CHAPTER 18 Lymphedema Risk Factors in Breast Cancer
KEY POINTS
Breast cancer treatment, one of the most common causes of lymphedema, affects more than one in five breast cancer survivors.
The presence of lymphedema has a substantial impact on a person’s physical, psychological, and social wellbeing.
Axillary surgery is one of the major risk factors for lymphedema.
The risk of lymphedema is not completely eliminated with sentinel node biopsy.
Postoperative radiation increases the risk of lymphedema by as much as 10-fold compared with surgery alone.
Exercise is beneficial.
Air travel, an elevated BMI, advanced age, and venous obstruction may contribute to the appearance or worsening of lymphedema.
Breast cancer treatment is one of the most common causes of lymphedema; more than one in five women who survive breast cancer will subsequently develop this chronic disease. Lymphedema after breast cancer treatment is characterized by regional swelling in the arm(s) ipsilateral to axillary staging and therapy; the acquired lymphatic vascular insufficiency leads to an accumulation of protein-rich interstitial fluid in the tissues distal to the obstructive lesion. 1 , 2 This high incidence of lymphedema has been linked to treatment variables, along with a variety of other stressors that are still under active investigation. The cumulative incidence of arm lymphedema increases over time and is most pronounced during the initial 2 years after breast cancer intervention. 3 , 4 Lymphedema has an extensive negative impact on the affected individual, including the physical symptoms of discomfort, pain, and limb tightness, accompanied by the loss of function in the limb. This functional deficit can compromise the individual’s work and social productivity and impact the ability to undertake self-care. 5 The disease produces various pathologic sequelae, including an increased risk of infection 6 – 9 and secondary malignancy. 10 – 13 The negative impact on social relationships, emotional self-confidence, and psychological wellbeing cannot be overstated. 14 , 15 The high incidence of lymphedema in breast cancer survivors, and its substantial impact on quality of life, suggest that the study of lymphedema and its associated risk factors is of high public health importance.
Treatment-Related Risk Factors for the Development of Lymphedema
Patients who are in the early stages of breast cancer typically undergo primary surgery on the breast (lumpectomy or mastectomy) and regional nodes, with or without radiotherapy. After this local therapy, the patient may undergo systemic adjuvant therapy, depending on the tumor characteristics. Patients may choose to undergo either breast-conserving therapy (BCT), which consists of a lumpectomy plus radiotherapy, or a total mastectomy.
A meta-analysis of 72 studies 3 strongly supported an association between axillary lymph node dissection, the extent of lymph nodes dissected, and mastectomy and the development of lymphedema. There is moderate evidence to support an association between the risk of lymphedema after treatment and a higher number of lymph nodes with metastasis and the use of radiotherapy and chemotherapy. There is less robust support for a link between lymphedema development and the use of axillary radiotherapy. 3 The diagnostic and treatment approaches to the management of breast cancer can have a significant impact on the risk of lymphedema after treatment, and an understanding of this can help physicians counsel patients appropriately.
AXILLARY LYMPH NODE DISSECTION
Axillary surgery is one of the major risk factors for lymphedema. A desire to minimize the adverse outcomes associated with axillary lymph node dissection (ALND) led to the development of the sentinel lymph node biopsy (SLNB) technique. SLNB as a standard means of axillary nodal assessment significantly reduced the number of women undergoing axillary surgery and thus the prevalence of breast cancer treatment–induced lymphedema. 16 A recent analysis suggests that the risk of lymphedema within 1 year of treatment is 2% after SLNB alone compared with 13% after SLNB combined with ALND. 17 Another meta-analysis of lymphedema after breast cancer showed that the incidence of lymphedema in women who underwent ALND was almost four times higher than in those women who had SLNB. 3
Because of the decreased adverse outcomes with SLNB, the American College of Surgeons Oncology Group initiated the Z0011 trial in 1999 to assess whether ALND improved outcomes in patients with sentinel node metastases who were undergoing BCT. The study demonstrated that SLNB alone did not result in inferior survival, a finding that has the potential to significantly change clinical practice. 17 Based on this study, it is assumed that only patients with clinically suspicious axillary lymph nodes and a positive biopsy finding should undergo ALND at the time of BCT surgery. Other indications for ALND include patients with positive sentinel nodes undergoing mastectomy without postsurgical radiotherapy or patients with more than three positive sentinel nodes who are undergoing BCT. Patients with a negative biopsy result or clinically negative axillary examination with no suspicious palpable axillary nodes should only undergo SLNB at the time of BCT surgery. This will help the surgeon make decisions regarding adjuvant systemic therapy and radiotherapy while minimizing the potential for complications and adverse outcomes, such as lymphedema. However, even with the SLNB technique, the risk of lymphedema is not completely eliminated. 18 , 19
It is not only axillary surgery but even more limited breast-conserving interventions (with or without local radiotherapy) that can increase the risk of developing lymphedema. 20 , 21 A study comparing patients with ALND and radical mastectomy with patients with ALND and BCT followed by local radiotherapy revealed that the incidence of lymphedema with mastectomy was more than twice that of the other group. 22
RADIOTHERAPY
Although surgical interventions significantly increase the risk that lymphedema will develop, the use of adjunctive radiotherapy in breast cancer treatment further increases this risk. 23 Postoperative radiotherapy increases the risk by as much as 10 times compared with surgery alone. A possible explanation for this effect may reside in the impact of radiation on the residual lymphatic structures within the radiation port. Radiation may also promote tissue fibrosis, thereby suppressing lymphatic regeneration. 24 The inclusion of the supraclavicular or posterior axillary regions within the target radiation field increases the risk of lymphedema twofold or threefold, respectively. To minimize the risk of lymphedema induced by radiotherapy used as an adjunct to surgical breast cancer treatment, radiation oncologists have adopted newer radiotherapy protocols and three-dimensional methods that minimize normal tissue exposure and conventional fractionation to the involved nodal regions. 23 , 25 , 26 This allows collateral lymphatic drainage and reduces the risk of lymphedema. 23
CHEMOTHERAPY
Traditionally it was assumed that chemotherapy did not increase the risk of lymphedema. 27 However, more recent studies have shown an increased risk of lymphedema after chemotherapy for breast cancer. This association between lymphedema and chemotherapy may exist because systemic chemotherapy is often used in more advanced stages of the disease requiring more extensive surgical treatment, which has a clear link to a higher incidence of lymphedema. The relationship between chemotherapy and lymphedema may also exist because more pharmacotherapy and chemotherapeutic agents are used today than in the past, resulting in an increase in adverse interactions between these agents and the lymphatic system, thereby leading to lymphedema. 3 , 28 , 29
Nontreatment-Related Risk Factors for the Development of Lymphedema
For many years there has been controversy regarding the impact of other risk factors on the incidence of lymphedema in breast cancer survivors, which resulted in much fear and frustration in the patient population. 30 Physicians long discouraged physical exercise of the affected limb with lymphedema in breast cancer patients because they believed that exercise would precipitate lymphedema in these patients or exacerbate the already extant limb swelling. 31 However, more recent studies and trials have challenged this belief and demonstrated that exercise does not worsen lymphedema. 32 – 36 On the contrary, the available evidence supports the concept that exercise can help control and improve lymphedema in these patients. 3 , 5 , 37 – 39
Airplane travel has also traditionally been thought to worsen lymphedema. A single-subject case study showed that interarm bioimpedance ratios (a measure of interstitial fluid volume disparities) worsened after flying. 38 A larger study used questionnaires to assess the role of aircraft travel in precipitating lymphedema or worsening the existing condition in patients who were treated for breast cancer; the observed relationship led to the hypothesis that the lowered aircraft cabin pressure can compromise the lymphatic function in the limb, either through obstruction of veins and lymphatics or diminished lymphatic pumping, thus leading to an accumulation of fluid in the limb. 40 , 41 However, given this mechanism, it can be conjectured that patients can reduce the flight-associated risk with the use of additional compression (for example, inflated splints or pressure bandages) during the flight. 40
Some studies contradict this general notion that air travel may trigger lymphedema. For example, one study observed athletic breast cancer survivors who traveled from Canada to Australia for a dragon boat competition without a demonstrable adverse relationship between air travel and arm lymphedema. 42 Air travel alone may not be enough to precipitate or worsen lymphedema in breast cancer patients after treatment but may be influenced by other factors such as exercise, which may confer a protective effect on the patients’ inherent predisposition to develop lymphedema. Certain stressors, such as air travel, may impose a significant load on an already stressed lymphatic system and thus may precipitate the lymphedema or induce an acute flare in the swelling. 30
Obesity is also considered a risk factor for lymphedema. Many studies suggest that a BMI greater than 25 or a sedentary lifestyle can increase the likelihood of developing lymphedema in breast cancer survivors. 43 – 47 Hypertension may also be an important comorbidity that predisposes patients with a history of breast cancer treatment to develop lymphedema. An infection of the affected arm can also increase the risk of lymphedema in this patient population. 43 , 48 , 49
More recent observations indicate that venous disruption in patients after mastectomy and radiation can also play a role in the pathogenesis of lymphedema. In a study of 81 patients, more than half had venous outflow obstruction on Doppler imaging of the venous flow of the upper extremity. 50 Our own case series suggests that venous outflow obstruction not only precipitates lymphedema, but also renders the swelling refractory to decongestive therapy. 51 This conclusion is further substantiated by the therapeutic response seen in residual arm lymphedema after the venous obstruction is treated with percutaneous venoplasty, with or without stenting. 51 Based on these findings, physicians have more opportunities to use nonsurgical techniques to help mitigate the swelling and enhance the responsiveness to conservative treatment of the lymphedema in patients with simultaneous venous flow abnormalities.
Inconclusive evidence exists to support other risk factors for lymphedema, such as demographic characteristics, dominant versus nondominant limb involvement, postoperative infection, and certain lifestyle-associated factors (for example, self-care, use of the affected arm, and education about lymphedema). 3 Also, a growing body of evidence suggests that inflammation plays a key role in the pathogenesis of lymphedema. 52 – 54
Although our understanding of lymphedema and the risk factors for precipitating or worsening this condition in breast cancer patients has increased significantly, there is still much that must be learned about the pathogenesis of this disease. Physicians who are knowledgeable about the many risk factors will be able to better educate their patients with a history of breast cancer on ways to significantly reduce their risk of developing posttreatment lymphedema. As a result, physicians will also dispel the myths and fears of these patients.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
