Late effects of breast cancer treatment and potentials for rehabilitation

Abstract

Background. Breast cancer is the most frequent malignant disease among women world wide. Survival has been improving leading to an increasing number of breast cancer survivors, in the US estimated to about 2.6 million. Material and methods. The literature was reviewed with focus on data from the Nordic countries. Results. Local therapies such as breast cancer surgery and radiotherapy may cause persistent pain in the breast area, arm, and shoulder reported by 30–50% of patients after three to five years, lymphedema in 15–25% of patients, and restrictions of arm and shoulder movement in 35%. Physiotherapy is the standard treatment for the latter while no pain intervention trials have been published. Chemotherapy may cause infertility and premature menopause, resulting in vasomotor symptoms, sexual dysfunction, and osteoporosis, which are similar to the side effects of endocrine treatment in postmenopausal women. Awareness of cardiotoxicity is needed since anthracyclines, trastuzumab, and radiotherapy can damage the heart. Breast cancer survivors have an increased risk of a major depression and far from all receive adequate anti-depressive treatment. Other psychological symptoms include fear of recurrence, sleep disturbances, cognitive problems, fatigue, and sexual problems. Discussion. To improve rehabilitation, specific goals have to be formulated into national guidelines and high priority directed towards research into developing and testing new interventions for alleviating symptoms and side effects experienced by breast cancer survivors.

Breast cancer is the most frequent malignant disease among women with an estimated 1.4 million new cases per year and about 460 000 deaths per year worldwide [1]. Modern treatment includes combinations of surgery (lumpectomy or mastectomy with sentinel node biopsy or axillary dissection), radiotherapy, chemotherapy with antracyclines and/or taxanes, endocrine therapy with tamoxifen or aromatase inhibitors (AIs), and anti-HER2-therapy with trastuzumab according to the biomarker profile of the primary tumour. This approach has resulted in documented survival benefits [2,3]. In the Nordic countries and in the US, 5- and 10-year relative survival rates have increased by 20–30 percentage points, the 5-year relative survival now being 79–90% [4,5]. Consequently, still more women are surviving with a diagnosis of breast cancer, in the US estimated to about 2.6 million [5] and in the UK to about 550 000 [6]. These numbers emphasise that more attention should be directed to how cancer survivors cope with the consequences of the often intensive treatment and how their quality of life evolves after completion of treatment.

According to the WHO, rehabilitation is a process aimed at enabling patients to reach and maintain optimal physical, intellectual, psychological, social, and spiritual levels of functioning. While cure for breast cancer remains the first and most important goal for treatment, it is of increasing importance how the cure is achieved. At the same time, it must be recognised that breast cancer keeps recurring for up to 20 years, especially if the tumour was estrogen receptor positive (ER+) [2,3]. In these cases, treatments are also long lasting, five or more years with tamoxifen or AIs. Therefore, the process of rehabilitation includes dealing with not only effects of completed treatments, such as surgery and radiotherapy, but also management of side effects to ongoing treatments, in addition to helping the women to overcome the psychological consequences of the cancer diagnosis, such as persistent fear of recurrence, a higher than normal rate of depression, and social implications like job loss. In this review, we focus on some of the most frequent problems after a diagnosis of and treatment for breast cancer (Table I).

Table I. Rehabilitation needs after early breast cancer.

Focal problems related to local therapies:
Pain
Lymphedema
Other arm and shoulder problems
Systemic problems related to treatment:
Neuropathy
Fertility
Premature menopause
Cardiovascular disease
Psychosocial problems as consequences of diagnosis and treatment:
Depression
Fear of recurrence
Sleep disturbances
Cognitive problems
Fatigue
Sexual problems
Social consequences of breast cancer

Material and methods

The literature was reviewed by searches in PubMed restricted to English language papers on human females with the key words “breast cancer” and “late effects” (n = 1 023), “pain” (n = 2 780), “lymphedema” (n = 873), “neuropathy” (n = 417), “fertility” (n = 818), “menopausal symptoms” (n = 6 245), “cardiovascular disease” (n = 4 683), “quality of life” (n = 3 853), and “rehabilitation” (n = 1 471). From these searches the most recent and comprehensive reviews were selected and their reference lists searched for relevant original papers. Wherever possible, the present paper focuses on data from the Nordic countries.

Focal problems related to local therapies

Pain

Pain after breast cancer surgery can result from injuries to muscle and ligaments which usually heal and are more likely to be transient, or neuropathic pain due to damage to the nerve tissue, which may become a more persistent problem [7]. In a review of 32 studies published prior to 2006, prevalence of pain in the arm and shoulder varied between 9% and 68% and in the breast area from 15 to 72% five to 56 months after surgery [8]. Some of the variation can be ascribed to differences in study design and methods of assessment but the main source of variation is attributed to the varying types of treatment. The symptoms tended to diminish with time since surgery but persisted in about 20% of the patients three years after surgery. A recent Danish survey of 3 253 breast cancer patients showed that 47% reported pain one to three years after surgery and among 13% of the patients, the pain was classified as severe [9]. In a multivariate analysis, age turned out to be the most significant predictor or pain, women aged less than 40 being 3.6 times more likely to report pain than women aged 60–69 years. Axillary dissection and radiotherapy were also associated with significantly more pain while there was no difference in pain according to the surgical procedure (breast conserving surgery vs. mastectomy) or use of chemotherapy. In another Danish survey, pain related to breast cancer was reported by 29% of patients surviving for at least five years without recurrence [10]. This estimate corresponds well with results from the START trial, where about 30% of the patients complained about pain in the arm and shoulder five years after treatment [11]. Many of these symptoms persisted from surgery and there was no difference with respect to the radiotherapy regimens given.

Despite the number of studies addressing the prevalence of pain, we have been able to identify only three intervention trials trying to relieve such pain. Among 25 patients, there was no effect of levetiracetam on the postmastectomy syndrome [12]. Two small trials of 19 to 23 patients have found a modest effect of topical capsaicin [13,14], but due to the burning sensation topical capsaicin is generally not satisfactory as sole therapy for chronic painful conditions [15]. For the alleviation of chronic neuropathic pain, common drugs such as gabapentin, nortriptyline, venlaflaxine, and clonazepam have been recommended [16]. In a questionnaire based study of Danish five-year survivors of breast cancer, 47% of the responders reported to use paracetamol, 17% ibuprofen, and 9% acetylsalisylic acid [10].

Lymphedema

Lymphedema arises through insufficient lymph transport caused by damage to the lymphatic vasculature by lymph node dissection and radiotherapy [17]. The prevalence of lymphedema following local therapies varies between studies, around 15–25% one to five years after diagnosis depending on method of assessment [8,11]. In a cohort followed for 20 years, 49% reported sensation of lymphedema and 13% measured severe arm swelling [18]. In the majority of patients the lymphedema occurred within the first three years after surgery and in the remaining the incidence was about 1% per year. A meta-analysis of 98 studies of risk factors for lymphedema concluded that the most consistently reported risk factors are mastectomy, radiotherapy, axillary dissection and tumour positive lymph nodes [19]. Others have identified young age as a risk factor [20].

The state-of-the-art therapeutic approach of lymphedema relies on physiotherapeutic techniques to reduce limp volume and to maintain the health of the skin and supporting structures. After repetitive physiotherapeutic interventions and bandage applications, edema volume will reach its nadir and maintenance of the therapeutic effect will require the use of fitted elastic garments. These recommendations have been validated in clinical studies though the additional effect of manual lymphatic drainage has been questioned in a randomised study [17,21,22]. Surgical approaches to improve lymphatic flow have been largely unsuccessful and pharmacological interventions absent [17]. For years it has been debated whether physical exercise would provoke or deteriorate lymphedema. However, recent trials have not demonstrated differences in arm volume or occurrence of lymphedema between patients randomised to either physical exercise or no exercises [23–25].

Other arm and shoulder problems

In addition to pain and lymphedema, surgery and radiotherapy may contribute to restrictions of arm and shoulder mobility. The prevalence varies from less than 10% to almost 70% depending on method of assessment (measured or self-reported), time since treatment, and type of surgery with greater impairment for mastectomy than lumpectomy and radiotherapy versus no radiotherapy [8]. Among Danish patients, about 35% had reduced arm and shoulder function three years after treatment [26]. Randomised trials have shown that exercise can result in improvements in arm and shoulder function, especially if it is implemented early postoperatively [27]. Physiotherapy may give additional benefits even if instituted as long as six months postoperatively [27,28].

Systemic problems related to treatment

Chemotherapy is associated with a number of acute toxicities which usually resolve when the treatment is completed. However, some of the side effects may persist and influence the quality of life of the women. Side effects to endocrine treatment are common and more problematic to endure because the recommended duration of treatment is at least five years. Additionally, systemic treatment with anthracyclines and trastuzumab and radiotherapy to left sided breast cancers may cause damage to vital organs like the heart.

Neuropathy

Peripheral neuropathy is a well known side effect to microtubule-stabilising agents such as paclitaxel and docetaxel but the mechanism of its origin remains unclear. The reported prevalence varies from a few percent to up 33% [29]. While neuropathy may be perceived as a minor problem in patients with metastatic breast cancer, it may be disabling if neuropathy persists after adjuvant treatment. Since taxanes have been included into adjuvant therapy quite recently, there is no evidence on the risk or persistence of neuropathy from long-term follow-up of patients receiving adjuvant taxanes. There is no specific treatment but gabapentin has been recommended due to its effect on neuropathic pain in general [29].

Fertility and premature menopause

About 20% of breast cancer patients are diagnosed before the age of 50 years, i.e. when they are premenopausal, and 9% are in their childbearing age. Chemotherapy with alkylating agents such as cyclophosphamide is gonadotoxic and the addition of taxanes to anthracycline based chemotherapy may increase the gonadotoxicity. Amenorrhea is often used as a proxy measure for infertility. The prevalence of amenorrhea depends on age at diagnosis and has been estimated to about 55% in patients aged less than 40 years and 90% in patients aged more than 40 years two years after chemotherapy with cyclophosphamide, anthracyclines, and taxanes [30]. Because ovarian stimulation with gonadotropins releases large amounts of estrogen, conventional fertility treatment with ovarian stimulation protocols is contraindicated in breast cancer patients. New treatment with letrozole and FSH may be safe on the short-term but long-term results are needed [30,31]. Though still experimental, other options include cryopreservation of ovarian tissue. As pointed out in the ASCO guidelines, oncologists have a responsibility to inform their patients that the treatment may result in permanent infertility and to discuss measures to preserve fertility [31].

The median age at natural menopause is 51 years. Women who experience premature menopause (before the age of 40 years) and early menopause (age 40–45 years) have an increased overall mortality, and increased risk of cardiovascular disease, vasomotor symptoms, vaginal dryness, dyspareunia, weight gain, and osteoporosis [32]. These symptoms can be ascribed largely to estrogen deficiency and are similar to the side effects of endocrine therapy with tamoxifen and AIs [33]. Estrogens, progestogens, and tibolone can alleviate some of these symptoms but are contraindicated in breast cancer patients due to the risk of relapse or contralateral breast cancer [34,35]. Based on results from several randomised, placebo-controlled trials, the centrally active antidepressant venlaflaxine and the anticonvulsant gabapentin constitute reasonable non-hormonal alternatives for the treatment of vasomotor symptoms whereas complementary alternative medicine therapies have limited effectiveness [35,36]. Patients with sexual dysfunction can benefit from brief counselling when it includes information on the proper use of vaginal moisturisers, the optimal use of vaginal lubricants, and training to relax the pelvic floor muscles [36].

Overweight or obese women are diagnosed at a more advanced stage of disease and have a poorer survival than lean patients [37]. Furthermore, many patients gain weight during chemotherapy and endocrine treatment. No intervention trials have been published showing that weight loss is beneficial with respect to prognosis. A meta-analysis of three trials including 94 patients randomised to exercise versus 53 patients in the control group has shown a non-significant weight loss associated with exercise but the effect on prognosis was not evaluated [38].

Accelerated bone loss can occur in patients with premature or early menopause and among postmenopausal women receiving AIs. Such patients should have a baseline assessment of bone mineral density (DXA-scan) within three months of ovarian suppression therapy, 12 months after postchemotherapy amenorrhea, or within three months of commencing AI therapy. Algorithms have been developed to stratify patients according to their T-score on DXA-scan and suggest management in terms of lifestyle advice, dietary supplementation with calcium and vitamin D, and treatment with bisphosphonates [39].

Cardiovascular disease

Cardiotoxicity is dose-limiting for chemotherapy with anthracyclines (doxorubicin and epirubicin). With the doses currently used for adjuvant therapy (about 240 mg doxorubicin) 24% of patients had an asymptomatic decline in left ventricular function of 10–20% and 7% a decline which precluded later treatment with trastuzumab [40]. Trastuzumab as monotherapy is also associated with cardiotoxicity and evidence from the metastatic setting has precluded concomitant use of anthracyclines and trastuzumab due to cardiac dysfunction in up to 27% of the patients [36]. With the sequential regimens currently used, the risk of heart failure is low, 0.5–4%, in patients with a normal left ventricular function before start of trastuzumab [40,41]. Among ER+ patients, there does not seem to be significant differences between tamoxifen and AIs in risk of heart disease [40]. Radiotherapy can damage the heart even when the mean cardiac dose is in the range of 3–17 Gy. The risk of death from heart disease starts to increase about 10 years after diagnosis. Data from over 30 000 women followed for 20 years from the Early Breast Cancer Trialists’ Collaborative Group indicate that the risk of death from heart disease increases by 3% per Gy to the heart [42]. Potential long-term interactions between medical treatment with anthracyclines and trastuzumab and radiotherapy remain to be studied. It is important that a multidisciplinary approach is used to assess and monitor the cardiovascular risk in breast cancer survivors [41].

Psychosocial problems as consequences of diagnosis and treatment

Being diagnosed with cancer can lead to many psychological and social problems. For the majority of patients a cancer diagnosis represents a threat to life which may result in anxiety and depression.

Depression

Several studies have shown an increased prevalence of depression among breast cancer patients compared to the general population [43]. However, the reported rates vary from a few percent up to 55% [44]. In a recent Danish population based study of 3 353 breast cancer patients, the prevalence of major depression was 14% compared to around 5% in the general population. The risk of having a major depression after a diagnosis of breast cancer was higher among young patients, patients with a history of prior psychiatric disease, and patients with low social status, for example, being unemployed. Furthermore, this study showed that only about half of the women with symptoms of a major depression were in some kind of anti-depressive treatment [45].

Fear of recurrence

Being diagnosed with and treated for cancer often changes the attitude of the patients and for most of the patients a fear of recurrence will be present permanently. This fear tends to diminish with time since diagnosis and treatment but for a substantial part of the women, the fear becomes a part of every day life. In a German study one fourth of the women showed moderate to high levels of fear of recurrence. This fear was more prevalent among young patients and patients with children, but there was no association between the degree of experienced fear of recurrence and time since treatment [46]. This indicates that for some women, fear becomes a chronic problem.

Sleep disturbances

Recently it has been recognised that a cancer diagnosis can result in the development of sleep disturbances. A questionnaire study of more than 2 600 breast cancer patients showed that 39% had clinically significant sleeping problems like insomnia. The disturbances were most prevalent among women with depressive symptoms and vasomotor side effects from endocrine treatment [47]. If insomnia lasts for a longer time it may lead to depression, chronic fatigue syndrome, and lower the cognitive capability of the patient.

Cognitive problems

Cognitive impairment as a late effect of cancer treatment has been studied for several years and the issue remains unsolved. Several studies have shown a negative effect upon short-term memory and the ability to concentrate. The largest effects have been reported in questionnaire based studies where women have been asked to rate their performance as compared with before the cancer was diagnosed [48]. In studies using neuropsychiatric testing the effects were minor if present at all [49]. While chemotherapy initially was suspected to cause cognitive impairment, more recent studies have also pointed to endocrine treatments as giving some degree of cognitive impairment. The issue is not easy to study since the diagnosis of breast cancer can lead to cognitive impairment even before adjuvant treatment is started [50,51]. It is therefore of importance to obtain assessments before adjuvant treatment is commenced and to employ adequate control groups. In addition, there is a complex interrelationship between cognitive impairment, depression, and sleeping disorders.

Fatigue

The National Comprehensive Cancer Network defines cancer-related fatigue as a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness or exhaustion that is not proportional to recent activity and interferes with usual functioning [52]. Like cognitive function, fatigue is not easy to study since there is a baseline prevalence in the general population which varies with age and comorbidity. A wide variety of methods of assessment and study designs (short vs. long term, cross sectional vs. longitudinal) have been employed which makes comparison between studies difficult. However, short-term studies seem to indicate that fatigue constitutes a significant problem among 20–30% of patients two years after treatment. In studies with follow-up for more than five years, fatigue seems to improve with time since treatment, but it remains a significant problem for 5–34% of the patients [53]. The effect of exercise to alleviate fatigue has been investigated in 12 randomised clinical trials including a total of 674 patients. Although there was some heterogeneity between the trials, the results supported a small, but significant beneficial effect of exercise [54].

Sexual problems

A review concerning sexual problems has shown that about 20–30% of the patients experienced sexual problems after being treated for breast cancer. The risk of having sexual problems was more pronounced among women treated with chemotherapy, those who became postmenopausal during treatment, and those who had experienced sexual problems in their relationship prior to the cancer diagnosis [55].

Social consequences of breast cancer

Married breast cancer patients receive considerable social support from their husband and divorce may affect the social network, socioeconomic status, and overall quality of life. While some studies indicate that breast cancer patients are at an increased risk for divorce, a recent Danish study including almost 25 000 women with breast cancer failed to detect an increased risk for divorce [56]. In the same Danish cohort, breast cancer survivors had a non-significantly 22% increased risk for unemployment which is comparable to other studies using a non-cancer control group. The chances for returning to work seem to increase with time since treatment [57].

Discussion

This review demonstrates that women treated for breast cancer may experience a substantial number side effects, physical, psychological as well as social, which can persist for years after their primary treatment. Over the past 30 years, the criteria for recommending adjuvant treatment have widened constantly leading to an increasing number of women with a very low risk of recurrence or death receiving systemic treatments which can be associated with late effects that we are not even aware of today.

Until recently, little attention has been paid to late effects after breast cancer treatment by the health care system these women attend. In a recent US study including 801 breast cancer patients, two thirds of the patients did not express unmet needs for supportive care after treatment, but the remaining third reported more than five unmet needs upon completion of treatment, and for 60% of these patients the situation did not improve after six months [58].

There are several reasons for the lack of attention to persisting side effects of breast cancer treatment. Firstly, since the primary goal of the treatment has been to cure the patient, follow-up programs after treatment for breast cancer have focused mainly on the detection of recurrence [59]. However, the Canadian guidelines for follow-up now recommend that psychosocial support should be encouraged and facilitated, that fatigue should be investigated, and that weight management, osteoporosis, and sexual functioning should be discussed [60]. Secondly, there is a lack of evidence-based treatments or support programs to manage many of the problems the women are facing. Thirdly, the majority of the problems are outside the problem area normally dealt with by the oncologist, therefore requiring either additional training or introduction of new collaborators into the follow-up programs. Finally, increased rehabilitation efforts are likely to entail additional costs to the health care system. However, not doing anything to increase the quality of the rehabilitation efforts will also lead to substantial costs for the society due to increased morbidity, reduced ability to perform a fulltime job, and premature retirement from the workforce. In follow-up for recurrence, however, adherence to guidelines is associated with lower costs than non-guideline follow-up [59].

Thus, there is a need to rethink our follow-up strategy. Firstly, tools, e.g. screening instruments, should be developed to help the treating physician to identify the women who are in need of rehabilitation efforts. Secondly, specific goals for rehabilitation should be formulated and implemented into national guidelines for follow-up. These guidelines should include programs which we already know are effective for specific side effects, e.g. physiotherapy for lymphedema. Thirdly, high priority should be directed towards research programs aiming at developing and testing new interventions for alleviating symptoms and side effects experienced by breast cancer survivors.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.