Introduction
In women, breast cancer is the most common cancer in the world and the second most common cause of cancer death after lung cancer in more developed regions [
1]. In Germany, about 70,000 women are diagnosed with breast cancer every year, the majority of them with early breast cancer [
2]. Patients with localized, operable breast cancer usually have a good prognosis, with a relative 5-year survival rate of up to 90% [
3]. The ten-year survival exceeds 70% in most European regions [
4,
5]. Increased use of (neo)adjuvant systemic treatment has considerably improved patients‘ survival [
6,
7] resulting in more breast cancer survivors than ever [
8].
Treatment decision making is complex and besides potential benefits, side effects also have to be considered [
9]. Lymphedema of hand, arm or shoulder are common side effects of breast cancer surgery and radiotherapy, affecting 10–50% of patients within the first three years after diagnosis [
8,
10,
11]. Other long-term side effects related to local breast cancer therapy comprise numbness or tightness, and stretching or pulling in arms, shoulders, or the chest wall [
7]. Both surgery and radiotherapy can lead to nerve damage resulting in chronic pain [
11,
12] which may affect 25–60% of survivors after breast cancer treatment [
8]. While short-term side effects of adjuvant chemotherapy predominantly occurring during the course of treatment have been studied extensively, there is still insufficient information on long-term side effects of several chemotherapeutic agents [
13]. A common long-term side effect of chemotherapy is cardiotoxicity, as several cytotoxic agents, especially anthracyclines, can lead to cardiac complications [
7,
8,
13]. Adjuvant systemic chemotherapy may also be associated with cognitive and neurological complications [
7]. Peripheral neuropathy is a frequent side effect of treatment with chemotherapeutic agents, such as taxanes [
14]. However, there is little evidence from long-term follow-up of patients with breast cancer receiving taxanes [
11,
15].
Due to the growing number of breast cancer survivors treated with curative intent, more attention should be paid to the consequences of the often intensive treatment, especially in terms of the long-term symptoms which may negatively affect patients’ quality of life. In this work, we focus on the early (4 weeks and 6 months) and late (3 years) long-term symptoms of early breast cancer treatment after (neo)adjuvant chemotherapy in German routine practice. We present data from the MaTox project, a patient-reported outcomes survey within the clinical cohort study TMK (Tumour Registry Breast Cancer), which evaluated the frequency, severity, and persistence of typical symptoms in patients with breast cancer in routine practice using a questionnaire specifically designed for this purpose.
Discussion
The MaTox project assessed long-term well-being after early breast cancer treatment in 453 patients receiving surgery, chemotherapy, and some also radiation and/or endocrine therapy in German routine practice. Our data show that especially impairments in memory/attention and symptoms of the musculoskeletal system as well as symptoms associated with surgery and neuropathy increased over time and were persistent 3 years after start of systemic treatment. Patients had a substantially increased risk of paraesthesia if those symptoms appeared shortly after start of treatment or if taxanes were given.
One limitation of this project is the exclusive enrolment of patients receiving chemotherapy, limiting generalizability regarding patients that only received endocrine treatment. Not all initially participating patients sent back the subsequent questionnaires, representing a potential limitation. Data comparing patients’ tumour and treatment characteristics as well as PROs at enrolment between patients who had sent back the 3-year questionnaire and those who had not show that patients in impaired condition (comorbidities at start of treatment), with inferior prognosis (triple-negative tumour, non-breast-conserving surgery) or with neoadjuvant chemotherapy treatment, are potentially slightly under-represented at 3 years. However, the return rate of the questionnaires is exceptionally high (>83% of patients alive and without recurrence at each time point), strengthening the generalizability of our data. Strengths of this project are the prospective, longitudinal data collection and the participation of oncologists from all over Germany recruiting a large, representative study cohort.
As soon as a woman is diagnosed with breast cancer, her quality of life is affected. Shock, sadness, anxiety, fatigue and depression are only some of the psychologically distressing symptoms which lead to a decreased quality of life [
18,
19]. Longitudinal assessment including pre-diagnosis data is hardly feasible in the oncological setting, and capturing data prior to systemic therapy is hardly possible in the non-interventional setting. Thus, the focus of our study was to assess which symptoms are present long after the initial treatment with surgery, systemic therapy and radiation independent of causal relation. We show the patients’ symptom burden at early and late time points after start of systemic treatment. It was striking to see that 3 years after start of chemotherapy, considerable symptoms persisted and affected patient’s well-being. While deterioration of symptoms associated with memory/attention and the musculoskeletal system could be due to factors not related to treatment (e.g. ageing), increased postoperative pain and paraesthesia are likely a result of the curative treatment approach.
The proportion of patients affected by an impairment of memory in our cohort increased from 49% at start to 78% after 3 years. Cognitive impairment as a late effect of cancer treatment has been studied for several years [
6,
11] and may comprise problems with memory/attention, learning, speed in mental processing, and executive or sensorimotor functions [
8]. Cognitive deficits have been associated with adjuvant chemotherapy [
6,
9]. However, several studies showing this association have been criticized due to methodological aspects such as heterogeneity in the types of chemotherapy applied, differences in assessing cognitive function and varieties in study duration [
13]. Furthermore, studies often did not control for potential confounders such as mood, menopausal status, endocrine therapy [
13] or demential syndromes, especially in older women [
6]. It is known that chemotherapy-related fatigue, depression and anxiety can contribute to poor cognitive performance [
7]. Thus, cognitive impairment seems to be linked to several factors besides systemic treatment. Independent of its cause, we believe the high frequency of this impairment reported in our project highlights a need for better management of cognitive dysfunction in cancer survivors, as also claimed by others [
8].
Cardiotoxicity is a well-known side effect of cytotoxic therapy [
20]. While reports about heart problems were low after 3 years in our cohort, there was a slight increase in patients reporting mild to strong respiratory symptoms or fluid retentions/oedema. These symptoms might be due to various reasons but could also be a sign for development of heart problems. As this long-term toxicity influences patients’ quality of life, efforts for prevention, treatment and follow-up care for cardiotoxicity are strongly encouraged [
7,
8,
20].
The development of musculoskeletal symptoms is a multicausal process, with endocrine therapy increasing the risk [
21]. According to our data, symptoms of the musculoskeletal system were present in at least half of the patients 4 weeks after start of treatment, but had further increased after 3 years, especially in patients who received endocrine therapy, confirming previous observations [
22]. However, it should be kept in mind that age is also associated with an increasing incidence of musculoskeletal symptoms [
23,
24].
Postoperative impairments comprise lymphedema, pain and mobility at the operated site. Lymphedema and subsequent swelling in the arm or chest is caused by insufficient lymph transport due to lymph node dissection and radiotherapy [
8,
25]. 46% of the MaTox patients reported minor to severe lymphedema 3 years after start of treatment. This number is consistent with previous studies, reporting that 10–50% of patients with breast cancer are affected by lymphedema [
7,
11]. Persistent pain after surgical treatment is also a well-known clinical problem in 25–50% of patients. Gärtner and colleagues showed that 47% of breast cancer patients still reported lingering pain years after surgery [
26]. While 73% of the MaTox patients (42% mild, 26% moderate and 5% strong) suffered from pain at the operated site 6 months after start of treatment, this number decreased only slightly to 67% (41% mild, 22% moderate and 4% strong) 3 years later. In our cohort, pain after surgery, which was persistent at 4 weeks after start of chemotherapy, was identified as a risk factor for long-term pain after breast cancer surgery. This is in accordance with other studies [
26,
27], whereas the risk factors age and tumour size could not be confirmed in our cohort [
8]. Although nerve-sparing operation techniques have reduced the incidence of chronic pain, additional strategies for improvement of the patients’ situation are obviously needed.
In the MaTox cohort, 30% of the patients reported symptoms of paraesthesia as early as 4 weeks after start of treatment and almost 60% of the patients reported paraesthesia symptoms 3 years later. Paraesthesia is often an early sign of chemotherapy-induced neuropathy, which may greatly affect patients’ quality of life [
14,
28,
29]. The extent of neuropathy is dependent on the chemotherapy agent [
14,
30‐
32], the dose used and may persist for years [
7,
33]. Logistic regression analysis in the MaTox cohort showed that patients with higher age and early paraesthesia symptoms as well as those patients receiving taxane-based chemotherapy had a higher risk of suffering from paraesthesia 3 years after treatment. It would be interesting to investigate whether early intervention in these patients, e.g. dose adjustment, could reduce the frequency of long-term neuropathy.