Breast cancer-related lymphedema: risk factors, precautionary measures, and treatments

Tessa C. Gillespie1, Hoda E. Sayegh1, Cheryl L. Brunelle2, Kayla M. Daniell1, Alphonse G. Taghian1. Gland Surg 2018;7(4): 379-403

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Breast cancer-related lymphedema: risk factors, precautionary measures, and treatments

Tessa C. Gillespie1, Hoda E. Sayegh1, Cheryl L. Brunelle2, Kayla M. Daniell1, Alphonse G. Taghian1. Gland Surg 2018;7(4): 379-403

Breast cancer-related lymphedema (BCRL) is a negative sequela of breast cancer treatment, and well-established risk factors include axillary lymph node dissection (ALND) and regional lymph node radiation (RLNR). BCRL affects approximately 1 in 5 patients treated for breast cancer, and it has a significant negative impact on patients’ quality of life after breast cancer treatment, serving as a reminder of previous illness. This paper is a comprehensive review of the current evidence regarding BCRL risk factors, precautionary guidelines, prospective screening, early intervention, and surgical and non-surgical treatment techniques. Through establishing evidence-based BCRL risk factors, researchers and clinicians are better able to prevent, anticipate, and provide early intervention for BCRL. Clinicians can identify patients at high risk and utilize prospective screening programs, which incorporate objective measurements, patient reported outcome measures (PROM), and clinical examination, thereby creating opportunities for early intervention and, accordingly, improving BCRL prognosis. Innovative surgical techniques that minimize and/or prophylactically correct lymphatic disruption, such as axillary reverse mapping (ARM) and lymphatic-venous anastomoses (LVAs), are promising avenues for reducing BCRL incidence. Nonetheless, for those patients with BCRL who remain unresponsive to conservative methods like complete decongestive therapy (CDT), surgical treatment options aiming to reduce limb volume or restore lymphatic flow may prove to be palliative or corrective. It is only through a strong team-based approach that such a continuum of care can exist, and a multidisciplinary approach to BCRL screening, intervention, and research is therefore strongly encouraged.

Main findings

  • Type of axillary surgery
    • Kilbreath and colleagues, who prospectively screened for lymphedema and found similar incidence rates when they stratified their data by number of nodes removed. For patients who have had more than five or more nodes removed, the incidence rate was 18.2%; for patients with less than five nodes removed, the incidence rate was 3.3% (18).
    • De Groef and colleagues cautioned against the assumption that SLNB does not substantially affect arm morbidity irrespective of BCRL. In their prospective study, 50% of patients who underwent SLNB reported pain and 49% of patients experienced impaired shoulder function 1 year after surgery (25). This, and the fact that SLNB itself poses a risk for LE development, must be considered during the development of new treatments and protocols for patients undergoing treatment for breast cancer.
  • Radiotherapy to the regional nodes.
    • Warren and colleagues demonstrated that RLNR, either supraclavicular with or without posterior axillary boost, significantly increased LE risk compared to breast/chest wall RT alone (HR: 1.70; 95% CI: 1.07–2.70). A new meta-analysis by Shaitelman and colleagues calculates the pooled incidence for patients undergoing breast/chest wall radiation alone as 7.4% (95% CI: 5.1–10.0), but the pooled incidence for various combinations of RLNR varies from 10.8% to 15.5%.
    • Patients undergoing RLNR, even without ALND, should be considered a high-risk group for developing lymphedema, and all patients undergoing ALND and/or RLNR should be prospectively screened.
  • Lack of breast reconstruction.
    • Unclear whether type of immediate reconstruction effects BCRL incidence.
  • Adjuvant and neoadjuvant chemotherapy.
    • While it is clear taxanes, specifically docetaxel, cause edema, there is not a clear consensus in the literature that taxane-based chemotherapy is a risk factor for BCRL. The effect of neoadjuvant chemotherapy on BCRL risk is unclear.
    • It has been suggested that neoadjuvant chemotherapy could, in theory, decrease BCRL incidence by reducing the number of positive lymph nodes.
    • More studies, using objective and standardized BCRL measurement techniques and definitions, are needed to define the role of neoadjuvant and adjuvant chemotherapy in BCRL risk.
  • BMI
    • High BMI at time of breast cancer diagnosis is a well-established risk factor for developing BCRL.
    • In addition to high BMI at diagnosis, there is some supporting evidence suggesting weight fluctuations during and after treatment may be a risk factor for BCRL.
  • Subclinical oedema
    • Subclinical edema has been shown to be a risk factor for BCRL. Specht and colleagues first studied the relationship between subclinical swelling and progression to lymphedema—defined as >10% relative volume change— to assess at what level of swelling would intervention be warranted.
    • Kilbreath and colleagues found that, for women with five or more lymph nodes removed, axillary swelling at 6 and 12 months postoperatively are independent risk factors for BCRL at 18 months.
  • Cellulitis
    • Cellulitis and BCRL may represent a feedback loop in which cellulitis increases BCRL risk and BCRL increases risk of further infections. More research is needed to fully delineate the relationship between cellulitis and BCRL to help mitigate risk of both.
  • Precautionary guidelines
    • There is a need for more rigorous research regarding precautionary behaviors prior to implementing practice changes. This recommendation is echoed in the 2016 International Society of Lymphedema Consensus document. They state, “The recent promulgation of lists of risk factors for secondary lymphedema has become a highlighted issue due to publications of ‘do’s and don’ts’. These are largely anecdotal and not sufficiently investigated. While some precautions rest on solid physiological principles, others are less supported.” It goes on to state that “standard use of some of these ‘don’ts’ for risk reduction of lymphedema may not be appropriate and possibly subjects patients to therapies which are unsupported until a point in the future when evaluation and prognostication evidence has demonstrated more clearly specific risks and the corresponding preventative measures”.
  • Screening programs an early intervention
    • Large, randomized trials are needed to fully evaluate the benefits of early intervention for subclinical edema. Nonetheless, the International Society for Lymphology upholds that prospective screening models and early intervention allow for greater treatment success and potential cost savings.
  • Improving treatment techniques.
    • New surgical techniques are being developed to minimize axillary lymphatic disruption in both SLNB and ALND procedures. The first procedure, axillary reverse mapping (ARM), has shown promise in recent years as a new method to map out and preserve axillary lymphatics during surgery and potentially reduce post-surgical lymphedema incidence in patients.
    • Six hundred and fifty-four ARM procedures were performed with either an SLNB or an ALND, and, except during the beginning of the study, benign-appearing ARM nodes and lymphatics were preserved during ALND (67.3% of ALND patients with ARM lymphatics identified). In a subset of patients for which ARM lymphatics were identified and preserved, objective BCRL rates at a median of 26 months after surgery were 1.2% for SLNB patients and 6.9% for ALND patients (110). These represent a marked decrease to typical BCRL incidence rates for SLNB and ALND.
    • Larger, randomized clinical trials comparing the efficacy and safety of ARM in conjunction with axillary surgery to SLNB and ALND alone are needed before clinical guidelines can implement ARM for lymphedema reduction in patient populations.
    • Lymphatic Microsurgical Preventative Healing Approach (LYMPHA) technique. LYMPHA involves constructing lymphatic-venous anastomoses (LVAs) between the arm lymphatics and a collateral branch of the axillary vein during axillary surgery.
    • LYMPHA in conjunction with ARM procedures may prove to be an effective adjustment to SLNB and ALND, particularly for those in which ARM lymphatics and nodes must be transected or removed. The technique could be implemented with relatively little burden to hospitals in which surgeons trained in microsurgical techniques work, particularly if performed at the time of mastectomy with immediate reconstruction.
  • Non invasive treatments
    • There has been less well-established research regarding the efficacy of each individual CDT component.
  • Surgical treatments
    • Large, randomized clinical trials are needed to fully evaluate the palliative benefits of LVAs alone and compared to other treatment techniques.