The advent of newer imaging technologies,1 and the hypothesis that baseline lymphatic defects amplify the effect of lymphatic injuries2 resulting in secondary lymphedema, provides potential actionable data to guide the adoption of newer technologies in the diagnosis, anticipation, prevention, and management of cancer-related lymphedema.
In the 2017 review article, “Evidence for Health Decision Making—Beyond Randomized, Controlled Trials,” Dr Thomas Frieden,3 MD, MPH, discussed limitations with randomized controlled trials, particularly with rare diseases and/or in situations that would present ethical and logistical difficulties. He goes on to discuss many options for gathering of improved data, such as ensuring standardized data collection, an issue that is known to be a substantial problem with cancer-related lymphedema research.4 This is highlighted in the recent work of Michelotti et al, published in the April edition of Breast, who stated, “To date, diagnostic methods and staging systems lack uniformity, leading to a possible underestimation of the real incidence of this condition, decreasing early detection and thus the possibility of an effective treatment.”4(p16)
Current methods of lymphedema diagnosis rely heavily on the physical measurements and observable characterization of excess limb volume and/or symptom report5 that denote changes of the soft-tissue matrix in the limb.1,6 In effect, we are only measuring the damage to the environment, without understanding the risk(s) that may have already been there. One could imagine the analogy of an impending flood due to saturated ground water levels and levees that are about to fail. We would not wait to evacuate people from the area about to flood. Waiting to measure the depths of the actual flooding is too late. Such is the case with cancer-related lymphedema, where we can now image the system before it is subjected to further insult.
Our expanded knowledge of the pathophysiology of lymphedema in relation to the genetic, inflammatory, and dysregulatory mechanisms that accompany this disease may provide the window of understanding and opportunity to challenge our current thinking about cancer-related lymphedema. The potential to redirect research efforts toward a precision-based approach to lymphedema risk stratification in the coming years, which focuses on the individual's baseline lymphatic function, could certainly be a viable option, particularly given the advent of novel surgical techniques such as LYMPHA7 and reverse axillary lymph node mapping.8 The rapid progression of imaging and the ability to quantify and describe functional lymphatics is being led, largely in part, by the rapid advances in lymphatic surgery.
Surgeons throughout the world are quantifying and classifying phenotypes of cancer-related lymphedema.1 The basic research questions postulated are propelling the field forward and bringing a realization that many of the cellular and molecular functions of the lymphatic endothelial cells and lymphatic system in general are not fully understood. The most recent article by Johnson et al7 in 2019, “The Impact of Taxane-Based Chemotherapy on the Lymphatic System,” found a novel method to quantify the contractility rates of the lymphatic system in patients receiving neoadjuvant taxane-based therapies compared with those not receiving the same therapies. Although it was a very small study, they found a diminished lymphatic contractility in the patients receiving taxane-based therapies.9 Such data, though early, compound the perceived need for increased research in this area to validate any potential associations with cancer-related lymphedemas. A shift in our strategies for combating cancer-related lymphedema could gain further traction from such research, as it harkens the potential need for baselines to occur at the time of diagnosis, not just presurgically.
A recent study that demonstrates this potential shift in focus is the work by Iyigun et al.10 Their study, “Preoperative Lymphedema-Related Risk Factors in Early-Stage Breast Cancer,” using bioimpedance spectroscopy (BIS) demonstrated that upwards of one-fifth patients had subclinical lymphedema associated with obesity and positive lymph nodes.10 The patients with subclinical evidence of increased extracellular fluid in the limb had no evidence of differences in arm circumference.10 This lends further credence to the logic of obtaining preoperative baseline measures and the potential need for further pretreatment imaging or surgical alternatives for these patients, as surgeons have been adjusting the way they surgically manage the axilla in recent years.
In the latter part of 2018, a study conducted by Ridner et al11 found similar elevated baseline BIS measurements in 7.8% of patients. Both of these studies point to a growing body of evidence that BIS can detect extracellular fluid changes before volume of the limb increases, allowing for the earlier identification of breast cancer–related lymphedema, and with the diagnosis of lymphedema at much earlier stages.12,13 Additional studies by Koelmeyer et al13 and Kilgore et al12 highlight successful models of prospective surveillance in both Australia and the United States.
Other noninvasive technologies that will likely play a role in the classification and treatment of cancer-related lymphedema include ultrasonography and tissue dielectric constant. Ultrasonography can be used to observe collecting lymphatic vessels and measure tissue depths, such as the thickness of the fatty tissue accumulation from chronic lymphedema.14 Tissue dielectric constant, which measures localized tissue water in the skin,15 has the distinct advantage of being able to be used in areas such as the breast and trunk, where other methods are not adaptable. These technologies promise the ability to easily quantify and track treatment of cancer-related lymphedema and have shown in a recent study to help surgeons preoperatively optimize the sites for lymphatic-venous anastomosis.14 Such insights into the structural and tissue changes of cancer-related lymphedema will be integral for the increased understanding and improved staging and management of this disease.9,16
Current trends in the research of cancer-related lymphedema will continue to elucidate the risk stratification and early identification of this dreaded disease. The potential effect on quality of life and health care–associated costs for the patient needs further research, as does the best way to manage this disease in preclinical stages, such as it is done with other chronic diseases, for example, diabetes and heart failure.
The work of Yuan and colleagues17 studying the new insights into the interplay between the immune system and the lymphatic vessels will potentially provide the window of understanding and open up the space for novel therapeutic approaches to the management of this disease. The focus of their work on the role of CD4+ T cells and macrophages in the proliferation of lymphatic endothelial cells and aberrant lymphangiogenesis, which contribute to the interstitial fluid accumulation in lymphedema, is not only groundbreaking but also gives hope for a future where we can improve both clinical outcomes and quality of life for patients at risk for cancer-related lymphedema.
The rapid advancements in this field will require the ongoing dissemination of new and possibly disruptive ideas that will likely challenge our previously held beliefs. The understanding that our ability to measure and detect lymphedema may be beyond our physical capabilities as humans is disconcerting. Our sensitivity to measure change is at the level of the tools we use. Volume change, regardless of how it is measured, may only represent the progression of lymphedema. Technological developments, perhaps artificial intelligence, as referenced by the work of Fu and colleagues,5 along with innate human curiosity and precision medicine perhaps in the form of wearable sensors,18 will propel us into the next era of lymphedema management.
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2. Hespe GE, Ly CL, Kataru RP, Mehrara BJ. Baseline lymphatic dysfunction amplifies the negative effects of lymphatic injury. Plast Reconstruct Surg. 2019;143(1):77e–87e.
3. Frieden TR. Evidence for health decision making—beyond randomized, controlled trials. N Engl J Med. 2017;377(5):465–475.
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18. Stout NL. Lymphedema management: the next decades. Rehabil Oncol. 2018;36(1):3–4.