest wall or in the chest with breast-conserving therapy, movement restrictions and a lymphedema [1402].
Consequences (acute and late toxicity) of the systemic drug therapy can be myelotoxicity, hepatotoxicity, alopecia, nephrotoxicity, ototoxicity, pulmotoxicity, cardiotoxicity, infections, thromboembolic events as well as osteoporosis, sterility, the climacteric syndrome, the occurrence of second cancers, cognitive impairment and many more [1400].
It is not possible to provide a complete overview of all problem areas, so only the most common ones are presented:
6.4.5.1 Lymphedema
The secondary lymphedema of the arm in breast cancer is with an incidence of 20-30% a frequent problem after axillary dissection [1379], [1380]. However, due to the routine use of sentinel lymph node excision, lymphedema has become significantly less frequent. The morbidity includes functional limitations, increase in circumference and associated impairment of quality of life.
All patients with axillary lymphadenectomy should be informed about the options for detection, prophylaxis and treatment of postoperative lymphedema.
Background 6.42
The main influencing factors are:
- the extent of the surgical intervention in the armpit
- the number of lymph nodes removed correlates significantly with the occurrence of lymphedema (p
- irradiation of the axillary lymph drainage area (RR 1.35; 95 % CI 1.00-1.83).
3 randomized studies prove the individual benefit of morbidity reduction with reduced surgical radicality by sentinel lymph node biopsy (SLN): absolute risk reduction for loss of sensitivity 8% (5% SLN versus 11% ALND), for arm lymphedema symptoms 20% (11% SLN versus 31% ALND) [1413], [1414], [1415], [1416].
Sentinel lymph node biopsy without further axillary lymphadenectomy is a primary prophylaxis of arm lymphedema for breast cancer patients. These patients must be informed about normal use of the arm postoperatively and should consult their specialist or family doctor if they experience functional disorders or signs of lymphedema.
Primary prophylaxis of lymphedema by lymphatic drainage in asymptomatic patients is not recommended.
Physiotherapeutic exercises can improve the mobility of the arm [1417], [1418], [1419].
6.4.5.2 Cardiotoxicity
Cardiotoxicity must be considered when using anthracyclines and trastuzumab [1420]. The simultaneous combination of both substance classes significantly increases the risk and is not recommended. Predisposing factors are age, obesity, pre-existing heart failure, arterial hypertension, diabetes mellitus, condition after myocarditis or infarction and left-sided radiation. In the development of acute and chronic myopathies with heart failure, a distinction is made between the acute and sub-acute dose-independent early form, the chronic form (within one year) and the late form. The extent ranges from a reduction of the left ventricular ejection fraction (LVEF) to clinically relevant heart failure (CHF). General reduction in performance or reduction in the physical capacity of the affected person should be clarified. Early clarification of cardiac damage is necessary to initiate appropriate supportive measures such as targeted therapy of heart failure etc., to improve the patient's quality of life and not to worsen the life prognosis [843], [1421], [1422].
6.4.5.3 Leukemia
6.4.5.4 Menopausal syndrome
The climacteric syndrome comprises the vegetative (hot flushes, sweating, dizziness, headache, tachycardia etc.), the psychological (insomnia, depression, abandonment anxiety, neurotic behavior, irritability, nervousness, lack of drive, lack of concentration etc.) and the organic climacteric syndrome (organ involution, metabolic changes etc.) [1425]. These physiological changes can be intensified by the therapies or by therapy-specific side effects. These include vaginal bleeding, thromboembolic events, muscle and joint pain, dry mucous membranes, etc. The climacteric syndrome can be induced in pre/perimenopausal patients or in postmenopausal patients by chemotherapy or endocrine system therapy [1426].
The perception of symptoms varies subjectively and depends, among other things, on the onset and duration of amenorrhoea or the duration of therapy, especially endocrine therapy. The treatment of the symptoms of climacteric syndrome is symptom-oriented. Hormone therapy after breast cancer is contraindicated. Therefore, it can only be discussed in extremely exceptional cases, with the greatest restraint, and only be considered if the quality of life is seriously impaired. In hormone receptor-positive breast cancer patients, hormone therapy is contraindicated in the current data situation [1427].
6.4.5.5 Antibody therpay
Reference can be made here to chapter 4.7.5 Antibody therapy.
6.4.5.6 Thromboembolic events
Thromboembolic events can occur as a paraneoplastic syndrome during primary therapy. They are often indications of a more extensive tumor or a metastasis [1428]. In endocrine systemic therapies, thromboembolic events are possible, especially in the context of long-term therapies [1429]. The diagnosis and therapy of thrombosis or pulmonary artery embolism and its prophylaxis are defined in interdisciplinary S2 or S3 guidelines of other professional societies (AWMF 065/002).
6.4.5.7 Osteoporosis
One of the main factors regulating bone metabolism is oestrogen. Physiologically, the reduction of bone substance at the beginning of the menopause is physiological. This can be intensified by triggering the premature menopause in premenopausal patients by chemotherapy or endocrine system therapy or in postmenopausal patients by the use of aromatase inhibitors. In patients with a significantly increased risk of developing osteoporosis or with known osteoporosis, appropriate medication should be recommended. In patients who are not yet ill, attention should be drawn to behavioural measures such as physical activity, modification of the diet or substitution with vitamin D and calcium [1400], [1430], [1431]. Detailed information about osteo-oncological medication options should be given.
In any case, it is important to diagnose bone stability at an early stage with a bone densitometry before and during a possibly necessary anti-hormonal therapy and a planned chemotherapy.
Bone densitometry should be recommended for breast cancer patients under aromatase inhibitor therapy, premenopausal patients under tamoxifen and/or GnRH therapy and patients with chemotherapy-induced premature menopause.
Depending on the result and other risk factors, the bone density measurement should be repeated at regular intervals.
Under prophylactic osteoprotective therapy, regular monitoring is not necessary.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2a
- Consensus
- Consent
- References
- [873]
6.4.5.8 Fatigue
6.4.5.9 Reprodction
Premenopausal breast cancer patients who wish to have children should be informed about the possibilities of further family planning after successful completion of the primary therapy of breast cancer [1434]. The originally anticipated increase of the risk of recurrence due to endocrine changes during pregnancy has not been confirmed in any study [1435]. However, the survival advantage of patients who became pregnant in the years following successful treatment of breast cancer, as postulated in some studies, is probably based on a "healthy mother effect" [1434], [1436]. As a general rule, the decision for or against the realisation of the desire to have children after completion of primary therapy for breast cancer should follow personal considerations of lifestyle and less vague medical hypotheses.
If there is an indication for contraception, either for medical reasons such as endocrine therapy, or because of personal lifestyle considerations, it should generally not be performed hormonally. The risks of hormonal contraception must be carefully weighed up.
6.4.6 Frequency of follow-up examinations
Follow-up examinations should be performed quarterly for the first 3 years, semi-annually for the 4th and 5th year and annually from the 6th year onwards.
Due to the tumor biology of the breast carcinoma, a follow-up phase of at least ten years should be considered [1379], [1437]. The therapy monitoring should be continued for at least 10 years.
A patient with breast cancer can no longer be included in normal mammography screening. However, it is possible to extend the aftercare intervals after a longer period of time, depending on the risk, and if necessary, to perform imaging at longer intervals.
Follow-up examinations should be carried out quarterly in the first 3 years after local primary therapy, half-yearly in the 4th and 5th year, and annually from the 6th year onwards. Annual screening examinations should be included.
- Consensus
- Strong consensus
Background 6.44
Other cancer screening tests should also be offered to patients.
The follow-up plan should be discussed with the patient. If risk factors are present, an appropriate allocation should be made.
Table 13: Follow-up examinations in breast cancer
|
Years after primary therapy
|
Aftercare |
Early detection
|
|
|
1st - 3rd year |
4th and 5th year |
6 and further years
|
|
|
Medical history Physical examination Reconnaissance/Information |
quarterly |
half-yearly |
annually |
|
Laboratory examinations, examinations using imaging techniques (exception: mammography and mammary sonography) |
only in case of clinical suspicion of recurrence and/or metastases
|
||
Table 14: Follow-up examinations for breast cancer – Breast diagnostics after BCT or mastectomy
|
Years after primary therapy |
1st - 3rd year |
from the fourth year |
|
Ipsilateral breast (BET): mammography, mammary sonography Mastectomy: Sonography |
at least once a year |
annually |
|
contralateral breast: mammography, sonography if necessary |
annually |
annually |
If the risk of relapse is low, after 10 years of follow-up, the X-ray frequency of mammography can be extended to 2 years. For normal as well as higher risk patients, follow-up is continued at annual intervals according to the table above.
Patients often ask for or request more intensive aftercare. They expect detailed information about their own risk and want to comply with this risk by intensifying aftercare [1438]. It turns out that the belief in the effectiveness of aftercare examinations is high and often unrealistic [1438].
More than two thirds of the patients believe that early diagnosis of metastasis and the associated earlier use of therapy is more likely to lead to healing. Most patients therefore wish for additional diagnostic measures. About 50% of patients also prefer a lifelong follow-up [1438] without a time limit. On the other hand, only 67% of patients actually use the annual mammography after the primary surgery [1439], [1440], [1441], [1442]. While 80% of patients have a mammography in the first year of follow-up, only 63% do so in the fifth year of follow-up. Only 33% of patients use a mammography in each of the first five years after surgery [1439]. Since the detection of recurrence is the central task of aftercare, it is therefore necessary to inform patients specifically about using the established examination measures (see above) at the recommended intervals.
Patients should be motivated to be physically active (> 2-3 h/week) and to normalize their body weight (in the case of an increased BMI) as part of aftercare. Support should be provided.
- Consensus
- Strong consensus
Background 6.45
Follow-up care should not only focus on the detection of a relapse of the disease, but also on general health maintenance with training and counselling. This includes information about lifestyle, e.g. exercise and nutrition, especially in the case of obesity with a BMI ≥ 30 kg/m². The increasing body weight is related to the mortality due to a breast cancer disease. Retrospective studies have shown that patients with a BMI ≥ 30 kg/m² have a significant 4% increased risk of developing distant metastases within the first ten years compared with those with a BMI < 25 kg/m², and a 38% higher risk of death from breast cancer 10 or more years after primary diagnosis [877]. Continued physical activity and the maintenance of body weight within the normal range produce a significant improvement in quality of life, less fatigue and greater physical function [874]. There is indeed evidence that regular exercise confers a survival benefit [878]. Notwithstanding, an improved outcome as a result of exercise interventions as part of follow-up care has not yet been demonstrated in prospective studies. [879].
An essential part of the aftercare is the constant motivation of the patient to regularly take the drugs prescribed for adjuvant therapy, especially the endocrine therapy (e.g. tamoxifen or aromatase inhibitors).
The patient must be asked in detail about tolerability or side effects of the therapy. Complaints are to be treated with suitable measures. A premature discontinuation of therapy can be prevented by changing the endocrine treatment.
- Consensus
- Strong consensus
Background 6.46
Endocrine therapies in the adjuvant situation of patients with hormone receptor-positive breast cancer (e.g. tamoxifen or aromatase inhibitors) are highly effective. The disadvantage is that these preparations must be taken continuously for at least five years. Since these therapies have side effects on the one hand, and the necessity of long-term continuous intake is not adequately accepted by patients on the other, long-term compliance is not sufficient for this therapy. After the first year of use, 40-50% of patients stop taking the prescribed medication. This reduces the disease-free and survival rates, so that it is necessary to repeatedly point out the compliance with the therapy in the follow-up care.
Predictors for a discontinuation of endocrine therapy are a younger (< 50 years) and older age (≥ 75 years), breast-conserving treatment (versus mastectomy), the presence of comorbidities (≥ 2), the prescription of smaller pack sizes, and higher top-up payments for medications (particularly among the elderly) [1394]. Predictors of reliable adherence are married life and previous administration of chemotherapy and radiotherapy. The aftercare consultation should address in detail the need for compliance with endocrine therapies, taking into account the predictors of compliance, and the possible reasons for discontinuation, such as side effects.
For the documentation of adjuvant therapy, it is important that not only the planning of the therapy is documented, but also the actual start and end as well as the adequate implementation.
6.5 Rehabilitation
The multimodal therapy of patients with breast cancer can lead to somatic and psychosocial secondary disorders that result in functional impairment in the sense of participation in everyday life. Medical rehabilitation measures to reduce or eliminate functional disorders are available to patients according to SGB IX if there is a need for and ability to rehabilitate and a positive rehabilitation prognosis can be given. The ICF (International Classification of Functioning, Disability and Health) is used to assess the functional disorders.
Pursuant to § 4 SGB IX, benefits for participation include social benefits (i.e. in this context, in particular medical rehabilitation benefits) in order, irrespective of the cause of the disability
- to avert or remove the disability, to prevent its aggravation or to mitigate its consequences,
- To avoid restrictions of the earning capacity or a need for care,
- to ensure participation in working life according to aptitudes and skills,
- to promote personal development in a holistic way to enable or facilitate independent participation in social life.
The cost units for rehabilitation measures are in particular the statutory health insurance funds, the statutory pension insurance funds and the social administration. According to § 19 SGB IX, rehabilitation can be provided in inpatient or outpatient form, taking into account personal circumstances. According to § 26 SGB IX, medical rehabilitation services include medical and nursing treatment, drug therapy, physiotherapy and use of aids, functional occupational therapy and psychosocial services.
For the medical rehabilitation of patients with breast cancer, the German Pension Insurance Association (DRV Bund) has drawn up rehabilitation therapy standards and updated them in 2016, in which evidence-based therapy modules are summarised (see http://www.deutsche-rentenversicherung-bund.de).
The tumor disease and its treatment through surgery, radiotherapy and systemic therapy can lead to disorders of varying severity, which require specific rehabilitative measures in the somatic and psychosocial field. Patients should be informed at an early stage about the possibilities of outpatient and inpatient rehabilitation measures as well as other claims arising from social law. The wishes of the patients should be taken into account when determining the indication and recommending the type of rehabilitation.
- Consensus
- Strong consensus
Exercise programmes with strength and endurance training are to be offered with the aim of reducing therapy-related limitations in physical performance, reducing fatigue and improving the quality of life of breast cancer patients.
Background 6.47 and 6.48
Fatigue in tumour diseases describes a persistent, multidimensional appearance, which includes subjectively perceived increased fatigue and physical exhaustion and can be associated with psychological stress. The symptoms often represent the greatest burden for the patient and restrict the quality of life and the ability to cope with stress in everyday life in the long term [1445], [1446]. In order to diagnose a tumor-associated fatigue and to assess the degree of its severity, a multidimensional approach is required in accordance with the clinical picture: a fatigue-related anamnesis, recording with the support of validated questionnaires, and somatic diagnostics. Since 1998, the American Fatigue Coalition has had a catalogue of criteria for the diagnosis of tumour-associated fatigue, which records the various dimensions of fatigue [1447]. A tumor-associated fatigue is considered to be accepted if at least 6 of the 11 criteria apply [1448]. The indication for treatment should be based on the National Comprehensive Cancer Network (NCCN) algorithm for the assessment of tumor-associated fatigue [1449].
An improvement of the symptoms of fatigue is mainly achieved by an exercise therapy individually adapted to the patient's capacity. There is a benefit for strength and endurance training. Five meta-analyses and one Cochrane analysis are available. 16-72 studies were included in the meta-analyses. With regard to the reduction of fatigue, the meta-analyses showed a moderate, significant improvement [1450], [1451], [1452], [1453], [1454]. The Cochrane analysis included 56 randomised trials and also showed a significant benefit for exercise therapy with regard to the improvement of fatigue. Both the NCCN Guideline and the Guideline of the American Society of Clinical Oncology (ASCO) therefore recommend exercise therapy for the treatment of fatigue [894], [1449]. In addition, three meta-analyses of psychosocial and behavioural therapy approaches also established their benefit [1281], [1455], [1456]. A small benefit could also be shown for relaxation methods such as yoga [1457]. Movement interventions can lead to an improvement in cancer-related fatigue [1450], [1458]. Training forms such as endurance and strength training or a combination of both seem particularly suitable. The question of the training frequency cannot be answered unambiguously, on average intervals of 2 - 3 times a week for 8 - 12 weeks are examined [871], [1377], [1457], [1459], [1460], [1461], [1462], [1463], [1464], [1465], [1466], [1467], [1468]. An important factor is the problem that it is always difficult to keep patients in line when it comes to movement interventions. However, additional cognitive interventions were not able to demonstrate clear results here [1461], [1465], [1467], [1469].
Recent studies show that there are differences in the benefit of physical training to improve fatigue for patients during primary therapy and for cancer survivors. A series of systematic reviews show that physical training after chemo- or radiotherapy is more effective with regard to fatigue than during therapy [532], [1470], [1471], [1472], [1473], [1474], [1475].
Background 6.49
After a surgical intervention for breast cancer, physiotherapeutic treatment aims in particular to regain mobility and strength in the arm and shoulder, to avoid movement restrictions and relieving postures after breast surgery and to overcome contractures.
Multifactorial physiotherapy and active exercise therapy bring positive results in terms of shoulder mobility and pain, as two systematic reviews show.
(Only) for lymphedema, a complex decongestive therapy (KPE) consisting of skin care, manual lymph drainage, exercise therapy and compression treatment should be performed.
Background 6.50
The removal of the lymph nodes or subsequent irradiation can lead to lymphedema in the upper extremities. The diagnosis of lymphedema is made by a precise clinical examination using the "skin fold test according to Stemmer" (lifting of tissue between thumb and forefinger), which is always carried out in a side by side comparison. With the help of a measuring tape, the circumference of the arms can be checked over the course of the procedure - it is always advisable to do this at the same places and without pulling on the measuring tape. The date and time of day should also be noted, as fluctuations in oedema occur throughout the day or depending on the season (summer/winter). Both arms should be measured before the surgery and regularly afterwards. Favourable measuring times are, for example, the oncological aftercare appointments. A combined physiotherapy consisting of skin care, manual lymph drainage, exercise therapy and compression is the most suitable treatment method here. However, this should only be used if lymphedema really exists. The use of treatment methods such as manual lymph drainage to prevent lymphedema has no effect. The exercise programme (e.g. for shoulder mobilisation) does not represent an increased risk for the occurrence of lymphoedema, but has a positive effect on mobility and quality of life. Compression with bandages appears to be more effective than pneumatic compression, although kinesio-tape may be an alternative to conventional bandages. The results summarised here are similarly reflected in the various international treatment recommendations.
Chemotherapy-induced polyneuropathy
In the case of chemotherapy-induced polyneuropathy (CIPN), the extent of the damage (symptoms, localisation) should be documented and the affected patients should be informed about the range of therapies available (pain, physiotherapy, occupational therapy).
- Consensus
- Strong consensus
Background 6.51
Cytostatic drug-induced polyneuropathy (CIPN) is increasingly proving to be a significant long-term toxicity in modern cytostatic therapy. The incidence is stated in the literature to be about 38% and depends on the substances used, the combination of cytostatic drugs and the type of application [1459]. CIPN manifests itself as sensory neuropathy with paresthesia in hands and/or feet. The symptoms usually begin with distally emphasized, stocking and glove-like dysesthesias, numbness and tingling paresthesias which may be accompanied by considerable pain sensations and proximal spread [1460]. Since chemotherapy in the treatment of patients with breast carcinoma usually contains a taxane, this long-term side effect is often to be expected.
In 80% of the patients the symptoms are spontaneously completely reversible, but in about 20% of the patients the symptoms are long-term. In addition, the symptoms can still worsen 2-6 months after the end of chemotherapy and 40% of these patients need another 6-8 months before a noticeable improvement occurs [1461]. In addition to anamnesis and clinical-neurological examination, the measurement of the nerve conduction velocity is diagnostically necessary to objectify the symptoms [1462], [1463]. Therapeutically, neuropathic pain can be treated with the combined serotonin-noradrenalin-reuptake inhibitor duloxetine [1377]. Therefore, the patient should be offered a therapeutic trial with this substance. In the context of rehabilitation often occupational therapy methods are used, but their effectiveness is unclear because no data are available. For magnetic field therapy, positive effects were shown in a phase II study [1464]. This was confirmed in a randomized placebo-controlled double-blind phase III study [1465]. Other stimulation therapies such as acupuncture and electrostimulation also show some benefit [1466], [1467]. For the stimulation procedures with rapeseed or hedgehog ball, which are often used in rehabilitation, no data on the effectiveness are available. Sports and exercise therapy may also have a positive effect on CIPN. In a randomized study, but with a small number of cases and in lymphoma patients, a significant improvement could be achieved [896]. Further information on cytostatic-induced polyneuropathy can also be found in the S3 guideline supportive medicine [871].
Cognitive performance limitations
Patients should be asked about cognitive performance limitations (concentration, executive functions, short-term memory) and, if necessary, further diagnostic clarification should be initiated.
Background 6.52
Cognitive dysfunction (CD) in oncological diseases is a short-term, long-term or even permanent functional disorder of the:
- Attention
- Ability to concentrate
- Thinking processes
- Memory performance (especially short-term memory)
- Learning ability
- Ability to perform complex tasks
The term KD dates back to the 1980s and was first described in patients with tumors of the central nervous system and in pediatric tumors. It was not until the 1990s that this clinical symptomatology received scientific attention and was perceived as an independent functional disorder [1468]. Depending on the tumor disease investigated, the prevalence of KD varies between 12% - 68% [1469], [1480]. According to subjective patient data, this number can increase up to 80% [1470] 6 months after chemotherapy. A KD after oncological therapy is described by patients up to 20 years after cancer therapy [532]. However, these studies are mostly small inhomogeneous collectives without control groups [1471].
Pathophysiologically, KD is most likely a multifactorial event. In addition to the actual tumor disease itself, genetic conditions and anti-tumor therapy play an important role. The interaction of these three components ultimately determines the severity of the cognitive dysfunction. In particular, drug therapy of tumors is associated with inflammatory processes and secondary changes such as vascular damage, hormonal and metabolic changes [1472] On the other hand, the world's largest multicenter study with 477 patients with early or locally advanced breast cancer showed that the administration of chemotherapy has no significant influence on the development of a KD. Rather, the symptoms of latent depression are associated with significantly increased rates of cognitive dysfunction [1481].
Therapy- or tumor-associated KD should be distinguished from a possible pre-existing dementia brain disorder. This can be achieved by means of a targeted collection of the patient's own and/or the patient's medical history. If this is not sufficient, the dementia test DemTect can be used [1473].
A systematic diagnosis of KD is not standardized and a gold standard does not exist yet. Neuropsychological test batteries have not found widespread application in clinical routine, as they are associated with high personnel and time expenditure (2-3 hours per patient, execution by psychological psychotherapist). They can therefore only be considered if a KD needs to be further examined in individual cases and there are consequences, e.g. for socio-medical assessment. If this is the case, a test battery should be chosen which includes the qualities attention, reaction time, memory and executive functions [1482]. To simplify the diagnosis of KD in oncological patients, the d2 test, the CogPack® test or the NeuroCog FX® test can be used [1475]. The latter computer-aided test contains all the qualities of a neuropsychological test battery and has been validated in patients with breast cancer [see above]. A psychometric test procedure that is also manageable in terms of time is the syndrome short test according to Erzigkeit (SKT), which tests the qualities of memory performance and attention [1474]. The DemTect or mini-mental test procedures commonly used in geriatrics and dementia diagnostics are not suitable for the diagnosis of oncological oncology patients. The classification into three degrees of severity can be made according to the Common Terminology Criteria for Adverse Events (CTCAE Version 4.0) of the National Cancer Institute (NCI) [1321].
There are no effective drug treatments for KD. The data on the use of Modafinil are inconstant. Therefore, its use outside of studies cannot be recommended at present [300]. Indications for the benefit of computer-assisted concentration and memory training are available from one phase II and three randomized phase III studies prior to [300], [1302], [1303], [1483]. Positive data on the benefit of behavioral therapy approaches are available from a case-control study prior to [1484]. For sports and exercise therapy, three randomized studies are currently available with a majority of patients with breast cancer. While one study examined walking and fitness training [1485], two other studies examined the use of yoga [1486], [1481]. All three studies found a significant improvement in cognitive function. A limiting factor, however, is that it was a heterogeneous therapy program over different therapy periods [873].
Therefore, patients with moderate and severe PD should be offered treatment with computer-assisted training programs in combination with psychotherapeutic interventions, exercise therapy and yoga according to the classification of NCI-CTCAE.
The application for oncological rehabilitation is usually submitted to the statutory health or pension insurance. The statutory health insurance company bears the costs for its insured persons (§ 40 SGB V). The pension insurance institutions provide oncological rehabilitation services for their insured persons (according to § 15 SGB VI) as well as for insured persons, pension recipients and their relatives (§ 31 para. 1 no. 3 SGB VI). Immediately after completion of the primary therapy, the application is submitted via the social services of the last hospital treating the patient, otherwise via the treating physician. Medical rehabilitation can be repeated if serious functional disorders persist due to the disease itself or the tumour therapy.
After completion of the oncological rehabilitation (see above) a socio-medical evaluation of the rehabilitated person is performed. On the basis of continuing functional deficits and available resources, it is assessed which restrictions or possibilities of participation in social life/working life arise for the affected person and by which measures restrictions can be counteracted if necessary. On the basis of socio-medical assessments, further benefit decisions are often made and benefits provided by the social service providers. These can be, for example, assistance with career advancement, measures to secure maintenance (reduced earning capacity pensions) or measures of secondary and tertiary prevention.
6.6 Complementary medicine
All patients should be asked whether they use complementary and/or alternative therapies. Patients who use such procedures should be informed about possible risks and, where appropriate, about interactions with standard therapies.
- Consensus
- Strong consensus
Background 6.53
It is important to note that there is no universally accepted definition of complementary and alternative medicine in oncology. In most cases, it is contrasted with so-called conventional medicine, without a clear definition of the boundaries being possible.
Complementary medicine is subject in its evaluation to the basic principles of evidence-based therapy. It is used in addition to the standard clinical therapy [1487]. On the other hand, alternative therapy methods are offered as a supposed substitute for an evidence-based therapy. The resulting therapy competition represents the greatest danger of the alternative therapy.
The integration of complementary measures to support evidence-based therapy is also known as "integrative oncology" [1488].
According to literature data, breast cancer patients seem to use complementary therapy methods in 50-90% of cases [1489], [1490], [1491], [1492].
Medical advice on the topic of complementary medicine can
- Strengthen the feeling of self-responsibility and control
- from dubious offers,
- Protect against damage caused by side effects or interactions,
- encourage the development of personal initiative (e.g. exercise, diet)
One risk of complementary therapies is that patients and therapists have so much confidence in the effectiveness of these complementary measures that they abandon conventional breast cancer therapy in favor of these measures. These are alternative procedures and should not be used because of the obvious risks to the patient's health.
The particular problem in the evidence evaluation of complementary procedures lies in their often less well defined effect spectra, complex mechanisms of action and interaction possibilities, as well as the lack of conventionally conducted studies on remedies that provide clear indications of effectiveness and benefit-risk ratio.
As part of the Oncology Guidelines Programme, complementary and alternative medical procedures in oncology will be evaluated in a separate S3 Guidelines process in the future (http://leitlinienprogramm-onkologie.de/Projekte.6.0.html).
In order to better describe the existing evidence at this point in time, the guideline report lists evidence tables of an American working group [1493], which has compiled studies on the effectiveness of complementary medicine procedures in patients with breast cancer.
The following Table 12 gives an overview of the most common complementary methods and substances used by patients with breast cancer and the possible interactions. These interactions can both attenuate and enhance (toxicity) the effect of an existing breast cancer therapy. Some of the methods and substances listed are discussed in further subchapters.
Table 15: Use of complementary methods, observed side effects, potential interactions
|
Substance/method |
Propagated use |
Side effects |
Interactions |
|
beta-carotene |
Prevention of recurrence, improvement of the tolerability of chemotherapy |
Increased incidence of tumours in smokers |
as antioxidant possible attenuation of chemo- and radiotherapy |
|
vitamin C |
Prevention of recurrence, improvement of the tolerability of chemotherapy |
in high dosage kidney damage possible |
as antioxidant possible attenuation of chemo- and radiotherapy |
|
High-dose vitamin C (infusions) |
Antitumoral action |
Vitamin C can promote tumour growth in vitro. |
as antioxidant possible attenuation of chemo- and radiotherapy |
|
vitamin D |
Prevention of osteoporosis Improvement of the forecast |
not known at normal dosage |
not known generally worse prognosis with low serum values |
|
vitamin E |
Prevention of recurrence, improvement of the tolerability of chemotherapy, reduction of menopausal complaints |
not known |
In vitro data with indications of attenuation of the effects of tamoxifen |
|
Selenium |
Prevention of recurrence, improvement of the tolerability of chemotherapy |
short-term, even high-dose use without side effects, long-term use only under mirror control |
No evidence of a reduction in the effect of anti-tumour therapies in preclinical or clinical data |
|
Zinc |
Prevention of recurrence, improvement of the tolerability of chemotherapy |
Zinc is important for tumor cell growth in vitro, a promotion of tumor growth cannot be excluded. |
not known |
|
Curcumin |
antitumoral action |
From 8 g/d increased gastrointestinal complaints |
in vitro isolated indications of antagonistic effects to chemotherapy |
|
EGCG (green tea) |
antitumoral effect, prevention of recurrence |
in high dosage caffeine-like side effects |
In-vitro data predominantly speak for synergies |
|
Omega-3 fatty acids |
Effect against cachexia |
None |
None |
|
Enzymes |
Prevention of recurrence, improvement of the tolerability of chemotherapy |
rarely upper abdominal discomfort |
None |
|
Mistletoe therapy |
antitumoral effect, prevention of recurrence, improvement of the tolerability of chemotherapy |
Allergies, in vitro in 2 studies Indications of increased tumor growth |
It is unclear whether immune stimulation can lead to an increased risk of hypersensitivity reactions to antitumoral drugs. |
|
Thymus therapy |
antitumoral effect, prevention of recurrence, improvement of the tolerability of chemotherapy |
not known |
not known, enhancement of immunological reactions possible |
|
medicinal mushrooms |
antitumoral effect, synergy with chemotherapy, improvement of the tolerability of chemotherapy |
not known |
not known, enhancement of immunological reactions possible |
|
Immunostimulants (organopeptides, complex polysaccharides) |
antitumoral effect, synergy with chemotherapy, improvement of the tolerability of chemotherapy |
not known |
Not known, enhancement of immunological reactions possible |
|
Herbs of TCM |
antitumoral effect, synergy with chemotherapy, improvement of the tolerability of chemotherapy |
not known, insufficient data situation |
not known, insufficient data situation |
|
Acupuncture/Acupressure |
improvement of side effects (nausea, pain, hot flushes) |
in one study evidence of an increase in oestradiol in non-tumour menopausal patients - no confirmatory data |
not known |
|
Homeopathy |
Reduction of side effects, improvement of quality of life |
none |
preparations with higher potency cannot have interactions, these cannot be excluded in mother tinctures and low potencies |
|
Soya extract |
Reduction of hot flushes |
Conflicting in vitro and in vivo data - breast cancer growth demonstrated in a number of studies |
Reduction of the effect of anti-hormonal therapy in vitro and in vivo |
|
Grape Silver Candle |
Reduction of hot flushes |
not known |
not known |
6.6.1 Diagnostics
The diagnostic measures offered within the framework of complementary and alternative therapy concepts, which are based on scientifically unproven concepts and/or misinterpretations of correlations between bodily functions, should not be recommended.
- Consensus
- Strong consensus
Background 6.54
Some diagnostic measures offered within the framework of complementary or alternative therapy concepts, such as iris diagnostics, dark field microscopy, bioresonance, so-called allergy diagnostics, etc., are based on scientifically unproven concepts and/or misinterpretations of interrelationships of bodily functions and should therefore not be recommended.
6.6.2 Complementary medical interventions for anxiety/anxiety disorders/depression
With regard to some complementary medical approaches for the treatment of anxiety disorders, reference is made to the S3 guideline Psycho-oncological Diagnosis, Counselling and Treatment of Adult Cancer Patients (see http://leitlinienprogramm-onkologie.de/Psychoonkologie.59.0.html).
There, the following interventions are commented on:
- Yoga/ massages
- Artistic therapies
- Music Therapies
- Relaxation method and imaginative method
The recommendations there also apply to patients with breast cancer.
In addition, patients with anxiety disorders or depression are referred to the corresponding S3 guidelines:
- Anxiety disorders: http://www.awmf.org/leitlinien/detail/ll/051-028.html
- Depression: http://www.versorgungsleitlinien.de/themen/depression/
In the review by Greenlee et al. 2014 [1493] a randomized study with 302 female volunteers [1494] was identified, in which acupuncture therapy showed a reduction of anxiety disorders (HADS [scale from 0-21]: -1.83 pts, 95% KI -2.69 -0.97) compared to standard therapy (no sham acupuncture).
6.6.3 Complementary medical interventions for fatigue
Regarding the therapy of fatigue syndrome by means of exercise therapy in patients with breast cancer, reference is made to the chapter on lifestyle factors that can be influenced (Chapter 4.7.7.) and rehabilitation (Chapter 6.5.) as well as to the S3 guideline Psycho-oncological Diagnosis, Counselling and Treatment of Adult Cancer Patients (see http://leitlinienprogramm-onkologie.de/Psychoonkologie.59.0.html).
In the review by Greenlee et al. 2014 [1493], randomized studies with breast cancer patients and partially positive effects were identified for the following interventions:
Studies on acetyl L-carnitine [1499] and guarana [1500] were also identified, but they did not show any positive effects with regard to fatigue.
6.6.4 Complementary medical interventions for the prophylaxis of chemotherapy-induced nausea and vomiting
The complementary use of different procedures such as acupuncture, acupressure, relaxation techniques, massages or ginger for the prophylaxis of chemotherapy-induced nausea and vomiting is discussed in the chapter Supportive Therapy (Chapter 6.3) or in the corresponding S3 guideline on Supportive Therapy in oncological patients.
A further overview of the studies available on this subject with breast cancer patients is provided in the review by Greenlee et al. 2014 [1493].
6.6.5 Complementary medical interventions for the prophylaxis and treatment of oral mucositis
The S3 Guidelines for Supportive Therapy in Oncological Patients comment on complementary medical procedures/approaches for the therapy or prophylaxis of oral mucositis.
6.6.6 Complementary medical interventions for the treatment of acute radiation-induced skin reactions
The S3 guideline on supportive therapy in oncological patients comments on complementary medical procedures for the prevention and therapy of acute radiogenic skin reactions.
6.6.7 Food supplements
During chemo-, hormone or radiation therapy, dietary supplements (micronutrients), such as vitamins and trace elements, should be supplied via the natural diet and according to the physiological requirements.
Proven deficiencies should be compensated.
- Consensus
- Strong consensus
Background 6.55
Dietary supplements are preparations of vitamins and trace elements, amino acids, fatty acids and secondary plant substances, some of which are offered as single substances or mainly as combination preparations. The composition varies considerably, only a few preparations are based on the actual physiological requirements.
The use of antioxidants can impair the effect of simultaneously administered chemo- and/or radiotherapy [1501], [1502], [1503]. These include vitamin C, E and beta-carotene. Folic acid can influence the effect of 5-fluorouracil in particular. Up to now there are only a few clinical studies with a sufficient number of patients which could clearly characterize the side effects and the effects of the antioxidants, so that one should be rather cautious with recommendations for such a therapy.
Vitamin D protects against the development of osteoporosis and should therefore be used prophylactically in time. Patients at increased risk of osteopenia or osteoporosis include patients on aromatase inhibitors, young patients who have become postmenopausal as a result of chemotherapy, patients who have taken or need to take corticosteroids long-term or repeatedly, or immobilised patients. In this context, the recommendations of the Dachverband Osteologie DVO e.V. should be referred to.
Vitamin E has occasionally been used prophylactically to protect against the development of neurotoxicity under cisplatin and taxol therapy.
As there are no sufficient data on efficacy and influence on survival available to date, the use of vitamin E outside of studies is not recommended [1504] [1505]. Furthermore, there are apparently biological differences in the effects of the various vitamin isomers and forms. In particular, alpha-tocopherol could have an inherent pro-carcinogenic effect under certain conditions (prostate carcinoma) [1506].
The clinical studies on the administration of selenium published to date have been presented in a review of the Cochrane Collaboration (Cochrane: Dennert et al. 2006 [1507]). While deficiencies should be compensated, the data do not show sufficient evidence for the general supportive use of selenium (Cochrane: Dennert et al. 2006 [1507]). There are no meaningful studies specifically on the use of selenium in breast cancer. Long-term selenium administration should only be carried out under consecutive serum level control. Overdoses must be avoided. A Cochrane review of 2014 did not yield consistent data on cancer prevention by selenium intake [1508].
For a number of secondary plant compounds such as curcumin, quercetin, EGCG, experimental preclinical data are available which indicate an antitumoral effect of these substances. However, these data in no way justify the use of these substances outside clinical studies. Since little is known about interactions of these plant substances with standard clinical therapy, their parallel use should be avoided. In general, natural substances have a considerable potential for interference. The uptake of secondary plant substances via a healthy fruit and vegetable rich diet is desirable [1509].
6.6.8 Mistletoe therapy
Mistletoe therapy does not prolong the survival of patients with breast cancer, and an improvement in quality of life is questionable according to current data.
- Consensus
- Strong consensus
Background 6.56
Both the Cochrane analysis by Horneber et al. (2008) [1487] and the systematic review by Ernst et al. 2003 [1510] come to the conclusion that most of the studies on mistletoe therapy published to date are not of sufficient quality. Methodologically robust studies show no effect of mistletoe therapy on relevant endpoints such as survival. A review on quality of life [1511] shows indications of an improvement in quality of life under mistletoe therapy, but the data are based on studies of significantly lower quality.
6.6.9 Traditional Chinese medicine (TCM)
6.6.9.1 Treatment with herbal products
The use of plant mixtures according to Traditional Chinese Medicine has been shown to have positive effects on quality of life and individual immune functions. Although two Cochrane reviews show positive effects for this therapy with regard to quality of life (Cochrane: Taixiang et al. 2005 [1512]; Cochrane: Zhang et al. 2007 [1513]), it became known after the reviews were prepared that randomised clinical trials from China could not fulfil the internationally recognised criteria of randomisation on a large scale. In addition, little information is available on interactions and side effects. There are a number of reports on impurities (heavy metals, pesticides, corticoids and coumarins) with sometimes fatal consequences. Some preparations contain phytoestrogens which should not be used uncritically in patients with hormone-dependent breast cancer.
Green tea
A meta-analysis of epidemiological studies suggests that green tea could reduce the risk of disease [1514]. Likewise, a meta-analysis that took into account two non-randomized studies (n=123, n=133) showed a lower risk of recurrence with increased consumption of green tea [1509]. A systematic review found possible positive interactions between green tea and tamoxifen and no negative interactions between green tea and aromatase inhibitors or fulvestrant [1416][1515]. Thus, green tea seems to be an interesting approach for recurrence prevention in breast cancer, especially since problematic side effects or interactions are not known.
Due to the bias potential of previous studies on relapse prevention (retrospective observational studies, mainly Asian collectives, partly not adjusted for known confounders (e.g. smoking)), further (prospective) studies are necessary until clear recommendations can be made.
Soy products
Since soya contains phytoestrogens that might interact with tamoxifen, soya could be a healthy or harmful food for women affected by breast cancer. Accordingly, soya is the subject of controversial discussion.
Two meta-analyses investigated the effects of soy. These included 9514 and 11206 patients from observational studies [1516], [1517]. In the analysis by Nechuta et al. (2012) a significantly reduced risk of recurrence was found based on three cohorts (HR: 0.75; 95 % CI: 0.61, 0.92). Chi et al (2013) found a better overall survival based on 5 cohorts, especially in ER-negative, ER+/PR+ and postmenopausal patients. It remains unclear whether this is particularly or exclusively valid for Asian women. Since the underlying studies are observational studies in which the compared populations differ in terms of socio-demographic parameters (ethnicity, education, age) and no data are available on known confounders (e.g. smoking), these results are not evidence of the effect of soy products in women after treated breast cancer. Further (prospective) studies are also necessary until clear recommendations can be made.
Cimicifuga (grape silver candle)
According to preclinical and clinical data, Cimicifuga is not a phytoestrogen, but has a SERM-like mechanism. Therefore, its use in breast cancer seems possible [1518], [1519], [1520], [1521], [1522], [1523], [1524], [1525]. So far there are only two studies on the reduction of hormone withdrawal symptoms in patients with breast cancer under anti-hormonal therapy. Here, an improvement of the symptoms was found with only moderate effect strength [1493], [1526], [1527].
Homeopathy
A therapeutic benefit - of homeopathy - in terms of improving progression-free or overall survival in breast cancer has not been proven.
There is no evidence for an improvement in progression-free and overall survival in breast cancer through the use of homeopathic drugs.
- Consensus
- Strong consensus
6.6.10 Meditation and mindfulness-based stress reduction
The terms meditation, "mindfulness based meditation", as well as "mindfulness based stress reduction" cover different therapeutic approaches. What they have in common is the attempt to increase the (self-)attentiveness of the patient and thus to achieve a better handling of the disease situation.
For the evaluation of such therapies, reference is made to the S3 guideline Psycho-oncological diagnosis, counselling and treatment of adult cancer patients.
In the review by Greenlee et al. 2014 [1493] several studies with breast cancer patients were identified, which show an improvement of quality of life through meditation. Mostly, the so-called MBSR, mindfulness-based stress reduction, or mindfulness-based stress reduction, is used as a meditation program. Crane-Okada et al. (2012) [1528] and Nidich et al. (2009) [1296] showed in two randomized controlled trials with less than 50 and 150 subjects, respectively, an improvement of quality of life in older breast cancer patients through meditation programs. In two randomized-controlled studies by Henderson et al. (2012 and 2013, respectively) [1529], [1530] with less than 200 subjects each, breast cancer patients in early stages between 20 and 65 years of age benefited in terms of quality of life. After 24 months no significant benefit could be demonstrated. A positive effect was also demonstrated in patients who received radiotherapy treatment during the program. A randomized controlled trial with more than 200 subjects [1531] showed the efficacy of MBSR after surgery, chemo- and radiotherapy until 12 weeks after the intervention. Overall, the small number of cases and the short follow-up time should be noted, long-term effects could not yet be shown.
6.6.11 Complementary medical interventions for the treatment of sleep disorders in breast cancer patients
An updated S3 guideline on sleep disturbances/non-restful sleep is expected to be available in October 2017. This also addresses complementary medical approaches: http://www.awmf.org/leitlinien/detail/anmeldung/1/ll/063-003.html
Stress management techniques can be considered for the treatment of sleep disorders.
- Consensus
- Strong consensus
Background 6.58
The randomized studies of Garssen et al. (2013) [1532] and Andersen (2012) [1533] with a small number of cases can demonstrate a significant effect on the improvement of fatigue and sleep quality through psychological short intervention and MBSR. However, the effects last only briefly in acute cases. No long-term effects could be observed.
Light Yoga
Studies with patients with breast cancer and sleep disorders were identified in the review by Greenlee et al. 2014 [1493] on light yoga [1498], [1534], [1535], [1536].
Two studies from 2010 and 2012 with very small case numbers n< < 100 showed an improvement in quality of life and vitality of breast cancer patients through various yoga regimens. The study by Danhauer et al. [1487] is not considered important due to the small number of cases. Worth emphasizing is the work by Mustian et al. (2013) [1488] with n=410 case numbers. A four-week yoga course with two units per week, consisting of pranayama, hatha yoga, asanas and meditation had a significant benefit on sleep problems. In general, it is important to note that the studies used different yoga regimens, meaning various techniques over different times./p>
6.6.12 Complememntary medical interventions for the treatment of pain in breast cancer patients
The therapy of tumor pain is addressed in the S3 guideline for palliative care:
In the review by Greenlee et al. 2014 [1493], studies with breast cancer patients were identified for the following complementary medicine interventions:
- Massage/healing touch [1537]: A randomized study from 2003 with 230 participants who received therapeutic massages could show, among other things, a reduction of pain.
- Emotion And Symptom-focused Engagement (EASE)-Intervention [1538]: A major study (n=292) investigated the influence of a telephone intervention/conversation with rules of conduct by an oncologically trained nurse in patients undergoing chemotherapy. With regard to the secondary endpoint "pain" there was as little evidence of a benefit of the programme as for the primary endpoints fatigue, sleep quality and functional status.
- Music therapy to reduce pain associated with surgery [1539], [1540]: Two randomized studies with small case numbers (n=120, n=30) from 2011 investigated the influence of music on postoperative pain after mastectomy and were able to show lower pain in the music intervention group compared to the control groups.
- A Cochrane review is also available on music therapy interventions in cancer patients in general. In a total of 7 studies (n=528), a significant reduction in pain was determined (SMD: -0.91, 95% CI -1.46 to -0.36), although the quality of the evidence was rated as low [1304].
- Training programs for the relief of pain associated with breast surgery [1541], [1542]: Two small randomized studies (n=66, n=44) showed significant improvements in neck and shoulder pain after an 8-week water sports intervention and an 8-week multidimensional program, respectively.
- Hypnosis for the relief of complaints associated with surgery [1543], [1544]: Two studies by Montgomery et al. from 2002 and 2007 showed that patients who received short hypnosis before a mammary PE had less propofol and lidocaine consumption and reported lower pain intensity, less nausea and fatigue postoperatively.
- Acupuncture or electro-acupuncture for short-term treatment of aromatase inhibitor-associated musculoskeletal complaints: In two small randomized studies [890], [1545] (n=21, n=38) there was evidence of a positive effect of acupuncture treatment on aromatase inhibitor-associated musculoskeletal pain. In a further study (n=47) [1546] no advantages could be determined compared to a sham acupuncture.
As for acupuncture [1547], [1548], only studies with small case numbers exist on the influence of electroacupuncture on aromatase inhibitor-associated pain. An improvement of pain was observed in one of the studies (n=67) [1548], but here it was compared with a waiting list group and not with sham acupuncture.
6.6.13 Complementary medical approaches for the treatment of taxane-induced neuropathy
Acetyl l-carnitine should not be recommended for the prevention of taxane-induced neuropathy due to the risk of damage.
- Consensus
- Strong consensus
There is no sufficient data base to evaluate the effectiveness of vitamin E or omega 3 fatty acids.
- Consensus
- Strong consensus
Background 6.59 and 6.60
Smaller studies by Ghoreishi et al. 2012 [1549] (n=69) and Argyriou et al. 2006 [1504] (n=37) provided evidence for a positive effect of omega-3 fatty acids and 300 mg vitamin E (versus placebo or "standard therapy") regarding the prophylaxis of paclitaxel-induced peripheral neuropathy in patients with breast cancer. Since there are no larger, randomized studies that could confirm these effects, the evidence base for these interventions is considered insufficient to make a recommendation (see also Greenlee et al. 2014 [1493]).
Acetyl-L-carnetine (ALC) is a natural substance involved in neuronal protection. While some previous studies had suggested that the use of ALC would be suitable for the prevention and therapy of taxane-induced peripheral neuropathy, a prospective placebo-controlled study by Hershman et al (2013) [1499] showed that after 12 weeks there was no effect of ALC on neuropathy, but after 24 weeks peripheral neuropathy was significantly increased. Since a risk without demonstrable benefit could be established by taking this food supplement, ALC should not be used for the purpose of neuroprotection in chemotherapy.
6.6.14 6.6.14. Complementary medical approaches for the treatment of hot flushes/vasomotor symptoms
Hot flushes and other vegetative regulation disorders are a relevant problem in clinical care. They occur particularly severely in pre- and perimenopausal patients after ovarian failure due to chemotherapy or ovarian dysfunction in the context of endocrine therapy. However, postmenopausal women also suffer an increased recurrence of these symptoms in the course of anti-oestrogenic therapy, especially with tamoxifen. Since causal therapy with estrogens is not possible, especially in hormone-responsive breast cancer, non-hormonal interventions are of particular clinical relevance. In this context, reference is made to the chapter "Gynaecological problems" in the collection of recommendations of the AGO's Breast Commission.
Soya supplements should not be recommended for the treatment of hot flushes in breast cancer patients due to their lack of efficacy.
Guidelines adaptation : Greenlee et al. 2014
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2b
- Consensus
- Strong consensus
Background 6.61
Three placebo-controlled studies from the years 2000 to 2005 with an average of about 120 test subjects showed no efficacy of soy products at the selected dosage and form of application. Due to the lack of efficacy and the fundamental problem of exposure to a food containing phytoestrogens, the use of soy products for the purpose of hot flush therapy should be avoided. In breast cancer a daily intake of less than 100 mg isoflavonoids seems to be of little concern [1550]. For the interventions Cimicifuga Racemosa, flaxseed, homeopathy, hypnosis, magnet therapy, meditation, peppermint, vitamin E the authors around Greenlee [1493] could not find sufficient evidence to make a recommendation.
6.6.15 Alternative medical methods
Alternative therapies should not be recommended to patients. In an empathetic counselling situation, the patient should be informed neutrally, competently and comprehensively about the damage and benefits of such a therapy.
- Consensus
- Consent
Background 6.62
Patients encounter many unfounded offers in their search for help. Some of these are based on the honest efforts of doctors to help and support their patients, especially in hopeless situations. In addition, however, there are numerous providers of alternative therapy concepts, for which economic aspects seem to be the main focus. It becomes dangerous if patients are deprived of effective standard therapies within the framework of these alternative methods (therapy competition). It is therefore important to protect patients from these offers by providing sufficient information.
Among the frequently used alternative therapy methods are Ukrain, vitamin B17 (apricot kernels, bitter almond), insulin potentiated therapy, vitamins according to Dr. Rath®, Germanic New Medicine®, autologous blood cytokines, zapper, various cancer diets, such as the Breuss cure and cell symbiosis therapy.
Some of the methods used are based on traditional empirical medicine. However, adaptations of modern branches of research (e.g. hyperthermia) or our own interpretations of carcinogenesis and immunological correlations (dendritic cells) are also used, which are difficult to recognise as dubious even for doctors specialising in oncology.
6.7 Documentation, care coordination and quality management
6.7.1 Documentation
Documentation of findings, treatments and courses of treatment
The course of disease of patients with breast cancer/DCIS should be reported by all health care providers involved in the care process in accordance with the requirements of the German Cancer Early Detection and Registry Act.
The evaluation of the data from the cancer registries and the annual reports of the DKG/DGS-certified breast cancer centres should be available to service providers, the public and health policy-makers.
- Consensus
- Strong consensus
Background 6.63
The recommendation is based on the knowledge and experience of the experts involved. Today, it is possible and also necessary to present the implementation of guidelines and the results achieved with them in a transparent manner over the long term. Overall survival, disease-related survival, local recurrences, regional recurrences, metastases and secondary malignancies provide evidence of success and failure of oncological care, depending on the constellation of findings and treatment. Long-term results (longitudinal data) are the basis for institutional, regional, national and international comparisons. Such correlations must be made transparent on a regular basis, both overall and for the specialist areas involved, with evaluations. A prerequisite is the systematic collection of relevant data available in interdisciplinary and intersectoral care. The data thus become a reflection of the patient-related network of the doctors and clinics involved. Data quality and care-related documentation of all service providers are two sides of the same coin and require an up-to-date information infrastructure. From the point of view of each individual health care provider, a specialty or a single physician involved in the supply chains of various centres, this data use can only be achieved with efficient cooperation in a regional cancer registry.
Each specialist area should make its own contribution to the cancer register. In part, this is done by transmitting findings and treatment reports from pathologies and radiotherapy, independently of other individual care providers. Particularly urgent is the establishment and expansion of a valid database of drug therapy, which should at least be provided by large centers.
The cancer registries must correctly combine the data from the various sources and make valid and integral data available to the service providers through multi-layered checks. The most important parameters for process and outcome quality must be prepared for each institution and for comparison for the entire catchment area. Prospectively collected clinical data from population-based cancer registries are particularly valuable for science, the public and health policy-makers because they can show changes in disease and care over time. Regional and international comparisons are also part of transparency and can provide impetus for improvements.
In the annual reports of the DKG/DGS-certified breast cancer centres, the implementation of the work in accordance with the guidelines is evaluated annually on the basis of the quality indicators [1551].
The reports (see https://www.krebsgesellschaft.de/jahresberichte.html) also include evaluations of the cooperation between the partners of the oncological network (e.g. presentation rates in interdisciplinary tumour conferences, study activities, etc.) as well as the expertise of the treatment partners over a period of 5 years and based on data from over 50,000 patients per year [1552]. This allows developments of the therapies carried out over time and between different treatment networks. The anonymised and individualised annual reports provide the individual networks with feedback on their results and are suitable for identifying concrete measures if certain results show potential for improvement.
The objectives described above have received a decisive impetus from health policy. Since April 2013, the Act on the Further Development of Cancer Early Diagnosis and Quality Assurance through Clinical Cancer Registries Cancer Early Diagnosis and Registry Act (KFRG) has been in force, according to which "the Länder establish clinical cancer registries to improve the quality of oncological care" (§ 65c, SGB V). "Clinical cancer registration is based on the nationwide uniform data set of the Association of German Tumour Centres and the Society of Epidemiological Cancer Registries in Germany for basic documentation for tumour patients and modules supplementing it, covering the entire country and as complete as possible" (§ 65c, SGB V).
The range of tasks for the clinical cancer registries also provides feedback to the service providers, which will range from differentiated evaluations to access to disease progression with recurrence, metastasis and date of death. The aim is to ensure that certified centres in particular and each participating specialty have access to their own data and that it is possible to maintain and update them.
In addition, regional conferences are required in which the data of certified and non-certified centres and the participating disciplines are analysed and discussed. The need for action can range from completeness and comprehensiveness to the improvement of care.
A further task that is important by law is to contribute to daily care and to fulfil the tasks of "promoting interdisciplinary, directly patient-related cooperation in cancer treatment" and "cooperation with centres in oncology" (§ 65c, SGB V). The "exchange of data with other regional clinical cancer registries" as well as with evaluation centres for clinical cancer registration at the state level" (§ 65c, SGB V) is intended to support the aforementioned care processes.
The objective of "transparency of care in a region" is to be achieved by increasingly improving interdisciplinary and intersectoral communication.
6.7.2 Care coordination and quality management
6.7.2.1 Structural elements of good care coordination
Essential structural features for quality-assured, interdisciplinary and intersectoral care of breast cancer patients are
- the nationwide implementation and further development of early detection measures (such as mammography screening, recording of genetic risk) with evidence-based and quality-assured information,
- the certification of interdisciplinary breast cancer centres according to DKG e.V. and DGS e.V,
- the implementation of the S3 guideline "Diagnosis, therapy and aftercare of breast cancer",
- improving communication in the supply chain for cross-sectoral patient aftercare
- the integration of social services, psycho-oncology, rehabilitation, physiotherapy, palliative medicine and self-help into the care concepts.
- Consensus
- Strong consensus
Background 6.64
The recommendation is based on the knowledge and experience of the experts involved. The diagnosis, therapy and aftercare of breast cancer requires a multidisciplinary concept. Not only the experience of the individual practitioner is important, but also the smooth organisation between the individual treatment disciplines.
Quality-assured early detection, professional imaging diagnostics, histopathological confirmation of findings, excellent surgical procedures, consistent radiation treatment, drug therapy using the latest therapeutic methods and professional aftercare, throughout the entire duration of therapy and beyond, must be part of an overall concept. This concept can only be sustainable through interdisciplinary and cross-sectoral cooperation.
Only the qualitative optimisation of this supply chain is suitable for reducing the morbidity and mortality of breast cancer. Thus, all measures to improve the care of women with breast cancer must not only relate to individual aspects, but always to the entire care chain.
All measures must be quality-assured and transparent. Structural, process and outcome quality must be queried and the relevant care data must be reported to cancer registries.
Annual audits and recertification at three-year intervals with presentation of patient and referring physician satisfaction, compliance with quality objectives, fulfilment of quality indicators and presentation of treatment quality are prerequisites for adequate quality management.
Those responsible in our health system are called upon to overcome particular interests and to make every effort to strive for and achieve optimal treatment conditions and results for the benefit of our patients.
Institutions that do not operate with quality assurance should be excluded from the care of breast cancer patients.
References
[29] Wildiers, H., Heeren, P., Puts, M., Topinkova, E., Janssen-Heijnen, M. L., Extermann, M., et.al. International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer, J Clin Oncol, 2014. 32(24): p. 2595-603.
[1246] Herschbach, Peter, Heußner, Pia, Einführung in die psychoonkologische BehandlungspraxisKlett-Cotta, 2008. 215:
[1247] Holland, J. C., History of psycho-oncology: overcoming attitudinal and conceptual barriers, Psychosom Med, 2002. 64(2): p. 206-21.
[1248] Weis, Joachim, Schwarz, Reinhold, Blettner, Gabriele, Psychoonkologische Versorgung in Deutschland: Qualität und Quantität/Psychooncological care in Germany: Quality and quantity, Zeitschrift für Psychosomatische Medizin und Psychotherapie, 2000. 46(1): p. 4-17.
[1249] Weis, J, Schumacher, A, Blettner, G, Determann, M, Reinert, E, Rüffer, JU, et.al. Psychoonkologie, Der Onkologe, 2007. 13(2): p. 185-194.
[1250] Koch, Uwe, Weis, Joachim, Krankheitsbewältigung bei Krebs und Möglichkeiten der Unterstützung, Stuttgart: Schattauer, 1998.
[1251] Turner, Jane, Zapart, Siggi, Pedersen, Karen, Rankin, Nicole, Luxford, Karen, Fletcher, Jane, Clinical practice guidelines for the psychosocial care of adults with cancer, Psycho‐Oncology, 2005. 14(3): p. 159-173.
[1252] (NHMRC)., National Health and Medical Research Council, Psychosocial practice guidelines: information, support and counselling for women with breast cancer., 1999.
[873] Runowicz, C. D., Leach, C. R., Henry, N. L., Henry, K. S., Mackey, H. T., Cowens-Alvarado, R. L., et.al. American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline, J Clin Oncol, 2016. 34(6): p. 611-35.
[1253] Edwards, A. G., Hailey, S., Maxwell, M., Psychological interventions for women with metastatic breast cancer, Cochrane Database Syst Rev, 2004. p. CD004253.
[28] NICE, The National Institute for Health and Care Excellence (NICE). Advanced breast cancer: diagnosis and treatment, 2009 [addendum 2014].
[37] Leinster, Samuel J, Ashcroft, Jennifer J, Slade, Peter, Dewey, Michael E, Mastectomy versus conservative surgery: psychosocial effects of the patient's choice of treatment, Journal of Psychosocial Oncology, 1989. 7(1-2): p. 179-192.
[1254] Burish, T. G., Snyder, S. L., Jenkins, R. A., Preparing patients for cancer chemotherapy: effect of coping preparation and relaxation interventions, J Consult Clin Psychol, 1991. 59(4): p. 518-25.
[1255] Burton, Mary V, Parker, Ronald W, Farrell, Anita, Bailey, Dianne, Conneely, Julia, Booth, Sue, et.al. A randomized controlled trial of preoperative psychological preparation for mastectomy, Psycho‐Oncology, 1995. 4(1): p. 1-19.
[1256] Flam, B., Spice-Cherry, P., Amsel, R., Effects of preparatory information of a myelogram on patients' expectations and anxiety levels, Patient Educ Couns, 1989. 14(2): p. 115-26.
[1257] Hathaway, D., Effect of preoperative instruction on postoperative outcomes: a meta-analysis, Nurs Res, 1986. 35(5): p. 269-75.
[1258] Johnston, Marie, Vögele, Claus, Benefits of psychological preparation for surgery: a meta-analysis, Annals of Behavioral Medicine, 1993. 15: p. 245-245.
[1259] Meyer, T. J., Mark, M. M., Effects of psychosocial interventions with adult cancer patients: a meta-analysis of randomized experiments, Health Psychol, 1995. 14(2): p. 101-8.
[1260] Hall, Angela, Fallowfield, Lesley J, A'Hern, Roger P, When Breast Cancer Recurs: A 3‐Year Prospective Study of Psychological Morbidity, The Breast Journal, 1996. 2(3): p. 197-203.
[1261] Jenkins, P. L., May, V. E., Hughes, L. E., Psychological morbidity associated with local recurrence of breast cancer, Int J Psychiatry Med, 1991. 21(2): p. 149-55.
[1262] Pinder, K. L., Ramirez, A. J., Black, M. E., Richards, M. A., Gregory, W. M., Rubens, R. D., Psychiatric disorder in patients with advanced breast cancer: prevalence and associated factors, Eur J Cancer, 1993. 29a(4): p. 524-7.
[1263] McArdle, J. M., George, W. D., McArdle, C. S., Smith, D. C., Moodie, A. R., Hughson, A. V., et.al. Psychological support for patients undergoing breast cancer surgery: a randomised study, Bmj, 1996. 312(7034): p. 813-6.
[1264] Christ, G. H., Siegel, K., Freund, B., Langosch, D., Hendersen, S., Sperber, D., et.al. Impact of parental terminal cancer on latency-age children, Am J Orthopsychiatry, 1993. 63(3): p. 417-25.
[1265] Nelson, D. V., Friedman, L. C., Baer, P. E., Lane, M., Smith, F. E., Subtypes of psychosocial adjustment to breast cancer, J Behav Med, 1994. 17(2): p. 127-41.
[1266] Faller, H., Schuler, M., Richard, M., Heckl, U., Weis, J., Kuffner, R., Effects of psycho-oncologic interventions on emotional distress and quality of life in adult patients with cancer: systematic review and meta-analysis, J Clin Oncol, 2013. 31(6): p. 782-93.
[1267] Devine, E. C., Westlake, S. K., The effects of psychoeducational care provided to adults with cancer: meta-analysis of 116 studies, Oncol Nurs Forum, 1995. 22(9): p. 1369-81.
[1268] Sheard, T., Maguire, P., The effect of psychological interventions on anxiety and depression in cancer patients: results of two meta-analyses, Br J Cancer, 1999. 80(11): p. 1770-80.
[1269] Antoni, M. H., Wimberly, S. R., Lechner, S. C., Kazi, A., Sifre, T., Urcuyo, K. R., et.al. Reduction of cancer-specific thought intrusions and anxiety symptoms with a stress management intervention among women undergoing treatment for breast cancer, Am J Psychiatry, 2006. 163(10): p. 1791-7.
[1270] Edgar, L., Rosberger, Z., Collet, J. P., Lessons learned: Outcomes and methodology of a coping skills intervention trial comparing individual and group formats for patients with cancer, Int J Psychiatry Med, 2001. 31(3): p. 289-304.
[1271] Gaston-Johansson, F., Fall-Dickson, J. M., Nanda, J., Ohly, K. V., Stillman, S., Krumm, S., et.al. The effectiveness of the comprehensive coping strategy program on clinical outcomes in breast cancer autologous bone marrow transplantation, Cancer Nurs, 2000. 23(4): p. 277-85.
[1272] Albert, U. S., Koller, M., Lorenz, W., Kopp, I., Heitmann, C., Stinner, B., et.al. Quality of life profile: from measurement to clinical application, Breast, 2002. 11(4): p. 324-34.
[1273] Burke, Susan, Kissane, David William, Psychosocial support for breast cancer patients provided by members of the treatment team: A summary of the literature 1976-1996NHMRC National Breast Cancer Centre, 1998.
[1274] Kalaitzi, C., Papadopoulos, V. P., Michas, K., Vlasis, K., Skandalakis, P., Filippou, D., Combined brief psychosexual intervention after mastectomy: effects on sexuality, body image, and psychological well-being, J Surg Oncol, 2007. 96(3): p. 235-40.
[1275] Schover, L. R., Yetman, R. J., Tuason, L. J., Meisler, E., Esselstyn, C. B., Hermann, R. E., et.al. Partial mastectomy and breast reconstruction. A comparison of their effects on psychosocial adjustment, body image, and sexuality, Cancer, 1995. 75(1): p. 54-64.
[1276] Aranda, S., Schofield, P., Weih, L., Milne, D., Yates, P., Faulkner, R., Meeting the support and information needs of women with advanced breast cancer: a randomised controlled trial, Br J Cancer, 2006. 95(6): p. 667-73.
[1277] Dowsett, S. M., Saul, J. L., Butow, P. N., Dunn, S. M., Boyer, M. J., Findlow, R., et.al. Communication styles in the cancer consultation: preferences for a patient-centred approach, Psychooncology, 2000. 9(2): p. 147-56.
[1278] Pistrang, N., Barker, C., The partner relationship in psychological response to breast cancer, Soc Sci Med, 1995. 40(6): p. 789-97.
[1239] Network, National Comprehensive Cancer, Distress management, NCCN Clinical Practice Guidelines in Oncology, 2008.
[1279] Goedendorp, M. M., Gielissen, M. F., Verhagen, C. A., Bleijenberg, G., Psychosocial interventions for reducing fatigue during cancer treatment in adults, Cochrane Database Syst Rev, 2009. p. CD006953.
[1280] Fillion, L., Gagnon, P., Leblond, F., Gelinas, C., Savard, J., Dupuis, R., et.al. A brief intervention for fatigue management in breast cancer survivors, Cancer Nurs, 2008. 31(2): p. 145-59.
[1281] Jacobsen, P. B., Donovan, K. A., Vadaparampil, S. T., Small, B. J., Systematic review and meta-analysis of psychological and activity-based interventions for cancer-related fatigue, Health Psychol, 2007. 26(6): p. 660-7.
[1282] Montgomery, G. H., Kangas, M., David, D., Hallquist, M. N., Green, S., Bovbjerg, D. H., et.al. Fatigue during breast cancer radiotherapy: an initial randomized study of cognitive-behavioral therapy plus hypnosis, Health Psychol, 2009. 28(3): p. 317-22.
[1283] Yates, P., Aranda, S., Hargraves, M., Mirolo, B., Clavarino, A., McLachlan, S., et.al. Randomized controlled trial of an educational intervention for managing fatigue in women receiving adjuvant chemotherapy for early-stage breast cancer, J Clin Oncol, 2005. 23(25): p. 6027-36.
[1284] Loscalzo, M., Psychological approaches to the management of pain in patients with advanced cancer, Hematol Oncol Clin North Am, 1996. 10(1): p. 139-55.
[1285] Fields, Howard L, Core curriculum for professional education in pain, RevIASP press, 1991.
[1286] Poppelreuter, M, Weis, J, Schmid, J, Bartsch, HH, Neuropsychologische Folgestörungen nach adjuvanter Therapie des Mammakarzinoms, Der Onkologe, 2006. 12(1): p. 27-35.
[1287] Moorey, Stirling, Greer, Steven, Watson, Maggie, Baruch, John DR, Robertson, Bernadette M, Mason, Anne, et.al. Adjuvant psychological therapy for patients with cancer: outcome at one year, Psycho‐Oncology, 1994. 3(1): p. 39-46.
[1288] Ley, P. Llewelyn, S., Improving patients understanding, recall, satisfaction and compliance., 1992.
[1289] Kissane, D. W., Bloch, S., Smith, G. C., Miach, P., Clarke, D. M., Ikin, J., et.al. Cognitive-existential group psychotherapy for women with primary breast cancer: a randomised controlled trial, Psychooncology, 2003. 12(6): p. 532-46.
[1290] Kissane, D. W., Love, A., Hatton, A., Bloch, S., Smith, G., Clarke, D. M., et.al. Effect of cognitive-existential group therapy on survival in early-stage breast cancer, J Clin Oncol, 2004. 22(21): p. 4255-60.
[1291] Kissane, D. W., Grabsch, B., Clarke, D. M., Smith, G. C., Love, A. W., Bloch, S., et.al. Supportive-expressive group therapy for women with metastatic breast cancer: survival and psychosocial outcome from a randomized controlled trial, Psychooncology, 2007. 16(4): p. 277-86.
[1292] Dolbeault, S., Cayrou, S., Bredart, A., Viala, A. L., Desclaux, B., Saltel, P., et.al. The effectiveness of a psycho-educational group after early-stage breast cancer treatment: results of a randomized French study, Psychooncology, 2009. 18(6): p. 647-56.
[1293] Bindemann, S., Soukop, M., Kaye, S. B., Randomised controlled study of relaxation training, Eur J Cancer, 1991. 27(2): p. 170-4.
[1294] Cohen, Miri, Fried, Georgeta, Comparing relaxation training and cognitive-behavioral group therapy for women with breast cancer, Research on Social Work Practice, 2007. 17(3): p. 313-323.
[1295] Lengacher, C. A., Johnson-Mallard, V., Post-White, J., Moscoso, M. S., Jacobsen, P. B., Klein, T. W., et.al. Randomized controlled trial of mindfulness-based stress reduction (MBSR) for survivors of breast cancer, Psychooncology, 2009. 18(12): p. 1261-72.
[1296] Nidich, S. I., Fields, J. Z., Rainforth, M. V., Pomerantz, R., Cella, D., Kristeller, J., et.al. A randomized controlled trial of the effects of transcendental meditation on quality of life in older breast cancer patients, Integr Cancer Ther, 2009. 8(3): p. 228-34.
[1297] Yoo, H. J., Ahn, S. H., Kim, S. B., Kim, W. K., Han, O. S., Efficacy of progressive muscle relaxation training and guided imagery in reducing chemotherapy side effects in patients with breast cancer and in improving their quality of life, Support Care Cancer, 2005. 13(10): p. 826-33.
[1298] Baucom, D. H., Porter, L. S., Kirby, J. S., Gremore, T. M., Wiesenthal, N., Aldridge, W., et.al. A couple-based intervention for female breast cancer, Psychooncology, 2009. 18(3): p. 276-83.
[1299] Manne, S. L., Ostroff, J. S., Winkel, G., Fox, K., Grana, G., Miller, E., et.al. Couple-focused group intervention for women with early stage breast cancer, J Consult Clin Psychol, 2005. 73(4): p. 634-46.
[1300] Northouse, L., Kershaw, T., Mood, D., Schafenacker, A., Effects of a family intervention on the quality of life of women with recurrent breast cancer and their family caregivers, Psychooncology, 2005. 14(6): p. 478-91.
[1301] Scott, J. L., Halford, W. K., Ward, B. G., United we stand? The effects of a couple-coping intervention on adjustment to early stage breast or gynecological cancer, J Consult Clin Psychol, 2004. 72(6): p. 1122-35.
[300] Forbes, J. F., Sestak, I., Howell, A., Bonanni, B., Bundred, N., Levy, C., et.al. Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial, Lancet, 2016. 387(10021): p. 866-73.
[1302] Kesler, S., Hadi Hosseini, S. M., Heckler, C., Janelsins, M., Palesh, O., Mustian, K., et.al. Cognitive training for improving executive function in chemotherapy-treated breast cancer survivors, Clin Breast Cancer, 2013. 13(4): p. 299-306.
[1303] Ercoli, L. M., Petersen, L., Hunter, A. M., Cognitive rehabilitation group intervention for breast cancer survivors: results of a randomized clinical trial, 2015. 24(11): p. 1360-7.
[1304] Bradt, J., Dileo, C., Magill, L., Teague, A., Music interventions for improving psychological and physical outcomes in cancer patients, Cochrane Database Syst Rev, 2016. p. Cd006911.
[1305] Burns, D. S., The effect of the bonny method of guided imagery and music on the mood and life quality of cancer patients, J Music Ther, 2001. 38(1): p. 51-65.
[1306] Hanser, S. B., Bauer-Wu, S., Kubicek, L., Healey, M., Manola, J., Hernandez, M., et.al. Effects of a music therapy intervention on quality of life and distress in women with metastatic breast cancer, J Soc Integr Oncol, 2006. 4(3): p. 116-24.
[1307] Puig, Ana, Lee, Sang Min, Goodwin, Linda, Sherrard, Peter AD, The efficacy of creative arts therapies to enhance emotional expression, spirituality, and psychological well-being of newly diagnosed Stage I and Stage II breast cancer patients: A preliminary study, The Arts in Psychotherapy, 2006. 33(3): p. 218-228.
[1308] Svensk, A. C., Oster, I., Thyme, K. E., Magnusson, E., Sjodin, M., Eisemann, M., et.al. Art therapy improves experienced quality of life among women undergoing treatment for breast cancer: a randomized controlled study, Eur J Cancer Care (Engl), 2009. 18(1): p. 69-77.
[1309] Mehnert, A., Lehmann, C., Cao, P., Koch, U., [Assessment of psychosocial distress and resources in oncology--a literature review about screening measures and current developments], Psychother Psychosom Med Psychol, 2006. 56(12): p. 462-79.
[1310] Aaronson, N. K., Ahmedzai, S., Bergman, B., Bullinger, M., Cull, A., Duez, N. J., et.al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology, J Natl Cancer Inst, 1993. 85(5): p. 365-76.
[1311] Cella, D. F., Tulsky, D. S., Gray, G., Sarafian, B., Linn, E., Bonomi, A., et.al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure, J Clin Oncol, 1993. 11(3): p. 570-9.
[1312] Albert, U. S., Koller, M., Lorenz, W., Kopp, I., Heitmann, C., Stinner, B., et.al. Quality of life profile: from measurement to clinical application, Breast, 2002. 11(4): p. 324-34.
[1313] Engel, J., Eckel, R., Aydemir, U., Aydemir, S., Kerr, J., Schlesinger-Raab, A., et.al. Determinants and prognoses of locoregional and distant progression in breast cancer, Int J Radiat Oncol Biol Phys, 2003. 55(5): p. 1186-95.
[1314] Lemieux, J., Goodwin, P. J., Bordeleau, L. J., Lauzier, S., Theberge, V., Quality-of-life measurement in randomized clinical trials in breast cancer: an updated systematic review (2001-2009), J Natl Cancer Inst, 2011. 103(3): p. 178-231.
[1315] Velikova, G., Wright, E. P., Smith, A. B., Cull, A., Gould, A., Forman, D., et.al. Automated collection of quality-of-life data: a comparison of paper and computer touch-screen questionnaires, J Clin Oncol, 1999. 17(3): p. 998-1007.
[1316] Velikova, G., Booth, L., Smith, A. B., Brown, P. M., Lynch, P., Brown, J. M., et.al. Measuring quality of life in routine oncology practice improves communication and patient well-being: a randomized controlled trial, J Clin Oncol, 2004. 22(4): p. 714-24.
[1317] Klinkhammer-Schalke, M., Koller, M., Steinger, B., Ehret, C., Ernst, B., Wyatt, J. C., et.al. Direct improvement of quality of life using a tailored quality of life diagnosis and therapy pathway: randomised trial in 200 women with breast cancer, Br J Cancer, 2012. 106(5): p. 826-38.
[1318] Aaronson, N. K., Ahmedzai, S., Bergman, B., Bullinger, M., Cull, A., Duez, N. J., et.al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology, J Natl Cancer Inst, 1993. 85(5): p. 365-76.
[1319] Mehnert, A., Lehmann, C., Cao, P., Koch, U., [Assessment of psychosocial distress and resources in oncology--a literature review about screening measures and current developments], Psychother Psychosom Med Psychol, 2006. 56(12): p. 462-79.
[871] Onkologie, Leitlinienprogramm, Supportive Therapie bei onkologischen PatientInnen-Konsultationsfassung, LangversionDeutsche Krebsgesellschaft, D.K., AWMF, 2016.
[1320] Onkologie, Leitlinienprogramm, S3-Leitlinie Palliativmedizin für Patienten mit einer nicht-heilbaren Krebserkrankung. Langversion 1.1, 2015. AWMF-Registernummer: 128/001OL, 2016.
[1321] (NCI)., National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE Version 4.03)., 2010.
[892] Furmaniak, A. C., Menig, M., Markes, M. H., Exercise for women receiving adjuvant therapy for breast cancer, Cochrane Database Syst Rev, 2016. 9: p. Cd005001.
[1322] Markes, M., Brockow, T., Resch, K. L., Exercise for women receiving adjuvant therapy for breast cancer, Cochrane Database Syst Rev, 2006. p. Cd005001.
[1323] Basch, E., Prestrud, A. A., Hesketh, P. J., Kris, M. G., Feyer, P. C., Somerfield, M. R., et.al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update, J Clin Oncol, 2011. 29(31): p. 4189-98.
[1324] Hesketh, P. J., Bohlke, K., Lyman, G. H., Basch, E., Chesney, M., Clark-Snow, R. A., et.al. Antiemetics: American Society of Clinical Oncology Focused Guideline Update, J Clin Oncol, 2016. 34(4): p. 381-6.
[1325] (MASCC), Mulitnational Association of Supportive Care in Cancer, Updated antiemetic consensus guidelines by MASCC/ESMO, 2016.
[1326] Roila, F, Herrstedt, Jørn, Aapro, M, Gralla, RJ, Einhorn, LH, Ballatori, E, et.al. Guideline update for MASCC and ESMO in the prevention of chemotherapy-and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference, Annals of Oncology, 2010. 21(suppl 5): p. v232-v243.
[1327] Warr, D. G., Hesketh, P. J., Gralla, R. J., Muss, H. B., Herrstedt, J., Eisenberg, P. D., et.al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy, J Clin Oncol, 2005. 23(12): p. 2822-30.
[1328] Aapro, M., Rugo, H., Rossi, G., Rizzi, G., Borroni, M. E., Bondarenko, I., et.al. A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy, Ann Oncol, 2014. 25(7): p. 1328-33.
[1329] Morrow, GR, Roscoe, JA, Anticipatory nausea and vomiting: models, mechanisms and management, Medical management of cancer treatment induced emesis. London: Martin Dunitz, 1997. p. 149-166.
[1330] Navari, R. M., Nagy, C. K., Gray, S. E., The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy, Support Care Cancer, 2013. 21(6): p. 1655-63.
[1331] Tipton, J. M., McDaniel, R. W., Barbour, L., Johnston, M. P., Kayne, M., LeRoy, P., et.al. Putting evidence into practice: evidence-based interventions to prevent, manage, and treat chemotherapy-induced nausea and vomiting, Clin J Oncol Nurs, 2007. 11(1): p. 69-78.
[1332] Aapro, M. S., Molassiotis, A., Olver, I., Anticipatory nausea and vomiting, Support Care Cancer, 2005. 13(2): p. 117-21.
[1333] Maranzano, E., De Angelis, V., Pergolizzi, S., Lupattelli, M., Frata, P., Spagnesi, S., et.al. A prospective observational trial on emesis in radiotherapy: analysis of 1020 patients recruited in 45 Italian radiation oncology centres, Radiother Oncol, 2010. 94(1): p. 36-41.
[1334] Wong, R. K., Paul, N., Ding, K., Whitehead, M., Brundage, M., Fyles, A., et.al. 5-hydroxytryptamine-3 receptor antagonist with or without short-course dexamethasone in the prophylaxis of radiation induced emesis: a placebo-controlled randomized trial of the National Cancer Institute of Canada Clinical Trials Group (SC19), J Clin Oncol, 2006. 24(21): p. 3458-64.
[1335] Enblom, A., Bergius Axelsson, B., Steineck, G., Hammar, M., Borjeson, S., One third of patients with radiotherapy-induced nausea consider their antiemetic treatment insufficient, Support Care Cancer, 2009. 17(1): p. 23-32.
[1336] Ruhlmann, C. H., Christensen, T. B., Dohn, L. H., Paludan, M., Ronnengart, E., Halekoh, U., et.al. Efficacy and safety of fosaprepitant for the prevention of nausea and emesis during 5 weeks of chemoradiotherapy for cervical cancer (the GAND-emesis study): a multinational, randomised, placebo-controlled, double-blind, phase 3 trial, Lancet Oncol, 2016. 17(4): p. 509-18.
[1337] Roila, F., Molassiotis, A., Herrstedt, J., Aapro, M., Gralla, R. J., Bruera, E., et.al. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients, Ann Oncol, 2016. 27(suppl 5): p. v119-v133.
[1338] Lyman, G. H., Dale, D. C., Culakova, E., Poniewierski, M. S., Wolff, D. A., Kuderer, N. M., et.al. The impact of the granulocyte colony-stimulating factor on chemotherapy dose intensity and cancer survival: a systematic review and meta-analysis of randomized controlled trials, Ann Oncol, 2013. 24(10): p. 2475-84.
[1339] Link, H., Maschmeyer, G., Meyer, P., Hiddemann, W., Stille, W., Helmerking, M., et.al. Interventional antimicrobial therapy in febrile neutropenic patients. Study Group of the Paul Ehrlich Society for Chemotherapy, Ann Hematol, 1994. 69(5): p. 231-43.
[1340] Link, H., Bohme, A., Cornely, O. A., Hoffken, K., Kellner, O., Kern, W. V., et.al. Antimicrobial therapy of unexplained fever in neutropenic patients--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO), Study Group Interventional Therapy of Unexplained Fever, Arbeitsgemeinschaft Supportivmassnahmen in der Onkologie (ASO) of the Deutsche Krebsgesellschaft (DKG-German Cancer Society), Ann Hematol, 2003. 82 Suppl 2: p. S105-17.
[1341] Schiel, X., Link, H., Maschmeyer, G., Glass, B., Cornely, O. A., Buchheidt, D., et.al. A prospective, randomized multicenter trial of the empirical addition of antifungal therapy for febrile neutropenic cancer patients: results of the Paul Ehrlich Society for Chemotherapy (PEG) Multicenter Trial II, Infection, 2006. 34(3): p. 118-26.
[1342] Link, H, Buchheidt, D, Maschmeyer, G, Böhme, A, Mahlberg, R, Mousset, S, et.al. Arbeitsgemeinschaft Infektionen in der Hämatologie und Onkologie (AGIHO) dDGfHuOeVD, Sektion Infektionen in der Hämatologie und Onkologie dP-E-GfCeVP, Arbeitsgemeinschaft Supportivmaßnahmen in der Onkologie dDKeVA, Deutschsprachige Mykologische Gesellschaft eV (DMykG)(2006) Infektionen bei Neutropenie–Diagnostik und Therapie 2006–Empfehlungen für die Praxis, 2006.
[1343] Bodey, G. P., Buckley, M., Sathe, Y. S., Freireich, E. J., Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia, Ann Intern Med, 1966. 64(2): p. 328-40.
[1344] Kuderer, N. M., Dale, D. C., Crawford, J., Cosler, L. E., Lyman, G. H., Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients, Cancer, 2006. 106(10): p. 2258-66.
[1345] Elting, L. S., Rubenstein, E. B., Rolston, K. V., Bodey, G. P., Outcomes of bacteremia in patients with cancer and neutropenia: observations from two decades of epidemiological and clinical trials, Clin Infect Dis, 1997. 25(2): p. 247-59.
[1346] Knight, K., Wade, S., Balducci, L., Prevalence and outcomes of anemia in cancer: a systematic review of the literature, Am J Med, 2004. 116 Suppl 7A: p. 11s-26s.
[1347] Ludwig, H., Van Belle, S., Barrett-Lee, P., Birgegard, G., Bokemeyer, C., Gascon, P., et.al. The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients, Eur J Cancer, 2004. 40(15): p. 2293-306.
[1348] Weiss, G., Goodnough, L. T., Anemia of chronic disease, N Engl J Med, 2005. 352(10): p. 1011-23.
[1349] Miller, C. B., Jones, R. J., Piantadosi, S., Abeloff, M. D., Spivak, J. L., Decreased erythropoietin response in patients with the anemia of cancer, N Engl J Med, 1990. 322(24): p. 1689-92.
[1350] Fleming, R. E., Bacon, B. R., Orchestration of iron homeostasis, N Engl J Med, 2005. 352(17): p. 1741-4.
[1351] Ganz, T., Hepcidin and iron regulation, 10 years later, Blood, 2011. 117(17): p. 4425-33.
[1352] Kautz, L, Jung, G, Nemeth, E, Ganz, T, The Erythroid Factor Erythroferrone and Its Role In Iron Homeostasis, Blood, 2013. 122(4):
[1353] Harrison, L. B., Shasha, D., White, C., Ramdeen, B., Radiotherapy-Associated Anemia: The Scope of the Problem, Oncologist, 2000. 5 Suppl 2: p. 1-7.
[676] Nagar, H., Boothe, D., Ginter, P. S., Sison, C., Vahdat, L., Shin, S., et.al. Disease-free survival according to the use of postmastectomy radiation therapy after neoadjuvant chemotherapy, Clin Breast Cancer, 2015. 15(2): p. 128-34.
[1354] Tonia, T., Mettler, A., Robert, N., Schwarzer, G., Seidenfeld, J., Weingart, O., et.al. Erythropoietin or darbepoetin for patients with cancer, Cochrane Database Syst Rev, 2012. 12: p. Cd003407.
[1355] Machtay, M, Zhang, Q, Suntharalingam, M, Hershock, D, Lustig, R, Nabid, A, et.al. Long-term Outcomes from RTOG 99-03: Radiation Therapy With or Without Erythropoietin for Anemic Head-and-Neck Cancer Patients, International Journal of Radiation Oncology* Biology* Physics, 2012. 84(3): p. S21.
[1356] Moebus, V., Jackisch, C., Schneeweiss, A., Huober, J., Lueck, H. J., du Bois, A., et.al. Adding epoetin alfa to intense dose-dense adjuvant chemotherapy for breast cancer: randomized clinical trial, J Natl Cancer Inst, 2013. 105(14): p. 1018-26.
[1357] Debus, J., Drings, P., Baurecht, W., Angermund, R., Prospective, randomized, controlled, and open study in primarily inoperable, stage III non-small cell lung cancer (NSCLC) patients given sequential radiochemotherapy with or without epoetin alfa, Radiother Oncol, 2014. 112(1): p. 23-9.
[1358] Nitz, U., Gluz, O., Zuna, I., Oberhoff, C., Reimer, T., Schumacher, C., et.al. Final results from the prospective phase III WSG-ARA trial: impact of adjuvant darbepoetin alfa on event-free survival in early breast cancer, Ann Oncol, 2014. 25(1): p. 75-80.
[1359] Ludwig, H., Muldur, E., Endler, G., Hubl, W., Prevalence of iron deficiency across different tumors and its association with poor performance status, disease status and anemia, Ann Oncol, 2013. 24(7): p. 1886-92.
[1360] Hastka, J, Heimpel, H, Metzgeroth, G, Deutsche Gesellschaft für Hämatologie und medizinische Onkologie (DGHO). Eisenmangel und Eisenmangelanämie–Leitlinie 2011, 2011.
[1361] Carson, J. L., Carless, P. A., Hebert, P. C., Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion, Cochrane Database Syst Rev, 2012. p. Cd002042.
[1362] Retter, A., Wyncoll, D., Pearse, R., Carson, D., McKechnie, S., Stanworth, S., et.al. Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients, Br J Haematol, 2013. 160(4): p. 445-64.
[1363] Hoppe, J.-D., Scriba, P. C., Klüter, H., Querschnitts-Leitlinien (BÄK) zur Therapie mit Blutkomponenten und Plasmaderivaten 4. überarbeitete und aktualisierte Auflage 2014., 2014.
[1364] Carson, J. L., Sieber, F., Cook, D. R., Hoover, D. R., Noveck, H., Chaitman, B. R., et.al. Liberal versus restrictive blood transfusion strategy: 3-year survival and cause of death results from the FOCUS randomised controlled trial, Lancet, 2015. 385(9974): p. 1183-9.
[1365] Berger, M. D., Gerber, B., Arn, K., Senn, O., Schanz, U., Stussi, G., Significant reduction of red blood cell transfusion requirements by changing from a double-unit to a single-unit transfusion policy in patients receiving intensive chemotherapy or stem cell transplantation, Haematologica, 2012. 97(1): p. 116-22.
[1366] Yerrabothala, S., Desrosiers, K. P., Szczepiorkowski, Z. M., Dunbar, N. M., Significant reduction in red blood cell transfusions in a general hospital after successful implementation of a restrictive transfusion policy supported by prospective computerized order auditing, Transfusion, 2014. 54(10 Pt 2): p. 2640-5.
[1367] Hicks, L. K., Bering, H., Carson, K. R., Kleinerman, J., Kukreti, V., Ma, A., et.al. The ASH Choosing Wisely(R) campaign: five hematologic tests and treatments to question, Blood, 2013. 122(24): p. 3879-83.
[1368] Park, Susanna B, Goldstein, David, Krishnan, Arun V, Lin, Cindy S‐Y, Friedlander, Michael L, Cassidy, James, et.al. Chemotherapy‐induced peripheral neurotoxicity: A critical analysis, CA: a cancer journal for clinicians, 2013. 63(6): p. 419-437.
[1369] Lee, J. J., Swain, S. M., Peripheral neuropathy induced by microtubule-stabilizing agents, J Clin Oncol, 2006. 24(10): p. 1633-42.
[1370] Seidman, A. D., Berry, D., Cirrincione, C., Harris, L., Muss, H., Marcom, P. K., et.al. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840, J Clin Oncol, 2008. 26(10): p. 1642-9.
[1371] Gradishar, W. J., Tjulandin, S., Davidson, N., Shaw, H., Desai, N., Bhar, P., et.al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer, J Clin Oncol, 2005. 23(31): p. 7794-803.
[1372] Ibrahim, N. K., Desai, N., Legha, S., Soon-Shiong, P., Theriault, R. L., Rivera, E., et.al. Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel, Clin Cancer Res, 2002. 8(5): p. 1038-44.
[1373] Gradishar, W. J., Krasnojon, D., Cheporov, S., Makhson, A. N., Manikhas, G. M., Clawson, A., et.al. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer, J Clin Oncol, 2009. 27(22): p. 3611-9.
[1374] Gradishar, W. J., Krasnojon, D., Cheporov, S., Makhson, A. N., Manikhas, G. M., Clawson, A., et.al. Phase II trial of nab-paclitaxel compared with docetaxel as first-line chemotherapy in patients with metastatic breast cancer: final analysis of overall survival, Clin Breast Cancer, 2012. 12(5): p. 313-21.
[1106] Blum, J. L., Savin, M. A., Edelman, G., Pippen, J. E., Robert, N. J., Geister, B. V., et.al. Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes, Clin Breast Cancer, 2007. 7(11): p. 850-6.
[1375] Hershman, D. L., Lacchetti, C., Dworkin, R. H., Lavoie Smith, E. M., Bleeker, J., Cavaletti, G., et.al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline, J Clin Oncol, 2014. 32(18): p. 1941-67.
[1376] Streckmann, F., Zopf, E. M., Lehmann, H. C., May, K., Rizza, J., Zimmer, P., et.al. Exercise intervention studies in patients with peripheral neuropathy: a systematic review, Sports Med, 2014. 44(9): p. 1289-304.
[1377] Smith, E. M., Pang, H., Cirrincione, C., Fleishman, S., Paskett, E. D., Ahles, T., et.al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial, Jama, 2013. 309(13): p. 1359-67.
[897] Cartoni, C., Brunetti, G. A., Federico, V., Efficace, F., Grammatico, S., Tendas, A., et.al. Controlled-release oxycodone for the treatment of bortezomib-induced neuropathic pain in patients with multiple myeloma, Support Care Cancer, 2012. 20(10): p. 2621-6.
[1378] Garassino, M. C., Piva, S., La Verde, N., Spagnoletti, I., Iorno, V., Carbone, C., et.al. Randomised phase II trial (NCT00637975) evaluating activity and toxicity of two different escalating strategies for pregabalin and oxycodone combination therapy for neuropathic pain in cancer patients, PLoS One, 2013. 8(4): p. e59981.
[1379] Khatcheressian, J. L., Wolff, A. C., Smith, T. J., Grunfeld, E., Muss, H. B., Vogel, V. G., et.al. American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting, J Clin Oncol, 2006. 24(31): p. 5091-7.
[1380] Saphner, T., Tormey, D. C., Gray, R., Annual hazard rates of recurrence for breast cancer after primary therapy, J Clin Oncol, 1996. 14(10): p. 2738-46.
[874] Grunfeld, E., Dhesy-Thind, S., Levine, M., Clinical practice guidelines for the care and treatment of breast cancer: follow-up after treatment for breast cancer (summary of the 2005 update), Cmaj, 2005. 172(10): p. 1319-20.
[1381] Rojas, M. P., Telaro, E., Russo, A., Moschetti, I., Coe, L., Fossati, R., et.al. Follow-up strategies for women treated for early breast cancer, Cochrane Database Syst Rev, 2005. p. Cd001768.
[1382] Gulliford, T., Opomu, M., Wilson, E., Hanham, I., Epstein, R., Popularity of less frequent follow up for breast cancer in randomised study: initial findings from the hotline study, Bmj, 1997. 314(7075): p. 174-7.
[1383] Hurria, A., Hudis, C., Follow-up care of breast cancer survivors, Crit Rev Oncol Hematol, 2003. 48(1): p. 89-99.
[1384] Palli, D., Russo, A., Saieva, C., Ciatto, S., Rosselli Del Turco, M., Distante, V., et.al. Intensive vs clinical follow-up after treatment of primary breast cancer: 10-year update of a randomized trial. National Research Council Project on Breast Cancer Follow-up, Jama, 1999. 281(17): p. 1586.
[1385] Pestalozzi, B. C., Luporsi-Gely, E., Jost, L. M., Bergh, J., ESMO Minimum Clinical Recommendations for diagnosis, adjuvant treatment and follow-up of primary breast cancer, Ann Oncol, 2005. 16 Suppl 1: p. i7-9.
[1386] Rosselli Del Turco, M., Palli, D., Cariddi, A., Ciatto, S., Pacini, P., Distante, V., Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up, Jama, 1994. 271(20): p. 1593-7.
[1387] Ferzoco, R. M., Ruddy, K. J., Optimal delivery of male breast cancer follow-up care: improving outcomes, Breast Cancer (Dove Med Press), 2015. 7: p. 371-9.
[1388] Selby, P., Gillis, C., Haward, R., Benefits from specialised cancer care, Lancet, 1996. 348(9023): p. 313-8.
[1389] (NBOCC)., National Breast and Ovarian Cancer Centre, Recommendations for follow-up of women with early breast cancer., 2010.
[1390] Dalberg, K., Mattsson, A., Sandelin, K., Rutqvist, L. E., Outcome of treatment for ipsilateral breast tumor recurrence in early-stage breast cancer, Breast Cancer Res Treat, 1998. 49(1): p. 69-78.
[1391] Riebe, E., Gunther, K., Schulz, K., Kohler, G., Schimming, A., Schwesinger, G., et.al. Recurrent disease after breast preserving therapy (BPT) and radiation therapy for breast cancer--diagnostic yield of palpation, mammography and ultrasonography, Ultraschall Med, 2007. 28(4): p. 394-400.
[1392] Wojcinski, S., Farrokh, A., Hille, U., Hirschauer, E., Schmidt, W., Hillemanns, P., et.al. Optimizing breast cancer follow-up: diagnostic value and costs of additional routine breast ultrasound, Ultrasound Med Biol, 2011. 37(2): p. 198-206.
[929] Haffty, B. G., Fischer, D., Beinfield, M., McKhann, C., Prognosis following local recurrence in the conservatively treated breast cancer patient, Int J Radiat Oncol Biol Phys, 1991. 21(2): p. 293-8.
[1393] Muuller, R. D., Barkhausen, J., Sauerwein, W., Langer, R., Assessment of local recurrence after breast-conserving therapy with MRI, J Comput Assist Tomogr, 1998. 22(3): p. 408-12.
[1394] Viehweg, P., Heinig, A., Lampe, D., Buchmann, J., Heywang-Kobrunner, S. H., Retrospective analysis for evaluation of the value of contrast-enhanced MRI in patients treated with breast conservative therapy, Magma, 1998. 7(3): p. 141-52.
[1395] Kollias, J., Evans, A. J., Wilson, A. R., Ellis, I. O., Elston, C. W., Blamey, R. W., Value of contralateral surveillance mammography for primary breast cancer follow-up, World J Surg, 2000. 24(8): p. 983-7; discussion 988-9.
[1396] Kuhl, C., Weigel, S., Schrading, S., Arand, B., Bieling, H., Konig, R., et.al. Prospective multicenter cohort study to refine management recommendations for women at elevated familial risk of breast cancer: the EVA trial, J Clin Oncol, 2010. 28(9): p. 1450-7.
[1397] Auvinen, A., Curtis, R. E., Ron, E., Risk of subsequent cancer following breast cancer in men, J Natl Cancer Inst, 2002. 94(17): p. 1330-2.
[1398] Aguiar-Bujanda, D., Bohn-Sarmiento, U., Aguiar-Morales, J., False elevation of serum CA 15-3 levels in patients under follow-up for breast cancer, Breast J, 2004. 10(4): p. 375-6.
[1399] Bornhak, Sven, Heidemann, Else, Herschlein, H-J, Simon, Wolfgang, Merkle, Elisabeth, Widmaier, Guenter, et.al. Symptom-oriented follow-up of early breast cancer is not inferior to conventional control. Results of a prospective multicentre study, Oncology Research and Treatment, 2007. 30(8-9): p. 443-449.
[1400] Hayes, D. F., Clinical practice. Follow-up of patients with early breast cancer, N Engl J Med, 2007. 356(24): p. 2505-13.
[1401] Rojas, M. P., Telaro, E., Russo, A., Fossati, R., Confalonieri, C., Liberati, A., Follow-up strategies for women treated for early breast cancer, Cochrane Database Syst Rev, 2000. p. Cd001768.
[1402] Brennan, M. J., Lymphedema following the surgical treatment of breast cancer: a review of pathophysiology and treatment, J Pain Symptom Manage, 1992. 7(2): p. 110-6.
[1403] Armer, J., Fu, M. R., Wainstock, J. M., Zagar, E., Jacobs, L. K., Lymphedema following breast cancer treatment, including sentinel lymph node biopsy, Lymphology, 2004. 37(2): p. 73-91.
[1404] Bani, H. A., Fasching, P. A., Lux, M. M., Rauh, C., Willner, M., Eder, I., et.al. Lymphedema in breast cancer survivors: assessment and information provision in a specialized breast unit, Patient Educ Couns, 2007. 66(3): p. 311-8.
[1405] Francis, W. P., Abghari, P., Du, W., Rymal, C., Suna, M., Kosir, M. A., Improving surgical outcomes: standardizing the reporting of incidence and severity of acute lymphedema after sentinel lymph node biopsy and axillary lymph node dissection, Am J Surg, 2006. 192(5): p. 636-9.
[1406] Golshan, M., Martin, W. J., Dowlatshahi, K., Sentinel lymph node biopsy lowers the rate of lymphedema when compared with standard axillary lymph node dissection, Am Surg, 2003. 69(3): p. 209-11; discussion 212.
[1407] Hamner, J. B., Fleming, M. D., Lymphedema therapy reduces the volume of edema and pain in patients with breast cancer, Ann Surg Oncol, 2007. 14(6): p. 1904-8.
[1408] Harris, S. R., Hugi, M. R., Olivotto, I. A., Levine, M., Clinical practice guidelines for the care and treatment of breast cancer: 11. Lymphedema, Cmaj, 2001. 164(2): p. 191-9.
[1409] Hayes, S., Cornish, B., Newman, B., Comparison of methods to diagnose lymphoedema among breast cancer survivors: 6-month follow-up, Breast Cancer Res Treat, 2005. 89(3): p. 221-6.
[1410] Moseley, A. L., Carati, C. J., Piller, N. B., A systematic review of common conservative therapies for arm lymphoedema secondary to breast cancer treatment, Ann Oncol, 2007. 18(4): p. 639-46.
[1411] Sanjuan, A., Vidal-Sicart, S., Zanon, G., Pahisa, J., Velasco, M., Fernandez, P. L., et.al. Clinical axillary recurrence after sentinel node biopsy in breast cancer: a follow-up study of 220 patients, Eur J Nucl Med Mol Imaging, 2005. 32(8): p. 932-6.
[1412] Torrenga, H., Fabry, H., van der Sijp, J. R., van Diest, P. J., Pijpers, R., Meijer, S., Omitting axillary lymph node dissection in sentinel node negative breast cancer patients is safe: a long term follow-up analysis, J Surg Oncol, 2004. 88(1): p. 4-7; discussion 7-8.
[1413] Clark, B., Sitzia, J., Harlow, W., Incidence and risk of arm oedema following treatment for breast cancer: a three-year follow-up study, Qjm, 2005. 98(5): p. 343-8.
[1414] Kokke, M. C., Jannink, I., Barneveld, P. C., van der Linden, J. C., Gelderman, W. A., Wissing, J. C., et.al. Incidence of axillary recurrence in 113 sentinel node negative breast cancer patients: a 3-year follow-up study, Eur J Surg Oncol, 2005. 31(3): p. 221-5.
[1415] Mansel, R. E., Fallowfield, L., Kissin, M., Goyal, A., Newcombe, R. G., Dixon, J. M., et.al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC Trial, J Natl Cancer Inst, 2006. 98(9): p. 599-609.
[1416] Purushotham, A. D., Upponi, S., Klevesath, M. B., Bobrow, L., Millar, K., Myles, J. P., et.al. Morbidity after sentinel lymph node biopsy in primary breast cancer: results from a randomized controlled trial, J Clin Oncol, 2005. 23(19): p. 4312-21.
[1417] McNeely, M. L., Campbell, K., Ospina, M., Rowe, B. H., Dabbs, K., Klassen, T. P., et.al. Exercise interventions for upper-limb dysfunction due to breast cancer treatment, Cochrane Database Syst Rev, 2010. p. Cd005211.
[1418] Devoogdt, N., Van Kampen, M., Geraerts, I., Coremans, T., Christiaens, M. R., Different physical treatment modalities for lymphoedema developing after axillary lymph node dissection for breast cancer: a review, Eur J Obstet Gynecol Reprod Biol, 2010. 149(1): p. 3-9.
[1419] Schmitz, K. H., Ahmed, R. L., Troxel, A., Cheville, A., Smith, R., Lewis-Grant, L., et.al. Weight lifting in women with breast-cancer-related lymphedema, N Engl J Med, 2009. 361(7): p. 664-73.
[1420] Bonneterre, J., Roche, H., Kerbrat, P., Fumoleau, P., Goudier, M. J., Fargeot, P., et.al. Long-term cardiac follow-up in relapse-free patients after six courses of fluorouracil, epirubicin, and cyclophosphamide, with either 50 or 100 mg of epirubicin, as adjuvant therapy for node-positive breast cancer: French adjuvant study group, J Clin Oncol, 2004. 22(15): p. 3070-9.
[843] Tan-Chiu, E., Yothers, G., Romond, E., Geyer, C. E., Jr., Ewer, M., Keefe, D., et.al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31, J Clin Oncol, 2005. 23(31): p. 7811-9.
[1421] Jensen, B. V., Cardiotoxic consequences of anthracycline-containing therapy in patients with breast cancer, Semin Oncol, 2006. 33(3 Suppl 8): p. S15-21.
[1422] Perez, E. A., Rodeheffer, R., Clinical cardiac tolerability of trastuzumab, J Clin Oncol, 2004. 22(2): p. 322-9.
[1423] Le Deley, M. C., Suzan, F., Cutuli, B., Delaloge, S., Shamsaldin, A., Linassier, C., et.al. Anthracyclines, mitoxantrone, radiotherapy, and granulocyte colony-stimulating factor: risk factors for leukemia and myelodysplastic syndrome after breast cancer, J Clin Oncol, 2007. 25(3): p. 292-300.
[1424] Smith, R. E., Risk for the development of treatment-related acute myelocytic leukemia and myelodysplastic syndrome among patients with breast cancer: review of the literature and the National Surgical Adjuvant Breast and Bowel Project experience, Clin Breast Cancer, 2003. 4(4): p. 273-9.
[1425] Stearns, V., Ullmer, L., Lopez, J. F., Smith, Y., Isaacs, C., Hayes, D., Hot flushes, Lancet, 2002. 360(9348): p. 1851-61.
[1426] Mom, C. H., Buijs, C., Willemse, P. H., Mourits, M. J., de Vries, E. G., Hot flushes in breast cancer patients, Crit Rev Oncol Hematol, 2006. 57(1): p. 63-77.
[1427] Pritchard, K. I., Khan, H., Levine, M., Clinical practice guidelines for the care and treatment of breast cancer: 14. The role of hormone replacement therapy in women with a previous diagnosis of breast cancer, Cmaj, 2002. 166(8): p. 1017-22.
[1428] Caine, G. J., Stonelake, P. S., Rea, D., Lip, G. Y., Coagulopathic complications in breast cancer, Cancer, 2003. 98(8): p. 1578-86.
[1429] Gail, M. H., Costantino, J. P., Bryant, J., Croyle, R., Freedman, L., Helzlsouer, K., et.al. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer, J Natl Cancer Inst, 1999. 91(21): p. 1829-46.
[1430] Hillner, B. E., Ingle, J. N., Chlebowski, R. T., Gralow, J., Yee, G. C., Janjan, N. A., et.al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer, J Clin Oncol, 2003. 21(21): p. 4042-57.
[1431] Winer, E. P., Hudis, C., Burstein, H. J., Wolff, A. C., Pritchard, K. I., Ingle, J. N., et.al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004, J Clin Oncol, 2005. 23(3): p. 619-29.
[1432] Edmonds, M., McGuire, H., Price, J., Exercise therapy for chronic fatigue syndrome, Cochrane Database Syst Rev, 2004. p. Cd003200.
[1433] Servaes, P., Prins, J., Verhagen, S., Bleijenberg, G., Fatigue after breast cancer and in chronic fatigue syndrome: similarities and differences, J Psychosom Res, 2002. 52(6): p. 453-9.
[1434] Petrek, J., Seltzer, V., Breast cancer in pregnant and postpartum women, J Obstet Gynaecol Can, 2003. 25(11): p. 944-50.
[1435] Velentgas, P., Daling, J. R., Malone, K. E., Weiss, N. S., Williams, M. A., Self, S. G., et.al. Pregnancy after breast carcinoma: outcomes and influence on mortality, Cancer, 1999. 85(11): p. 2424-32.
[1436] Sankila, R., Heinavaara, S., Hakulinen, T., Survival of breast cancer patients after subsequent term pregnancy: "healthy mother effect", Am J Obstet Gynecol, 1994. 170(3): p. 818-23.
[1437] Donnelly, J., Mack, P., Donaldson, L. A., Follow-up of breast cancer: time for a new approach?, Int J Clin Pract, 2001. 55(7): p. 431-3.
[1438] Renton, J. P., Twelves, C. J., Yuille, F. A., Follow-up in women with breast cancer: the patients' perspective, Breast, 2002. 11(3): p. 257-61.
[1439] Doubeni, C. A., Field, T. S., Ulcickas Yood, M., Rolnick, S. J., Quessenberry, C. P., Fouayzi, H., et.al. Patterns and predictors of mammography utilization among breast cancer survivors, Cancer, 2006. 106(11): p. 2482-8.
[1440] Grunfeld, E., Noorani, H., McGahan, L., Paszat, L., Coyle, D., van Walraven, C., et.al. Surveillance mammography after treatment of primary breast cancer: a systematic review, Breast, 2002. 11(3): p. 228-35.
[1441] Hollowell, K., Olmsted, C. L., Richardson, A. S., Pittman, H. K., Bellin, L., Tafra, L., et.al. American Society of Clinical Oncology-recommended surveillance and physician specialty among long-term breast cancer survivors, Cancer, 2010. 116(9): p. 2090-8.
[1442] Katz, M. L., Donohue, K. A., Alfano, C. M., Day, J. M., Herndon, J. E., 2nd, Paskett, E. D., Cancer surveillance behaviors and psychosocial factors among long-term survivors of breast cancer. Cancer and Leukemia Group B 79804, Cancer, 2009. 115(3): p. 480-8.
[879] Calle, E. E., Rodriguez, C., Walker-Thurmond, K., Thun, M. J., Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults, N Engl J Med, 2003. 348(17): p. 1625-38.
[1443] Scott, D. A., Mills, M., Black, A., Cantwell, M., Campbell, A., Cardwell, C. R., et.al. Multidimensional rehabilitation programmes for adult cancer survivors, Cochrane Database Syst Rev, 2013. p. Cd007730.
[1444] Fong, D. Y., Ho, J. W., Hui, B. P., Lee, A. M., Macfarlane, D. J., Leung, S. S., et.al. Physical activity for cancer survivors: meta-analysis of randomised controlled trials, Bmj, 2012. 344: p. e70.
[1445] Berger, A. M., Mooney, K., Alvarez-Perez, A., Breitbart, W. S., Carpenter, K. M., Cella, D., et.al. Cancer-Related Fatigue, Version 2.2015, J Natl Compr Canc Netw, 2015. 13(8): p. 1012-39.
[1446] Weis, J., Cancer-related fatigue: prevalence, assessment and treatment strategies, Expert Rev Pharmacoecon Outcomes Res, 2011. 11(4): p. 441-6.
[1447] Cella, D., Peterman, A., Passik, S., Jacobsen, P., Breitbart, W., Progress toward guidelines for the management of fatigue, Oncology (Williston Park), 1998. 12(11a): p. 369-77.
[1448] Heim, Manfred E, Weis, Joachim, Fatigue bei Krebserkrankungen: Erkennen–Behandeln–VorbeugenSchattauer Verlag, 2014.
[1449] Network, National Comprehensive Cancer, NCCN GUIDELINES FOR SUPPORTIVE CARE-Cancer Related Fatigue, Version 1, 2015
[1450] Brown, J. C., Huedo-Medina, T. B., Pescatello, L. S., Pescatello, S. M., Ferrer, R. A., Johnson, B. T., Efficacy of exercise interventions in modulating cancer-related fatigue among adult cancer survivors: a meta-analysis, Cancer Epidemiol Biomarkers Prev, 2011. 20(1): p. 123-33.
[1451] Puetz, T. W., Herring, M. P., Differential effects of exercise on cancer-related fatigue during and following treatment: a meta-analysis, Am J Prev Med, 2012. 43(2): p. e1-24.
[1452] McMillan, E. M., Newhouse, I. J., Exercise is an effective treatment modality for reducing cancer-related fatigue and improving physical capacity in cancer patients and survivors: a meta-analysis, Appl Physiol Nutr Metab, 2011. 36(6): p. 892-903.
[1453] Speck, R. M., Courneya, K. S., Masse, L. C., Duval, S., Schmitz, K. H., An update of controlled physical activity trials in cancer survivors: a systematic review and meta-analysis, J Cancer Surviv, 2010. 4(2): p. 87-100.
[1454] Tomlinson, D., Diorio, C., Beyene, J., Sung, L., Effect of exercise on cancer-related fatigue: a meta-analysis, Am J Phys Med Rehabil, 2014. 93(8): p. 675-86.
[894] Bower, J. E., Bak, K., Berger, A., Breitbart, W., Escalante, C. P., Ganz, P. A., et.al. Screening, assessment, and management of fatigue in adult survivors of cancer: an American Society of Clinical oncology clinical practice guideline adaptation, J Clin Oncol, 2014. 32(17): p. 1840-50.
[1455] Duijts, S. F., Faber, M. M., Oldenburg, H. S., van Beurden, M., Aaronson, N. K., Effectiveness of behavioral techniques and physical exercise on psychosocial functioning and health-related quality of life in breast cancer patients and survivors--a meta-analysis, Psychooncology, 2011. 20(2): p. 115-26.
[1456] Kangas, M., Bovbjerg, D. H., Montgomery, G. H., Cancer-related fatigue: a systematic and meta-analytic review of non-pharmacological therapies for cancer patients, Psychol Bull, 2008. 134(5): p. 700-41.
[1457] Buffart, L. M., van Uffelen, J. G., Riphagen, II, Brug, J., van Mechelen, W., Brown, W. J., et.al. Physical and psychosocial benefits of yoga in cancer patients and survivors, a systematic review and meta-analysis of randomized controlled trials, BMC Cancer, 2012. 12: p. 559.
[1458] Cramp, F., Daniel, J., Exercise for the management of cancer-related fatigue in adults, Cochrane Database Syst Rev, 2008. p. Cd006145.
[1459] Cavaletti, G., Cornblath, D. R., Merkies, I. S., Postma, T. J., Rossi, E., Frigeni, B., et.al. The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings, Ann Oncol, 2013. 24(2): p. 454-62.
[1460] Thompson, S. W., Davis, L. E., Kornfeld, M., Hilgers, R. D., Standefer, J. C., Cisplatin neuropathy. Clinical, electrophysiologic, morphologic, and toxicologic studies, Cancer, 1984. 54(7): p. 1269-75.
[1461] Argyriou, A. A., Bruna, J., Marmiroli, P., Cavaletti, G., Chemotherapy-induced peripheral neurotoxicity (CIPN): an update, Crit Rev Oncol Hematol, 2012. 82(1): p. 51-77.
[1462] Wiederholt, W. C., Threshold and conduction velocity in human median nerve sensory fibers, Electroencephalogr Clin Neurophysiol, 1969. 27(7): p. 718.
[1463] Bock, W. J., Liesegang, J., [Comparative measurement of neural conduction velocity using surface and needle electrodes], Zentralbl Neurochir, 1972. 33(1): p. 45-51.
[1464] Geiger, G., Mikus, E., Dertinger, H., Rick, O., Low frequency magnetic field therapy in patients with cytostatic-induced polyneuropathy: a phase II pilot study, Bioelectromagnetics, 2015. 36(3): p. 251-4.
[1465] Rick, O, Mikus, E, Dertinger, H, Geiger, G, Treatment of chemotherapy-induced polyneuropathy with magnetic field therapy: A randomized, double-blind placebo-controlled comparative phase Iii study, Oncology Research and Treatment, 2014. 37: p. 189.
[1466] Franconi, G., Manni, L., Schroder, S., Marchetti, P., Robinson, N., A systematic review of experimental and clinical acupuncture in chemotherapy-induced peripheral neuropathy, Evid Based Complement Alternat Med, 2013. 2013: p. 516916.
[1467] Pachman, D. R., Weisbrod, B. L., Seisler, D. K., Barton, D. L., Fee-Schroeder, K. C., Smith, T. J., et.al. Pilot evaluation of Scrambler therapy for the treatment of chemotherapy-induced peripheral neuropathy, Support Care Cancer, 2015. 23(4): p. 943-51.
[1468] oder Chemobrain, Kognitive Dysfunktion, GMS Onkologische Rehabilitation und Sozialmedizin
[1469] Shilling, V., Jenkins, V., Trapala, I. S., The (mis)classification of chemo-fog--methodological inconsistencies in the investigation of cognitive impairment after chemotherapy, Breast Cancer Res Treat, 2006. 95(2): p. 125-9.
[532] Koppelmans, V., Breteler, M. M., Boogerd, W., Seynaeve, C., Gundy, C., Schagen, S. B., Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy, J Clin Oncol, 2012. 30(10): p. 1080-6.
[1470] Kohli, S., Griggs, J. J., Roscoe, J. A., Jean-Pierre, P., Bole, C., Mustian, K. M., et.al. Self-reported cognitive impairment in patients with cancer, J Oncol Pract, 2007. 3(2): p. 54-9.
[1471] Ahles, T. A., Root, J. C., Ryan, E. L., Cancer- and cancer treatment-associated cognitive change: an update on the state of the science, J Clin Oncol, 2012. 30(30): p. 3675-86.
[1472] Vardy, J., Wefel, J. S., Ahles, T., Tannock, I. F., Schagen, S. B., Cancer and cancer-therapy related cognitive dysfunction: an international perspective from the Venice cognitive workshop, Ann Oncol, 2008. 19(4): p. 623-9.
[1473] Kalbe, E., Kessler, J., Calabrese, P., Smith, R., Passmore, A. P., Brand, M., et.al. DemTect: a new, sensitive cognitive screening test to support the diagnosis of mild cognitive impairment and early dementia, Int J Geriatr Psychiatry, 2004. 19(2): p. 136-43.
[1474] Erzigkeit, H, Kurztest zur Erfassung von Gedächtnis-und Aufmerksamkeitssterungen, SKT-Manual (24. Auflage), Herzogenaurach: Geromed, 2001.
[1475] König, V., Chemobrain – Was kann ich dagegen tun?, GMS Onkologische Rehabilitation und Sozialmedizin., 2014.
[888] De Groef, A., Van Kampen, M., Dieltjens, E., Christiaens, M. R., Neven, P., Geraerts, I., et.al. Effectiveness of postoperative physical therapy for upper-limb impairments after breast cancer treatment: a systematic review, Arch Phys Med Rehabil, 2015. 96(6): p. 1140-53.
[1476] Chan, D. N., Lui, L. Y., So, W. K., Effectiveness of exercise programmes on shoulder mobility and lymphoedema after axillary lymph node dissection for breast cancer: systematic review, J Adv Nurs, 2010. 66(9): p. 1902-14.
[1477] Chung, C., Lee, S., Hwang, S., Park, E., Systematic review of exercise effects on health outcomes in women with breast cancer, Asian Nurs Res (Korean Soc Nurs Sci), 2013. 7(3): p. 149-59.
[1478] Lasinski, B. B., McKillip Thrift, K., Squire, D., Austin, M. K., Smith, K. M., Wanchai, A., et.al. A systematic review of the evidence for complete decongestive therapy in the treatment of lymphedema from 2004 to 2011, Pm r, 2012. 4(8): p. 580-601.
[1479] Dayes, I. S., Whelan, T. J., Julian, J. A., Parpia, S., Pritchard, K. I., D'Souza, D. P., et.al. Randomized trial of decongestive lymphatic therapy for the treatment of lymphedema in women with breast cancer, J Clin Oncol, 2013. 31(30): p. 3758-63.
[896] Streckmann, F., Kneis, S., Leifert, J. A., Baumann, F. T., Kleber, M., Ihorst, G., et.al. Exercise program improves therapy-related side-effects and quality of life in lymphoma patients undergoing therapy, Ann Oncol, 2014. 25(2): p. 493-9.
[1480] Ahles, T. A., Saykin, A. J., Noll, W. W., Furstenberg, C. T., Guerin, S., Cole, B., et.al. The relationship of APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy, Psychooncology, 2003. 12(6): p. 612-9.
[1481] Janelsins, M. C., Peppone, L. J., Heckler, C. E., Kesler, S. R., Sprod, L. K., Atkins, J., et.al. YOCAS(c)(R) Yoga Reduces Self-reported Memory Difficulty in Cancer Survivors in a Nationwide Randomized Clinical Trial: Investigating Relationships Between Memory and Sleep, Integr Cancer Ther, 2016. 15(3): p. 263-71.
[1482] Scherwath, A., Poppelreuter, M., Weis, J., Schulz-Kindermann, F., Koch, U., Mehnert, A., [Psychometric evaluation of a neuropsychological test battery measuring cognitive dysfunction in cancer patients--recommendations for a screening tool], Fortschr Neurol Psychiatr, 2008. 76(10): p. 583-93.
[1483] Bray, V. J., Dhillon, H. M., Bell, M. L., Kabourakis, M., Fiero, M. H., Yip, D., et.al. Evaluation of a Web-Based Cognitive Rehabilitation Program in Cancer Survivors Reporting Cognitive Symptoms After Chemotherapy, J Clin Oncol, 2017. 35(2): p. 217-225.
[1484] Ferguson, R. J., McDonald, B. C., Rocque, M. A., Furstenberg, C. T., Horrigan, S., Ahles, T. A., et.al. Development of CBT for chemotherapy-related cognitive change: results of a waitlist control trial, Psychooncology, 2012. 21(2): p. 176-86.
[1485] Mustian, Karen Michelle, Janelsins, Michelle Christine, Peppone, Luke Joseph, Kamen, Charles Stewart, Guido, Joseph John, Heckler, Charles E, EXCAP exercise effects on cognitive impairment and inflammation: A URCC NCORP RCT in 479 cancer patientsAmerican Society of Clinical Oncology, 2015.
[1486] Derry, H. M., Jaremka, L. M., Bennett, J. M., Peng, J., Andridge, R., Shapiro, C., et.al. Yoga and self-reported cognitive problems in breast cancer survivors: a randomized controlled trial, Psychooncology, 2015. 24(8): p. 958-66.
[1487] Horneber, M. A., Bueschel, G., Huber, R., Linde, K., Rostock, M., Mistletoe therapy in oncology, Cochrane Database Syst Rev, 2008. p. Cd003297.
[1488] Kalder, M., Muller, T., Fischer, D., Muller, A., Bader, W., Beckmann, M. W., et.al. A Review of Integrative Medicine in Gynaecological Oncology, Geburtshilfe Frauenheilkd, 2016. 76(2): p. 150-155.
[1489] Horneber, M., Bueschel, G., Dennert, G., Less, D., Ritter, E., Zwahlen, M., How many cancer patients use complementary and alternative medicine: a systematic review and metaanalysis, Integr Cancer Ther, 2012. 11(3): p. 187-203.
[1490] Micke, Oliver, Bruns, Frank, Glatzel, Michael, Schönekaes, Klaus, Micke, Patrick, Mücke, Ralph, et.al. Predictive factors for the use of complementary and alternative medicine (CAM) in radiation oncology, European Journal of Integrative Medicine, 2009. 1(1): p. 19-25.
[1491] Zeller, T., Muenstedt, K., Stoll, C., Schweder, J., Senf, B., Ruckhaeberle, E., et.al. Potential interactions of complementary and alternative medicine with cancer therapy in outpatients with gynecological cancer in a comprehensive cancer center, J Cancer Res Clin Oncol, 2013. 139(3): p. 357-65.
[1492] Huebner, J., Muenstedt, K., Prott, F. J., Stoll, C., Micke, O., Buentzel, J., et.al. Online survey of patients with breast cancer on complementary and alternative medicine, Breast Care (Basel), 2014. 9(1): p. 60-3.
[1493] Greenlee, H., Balneaves, L. G., Carlson, L. E., Cohen, M., Deng, G., Hershman, D., et.al. Erratum. Clinical Practice Guidelines on the Use of Integrative Therapies as Supportive Care in Patients Treated for Breast Cancer, J Natl Cancer Inst Monogr, 2015. 2015(51): p. 98.
[1494] Molassiotis, A., Bardy, J., Finnegan-John, J., Mackereth, P., Ryder, D. W., Filshie, J., et.al. Acupuncture for cancer-related fatigue in patients with breast cancer: a pragmatic randomized controlled trial, J Clin Oncol, 2012. 30(36): p. 4470-6.
[1495] Montgomery, G. H., David, D., Kangas, M., Green, S., Sucala, M., Bovbjerg, D. H., et.al. Randomized controlled trial of a cognitive-behavioral therapy plus hypnosis intervention to control fatigue in patients undergoing radiotherapy for breast cancer, J Clin Oncol, 2014. 32(6): p. 557-63.
[1496] Barton, D. L., Liu, H., Dakhil, S. R., Linquist, B., Sloan, J. A., Nichols, C. R., et.al. Wisconsin Ginseng (Panax quinquefolius) to improve cancer-related fatigue: a randomized, double-blind trial, N07C2, J Natl Cancer Inst, 2013. 105(16): p. 1230-8.
[1497] Deng, G., Chan, Y., Sjoberg, D., Vickers, A., Yeung, K. S., Kris, M., et.al. Acupuncture for the treatment of post-chemotherapy chronic fatigue: a randomized, blinded, sham-controlled trial, Support Care Cancer, 2013. 21(6): p. 1735-41.
[1498] Bower, J. E., Garet, D., Sternlieb, B., Ganz, P. A., Irwin, M. R., Olmstead, R., et.al. Yoga for persistent fatigue in breast cancer survivors: a randomized controlled trial, Cancer, 2012. 118(15): p. 3766-75.
[1499] Hershman, D. L., Unger, J. M., Crew, K. D., Minasian, L. M., Awad, D., Moinpour, C. M., et.al. Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy, J Clin Oncol, 2013. 31(20): p. 2627-33.
[1500] da Costa Miranda, V., Trufelli, D. C., Santos, J., Campos, M. P., Nobuo, M., da Costa Miranda, M., et.al. Effectiveness of guarana (Paullinia cupana) for postradiation fatigue and depression: results of a pilot double-blind randomized study, J Altern Complement Med, 2009. 15(4): p. 431-3.
[1501] Bairati, I., Meyer, F., Gelinas, M., Fortin, A., Nabid, A., Brochet, F., et.al. Randomized trial of antioxidant vitamins to prevent acute adverse effects of radiation therapy in head and neck cancer patients, J Clin Oncol, 2005. 23(24): p. 5805-13.
[1502] Bairati, I., Meyer, F., Gelinas, M., Fortin, A., Nabid, A., Brochet, F., et.al. A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer patients, J Natl Cancer Inst, 2005. 97(7): p. 481-8.
[1503] Camphausen, K., Citrin, D., Krishna, M. C., Mitchell, J. B., Implications for tumor control during protection of normal tissues with antioxidants, J Clin Oncol, 2005. 23(24): p. 5455-7.
[1504] Argyriou, A. A., Chroni, E., Koutras, A., Iconomou, G., Papapetropoulos, S., Polychronopoulos, P., et.al. A randomized controlled trial evaluating the efficacy and safety of vitamin E supplementation for protection against cisplatin-induced peripheral neuropathy: final results, Support Care Cancer, 2006. 14(11): p. 1134-40.
[1505] Argyriou, A. A., Chroni, E., Koutras, A., Iconomou, G., Papapetropoulos, S., Polychronopoulos, P., et.al. Preventing paclitaxel-induced peripheral neuropathy: a phase II trial of vitamin E supplementation, J Pain Symptom Manage, 2006. 32(3): p. 237-44.
[1506] Thompson, I., Jr., Kristal, A., Platz, E. A., Prevention of prostate cancer: outcomes of clinical trials and future opportunities, Am Soc Clin Oncol Educ Book, 2014. p. e76-80.
[1507] Dennert, G., Horneber, M., Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients, Cochrane Database Syst Rev, 2006. p. Cd005037.
[1508] Vinceti, M., Dennert, G., Crespi, C. M., Zwahlen, M., Brinkman, M., Zeegers, M. P., et.al. Selenium for preventing cancer, Cochrane Database Syst Rev, 2014. p. Cd005195.
[1509] Ogunleye, Adeyemi A, Xue, Fei, Michels, Karin B, Green tea consumption and breast cancer risk or recurrence: a meta-analysis, Breast cancer research and treatment, 2010. 119(2): p. 477.
[1510] Ernst, E., Schmidt, K., Steuer-Vogt, M. K., Mistletoe for cancer? A systematic review of randomised clinical trials, Int J Cancer, 2003. 107(2): p. 262-7.
[1511] Kienle, G. S., Kiene, H., Review article: Influence of Viscum album L (European mistletoe) extracts on quality of life in cancer patients: a systematic review of controlled clinical studies, Integr Cancer Ther, 2010. 9(2): p. 142-57.
[1512] Taixiang, W., Munro, A. J., Guanjian, L., Chinese medical herbs for chemotherapy side effects in colorectal cancer patients, Cochrane Database Syst Rev, 2005. p. Cd004540.
[1513] Zhang, M., Liu, X., Li, J., He, L., Tripathy, D., Chinese medicinal herbs to treat the side-effects of chemotherapy in breast cancer patients, Cochrane Database Syst Rev, 2007. p. Cd004921.
[1514] Sun, C. L., Yuan, J. M., Koh, W. P., Yu, M. C., Green tea, black tea and breast cancer risk: a meta-analysis of epidemiological studies, Carcinogenesis, 2006. 27(7): p. 1310-5.
[1515] Yiannakopoulou, ECh, Effect of green tea catechins on breast carcinogenesis: a systematic review of in-vitro and in-vivo experimental studies, Eur J Cancer Prev, 2014. 23(2): p. 84-9.
[1516] Chi, F., Wu, R., Zeng, Y. C., Xing, R., Liu, Y., Xu, Z. G., Post-diagnosis soy food intake and breast cancer survival: a meta-analysis of cohort studies, Asian Pac J Cancer Prev, 2013. 14(4): p. 2407-12.
[1517] Nechuta, S. J., Caan, B. J., Chen, W. Y., Lu, W., Chen, Z., Kwan, M. L., et.al. Soy food intake after diagnosis of breast cancer and survival: an in-depth analysis of combined evidence from cohort studies of US and Chinese women, Am J Clin Nutr, 2012. 96(1): p. 123-32.
[1518] Henneicke-von Zepelin, H. H., Meden, H., Kostev, K., Schroder-Bernhardi, D., Stammwitz, U., Becher, H., Isopropanolic black cohosh extract and recurrence-free survival after breast cancer, Int J Clin Pharmacol Ther, 2007. 45(3): p. 143-54.
[1519] Hirschberg, A. L., Edlund, M., Svane, G., Azavedo, E., Skoog, L., von Schoultz, B., An isopropanolic extract of black cohosh does not increase mammographic breast density or breast cell proliferation in postmenopausal women, Menopause, 2007. 14(1): p. 89-96.
[1520] Liske, E., Hanggi, W., Henneicke-von Zepelin, H. H., Boblitz, N., Wustenberg, P., Rahlfs, V. W., Physiological investigation of a unique extract of black cohosh (Cimicifugae racemosae rhizoma): a 6-month clinical study demonstrates no systemic estrogenic effect, J Womens Health Gend Based Med, 2002. 11(2): p. 163-74.
[1521] Raus, K., Brucker, C., Gorkow, C., Wuttke, W., First-time proof of endometrial safety of the special black cohosh extract (Actaea or Cimicifuga racemosa extract) CR BNO 1055, Menopause, 2006. 13(4): p. 678-91.
[1522] Rebbeck, T. R., Troxel, A. B., Norman, S., Bunin, G. R., DeMichele, A., Baumgarten, M., et.al. A retrospective case-control study of the use of hormone-related supplements and association with breast cancer, Int J Cancer, 2007. 120(7): p. 1523-8.
[1523] Reed, S. D., Newton, K. M., LaCroix, A. Z., Grothaus, L. C., Grieco, V. S., Ehrlich, K., Vaginal, endometrial, and reproductive hormone findings: randomized, placebo-controlled trial of black cohosh, multibotanical herbs, and dietary soy for vasomotor symptoms: the Herbal Alternatives for Menopause (HALT) Study, Menopause, 2008. 15(1): p. 51-8.
[1524] Ruhlen, R. L., Haubner, J., Tracy, J. K., Zhu, W., Ehya, H., Lamberson, W. R., et.al. Black cohosh does not exert an estrogenic effect on the breast, Nutr Cancer, 2007. 59(2): p. 269-77.
[1525] Walji, R., Boon, H., Guns, E., Oneschuk, D., Younus, J., Black cohosh (Cimicifuga racemosa [L.] Nutt.): safety and efficacy for cancer patients, Support Care Cancer, 2007. 15(8): p. 913-21.
[1526] Hernandez Munoz, G., Pluchino, S., Cimicifuga racemosa for the treatment of hot flushes in women surviving breast cancer, Maturitas, 2003. 44 Suppl 1: p. S59-65.
[1527] Jacobson, J. S., Troxel, A. B., Evans, J., Klaus, L., Vahdat, L., Kinne, D., et.al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer, J Clin Oncol, 2001. 19(10): p. 2739-45.
[1528] Crane-Okada, R., Kiger, H., Sugerman, F., Uman, G. C., Shapiro, S. L., Wyman-McGinty, W., et.al. Mindful movement program for older breast cancer survivors: a pilot study, Cancer Nurs, 2012. 35(4): p. E1-13.
[1529] Henderson, V. P., Clemow, L., Massion, A. O., Hurley, T. G., Druker, S., Hebert, J. R., The effects of mindfulness-based stress reduction on psychosocial outcomes and quality of life in early-stage breast cancer patients: a randomized trial, Breast Cancer Res Treat, 2012. 131(1): p. 99-109.
[1530] Henderson, V. P., Massion, A. O., Clemow, L., Hurley, T. G., Druker, S., Hebert, J. R., A randomized controlled trial of mindfulness-based stress reduction for women with early-stage breast cancer receiving radiotherapy, Integr Cancer Ther, 2013. 12(5): p. 404-13.
[1531] Hoffman, C. J., Ersser, S. J., Hopkinson, J. B., Nicholls, P. G., Harrington, J. E., Thomas, P. W., Effectiveness of mindfulness-based stress reduction in mood, breast- and endocrine-related quality of life, and well-being in stage 0 to III breast cancer: a randomized, controlled trial, J Clin Oncol, 2012. 30(12): p. 1335-42.
[1532] Garssen, B., Boomsma, M. F., Meezenbroek Ede, J., Porsild, T., Berkhof, J., Berbee, M., et.al. Stress management training for breast cancer surgery patients, Psychooncology, 2013. 22(3): p. 572-80.
[1533] Andersen, S. R., Wurtzen, H., Steding-Jessen, M., Christensen, J., Andersen, K. K., Flyger, H., et.al. Effect of mindfulness-based stress reduction on sleep quality: results of a randomized trial among Danish breast cancer patients, Acta Oncol, 2013. 52(2): p. 336-44.
[1534] Chandwani, K. D., Thornton, B., Perkins, G. H., Arun, B., Raghuram, N. V., Nagendra, H. R., et.al. Yoga improves quality of life and benefit finding in women undergoing radiotherapy for breast cancer, J Soc Integr Oncol, 2010. 8(2): p. 43-55.
[1535] Danhauer, S. C., Mihalko, S. L., Russell, G. B., Campbell, C. R., Felder, L., Daley, K., et.al. Restorative yoga for women with breast cancer: findings from a randomized pilot study, Psychooncology, 2009. 18(4): p. 360-8.
[1536] Mustian, K. M., Sprod, L. K., Janelsins, M., Peppone, L. J., Palesh, O. G., Chandwani, K., et.al. Multicenter, randomized controlled trial of yoga for sleep quality among cancer survivors, J Clin Oncol, 2013. 31(26): p. 3233-41.
[1537] Post-White, J., Kinney, M. E., Savik, K., Gau, J. B., Wilcox, C., Lerner, I., Therapeutic massage and healing touch improve symptoms in cancer, Integr Cancer Ther, 2003. 2(4): p. 332-44.
[1538] Barsevick, A., Beck, S. L., Dudley, W. N., Wong, B., Berger, A. M., Whitmer, K., et.al. Efficacy of an intervention for fatigue and sleep disturbance during cancer chemotherapy, J Pain Symptom Manage, 2010. 40(2): p. 200-16.
[1539] Li, X. M., Yan, H., Zhou, K. N., Dang, S. N., Wang, D. L., Zhang, Y. P., Effects of music therapy on pain among female breast cancer patients after radical mastectomy: results from a randomized controlled trial, Breast Cancer Res Treat, 2011. 128(2): p. 411-9.
[1540] Binns-Turner, P. G., Wilson, L. L., Pryor, E. R., Boyd, G. L., Prickett, C. A., Perioperative music and its effects on anxiety, hemodynamics, and pain in women undergoing mastectomy, Aana j, 2011. 79(4 Suppl): p. S21-7.
[1541] Cantarero-Villanueva, I., Fernandez-Lao, C., Fernandez-de-Las-Penas, C., Lopez-Barajas, I. B., Del-Moral-Avila, R., de la-Llave-Rincon, A. I., et.al. Effectiveness of water physical therapy on pain, pressure pain sensitivity, and myofascial trigger points in breast cancer survivors: a randomized, controlled clinical trial, Pain Med, 2012. 13(11): p. 1509-19.
[1542] Fernandez-Lao, C., Cantarero-Villanueva, I., Fernandez-de-Las-Penas, C., del Moral-Avila, R., Castro-Sanchez, A. M., Arroyo-Morales, M., Effectiveness of a multidimensional physical therapy program on pain, pressure hypersensitivity, and trigger points in breast cancer survivors: a randomized controlled clinical trial, Clin J Pain, 2012. 28(2): p. 113-21.
[1543] Montgomery, G. H., Bovbjerg, D. H., Schnur, J. B., David, D., Goldfarb, A., Weltz, C. R., et.al. A randomized clinical trial of a brief hypnosis intervention to control side effects in breast surgery patients, J Natl Cancer Inst, 2007. 99(17): p. 1304-12.
[1544] Montgomery, G. H., Weltz, C. R., Seltz, M., Bovbjerg, D. H., Brief presurgery hypnosis reduces distress and pain in excisional breast biopsy patients, Int J Clin Exp Hypn, 2002. 50(1): p. 17-32.
[890] Crew, K. D., Capodice, J. L., Greenlee, H., Brafman, L., Fuentes, D., Awad, D., et.al. Randomized, blinded, sham-controlled trial of acupuncture for the management of aromatase inhibitor-associated joint symptoms in women with early-stage breast cancer, J Clin Oncol, 2010. 28(7): p. 1154-60.
[1545] Crew, K. D., Capodice, J. L., Greenlee, H., Apollo, A., Jacobson, J. S., Raptis, G., et.al. Pilot study of acupuncture for the treatment of joint symptoms related to adjuvant aromatase inhibitor therapy in postmenopausal breast cancer patients, J Cancer Surviv, 2007. 1(4): p. 283-91.
[1546] Bao, T., Cai, L., Giles, J. T., Gould, J., Tarpinian, K., Betts, K., et.al. A dual-center randomized controlled double blind trial assessing the effect of acupuncture in reducing musculoskeletal symptoms in breast cancer patients taking aromatase inhibitors, Breast Cancer Res Treat, 2013. 138(1): p. 167-74.
[1547] Oh, B., Kimble, B., Costa, D. S., Davis, E., McLean, A., Orme, K., et.al. Acupuncture for treatment of arthralgia secondary to aromatase inhibitor therapy in women with early breast cancer: pilot study, Acupunct Med, 2013. 31(3): p. 264-71.
[1548] Mao, J. J., Xie, S. X., Farrar, J. T., Stricker, C. T., Bowman, M. A., Bruner, D., et.al. A randomised trial of electro-acupuncture for arthralgia related to aromatase inhibitor use, Eur J Cancer, 2014. 50(2): p. 267-76.
[1549] Ghoreishi, Z., Esfahani, A., Djazayeri, A., Djalali, M., Golestan, B., Ayromlou, H., et.al. Omega-3 fatty acids are protective against paclitaxel-induced peripheral neuropathy: a randomized double-blind placebo controlled trial, BMC Cancer, 2012. 12: p. 355.
[1550] Hanf, V., Schutz, F., Liedtke, C., Thill, M., AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2015, Breast Care (Basel), 2015. 10(3): p. 189-97.
[1551] Deutsche Krebsgesellschaft, Deutsche Gesellschaft für Senologie., Jahresbericht der zertifizierten Brustkrebszentren. Kennzahlenauswertung 2017., 2017.
[1552] Deutsche Krebsgesellschaft, Deutsche Gesellschaft für Senologie., Individueller Jahresbericht der zertifizierten Brustkrebszentren. Kennzahlenauswertung 2017., 2017.