BREAST CANCER-RELATED LYMPHEDEMA
Breast cancer-related lymphedema (BCRL) is a serious, chronic, debilitating, and common consequence of breast cancer treatment and has been addressed as incurable, or at least as refractory, to conventional treatment modalities. Multiple lifelong morbidities include deformity, pain, a reduction in limb use, and extreme emotional distress often resulting in isolation.328-330 Many patients fear the development of lymphedema even more so than the diagnosis of the cancer itself or the loss of a breast.328,329,331-333 Upwards of one in five patients may face the consequences of this irreversible, lifelong condition.330 In BCRL, there is an ongoing, progressive accumulation of protein-rich fluids and subsequent fibrosis in the affected limb because of the disruption of lymphatic anatomy.10,334-337 This condition remains poorly understood despite extensive research directed in attempts to identify its exact etiology.10,335,338
BCRL is a well-recognized sequela of the treatment of breast cancer, including surgery and adjuvant therapies employed.10,339 The risk of the development of BCRL is a lifetime risk. Fibrosis may be slow to develop, which may account for the delay in the development of BCRL.334,337 BCRL may develop at any time after treatment; however, the condition develops in most patients within the first two to three years after treatment.332,340-342
The incidence of BCRL, as reported, is incredibly misleading and quite confusing because it varies from 6% to 62%. This range represents an enormous variation and underscores our poor understanding of the condition.331,338,343-345 Some estimates of the incidence of BCRL even exceed 80%.332 Discrepancy of the reported incidence of BCRL appears to result from multifactorial variations of the definition of the condition, the absence of any standardized uniform measurements, the lack of patient symptom reporting, inadequate follow-up of complaints relating to BCRL symptoms, varying follow-up periods, weak study designs, and finally, poor documentation by health care professionals involved in the treatment of patients with BCRL.10,338,346-348 In addition, BCRL may develop in other regions, including the chest wall and/or the remaining breast tissue, an issue that has received little attention in the medical community.349-352
Numerous predisposing risk factors for BCRL have been identified. These risks can be stratified into two major categories: disease specific (factors beyond the patient’s control) and lifestyle risks (factors that may be influenced or controlled by the patient’s proactive involvement). Although some of these risk factors may overlap, many nonmedical factors remain beyond the patient’s control. Factors beyond the patient’s control include the age at diagnosis, stage of disease, extent of surgical manipulation, need for adjuvant therapies, development of postoperative infections, and formation of seromas.10,353,354 Age has been addressed in several studies, and the evidence for this as being a definitive risk factor for the development of BCRL remains conflicting.10,353,354An urgent and more recent concern is that breast cancer is being diagnosed in younger women. Because development of BCRL is a lifelong risk, the long-term survival of younger patients may result in an increased risk of BCRL over time, as with the risk of CVD.25,26
The surgical treatment of breast cancer appears to be the primary predisposing factor for the development of BCRL. Therefore, the risk of BCRL may differ depending on the initial surgical option chosen by the patient. Mastectomy, as opposed to lumpectomy, may result in a significantly higher risk (a twofold to sixfold increase) of BCRL.341,355,356 The extent of axillary dissection and the ratio of positive to negative lymph nodes have also been identified as factors that may increase the potential for BCRL development.330,338,357-359
Intuitively, it appears to make sense that the number of lymph nodes removed and, furthermore, those that are found to be involved with metastatic disease would increase the chance of BCRL developing owing to the disruption of the anatomic flow of lymph. Several studies do not support this concept and, in fact, offer little evidence for the mechanism of this pathologic event.339,354,360 A potential explanation offered is the fact that lymph node involvement early in the disease process allows the development of collateral channels for lymphatic drainage.360 On the other hand, multiple additional studies lend support to the hypothesis that the extent of nodal dissection or involvement with the disease are, indeed, factors that increase the propensity for the BCRL.330,338,340,357-359,361 Replacing the radical axillary dissections of decades ago, sentinel lymph node sampling is now the currently accepted, minimally invasive, approach to breast cancer treatment in early-stage disease.328,362 Compared with traditional axillary dissection, multiple studies have well documented that sentinel lymph node biopsy for assessing and staging breast cancer results in a significant reduction in the development of BCRL.328,355,363-366 Nonetheless, despite the rapid adoption of sentinel lymph node biopsy, BCRL remains a concern; according to recent data, there is still more than a 7% or 8% chance of BCRL developing within the first 6 months after the biopsy procedure.328,353,367
Chemotherapy has been well documented as an extremely effective adjuvant therapy to decrease recurrence and increase the OS of patients with breast cancer.368,369 Interestingly, the percentage of patients receiving such adjuvant therapies as related to the development of BCRL is poorly documented because of incomplete information gathering and secondarily, in large part, because of the outpatient administration of chemotherapy.370 The addition of chemotherapy to the breast cancer treatment regimen and its relationship to the incidence of BCRL remains largely unresolved. As the multidisciplinary approach to breast cancer increases, it is becoming increasingly difficult to separate various therapies and their long-term consequences. This is particularly true in the setting of BCRL. Polyagent therapies have been implicated with an increase in the incidence of BCRL.371-373 Particular attention has focused on the anthracycline-based therapies.374 It remains unclear why the addition of chemotherapy to the treatment of breast cancer may increase the incidence of BCRL. The issue of more advanced disease requiring adjuvant chemotherapy may skew the population that is more likely to experience BCRL. No studies, to our knowledge, have addressed or isolated a primary association. Therefore, it seems wise to be aware of the fact that chemotherapy, particularly anthracycline-based regimens, should be considered as a potential contributing risk factor for BCRL.
As previously mentioned, RT has become a mainstay in the adjuvant treatment of breast cancer.59-75 Although the ultimate role of adjuvant RT in the development of BCRL is currently under review, substantial evidence has been reported supporting the idea that axillary RT increases the risk of BCRL.335,338,375,376 Presumably, RT-induced fibrosis results in scarring of the lymphatic system, resulting in further lymphatic flow disruption and the subsequent development of BCRL. Other studies have reported no increase in the incidence of BCRL after adjuvant axillary RT.372-374 Contemporary therapy involves sophisticated computed tomographic planning for appropriate simulation and allows for a more exact “targeted” zone for RT. As such, the potential for BCRL secondary to RT will, one hopes, be minimized in the near future.
Additional risk factors for BCRL include the postoperative complications of infection and seroma formation.336,352,355 Trauma, such as a shearing chest wall injury or dermal intrusion secondary to activities such as gardening and hiking, may also predispose a patient to the development of late-onset BCRL. Furthermore, surgery on the dominant side may also increase the incidence of BCRL.377
Lifestyle issues that are modifiable by a patient’s behavior may also play an important role in BCRL risk. The most important modifiable risk factor is related to obesity as determined by BMI.330,338,354,355 A sedentary lifestyle contributes to obesity, and therefore increasing physical activity may help decrease a patient’s BMI. In fact, multiple studies have demonstrated the benefits of exercise to not only decrease BMI but also to decrease the risk of BCRL.10,354,378-380 In addition, exercise has been shown to have significant beneficial effects in cancer rehabilitation and, when coupled with an effective diet, including high vegetable and fruit consumption, has been shown to increase OS after breast cancer.381-383 Finally, DM and hypertension, both associated with an increased BMI, have been identified as potential risk factors for BCRL, and these conditions may be altered by an effective diet and exercise program.10,338,354,355,381,383 Obesity, DM, and hypertensive states also increase the risk of CVD as previously discussed. (See Sidebar: Risk Factors for Breast Cancer-Related Lymphedema.)