Does Exercise Have a Preventive Effect on Secondary Lymphedema in Breast Cancer Patients Following Local Treatment - A Systematic Review

Over 1.8 million women worldwide are diagnosed with breast cancer every year [1]. Due to improved medical treatment options and early screening and detection, breast cancer survival rates have increased significantly in the last years, and more than 80% of patients can be cured [1]. Given the improved survival rates, dealing with treatment-associated side effects such as secondary lymphedema (SL) is a new challenge in cancer care [2]. SL is likely to occur after the surgical removal of lymph nodes or in conjunction with radiotherapy [3]. SL is generally described as ‘arm swelling and dysfunction' [4] and is defined as an increase in arm circumference by more than 2 cm [5] or as an accumulation of excessive protein-rich liquid in a part of the body where lymphatic vessels have been damaged [6]. About 20-30% of all breast cancer patients develop SL [7].

The American College of Sports Medicine (ACSM) roundtable on exercise guidelines for cancer survivors describes that exercise during and after cancer treatment is safe and can help patients improve their physical capacity and quality of life [8]. The ACSM guidelines indicate specific exercise programs oriented towards impairments associated with disease and medical treatment [8]. Strength exercise does not have any negative effects on an existing SL [9]; instead, it has beneficial effects such as improvement of strength [2] and lower exacerbation rates [10].

However, these recommendations do not include any information about the prevention of SL in breast cancer patients. According to our knowledge, no systematic review on solely the topic of prevention has been published so far. Therefore, we conducted a systematic review to analyze possible preventive effects of exercise on the incidence of SL in breast cancer patients.

In order to analyze the possible preventive effect of exercise on SL in breast cancer patients, a comprehensive literature search was performed. 3 reviewers independently searched the available literature in the PubMed, LIVIVO, and Cochrane Library databases in order to identify randomized controlled exercise intervention studies with breast cancer patients focusing on the prevention of SL. The literature search was completed in June 2016. The keywords ‘breast cancer', ‘lymphedema', ‘prevention', ‘exercise', ‘physical activity', ‘physical fitness', ‘physical exercise', ‘sport endurance', ‘resistance training', ‘strength training', ‘weight training', ‘physiotherapy', ‘physical therapy', ‘kinesiotherapy', ‘movement, ‘aerobic', and ‘sport' were used. Only randomized and controlled studies with more than 20 subjects were included. Parameters such as inclusion and exclusion criteria were defined and are listed in table 1.

A total of 8 randomized controlled intervention studies investigating the preventive effects of exercise on the development of SL in breast cancer patients were identified (tables 2, 3, fig. 1). The studies by Schmitz et al. [11], Sagen et al. [12], Torres Lacomba et al. [5], De Rezende et al. [13], and Zimmermann et al. [14] enrolled only subjects without lymphedema at study entry. The studies by Ahmed et al. [15], Devoogdt et al. [16], and Zhang et al. [17 ]included both subjects with and without lymphedema at study entry. In total, 1,810 participants were investigated, and 1,780 of these were included in the post-analysis. 5 studies provided details on age; participants were on average 54 years old. 4 studies reported that their subjects received radiotherapy, chemotherapy, or hormone therapy during the intervention period.

The exercise intervention comprised either resistance training (n = 3) [11,12,15] or a combined exercise therapy (n = 5) consisting of physiotherapy, physical therapy, manual lymphatic drainage (MLD), stretching, massage, and/or kinesiotherapy [5,13,14,16,17]. Resistance training started between 4 months and 5 years after the end of primary treatment. 2 studies started combined exercise therapy 24-48 h after surgery. Intervention programs lasted from a minimum of 3 weeks to a maximum of 12 months. MLD in addition to exercise was administered in 4 studies [5,14,16,17].

Preventive effects of exercise in relation to SL in breast cancer were observed. Significant effects could be identified in 5 studies [5,11,13,14,17]. 3 studies recognized significant effects of exercise in combination with MLD [5,14,17]. Schmitz et al. [11] reported only a minor incidence of SL in the intervention group undergoing a 1-year (twice weekly) progressive weightlifting intervention compared to the control group. This difference was even bigger in women who had at least 5 lymph nodes removed. The study conducted by Torres Lacomba et al. [5] observed a significantly lower incidence of lymphedema in the intervention group receiving physiotherapy (MLD, massage, stretching, progressive exercise, and educational therapy) compared to the control group receiving only educational material. Moreover, in the control group, onset of lymphedema was diagnosed 4 times earlier compared to the exercise group [5]. In the study by De Rezende et al. [13], the intervention group showed statistically significant better recovery of flexion, abduction, and external movements in the shoulder compared to the control group. Zimmermann et al. [14] performed a 6-month MLD intervention and showed 6 months after surgery a significant increase in arm volume on the operated side in the control group. Zhang et al. [17] combined physical exercise with self-administered MLD in their trial and showed that the combined intervention significantly reduced upper limb lymphedema after surgery compared to physical exercise alone.

The aim of this study was to analyze the potential preventive effects of exercise-based therapies on SL incidence after breast cancer. To our knowledge, a systematic review on solely the topic of prevention was not conducted before. 8 randomized controlled studies [5,11,12,13,14,15,16,17] could be identified. They showed that exercise in the form of progressive resistance training as well as combined exercise therapies consisting of physiotherapy, physical therapy, MLD, stretching, massage, and/or kinesiotherapy are safe and might have a preventive effect on SL incidence.

In the past, physicians believed that cancer patients must avoid exercise [8], and literature indicating that exercise can cause or exacerbate lymphedema still exists [15]. However, the present review revealed that 5 out of 8 trials reported significant preventive effects of resistance training and exercise on SL incidence. Park et al. [18] investigated the incidence and risk factors of SL in breast cancer patients. They demonstrated that women who exercised regularly, performed preventive self-care, and received information about the possible appearance of a lymphedema before local treatment had a lower risk of developing lymphedema. Proposed mechanisms included that exercise promotes the contractility of the skeletal muscles and subsequently provides primary pump mechanisms for lymph and venous drainage [19,20].

Besides radiation and the number of surgically removed lymph nodes [16], overweight also contributes crucially to the development of SL [21,22,23]. In the study by Sagen et al. [12], a significant risk increase was observed in patients with a body mass index of >25 kg/m² (p = 0.005). Shaw et al. [24] also referred to the relationship between overweight/obesity and the development of lymphedema [25]. According to Bicego et al. [19], further risk factors include obstruction, trauma, and inflammation [26]. Physical inactivity results in a decrease in lymph circulation. Physical exercise maintaining or improving the ‘range of motion' of the shoulder therefore seems to be an effective and preventive measure. Additional benefits include improved muscle strength/fitness and maintenance of body weight.

A limitation of this systematic review is that probably not all studies covering the preventive effect of exercise on SL in breast cancer were identified in the literature. Also, we must take into consideration that other risk factors contribute to the development of SL as previously described. In this review, we included studies performed between 2006 and 2016 during which period surgical treatment and especially axillary staging shifted from axillary dissection level I-III to sentinel lymph node dissection. The risk of SL decreased during that time, making it difficult to compare these studies.

Due to the fact that the included studies evaluated different exercise intervention regimens, we are currently unable to provide clear and evidence-based exercise recommendations. The results published by Cavanaugh [27] underline the urgency of individualizing exercise guidelines. Further, Ahmed et al. [15] recommend that breast cancer patients should perform strength training of the upper body because this does not promote the risk or symptoms of lymphedema. Besides, Sagen et al. [12] recommend that patients with axillary lymph node dissection continue to exercise without restriction in daily living. In addition, considering early exercise intervention in women with breast cancer is important and necessary [27]. The studies by Ahmed et al. [15] and Schmitz et al. [11] show that progressive strength training can generate a preventive effect. Combined exercise therapy can result in similar effects [5,14,17]. Exercise additionally supports muscular pump function and should be performed at a moderate level of intensity and with a small number of repetitions. The application of MLD seems to have prophylactic effects only in combination with exercise, and current data does not show any evidence for MLD as a single primary prophylactic method [28]. To guarantee the safe and effective performance of the exercises, the support of a certified exercise therapist during the first months of the strength training is also advised [29].

A total of 8 randomized controlled trials yielded promising data supporting the preventive effect of exercise on SL in breast cancer patients. Results showed that exercise is safe and that it is important to maintain exercise in daily living. Exercise in the form of progressive resistance training as well as combined exercise therapies are safe and might have a preventive effect on SL incidence. Future investigations will have to differentiate between patients with and without axillary surgery, and exact exercise recommendations for therapists and the rehabilitation system should be based on further studies.

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.