Abstract
Purpose
Mild breast cancer-related lymphedema (BCRL) is clinically diagnosed as a 5%–10% increase in arm volume, typically measured no earlier than 3–6 months after locoregional treatment. Early BCRL treatment is associated with better outcomes, yet amid increasing evidence that lymphedema exists in a latent form, treatment is typically delayed until arm swelling is obvious. In this study, we investigated whether near-infrared fluorescence lymphatic imaging (NIRF-LI) surveillance could characterize early onset of peripheral lymphatic dysfunction as a predictor of BCRL.
Methods
In a prospective, longitudinal cohort/observational study (NCT02949726), subjects with locally advanced breast cancer who received axillary lymph node dissection and regional nodal radiotherapy (RT) were followed serially, between 2016 and 2021, before surgery, 4–8 weeks after surgery, and 6, 12, and 18 months after RT. Arm volume was measured by perometry, and lymphatic (dys) function was assessed by NIRF-LI.
Results
By 18 months after RT, 30 of 42 study subjects (71%) developed mild–moderate BCRL (i.e., ≥ 5% arm swelling relative to baseline), all manifested by “dermal backflow” of lymph into lymphatic capillaries or interstitial spaces. Dermal backflow had an 83% positive predictive value and 86% negative predictive value for BCRL, with a sensitivity of 97%, specificity of 50%, accuracy of 83%, positive likelihood ratio of 1.93, negative likelihood ratio of 0.07, and odds ratio of 29.00. Dermal backflow appeared on average 8.3 months, but up to 23 months, before the onset of mild BCRL.
Conclusion
BCRL can be predicted by dermal backflow, which often appears months before arm swelling, enabling early treatment before the onset of edema and irreversible tissue changes.
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Introduction
Breast cancer-related lymphedema (BCRL) is a chronic, incurable condition experienced by approximately 15%–40% of breast cancer survivors [1]. BCRL has been associated with patient-reported pain, depression, employment disability, and cellulitis with associated hospitalizations, all of which have significant socioeconomic costs and affect millions of breast cancer survivors worldwide [2,3,4,5]. Several factors contribute to the development of BCRL, including metastatic disease in regional lymph nodes (LNs) occluding normal lymphatic flow, as well as surgical and radiotherapy (RT)-induced interruption of lymphatic function in the treatment field [6,7,8]. These treatments cause the release of inflammatory cytokines that can arrest lymphangion pum** action [9, 10], a function that is essential for moving lymph and waste products from peripheral tissues [11, 12]. Without lymphangion activity to move lymph from the capillaries into collectors, regional lymph stasis appears as retention of fluid in interstitial spaces, and perhaps backward seepage from lymphatic collector vessels into lymphatic capillaries, and is commonly referred to as “dermal backflow.” Dermal backflow may be a compensation for lymphedema, or may be a harbinger of irreversible tissue changes, including accumulation of subcutaneous fat, immune cells, and the development of fibrosis [13].
No diagnostic method has been universally accepted for accurate detection of early changes in lymphatic function before the onset of irreversible BCRL tissue changes, yet early diagnosis may lead to the best chance of treatment efficacy [14,15,16,17]. Instead, the objective, albeit non-standardized, diagnostic criterion for cancer-acquired lymphedema is an increase in arm volume, which is typically measured no earlier than 3–6 months after locoregional treatment to avoid the transient swelling attributable to surgery and RT [18]. The most frequently used screening tools used for BCRL are self-reported symptoms, tape measure assessment of arm volume, and bioimpedance spectroscopy [19]. Bioimpedance measurement of increased tissue water content may provide a surrogate appraisal of lymphatic dysfunction in breast cancer survivors, but recent studies suggest that bioimpedance is sensitive only after the appearance of the clinical sign overt swelling, and even then, has a high false negative rate [20,21,22,23], although at least one study has reported positive outcomes when the device was used appropriately [24] There remains no accepted predictive sign or symptom indicating which patients will develop BCRL before it is grossly apparent by significant arm swelling. Moreover, risk reduction strategies including education, self-monitored use of compression sleeves, and exercise have failed to affect the incidence of BCRL [25]. A significant, unmet need thus exists to identify early-onset changes in the lymphatics, preceding irreversible lymphedema, for reliable use in a variety of practice settings to reduce the incidence of lymphedema and its sequelae that impair the quality of life of cancer survivors.
In this study, we longitudinally assessed arm lymphatics in patients with locally advanced breast cancer before surgery, after surgery, and up to 18 months after regional nodal RT, by using near-infrared fluorescence lymphatic imaging (NIRF-LI) to detect the first signs of lymphatic dysfunction. In prior studies, we showed that dermal backflow characterizes primary and secondary lymphedema and is not present in healthy individuals. Previous studies by us and others showed that NIRF-LI surveillance of breast cancer patients detected lymphatic dysfunction before overt arm swelling was noted [26,27,28]. In this study, we hypothesized that dermal backflow is an early harbinger of BCRL, can reliably predict the future onset of objectively diagnosed BCRL, and, in the future, could be used to direct the acute treatment of lymphatic dysfunction before chronic, irreversible tissue changes occur.
Methods
Study subjects and imaging
Signed informed consent was obtained from 60 study subjects (for 300 planned imaging study sessions) in a study conducted between 2016 and 2022 under the approval of the institutional review boards of both The University of Texas Health Science Center at Houston and The University of Texas MD Anderson Cancer Center (under FDA combinational investigational new drug application 106,345 for off-label intradermal administration of indocyanine green [ICG] dye with NIRF-LI [NCT 02949726]). Inclusion/exclusion criteria are listed in the study protocol (Supplementary material/appendix). Of the 60 study subjects consented, 18 were excluded from our analysis–seven passed away before completing the study (breast cancer), seven dropped out, one progressed to breast cancer on both sides, and three missed multiple visits due to SARS-CoV-2. Demographic and other data for the remaining 42 study subjects are shown in Table 1. Subjects with locally advanced breast cancer were longitudinally imaged with NIRF-LI to detect changes in lymphatic anatomy before axillary lymph node dissection (ALND), after ALND but before RT (given 4–8 weeks after surgery), and then at approximately 6 months, 12 months, and 18 months after RT. The imaging procedure consisted of two intradermal injections of 0.1 cm3/25 μg of ICG (Akorn, HUB Pharmaceuticals, or Diagnostic Green, LLC) in each dorsal hand and ventral/volar wrist for a total of eight aseptic injections (200 μg total ICG dose) at the start of each study session. Of note, no infections occurred due to ICG injection. Skin surfaces were illuminated with < 1·9 mW/cm2, 785 nm excitation light, and emitted fluorescence was captured by using a custom, variable focus and field of view (350–1900 cm2) NIRF-LI system described elsewhere [28]. ICG microdose injection and NIRF-LI was completed in 30–45 min to provide real-time images of lymphatic vessels or dermal backflow. Images were analyzed for presence of fluorescence outside of pulsing lymphatic vessels or lymph nodes (dermal backflow) using ImageJ software (ImageJ version 1.2.4, RRID: SCR_003070). For subject sessions that were interrupted due to SARS-2-Covid restrictions, yet perometer readings were available from other, routine checkup visits at the prescribed dates, the presence of dermal backflow was reported as present if detected at both the previous and immediately following study visits (9 of the 210 total study sessions).
Perometry and objective/clinical diagnosis of lymphedema
At each study visit, arm volume was calculated by averaging three measurements per arm, acquired with a horizontal Perometer 400NT (Perosystem) as described previously [29]. The formula used to calculate relative volume change (RVC) of each arm from baseline (before ALND) measurements was RVC = (A2U1)/(U2A1) − 1, where A1 and A2 are arm volumes on the affected (ipsilateral) side at two different time points, and U1 and U2 are arm volumes on the opposite, unaffected (contralateral) side [30]. Objective diagnoses of mild to moderate BCRL were made based on an RVC of ≥ 5% measured at 6 months after RT or thereafter, as compared with the before-ALND baseline [15, 31].
As standard of care at MD Anderson Cancer Center, subjects were informed of strategies for reducing the risk of lymphedema, which included exercise, by their primary oncology team and in most cases, also by physiotherapists. Daily use of compression garments was prescribed after an objective diagnosis of moderate lymphedema (typically RVC ≥ 10%). Subjects could view the NIRF-LI process in real time during the study, and were informed of any abnormalities found. In a few cases, subjects independently sought physiotherapy treatments for BCRL before diagnosis. One study subject received lymphovenous bypass (LVB) at the time of ALND (subject #50), and 3 subjects received both LVB and vascularized lymph node transplant (VLNT) between 6 and 12 months after RT (subject #5) or between 12 and 18 months after RT (subject #s 6 and 12). Study data were collected and managed using REDCap electronic data capture tools hosted at MD Anderson Cancer Center [32, 33].
Statistical analysis
Accuracy, sensitivity, and specificity of NIRF-LI for BCRL were calculated as previously described [34]. Accuracy was calculated as the proportion of true positive results in the population. Sensitivity was calculated as the number of true positives divided by the sum of the numbers of true positives and false negatives. Specificity was calculated as the number of true negatives divided by the sum of the numbers of true negatives and false positives. Positive likelihood ratio was calculated as sensitivity divided by (100-specificity). Negative likelihood ratio was calculated as (100-sensitivity) divided by specificity. Positive predictive value was calculated as the number of true positives divided by the sum of the numbers of true positives and false positives, times 100. Negative predictive value was calculated as the number of true negatives divided by the sum of the numbers of true negatives and false negatives, times 100.
Results
Appearance of dermal backflow during lymphedema development
As an example of longitudinal NIRF-LI imaging, Fig. 1 illustrates the development and subsequent persistence of dermal backflow in study subject number 13. Her RVC values were 4.75% after surgery but before RT, 18.66% at 6 months after RT, 14.93% at 12 months after RT, and 14.50% at 18 months after RT, with extensive dermal backflow appearing at 6 months post-RT. Notably, dermal backflow often appeared months before the development of clinically diagnosable BCRL (RVC values ≥ 5%), as shown in Fig. 2, which provides NIRF-LI images for three separate study subjects (study subject numbers 3, 12, and 16), all displaying dermal backflow at 6 months after RT, even though all had RVC values below 5% at that time. All three subjects ultimately developed arm swelling of ≥ 5% at later study visits.
Near-infrared fluorescence lymphatic imaging (NIRF-LI) images of the left axilla (left to right) before axillary lymph node dissection (ALND), 4 weeks after ALND, 6 months after radiotherapy (RT), 12 months after RT, and 18 months after RT in study subject number 13. Dermal backflow appears as a cloudy dispersion of lymph (seen at 6, 12, and 18 months after RT), as opposed to linear lymphatic collector vessels (seen before and at 4 weeks after ALND). This study subject received physiotherapy for breast cancer-related lymphedema beginning at 6 months after RT. RVC, relative volume change (from baseline)
Longitudinal surveillance of backflow appearance and arm swelling of ≥ 5%
A modified swimmer plot for all 42 study subjects denoting findings at each surveillance visit is shown in Fig. 3. A total of 36 study subjects (83%) presented with dermal backflow, and a total of 30 study subjects (71%) were objectively diagnosed with mild to moderate BCRL (i.e., ≥ 5% RVC) during this study. Dermal backflow was observed in all but one (subject #49) of the 30 BCRL subjects prior to or at the time of diagnosis. Of these 30 with BCRL, 14 were diagnosed 6 months after RT. In five of these 14 subjects, ≥ 5% RVC and dermal backflow were simultaneously first observed at 6 months post-RT. The long (8–10 month) window between post-surgical assessment and the first (6 months) post-RT surveillance session precluded any assessment of dermal backflow appearing before BCRL in these five subjects. Of these 14 subjects diagnosed 6 months after RT, eight had dermal backflow before or immediately after ALND (but before RT). Sixteen subjects were diagnosed with BCRL at 12 or 18 months after RT. All of these 16 subjects presented with backflow before BCRL. Conversely, six of the 36 subjects presenting with dermal backflow had not developed BCRL by the end of the study. Only six of 42 subjects did not present with dermal backflow or manifest BCRL during the course of this study. After excluding study subjects who had missed multiple study visits, including the 18-month follow-up, because of SARS-CoV-2, the mean delay between onset of dermal backflow and objective diagnosis of BCRL (by ≥ 5% RVC) was 8.3 months (range 0–23 months). Of note, blank spots on the plot at 12 and 18 months post-RT do not represent subjects that dropped out, but rather are left blank to allow quick visualization of BCRL onset at or after 6 months post-RT. Table 2 lists the diagnostic statistics for dermal backflow being an indicator, predictor, or both, of BCRL. Notably, backflow by NIRF-LI had an 83% positive predictive value and an 86% negative predictive value for the development of mild BCRL by 18 months after RT. The odds ratio for develo** BCRL by 18 months after RT among subjects found to have dermal backflow by NIRF-LI was 29.00, with a positive likelihood ratio of 1.93, a negative likelihood ratio of 0·07, accuracy of 83%, sensitivity of 97%, and specificity of 50%. Notably, we observed unremarkable distribution of dermal backflow and BCRL by underweight, normal weight, overweight, and obese body mass index (BMI) status (Table 3).
Modified swimmer plot denoting, at each surveillance visit, the absence of lymphatic dysfunction (green figures), appearance of dermal backflow (yellow), and objective diagnoses of breast cancer-related lymphedema (BCRL) from ≥ 5% RVC on the affected-side arm at 6 months after radiotherapy (RT) or later (red figures). Half-yellow/half-red figures represent subjects who displayed after-RT backflow and ≥ 5% swelling at the same visit. Asterisks denote clinical study interruption due to the SARS-CoV-2 pandemic. Blank spots after subjects developed BCRL/ ≥ 5% arm swelling do not represent subjects drop** out of the study—blank spots at 12 and 18 months post-RT allow quick visualization of BCRL onset at or after 6 months post-RT
Discussion
In our study, dermal backflow was detected by NIRF-LI over eight months, on average, before the clinical development of BCRL and had a diagnostic odds ratio of 29 for the development of gross arm volumetric-assessed lymphedema. These results are consistent with lymphatic dysfunction as the initiating cause of lymphedema. The exact time frame between development of clinically measurable edema and irreversible changes that are not responsive to complete decongestive therapy (CDT) or reparative microsurgeries is unknown, but dermal backflow may be an effective and objective measure of lymphatic dysfunction at very early stages of BCRL progression. Significantly, these findings support the importance of early monitoring to implement physiotherapy to reverse dysfunction and restore fluid homeostasis, as suggested by non-imaging studies [14, 35] and shown by imaging in a NIRF-LI study of early head and neck cancer-related lymphedema treated with pneumatic compression therapy, in which dermal backflow disappeared or was reduced with physiotherapy [36].
Our study population was at particularly high risk of develo** BCRL and, indeed, 19 subjects exhibited early-onset changes in the lymphatics, as visualized by NIRF-LI, before surveillance for lymphedema typically begins. Our cohort had aggressive local–regional disease with notable lymphatic metastatic burden, with 19 of 42 study subjects having cN3 disease. Notably, dermal backflow was seen in seven subjects at baseline (before surgery and RT), suggesting that factors other than ALND, such as neoadjuvant chemotherapy or cancer that has metastasized to lymph nodes, can influence BCRL development. Several reports have shown that receipt of doxorubicin and taxanes, both commonly prescribed as neoadjuvant chemotherapy for breast cancer, inhibits normal lymphatic flow [37, 38]. Also noteworthy is that in another eight of the 30 subjects diagnosed with BCRL, dermal backflow was first observed at the after-ALND-but-before-RT visit, which typically took place up to 10 months before surveillance for BCRL began (often scheduled for 3–6 months after the completion of RT), resulting in long lead times between observed lymphatic dysfunction and BCRL diagnosis with prescription of CDT. The early-onset changes visualized on NIRF-LI underscore the chronic duration of dysfunction that is associated with tissue changes that may become irreversible and render BCRL incurable.
Our study had some limitations. First, BCRL usually becomes evident within 18 months, but can manifest as late as decades, after cancer treatment, so some subjects may develop BCRL beyond our study timeline; thus, our false positive rate of 50% may reflect a substantial delay between the onset of dermal backflow and objective diagnosis. Second, our study cohort was too small to assess the effects of BMI on propensity to develop BCRL and BCRL temporal progression. Third, SARS-CoV-2 and its associated restrictions led to cancellation of some study visits, which confounded the accurate determination of backflow onset in some subjects. Fourth, the unique population studied (women with locally advanced breast cancer) was very well versed on risk reduction strategies and were offered therapeutic interventions as deemed clinically appropriate. Any use of prophylactic compression garments by those subjects who observed dermal backflow at imaging could have delayed or prevented the onset of BCRL-associated arm swelling and increased the number of false positives during the short timeframe of the program. As an example, at 6 months post-RT, study subject number 60 exhibited dermal backflow, but ≤ 5% RVC (no BCRL diagnosis). She started physiotherapy for BCRL prevention at that time, and at 12- and 18 months post-RT, although she still exhibited backflow, her RVCs were − 3.52 and 0.44%, respectively, at those visits (no BCRL diagnosis). Our study cohort included patients with particularly advanced nodal involvement, with 68% of patients having clinical N2–N3 disease at diagnosis and 14% with a diagnosis of inflammatory breast cancer. Our cohort’s cancer severity could explain why we observed only two subjects (#4 and #14) ever showing regression/reversal of backflow, compared to a previous study that observed 15/50 patients, with less advanced disease and no radiation treatment, reversing dermal backflow with compression sleeve use [26]. This general persistence of dermal backflow is consistent with our past longitudinal studies of head and neck cancer patients who also underwent lymph node dissection and radiation [39]. The four subjects in our study who underwent prophylactic or reparative microsurgeries did not display prevention or amelioration of BCRL. It is possible that the severity of our cohort’s breast cancers, or potential iatrogenic lymphatic damage from lymphatic microsurgeries, contributed to this result. NIRF-LI is considered an invasive procedure due to the intradermal injection of microdoses of ICG, and lymphedema patients are particularly concerned about possible infection risk. Aseptic injection technique was used in this study, and none of the subjects experienced infection due to ICG injections. Other BCRL surveillance methods, particularly limb measurement and BIS, are commonly used because they are inexpensive and noninvasive, but do not detect dermal backflow. The prospects for lymphedema “cure” will depend upon effective diagnosis at the first sign of lymphatic dysfunction to prevent progression from sub-clinical to symptomatic lymphedema. The impact of early detection on total healthcare costs for BCRL patients deserves more study [40, 41].
Conclusions
Our findings suggest that BCRL can be predicted by using NIRF-LI surveillance for dermal backflow, which may precede the appearance of BCRL by over 8 months. Scheduling NIRF-LI surveillance at 3 months after RT could provide an earlier opportunity to predict BCRL prior to swelling. Starting complete decongestive therapy or restorative microsurgical treatment at the time of dermal backflow detection, before the development of mild BCRL and any irreversible tissue changes, may provide a unique opportunity to improve patient outcomes [42].
Data availability
Individual participant data that underlie the results reported in the article, after de-identification (text, tables, figures, and appendix), will be made available in case of reasonable request with investigators whose proposed use of the data has been approved by the authors.
References
Shaitelman SF, Cromwell KD, Rasmussen JC, Stout NL, Armer JM, Lasinski BB, Cormier JN (2015) Recent progress in the treatment and prevention of cancer-related lymphedema. CA Cancer J Clin 65:55–81
De Vrieze T, Nevelsteen I, Thomis S, De Groef A, Tjalma WAA, Gebruers N, Devoogdt N (2020) What are the economic burden and costs associated with the treatment of breast cancer-related lymphoedema? a systematic review. Support Care Cancer 28:439–449. https://doi.org/10.1007/s00520-019-05101-8
Basta MN, Fox JP, Kanchwala SK, Wu LC, Serletti JM, Kovach SJ, Fosnot J, Fischer JP (2016) Complicated breast cancer-related lymphedema: evaluating health care resource utilization and associated costs of management. Am J Surg 211:133–141. https://doi.org/10.1016/j.amjsurg.2015.06.015
Roberson ML, Strassle PD, Fasehun LKO, Erim DO, Deune EG, Ogunleye AA (2021) Financial burden of lymphedema hospitalizations in the United States. JAMA Oncol 7:630–632
Sun H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249
Rasmussen JC, Kwon S, Sevick-Muraca EM, Cormier JN (2012) The role of lymphatics in cancer as assessed by near-infrared fluorescence imaging. Ann Biomed Eng 40:408–421. https://doi.org/10.1007/s10439-011-0476-1
Padera TP, Meijer EFJ, Munn LL (2016) The lymphatic system in disease processes and cancer progression. Annu Rev Biomed Eng 18:125–158. https://doi.org/10.1146/annurev-bioeng-112315-031200
Swartz MA (2014) Immunomodulatory roles of lymphatic vessels in cancer progression. Cancer Immunol Res 2:701–707. https://doi.org/10.1158/2326-6066.cir-14-0115
Hernandez C, Huebener P, Schwabe RF (2016) Damage-associated molecular patterns in cancer: a double-edged sword. Oncogene 35:931–941. https://doi.org/10.1038/onc.2016.104
Ashrafizadeh M, Farhood B, Musa AE, Taeb S, Najafi M (2020) Damage-associated molecular patterns in tumor radiotherapy. Int Immunopharmacol 86:106761. https://doi.org/10.1016/j.intimp.2020.106761
Aldrich MB, Sevick-Muraca EM (2013) Cytokines are systemic effectors of lymphatic function in inflammation. Cytokine 64:362–369. https://doi.org/10.1016/j.cyto.2013.05.015
Chen Y, Rehal S, Roizes S, Zhu HL, Cole WC, von der Weid P (2017) The pro-inflammatory cytokine TNF-alpha inhibits lymphatic pum** via activation of the NFkB-iNOS signaling pathway. Microcirculation. https://doi.org/10.1111/micc.12364
Oliver G, Kipnis J, Randolph GJ, Harvey NL (2020) The lymphatic vasculature in the 21st century: novel functional roles in homeostasis and disease. Cell 182:270–296. https://doi.org/10.1016/j.cell.2020.06.039
Rafn BS, Christensen J, Larsen A, Bloomquist K (2022) Prospective surveillance for breast cancer-related arm lymphedema: a systematic review and meta-analysis. J Clin Oncol. https://doi.org/10.1200/jco.21.01681
Stout Gergich NL, Pfalzer LA, McGarvey C, Springer B, Gerber LH, Soballe P (2008) Preoperative assessment enables the early diagnosis and successful treatment of lymphedema. Cancer 112:2809–2819. https://doi.org/10.1002/cncr.23494
Bucci LK, Brunelle CL, Bernstein MC, Shui AM, Gillespie TC, Roberts SA, Naoum GE, Taghian AG (2021) Subclinical lymphedema after treatment for breast cancer: risk of progression and considerations for early intervention. Ann Surg Oncol 28:8624–8633. https://doi.org/10.1245/s10434-021-10173-0
Kassamani YW, Brunelle CL, Gillespie TC, Bernstein MC, Bucci LK, Nassif T, Taghian AG (2022) Diagnostic criteria for breast cancer-related lymphedema of the upper extremity: the need for universal agreement. Ann Surg Oncol 29:989–1002. https://doi.org/10.1245/s10434-021-10645-3
Barrio AV, Eaton A, Frazier TG (2015) A prospective validation study of bioimpedance with volume displacement in early-stage breast cancer patients at risk for lymphedema. Ann Surg Oncol 22(Suppl 3):S370–S375. https://doi.org/10.1245/s10434-015-46830
DeSnyder SM, Yi M, Boccardo F, Feldman S, Klimberg VS, Smith M, Thiruchelvam PTR, McLaughlin S (2021) American Society of Breast Surgeons’ practice patterns for patients at risk and affected by breast cancer-related lymphedema. Ann Surg Oncol 28:5742–5751. https://doi.org/10.1245/s10434
Bundred N, Foden P, Todd C, Morris J, Watterson D, Purushotham A, Bramley M, Riches K, Hodgkiss T, Evans A, Skene A, Keeley V, Investigators of BEA, PLACE studies, (2020) Increases in arm volume predict lymphoedema and quality of life deficits after axillary surgery: a prospective cohort study. Br J Cancer 123:17–25. https://doi.org/10.1038/s41416-020-0844-4
Spitz JA, Chao AH, Peterson DM, Subramaniam V, Prakash S, Skoracki RJ (2019) Bioimpedance spectroscopy is not associated with a clinical diagnosis of breast cancer-related lymphedema. Lymphology 52:134–142
Wiser I, Mehrara BJ, Coriddi M, Kenworthy E, Cavalli M, Encarnacion E, Dayan JH (2020) Preoperative assessment of upper extremity secondary lymphedema. Cancers 12:135. https://doi.org/10.3390/cancers12010135
Qin ES, Bowen MJ, Chen WF (2018) Diagnostic accuracy of bioimpedance spectroscopy in patients with lymphedema: a retrospective cohort analysis. J Plast Reconstr Aesthet Surg 71:1041–1050. https://doi.org/10.1016/j.bjps.2018.02.012
Ridner Sh, Shah C, Boyages J, Koelmeyer L, Ajkay N, DeSnyder SM, McLaughlin SA, Dietrich MS (2020) L-Dex, arm volume, and symptom trajectories 24 months after breast cancer surgery. Cancer Med 9:5164–5173. https://doi.org/10.1002/cam4.3188
Paskett ED, Le-Rademacher J, Oliveri JM et al (2021) A randomized study to prevent lymphedema in women treated for breast cancer: CALGB 70305 (Alliance). Cancer 127:291–299. https://doi.org/10.1002/cncr.33183
Akita S, Nakamura R, Yamamoto N, Tokumoto H, Ishigaki T, Yamaji Y, Sasahara Y, Kubota Y, Mitsukawa N, Satoh K (2016) Early detection of lymphatic disorder and treatment for lymphedema following breast cancer. Breast 138:19e–202e. https://doi.org/10.1097/PRS.0000000000002337
Yamamoto T, Yamamoto N, Doi K, Oshima A, Yoshimatsu H, Todokoro T, Ogata F, Mihara M, Narushima M, Iida T, Koshima I (2011) Indocyanine green-enhanced lymphography for upper extremity lymphedema: a novel severity staging system using dermal backflow patterns. Plast Reconstr Surg 128:941–947. https://doi.org/10.1097/PRS.0b013e312268cd9
Rasmussen JC, Tan I-C, Marshall MV, Adams KE, Kwon S, Fife CE, Maus EA, Smith LA, Covington KR, Sevick-Muraca EM (2010) Human lymphatic architecture and dynamic transport imaged using near-infrared fluorescence. Transl Oncol 3:362–372. https://doi.org/10.1593/lo.10190
DeSnyder SM, Kheirkhah P, Travis ML, Lilly SE, Bedrosian I, Buchholz TA, Schaverien MV, Shaitelman SF (2019) Optimizing patient positioning to reduce variation in the measurement of breast cancer-related lymphedema. Lymphat Res Biol 17:440–446. https://doi.org/10.1089/lrb.2018.0018
Ancukiewicz M, Russell TA, Otoole J et al (2011) Standardized method for quantification of develo** lymphedema in patients treated for breast cancer. Int J Radiat Oncol Biol Phys 79:1436–1443. https://doi.org/10.1016/j.ijrobp.2010.01.001
Bundred NJ, Stockton C, Keeley V, Riches K, Ashcroft L, Evans A, Skene A, Purushotham A, Bramley M, Hodgkiss T, Investigators of BEA/PLACE (2015) Comparison of multi-frequency bioimpedance with perometry for the early detection of lymphoedema after axillary node clarance for breast cancer. Breast Cancer Res Treat 151:121–129. https://doi.org/10.1007/s10549-015-3357-8
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG (2009) Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 42:377–381. https://doi.org/10.1016/j.jbi.2008.08010
Harris PA, Taylor R, Minor BL et al (2019) The REDCap consortium: building an international community of software partners. J Biomed Inform 95:103208. https://doi.org/10.1016/j.jbi.2019.103208
Baratloo A, Hosseini M, Negida A, El Ashal G (2015) Part 1: simple definition and calculation of accuracy, sensitivity and specificity. Emerg (Tehran) 3:48–49
Can AG, Ekşioğlu E, Çakçi FA (2019) Early detection and treatment of subclinical lymphedema in patients with breast cancer. Lymph Res Biol 17:68–73. https://doi.org/10.1089/lrb.2018.0033
Gutierrez C, Karni RJ, Naqvi S, Aldrich MB, Zhu B, Morrow JR, Sevick-Muraca EM, Rasmussen JC (2019) Head and neck lymphedema: treatment response to single and multiple sessions of advanced pneumatic compression therapy. Otolaryngol Head Neck Surg 160:622–626. https://doi.org/10.1177/0194599818823180
Johnson AR, Granoff MD, Lee BT, Padera TP, Bouta EM, Singhal D (2019) The impact of taxane-based chemotherapy on the lymphatic system. Ann Plast Surg 82(4S Suppl 3):S173–S178. https://doi.org/10.1097/sap.0000000000001884
Stolarz AJ, Sarimollaoglu M, Marecki JC, Fletcher TW, Galanzha EI, Rhee SW, Zharov VP, Klimberg VS, Rusch NJ (2019) Doxorubicin activates ryanodine receptors in rat lymphatic muscle cells to attenuate thymic contractions and lymph flow. J Pharmacol Exp Ther 371:278–289. https://doi.org/10.1124/jpet.119.257592
Rasmussen JC, Tan IC, Naqvi S, Aldrich MB, Maus EA, Blanco AI, Karni RJ, Sevick-Muraca EM (2017) Longitudinal monitoring of the head and neck lymphatics in response to surgery and radiation. Head Neck 39:1177–1188. https://doi.org/10.1002/hed.24750
Stout NL, Pfalzer LA, Springer b, Levy E, McGarvey CL, Danoff JV, Gerber LH, Soballe PW (2012) Breast cancer-related lymphedema: comparing direct costs of a prospective surveillance model and a traditional model of care. Phys Ther 92:152–163. https://doi.org/10.2522/ptj.20100167
Dean LT, Ransome Y, Frasso-Jaramillo L, Moss SL, Zhang Y, Ashing K, Denis GV, Frick KD, Visvanathan K, Schmitz KH (2019) Drivers of cost differences between US breast cancer survivors with or without lymphedema. J Cancer Surviv 13:804–814. https://doi.org/10.1007/s11764-019-00799-1
Mihara M, Hara H, Furniss D, Narushima M, Iida T, Kikuchi K, Ohtsu H, Gennaro P, Gabriele G, Murai N (2014) Lymphaticovenular anastomosis to prevent cellulitis associated with lymphedema. Brit J Surg 101:1391–1396. https://doi.org/10.1002/bjs.9588
Acknowledgements
This study was funded by National Institutes of Health/National Cancer Institute grant 5R01CA201487 (MBA and SFS) and NIH P30CA016672 (MD Anderson Cancer Center core grant). The authors wish to thank Alma Faust, PhD, for her input in framing the scientific need for the study proposed (funded by the Radiation Oncology Department at MD Anderson Cancer Center at the time of input), Christine F. Wogan for her editing work (funded by the Radiation Oncology Department at MD Anderson Cancer Center), and Matricia Morrison, RN, for her assistance in running the clinical study.
Funding
This study was funded by National Institutes of Health/National Cancer Institute Grant Nos. 5R01CA201487 (MBA and SFS) and NIH P30CA016672 (MD Anderson Cancer Center core grant).
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MBA: conceptualization, funding acquisition, data verification, analysis and interpretation, statistical analysis, manuscript drafting, writing review and editing, approval of final submitted version. SFS: conceptualization, funding acquisition, data analysis and interpretation, identification and recruitment/enrollment of study subjects, writing review and editing, approval of final submitted version. JCR: conceptualization, data verification, analysis and interpretation, statistical analysis, writing review and editing, approval of final submitted version. EAM: conceptualization, writing review and editing, approval of final submitted version. EMS-M: conceptualization, data analysis and interpretation, statistical analysis, writing review and editing, approval of final submitted version. WC: conceptualization, data analysis and interpretation, statistical analysis, writing review and editing, approval of final submitted version. LEI: identification, recruitment, and enrollment of study subjects, writing review and editing, approval of final submitted version. SMD, WAW, BDS, MCS, EAS, GHP, KEH, MPM, and CHB: identification of study subjects, writing review and editing, approval of final submitted version. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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Conflict of interest
EMS-M and JCR are listed as inventors on patents related to the near-infrared fluorescence lymphatic imaging used in this study, and may receive future financial benefit from its commercialization. EMS-M, JCR, and The University of Texas Health Science Center at Houston (UTHealth) have research-related financial interests in Lymphatic Science, Inc. SFS has grant funding from the Emerson Collective Foundation and research contract support from Artios Pharmaceuticals, Alpha Tau, and Exact Sciences. The remaining authors have no financial relationships or competing interests relevant to this article to disclose.
Ethical approval
The study was conducted in line with the principles of the 1964 Declaration of Helsinki and later amendments, with offlabel use of indocyanine green under FDA Investigational New Drug (IND) application 106,345. Approval was granted by the Institutional Review Boards/Committees for the Protection of Human Subjects at both UTHealth and MD Anderson Cancer Center. The study was conducted under the approval of the institutional review boards of both The University of Texas health Science Center at Houston and The University of Texas MD Anderson Cancer Center (under FDA combinational investigational new drug application 106,345 for off-label intradermal administration of indocyanine green (ICG) dye with NIRF-LI [NCT 02949726]).
Informed consent
Written informed consent was obtained from all individual participants in the study, including consent for publication of de-identified images. Signed informed consent for participation and publication of results was obtained from all study subjects.
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Aldrich, M.B., Rasmussen, J.C., DeSnyder, S.M. et al. Prediction of breast cancer-related lymphedema by dermal backflow detected with near-infrared fluorescence lymphatic imaging. Breast Cancer Res Treat 195, 33–41 (2022). https://doi.org/10.1007/s10549-022-06667-4
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DOI: https://doi.org/10.1007/s10549-022-06667-4