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The grading of lymphedema in oncology clinical trials
The Grading of Lymphedema in Oncology Clinical Trials Andrea L. Cheville, Charles L. McGarvey, Jeanne A. Petrek, Sandra A. Russo, Saskia R.J. Thiadens, and Marie E. Taylor Lymphedema is a common late toxicity of cancer therapy. This article describes the rationale and process utilized by the Lymphedema Working Group for the revision and expansion of the Common Toxicity Criteria version 2 (CTC v2.0) lymphedema criteria to produce the CTC v3.0 lymphedema criteria. Established clinician-based rating scales and quantitative instruments are reviewed in this article. None of the extant rating scales have been formally validated, nor has their reliability been assessed. Drawbacks of current scales were considered in formulating CTC v3.0 criteria. Most rely exclusively on volume to diagnose and grade lymphedema. This imposes significant clinical limitations, particularly in the assessment of toxicity in oncology clinical trials. Volume-based rating scales are of little value in rating the severity of bilateral limb and nonlimb edema. Problems with nonvolumetric staging systems (eg, CTC v2.0) include insufficient detail to permit useful discrimination of severity among the majority of lymphedema patients. Technologies for objec-
tively quantifying lymphedema have been developed and validated. Although these are briefly reviewed, it is recognized that cost and access issues limit their widespread clinical utility and, as such, were not considered in developing the CTC v3.0 criteria. The CTC v3.0 lymphedema criteria adopted several innovations. Principle among these was the decision to generate separate criteria for volumetric increase, dermal changes, and subcutaneous fibrosis. We anticipate the use of the new CTC v3.0 lymphedema criteria to begin in mid-2003 for grading the key clinical features of this disorder in oncology clinical trials. The purpose of this article is to familiarize the reader with (1) background on the clinical features of lymphedema, (2) information on established lymphedema rating systems, (3) the consensus process and rationale of the Lymphedema Working Group, (4) the new CTC v3.0, and (5) quantitative techniques for assessment of lymphedema. © 2003 Elsevier Inc. All rights reserved.
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multiple lymphatic structures leading to truncal lymph stasis. Lymphedema may be described as primary or secondary based on its presumed etiology. Primary lymphedema describes cases for which no source of lymphatic compromise can be identified. Secondary lymphedema is the most common cause of lymphedema both in the United States and worldwide. It arises from lymphatic obstruction, obliteration, or functional insufficiency because of a pathological process exogenous to the lymphatic system. Such processes are commonly iatrogenic (eg, surgery or radiation therapy). Infection, traumatic injury, cancerous invasion or compression, and inflammation are frequent noniatrogenic causes of secondary lymphedema. Cancer patients are subject to a variety of clinical factors that can induce lymphedema. Lymphatic injury may occur through surgical disruption of lymph nodes or vessels. External-beam radiation therapy extrinsically damages the lymphatic system leading to fibrosis and compromise of lymph transport.2,3 Any patient who has undergone lymphadenectomy or received radiation to lymph nodes or vessels is at risk for the eventual development of lymphedema. This risk may be compounded by comorbid conditions including
ymphedema is defined as an abnormal accumulation of protein-rich fluid in a body part secondary to insufficiency of the lymphatic system. Lymphatic compromise occurs when the lymphatic system is unable to adequately sequester and/or transport lymph.1 This may arise from an iatrogenic or infectious injury to the system or to congenital hypoplasia or aplasia of the lymphatic structures. Generally limbs are affected, although viscera and axial structures may be subject to lymphedema as well. This is particularly true of cancer patients who often sustain injury to
From the Department of Rehabilitation Medicine, University of Pennsylvania Health System, Philadelphia, PA; Rehabilitation Medicine Department, Warren Magnuson Clinical Center, National Institutes of Health, Bethesda, MD; Evelyn H. Lauder Breast Center, Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Radiation Oncology, Columbia Presbyterian Medical Center, New York, NY; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO; and National Lymphedema Network, Oakland, CA. Address reprint requests to Andrea L. Cheville, MD, Department of Rehabilitation Medicine, University of Pennsylvania Health System, 5 West Gates, 3400 Spruce Street, Philadelphia, PA 19104. © 2003 Elsevier Inc. All rights reserved. 1053-4296/03/1303-0006$30.00/0 doi:10.1016/S1053-4296(03)00038-9
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Seminars in Radiation Oncology, Vol 13, No 3 ( July), 2003: pp 214-225
The Grading of Lymphedema
venous or arterial insuffiency, diabetes, neurogenic motor deficits, and hypoproteinemia, which are commonly seen in oncology populations. Lymphedema may manifest in any area of the body. The extremities are most commonly affected. This is explained by the limited opportunity for development of collateral lymphatic drainage. Limb edema may extend to involve the associated truncal quadrant (eg, anterior and posterior aspects of the ipsilateral lower truncal quadrant and external genitalia in cases of lowerextremity lymphedema). Although the extremities are most commonly involves the extremities, lymphedema may also develop in the craniocervical region, abdomen, breast, trunk, and genitals. The distribution of all secondary lymphedema is determined by the nature and location of the lymphatic disruption, as well as by the resilience of patients’ baseline lymphatic function. When the lymphatic system fails to transport the lymph produced by a body part, congestion results. The solid and fluid constituents of lymph accumulate in the interstitial space. Increased density of solid debris (eg, large proteins, long chain fatty acids, nonfunctional erythrocytes, and leukocytes) leads to the recruitment of neutrophils, macrophages, and fibroblasts. The resultant chronic, low-grade inflammation triggers the deposition of disorganized collagen fibers. Fibrosis may engulf any residual functioning lymph collectors, further aggravating lymph stasis. As histopathologic tissue changes progress, metaplasia may develop in the overlying skin. Dermal keratinification and papillomas are the stigmata of advanced lymphedema or lymphostatic elephantiasis. Their presence indicates that significant subcutaneous fibrosis has occurred. With soft-tissue changes, bacterial and fungal infections may become increasingly frequent. Cellulitic infections further injure superficial lymphatics and hasten hyperkeratotic changes. The presence and degree of subdermal fibrosis and dermal metaplasia are important reflections of lymphedema severity. The adverse functional consequences of lymphedema have not been adequately characterized in either a qualitative or quantitative fashion. In cancer patients, lymphedema is often associated with other function-compromising toxicities such as fibrosis, skin breakdown, pain, neuropathy, arthropathy, and myopathy. It therefore becomes challenging to ascribe particular deficits
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exclusively to lymphedema. Light is shed on this problem by the functional impairments noted in primary lymphedema patients. The vast majority of these patients have lower-extremity lymphedema. When advanced, impaired mobility and capacity for self-care are common.4 Negotiating the weight and bulk of a lymphedematous limb can lead patients to adopt dysfunctional biomechanical patterns. These often increase energy expenditure and lead to abnormal joint forces, which may accelerate degeneration. Significant psychosocial morbidity has been associated with breast cancer–related lymphedema.5-7 Breast cancer patients with lymphedema are more likely to experience vocational, familial, and sexual dysfunction.5,6 A recent study reported that 11% of a large cohort of lymphedema patients (the majority related to cancer treatment) were receiving disability compensation.8
Clinician- and Patient-Rated Measures of Lymphedema Measures of pathological conditions generally detect or quantify deviation from a “norm.” The absence of a universally accepted “norm” has been an impediment to the development of lymphedema metrics. In the case of cancer-related lymphedema, the “norm” that defines pathology is either an uninvolved contralateral extremity or the patient’s hypothetical baseline. Baseline interlimb volume discrepancy because of arm dominance, neurogenic atrophy, or differential muscle hypertrophy is a problem inherent in the first approach. Assessment of bilateral limb or truncal lymphedema must rely on the second approach, each patient’s hypothetical baseline. This is a generated from patient recollection and clinician interpretation. Problems arise in the absence of premorbid photographs or measurements because of the highly subjective nature of this “norm.” Additionally, many factors can influence soft-tissue volume and texture (eg, weight gain and muscle hypertrophy) other than lymphedema. A variety of subjective and objective parameters have been used to grade the severity of lymphedema. These are listed in Table 1. Subjectively, many patients describe sensations of heaviness, tightness, and aching in their affected limbs. The specificity of these sensations to lymphedema has not been determined, nor has
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Table 1. Subjective and Objective Parameters Used to Rate Lymphedema
Parameter Subjective Sensations Objective Volume
Limb circumference Deviation from “normal” appearance Tissue texture Tissue reponse to pressure Tissue response to gravity Presence of Dermal change
Measurement Strategy/Descriptor
Level of Measurement
Used in Clinical Trials/Scales (Reference)
Heavy, numb, tingly, achey
Categorical
Water displacement Calculation from serial circumferential measurements Optoelectrial volumetry Clinician rated scale None-mildmoderate-severe Patient rated scale None-mildmoderate-severe Loss of limb contour, Obscuration of anatomic architecture Spongy, fatty, fibrotic Pitting 1⫹ to 3⫹ Resolution with elevation, Exacerbation with dependency Presence of keratinification/ papillomas
Used in Staging Systems
Formally Validated
Utility in Nonlimb Lymphedema
Yes9,10
No
No
Yes
Interval Interval
Yes15 Yes10
No No
Yes Yes
No No
Interval
Yes18
No
Yes
No
Ordinal
Yes19
Yes
No
Yes
Ordinal
Yes9
No
No
Yes
Interval Ordinal
Yes20-26,28,29,30 No
Yes No
No No
No Yes
Categorical Ordinal
No No
No No
No No
Yes Yes
Categorical
Yes27
Yes
Yes
Yes
Categorical
Yes27
Yes
Yes
Yes
their prognostic significance. Nonetheless, they have been the basis of lymphedema detection in several epidemiological studies.9,10 Objective measures are based predominantly on changes in volume and tissue texture/appearance. Volume increase can be precisely quantified through water displacement, serial circumferential measurements, and optoelectric volumetry.11-14 Each of these methods has been widely used in both epidemiological incidence studies and clinical trials of lymphedema.10,15-18 They are not practical for routine clinical use because of time, training, and equipment requirements. These problems can be obviated through the use of a patient- or clinician-rated ordinal scale using none, mild, moderate, or severe classifications.9,19 This approach to rating has not been validated, nor has its reliability been
established. Interlimb circumferential discrepancy has been the most widely used outcome measure and has been incorporated into many formal rating scales.20-26 Measurement taken by patients or clinicians at sites defined by bony landmarks (eg, ulnar styloid and olecranon) are taken to accurately reflect limb volume. This assumption has not been validated, nor has a structured approach (designated measurement sites and degree of tension on the tape measure) to circumferential measurement been formulated. However, because circumferential measurements can be obtained by anyone without special training or equipment, they remain the most common approach to lymphedema measurement. Qualitative descriptors are widely used clinically to characterize soft-tissue changes associated with lymphedema. To date, no formal tax-
The Grading of Lymphedema
Table 2. American Physical Therapy Association Lymphedema Criteria28 Lymphedema Grade
Interlimb Circumference Discrepancy ⬍3 cm 3-5 cm ⬎5 cm
Mild Moderate Severe
onomy has been developed to allow consistent use of descriptors in research or clinical discourse. Many soft-tissue characteristics can be described and some have been incorporated into lymphedema rating scales.27 Alternations in “normal” soft-tissue appearance can be qualitatively detailed including loss of contour and obscuration of anatomic architecture (eg, veins, tendons, and bony landmarks). Soft-tissue texture and its response to pressure or gravity are frequently described because these characteristics presumably reflect the extent to which subdermal fibrosis has occurred.27 The presence of dermal change, generally characterized categorically as present or absent, is an additional clinically relevant softtissue finding. Although ubiquitous in clinical lymphedema practice, the qualitative description of soft tissue has not been used by the oncological community in detecting or rating cancer-related lymphedema. The majority of extant lymphedema rating scales reflect the oncological community’s prevailing and past focus on breast cancer–related lymphedema. Approaches to rating lymphedema have been driven by the anatomy of the involved body part (eg, upper extremity). The availability of an uninvolved arm has led to reliance on comparison interlimb volume or circumference. For compelling reasons of convenience, circumferential comparisons have been the basis of most lymphedema rating scales. Three of the 4 extant rating scales are predominantly volume based. These are as follows:
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1. American Physical Therapy Association (APTA)28: the APTA’s lymphedema rating system is a 3-point scale based exclusively on discrepancy in limb circumference (Table 2). Lymphedema is graded mild, moderate, or severe contingent on the amount of interlimb circumferential discrepancy. No specifications are provided regarding where measurements should be obtained. The scale has been used predominantly as a means of anticipating the number of physical therapy visits that will be required to achieve anticipated goals within an episode of care. The reliability and validity of this scale have not been assessed. 2. The Late Effects of Normal Tissues (LENT)/ SOMA: the LENT/SOMA measure, when LENT denotes late effects of normal tissues, includes 3 lymphedema-related items (Table 3).29,30 The LENT/SOMA measure subdivides items into subjective, objective, management, and analytic components (SOMA). There are no subjective LENT/SOMA items related to lymphedema. The objective, management, and analytic components are rated on a 4-point scale ranging from present to severe dysfunction. The objective and analytical items are based on measurement of arm circumference at an unspecified site. A problem inherent in management-based lymphedema rating is the lack of practice standardization in lymphedema treatment. The LENT/SOMA lymphedema items have not been validated, nor has their reliability been assessed. 3. CTC v2.0: the CTC v2.0 lymphedema criteria19 (Table 4) are based on a 4-point system ranging from normal to severe lymphedema limiting function with ulceration. The rater is provided with no volumetric or circumferential criteria to distinguish between grades of lymphedema. Management requirements (eg, requiring surgery and compression) and the presence of functional impairment are used to
Table 3. LENT/SOMA Lymphedema-Related Items29,30 Objective
Arm Circumference
Management
Analytic
Tape measure
Grade 1 2 cm-4 cm
Grade 2 ⬎4 cm-6 cm
Grade 3 ⬎6 cm
Grade 4 Useless Arm
Elevate arm, elastic stocking
Compression wrapping, intensive physiotherapy
Surgical intervention/ amputation
Assessment of forearm diameter
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Table 4. CTCv2.0 Lymphedema Grades and Criteria19 Grade
0
1
2
3
4
Criteria Normal Mild lymphedema Moderate lymphedema Severe lymphedema Severe lymphedema requiring limiting function, limiting function compression; lymphocyst requiring with ulceration lymphocyst surgery
discriminate between grades 3 and 4. A desirable aspect of the CTC v2.0 stems from the lack of specific volumetric criteria. This allows this system to be used in grading nonlimb edema and bilateral edema. The validity and reliability of this system have not been formally assessed. The APTA, LENT/SOMA, and CTC v2.0 lymphedema rating systems have not been widely used in lymphedema-specific research. Many epidemiological studies have been conducted to determine the incidence of breast cancer–related lymphedema. Most have used independently developed, nonvalidated diagnostic, and rating criteria. The majority is volume based, but several use symptom- and management-based criteria. Table 5 lists 11 reports, all of which used different measurement techniques and diagnostic criteria.9,10,15,20-26,31 The problems inherent in using nonstandardized measurement techniques are illustrated in the wide variance in reported incidences of breast cancer–related lymphedema (11%-56%). The variance persists when samples are substratified by type of primary breast cancer treatment. The marked inconsistency between studies can be explained in part through discrepancies in the number and location of circumferential measurements, the amount of tension on the tape measure, the duration and frequency of patient follow-up, and the criteria for diagnosing lymphedema. An unfortunate consequence of volume- or circumference-based lymphedema grading systems is the inability to use these systems in the assessment of nonlimb edema or bilateral limb edema. This has given rise to an almost complete lack of information on lymphedema incidence after the treatment of nonbreast malignancies, particularly those associated with axial lymphedema (eg, bladder, prostate, ovarian, cervical, endometrial, and colon cancers). Despite inherent limitations in this approach, the validity of circumference- and volume-based measurement is attested by the correlation between treatment intensity and lymphedema risk.
Reported incidences vary, yet more aggressive axillary perturbation (eg, greater numbers of resected lymph nodes, higher dose, and more extensive irradiation volume) has been consistently shown to increase the probability that lymphedema will develop and become severe. For example, Goltner et al18 reported a 25% incidence of lymphedema in breast cancer patients treated with lumpectomy and lymph node dissection, versus a 42% incidence in patients treated with modified radical mastectomy and radiation to axilla and chest wall. These data suggest that volume assessment may be a clinically valid approach reflecting the severity of change, but that lack of standardized assessment procedures undermines the reliability and accuracy of volume-based grading systems. Most epidemiological studies have relied exclusively on interlimb volumetric discrepancy; however, several investigators, recognizing the relevance of other clinical variables, have devised grading systems that use symptom self-report, functional limitations, and/or management criteria to define lymphedema grades. These multidimensional assessment systems differ in the incorporated variables, but all acknowledge the relevance of clinical criteria other than volume. Schrenk et al9 devised the following scale: none ⫽ no arm swelling, tightness, or heaviness; mild ⫽ periods of arm swelling but no constant increase in greatest diameter and clothes fit the same; moderate ⫽ constant arm swelling and heaviness, clothes do not fit the same, physical discomfort but no decrease in functional activity; and severe ⫽ constant arm heaviness, disability, decreased functional activity, huge arm swelling. Liljegren and Holmberg10 similarly emphasized symptom self-report in the diagnosis of lymphedema. He surveyed patients as to the presence of pain, numbness, impaired shoulder mobility, and weakness. Senofsky et al31 used management-based grades in devising the following system: grade 1 ⫽ minimal to mild edema, requiring no intervention or only elevation on 1 or 2 pillows
The Grading of Lymphedema
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Table 5. Epidemiological Trials of Lymphedema Incidence After Primary Breast Cancer Treatment Author, Year Petrek, 2001
20
Schrenk, 20009
Lijegren, 199710 Kiel, 199625
Keramopoulos, 199324
Gerber, 199221
Segerstrom, 199115 Werner, 199123
Lin, 199322
Paci, 199626
Senofsky, 199131
Lymphedema Measurement Method Self-reported arm circumference Measured 2 in and 6 in above, and 4 in below the olecranon
Lymphedema Definition
Inter-limb descrepancy “Mild” lymphedema ⬍ 0.5 in ⫹ self report of “enlargement” or “heaviness” “Moderate” lymphedema 0.5-2.0 in “Severe” ⬎2.0 in Self-reported arm symptoms Subjective self-report of arm and grading of edema as swelling as none, mild, “none, mild, moderate, or moderate, severe severe” Volume calculated from ⬎100 mL inter-limb volume serial circumferencial discrepancy measurements Arm circumference ⬎1 cm change compared to Measured 15 cm above previous measurements and 10 cm below olecranon Arm circumference ⬎2 cm inter-limb Measured 15 cm above discrepancy and 10 cm below lateral epicondyle Arm circumference ⬎2cm inter-limb discrepancy Measured at ulnar styloid, olecranon, and 35 cm proximal to ulnar syloid Volume by water ⬎150 mL inter-limb volume displacement discrepancy Arm circumference ⬎2.5 cm inter-limb Measured 13 cm above discrepancy and 10 cm below olecranon Arm circumference ⬎2.0 cm inter-limb Measured 10 cm above discrepancy and 10 cm below olecranon Arm circumference Inter-limb discrepancy Measured at 6 points “light” edema ⬎4 cm “moderate” edema 4-8 cm “heavy” edema ⬎8 cm Grade I-IV, ordinal scale ⬎ “minimal to mild” based on management lymphedema requirements
at night, grade 2 ⫽ required an external compression stocking for satisfactory control, grade 3 ⫽ required use of lymphedema pump and stocking for control, grade 4 ⫽ poorly controlled lymphedema or edema complicated by lymphangitis. These multidimensional rating scales have not been validated, nor have they been used in studies other than those of the investigators that generated them.
Reported Incidence “Mild” 19% “Moderate” 17% “Severe” 13%
SLN 0% Axillary dissection: “Mild” edema 40% “Moderate” edema 14% 11.20% 35%
17%
56%
43% 19.50%
24%
46.70%
9.40%
Criteria used by physicians and physical/occupational therapists with specialized training in lymphedema management differ from those used to detect breast cancer–related lymphedema. This reflects a significant shift in clinical focus. Lymphedema specialists are concerned with factors (eg, fibrosis and dermal metaplasia) other than volume, having long recognized that volume is a poor indicator of lymphedema severity, prog-
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nosis, or treatment responsiveness. In addition, specialists frequently manage lymphedema involving axial structures such as the craniocervical region, trunk, and genitalia, as well as bilateral limb edema. In axial lymphedema volumetric measurement is not feasible, whereas for bilateral edema, volume can be used as a means of measuring treatment response but is of little utility in diagnosing lymphedema. The extent of subdermal fibrosis and dermal metaplasia are the primary variables used in conventional lymphedema staging.27 This emphasis is based on current understanding of the pathophysiology, histopathology, and national history of lymphedema outlined previously in this article. Casley-Smith27 proposed a 3-part lymphedema staging system based on the affected region’s response to gravity and whether dermal change has occurred (Table 6). This has been widely adopted by lymphedema specialists. Stage 1 lymphedema (spontaneously reversible) is characterized by a return of the affected body part to its baseline volume with elevation. The capacity of a limb to normalize with elevation suggests that little or no subcutaneous fibrosis has developed. A limb with stage 2 lymphedema (spontaneously irreversible) fails to return to its baseline volume despite protracted elevation. The incomplete reduction of stage 2 limbs is assumed to reflect the presence of subcutaneous fibrosis. Stage 3 lymphedema or lymphostatic elephantiasis is distinguished by the presence of skin changes. Table 6 describes clinical findings typical of each stage of lymphedema. Although widely used, this staging system has not been formally validated, nor has its reliability been determined. A significant drawback is the fact that it offers limited prognostic information because the majority of lymphedema patients present at stage 2. Frequently, lymphedema stage does not meaningfully influence management. A recent study found that volume discrepancy and lymphedema stage predicted only 7% of treatment response based on regression modeling.32
A single multidimensional clinician administered, self-report measure for detecting the presence and degree of lymphedema has been validated and reported in the literature.33 For the diagnosis of moderate lymphedema (difference in upper-extremity circumference ⬎2.0 cm.), sensitivity of the questionnaire ranged from 0.93 to 0.96, and the specificity was 0.90. The results of the survey were validated against the assessment of 2 experienced lymphedema therapists. This instrument represents a valuable resource for clinical investigation; however, its length makes it unfeasible for routine clinical assessment.
CTCAE v3.0 The National Cancer Institute Common Toxicity Criteria (NCI-CTC) are a collection of grading scales designed for the ranking of severity of adverse events (treatment- or tumor-related or comorbidity events), which patients may experience while participating in NCI-sponsored oncology clinical trials. Adverse events are considered important secondary endpoints (primary endpoints are usually survival, tumor response/control). Adverse event data are intended to allow clinicians and investigators to evaluate the toxicity profile of a new treatment approach. The NCI-CTC was first created in 1988 and revised in 1998 (CTC v2.0).19 The most recent revision, Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) includes a significant revision and expansion of radiotherapy, surgical, and pediatric criteria. There is a particular emphasis on the chronic and delayed effects of cancer treatment. Electronic dissemination by NCI via web site of CTCAE v3.0 is anticipated to occur in spring 2003. Development of CTCAE v3.0 Criteria for Lymphedema In April, 2002, the National Cancer Institute sponsored the LENT IV in St Petersburg, Florida. More than 90 international, multidisciplinary investigators participated in presentations and
Table 6. Casley-Smith’s Proposed 3-Part Lymphedema Staging System27
Stage 1 Stage 2 Stage 3
Fibrosis
Pitting
Elevation
Skin
None or minimal Moderate Substantial
Pits on pressure May be present May be present
Reduces edema Minimal to no reduction No reduction
No change No change Trophic changes
The Grading of Lymphedema
working groups to address the measurement and reporting of late effects. The overarching goal of the LENT Lymphedema Working Group at this workshop was to devise a clear, user-friendly grading system that could be readily applied in the oncology clinical trials setting by clinicians unfamiliar with traditional lymphedema metrics and that required no special equipment. The new criteria developed by the group are intended to replace existing lymphedema criteria in CTC v2.0. The Lymphedema Working Group comprised an interdisciplinary team of clinicians: Andrea L. Cheville, MD (rehabilitation medicine); Charles McGarvey, PT (physical therapy); Jeanne Petrek, MD (surgical oncology); Sandra Russo, MD (radiation oncology); Marie Taylor, MD (radiation oncology); and Saskia Thiadens (lymphedema nursing). Because the validity and reliability of all extant lymphedema staging systems has yet to be established, the Working Group did not believe it was appropriate to use these systems as a basis for revising the CTC v2.0. Group consensus was established regarding the following principles in developing a novel lymphedema staging system: (1) avoid exclusive reliance on volume-based measurement, (2) avoid use of managementbased criteria given the absence of a widely acknowledged standard of care, (3) use language and physical examination findings familiar to all medical disciplines, (4) include symptom grading and language reflecting indication for the level of medical intervention, (5) limit function-based criteria given the potential for other sources of impairment to confound accurate grading, (6) ensure that the grading system were applicable to any body part, (7) establish clear intergrade distinctions, (8) separate lymphedema characteristics (eg, volume, fibrosis, and dermal change) that might be inadvertently under- or overemphasized with a summed score, and (9) ensure that a significant distinction in morbidity occurred between grades 2 and 3. CTCAE v3.0 lymphedema criteria are presented in Table 7. A concerted effort was made by the working group to avoid using specific (eg, ⱖ2 cm) differences in interlimb circumference as the basis for detecting or grading lymphedema. This has been a common past approach that is of limited clinical relevance because 2 cm may produce a visibly undetectable difference in a large arm but marked asymmetry in a small arm. Many individ-
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uals without lymphedema may display inherent anatomic variations or baseline differences between dominant and nondominant limbs related to differences in muscle mass. In addition, the utilization of anatomic landmarks to determine where measurements are taken can lead clinicians to inadvertently overlook lymphedema if it occurs outside of a measurement site. For patients with an uninvolved limb, the lymphedema working group incorporated quantitative volumetric criteria. However, rather than choosing an arbitrary, absolute value (eg, 2 cm), the percent difference in total limb volume and in limb circumference at the point of greatest visible discrepancy were used as the basis for determining lymphedema grade. The group developed vocabulary describing volumetric change that could be applied with equal ease to limb, truncal, and head and neck lymphedema. Obscuration of anatomic architecture (eg, blood vessels, tendons, and bony landmarks), obliteration of skin folds, deviation from normal anatomic contour, and the presence of pitting were incorporated into the criteria as a basis for detecting and grading lymphedema in all body parts. Lymphorrhea (exudation of lymph fluid through intact skin) was incorporated into the CTCAE v3.0 criteria as a means of clearly distinguishing severe, grade 3 lymphedema. Group consensus established that volume, soft-tissue change, and dermal change would be graded separately. This represented a marked departure from CTC v2.0. Another significant change from CTC v2.0 arose from the group’s acknowledgment that appendicular and axial lymphedema were distinct phenomena and should be measured and described separately. Hence, the group generated specific criteria for head/neck edema, limb edema, and truncal/genital edema. Criteria and descriptors from established lymphedema staging systems (eg, circumferential measurement and presence of dermal change) were selectively incorporated into the CTC v2.0 revisions to produce a more comprehensive grading system. Although these criteria will be immediately introduced and used for toxicity grading in NCI-sponsored clinical trials, the validity, accuracy, and reliability of the CTCAE v3.0 should be tested in future studies. Lymphatic toxicities were restricted to somatic lymphedema in the CTC v2.0. These were expanded in the CTCAE v3.0 to include lympho-
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Table 7. CTC v.3.0 Lymphedema Criteria Lymphatics Grade Adverse Event Chyle or lymph leakage
Short Name Chyle or lymph leakage
1
2
3
Asymptomatic; clinical or radiographic findings
Symptomatic; medical intervention indicated
Symptomatic and interventional radiology or operative intervention indicated
Trace thickening or faint discoloration
Marked discoloration — or leathery skin texture or papillary formation
4 Life-threatening complications
Also consider: Chylothorax. Dermal change lymphedema, phlebolymphed ema
Dermal change
—
Remarks: Dermal change lymphedema, phlebolymphedema refers to changes due to venous stasis. Also consider: Ulceration. Edema-head and neck
Edema-head and neck
Localized to Localized facial or dependent areas neck edema with and no disability or functional functional impairment impairment
Edema-limb
Edema-limb
5%-10% inter-limb discrepancy in volume or circumference at point of greatest visible difference; swelling or obscuration of anatomic architecture on close inspection; pitting edema
Edema-trunk/genital
Edema-trunk/genital
Swelling or obscuration of anatomic architecture on close inspection; pitting edema
Edema-viscera
Edema-viscera
Asymptomatic; clinical or radiographic findings only
⬎10-30% inter-limb discrepancy in volume or circumference at point of greatest visible difference; readily apparent obscuration of anatomic architecture; obliteration of skin folds; readily apparent deviation from normal anatomic contour Readily apparent obscuration of anatomic architecture; obliteration of skin folds; readily apparent deviation from normal anatomic contour Symptomatic; medical intervention indicated
Lymphedema-related Lymphedema-related Minimal to moderate Marked increase in fibrosis fibrosis redundant soft density and tissue unresponsive firmness, with or to elevation or without tethering compression with moderately firm texture or spongy feel Lymphocele Lymphocele Asymptomatic, Symptomatic; clinical or medical radiographic intervention findings only indicated Phlebolymphatic cording
Phlebolymphatic cording
Asymptomatic, clinical findings only
Symptomatic; medical intervention indicated
Lymphatics-other (Specify)
Lymphatics-other (Specify)
Mild
Moderate
Generalized facial or Severe with neck edema with ulceration or functional cerebral edema; impairment (e.g., tracheotomy or difficulty in turning feeding tube neck or opening indicated mouth compared to baseline) ⬎30% inter-limb Progression to discrepancy in malignancy (i.e., volume; lymphangiosarcoma); lymphorrhea; gross amputation deviation from indicated; disabling normal anatomic contour; interfering with ADL
Lymphorrhea; interfering with ADL; gross deviation from normal anatomic contour
Progression to malignancy (ie lymphangiosarcoma); disabling
Symptomatic and unable to aliment adequately orally; interventional radiology or operative intervention indicated Very marked density and firmness with tethering affecting ⱖ40% of the edematous area
Life-threatening consequences
Symptomatic and interventional radiology or operative intervention indicated Symptomatic and leading to contracture or reduced range of motion Severe
—
—
—
Life-threatening; disabling
The Grading of Lymphedema
coele, chyle/lymph leak, and visceral edema. No previous systems have been formulated to grade any of these complications. Therefore, the group incorporated standard language widely used throughout CTCAE v3.0 for visceral complications. For each of these, the following grading system was adopted: grade 1: asymptomatic, clinical or radiographic findings only; grade 2: symptomatic, medical intervention indicated; grade 3: symptomatic and interventional radiology or operative intervention indicated. This approach offers the opportunity to capture the key features of treatment-related lymphatic morbidity. Criteria on phlebolymphatic cording were also added to CTCAE v3.0. This is a relatively common phenomenon arising predominantly in the axilla from the clipping of small axillary veins and the removal of lymph nodes. Phlebolymphatic cording is noted very soon after surgery and therefore has not been attributed to venous collapse and clotting secondary to intravenous therapy or irritating chemotherapeutic agents. Veins and lymphatics whose proximal termini are occluded will eventually sclerose and be reabsorbed. Until this occurs, they can be a source of significant discomfort and limit shoulder mobility. The criteria for phlebitis, including superficial venous thrombosis, are graded separately in CTCAE v3.0 as a vascular event. Quantitative Measures of Lymphedema Various quantitative approaches have been adopted to characterize soft-tissue changes in lymphedema. These may be useful to validate clinical grading systems and to provide more objective endpoints in toxicity intervention studies. They can be divided into 3 distinct approaches: (1) soft-tissue imaging, (2) quantification of changes in electrical conductance, and (3) quantification of changes in biomechanical properties. Conventional imaging modalities have been used to characterize soft-tissue changes in lymphedema. Low-frequency ultrasound (3.5-10 MHz), despite its capacity to detect subcutaneous fibrosclerosis, has thus far proved to be of limited utility.34,35 In contrast, high-frequency ultrasound may offer a useful means of discriminating between lymphedema and edema arising from venous insufficiency or cardiac failure. Changes in dermal echogenicity measured by high-frequency ultrasonography are a valid surrogate measure for changes in dermal water content.36 Magnetic
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resonance imaging (MRI) soft-tissue changes in lymphedema include dermal and subcutaneous thickening, increased subcutaneous fat, and trabecular structures in the subcutis.37-42 The anatomic, pathophysiologic, and prognostic relevance of these structures has yet to be determined. High resolution MRI of skin and subcutis by using a specialized surface gradient coil is able to precisely quantify increases in the water content and size of dermal structures. It may provide a means of tracking change in lymphedema over time. The development of MRI contrast agents of sufficient molecular size to be sequestered and transported by the lymphatics has been the focus of several investigations.43 Computed tomography scanning offers little advantage over MRI aside from cost. Cornish and colleagues have pioneered the use of electrical impedance to assess soft-tissue change in lymphedema.44 The information provided by bioimpedance is confined to changes in soft-tissue water content. Nonetheless, bioimpedance was shown to reproducibly detect increased water content in progressive stages of lymphedema.45 With decongestive therapy, bioimpedance measures decreases in water content that correlate with limb volume reduction.46 Perhaps most significantly, bioimpedance was recently shown to detect subclinical lymphedema after axillary dissection in breast cancer patients.47 Tissue texture, elasticity, and compressibility change in response to fluid and fibrosis in the interstitial space. Biomechanical measurements have been used to characterize these alterations in lymphedema. Objective determination the depth of tissue pitting can be obtained with the tonometer,48 a device that measures the depth of compression by an applied mass after a fixed time period. Alternate approaches to biomechanical characterization involve the generation of indentation and impression force curves.49,50 These techniques capitalize on the fact that edematous and fibrotic tissues respond very differently over time to sustained compression. They have yet to be validated for the assessment of lymphedema or widely integrated into clinical practice.
Summary Lymphedema is an important adverse effect of cancer and its treatment. Because of its diffuse
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nature, clinical recognition and severity ranking can be difficult for even trained observers. The lymphedema criteria generated by the LENT Lymphedema Working Group, and subsequently incorporated in CTCAE v3.0, include key clinical descriptive elements available for assessment and grading in clinical trials. Further work is needed to establish their validity and reliability, including correlation with quantitative technologies and patient-rated instruments.
References 1. Harwood CA, Mortimer PS: Causes and clinical manifestations of lymphatic failure. Clin Dermatol 13:459-471, 1995 2. Johansson S, Svensson H, Denekamp J: Dose response and latency for radiation-induces fibrosis, edema, and neuropathy in breast cancer patients. Int J Radiat Oncol Biol Phys 52:1207-1219, 2002 3. Meek AG: Breast radiotherapy and lymphoedema. Cancer 83:2788-2797, 1998 (suppl 12) 4. Ramaiah KD, Kumar KN, Ramu K, et al: Functional impairment caused by lymphatic filariasis in rural areas of south India. Trop Med Int Health 2:832-838, 1997 5. Tobin M, Lacey HJ, Meyer L, et al: The psychological morbidity of breast cancer-related arm swelling. Cancer 172:3248-3252, 1993 6. Maunsell E, Brisson J, Deschenes L: Arm problems and psychological distress after surgery for breast cancer. Can J Surg 36:315-320, 1993 7. Passik SD, Newman M, Brennan M, et al: Predictors of psychological distress, sexual dysfunction and physical functioning among women with upper extremity lymphedema related to breast cancer. Psychooncology 4:255-263, 1995 8. Cheville A, Packel L. Psychological and functional patient burden associated with chronic lymphedema management. Academy of Physical Medicine and Rehabilitation Annual Assembly, Poster Presentation, Orlando, FL, 2002 9. Schrenk P, Rieger R, Shamiyeh A, et al: Morbidity following sentinel lymph node biopsy versus axillary lymph node dissection for patients with breast carcinoma. Cancer 88:608-614, 2000 10. Liljegren G, Holmberg L: Arm morbidity after sector resection and axillary dissection with or without postoperative radiotherapy in breast cancer stage I: Results from a randomised trial. Uppsala-Orebro Breast Cancer Study Group. Eur J Cancer 33:193-199, 1997 11. Lactchford S, Casley-Smith JR: Estimating limb volumes and alterations in peripheral edema from circumferences measured at different intervals. Lymphology 30:161-164, 1997 12. Sander AP, Hajer NM, Hemenway K, et al: Upper-extremity volume measurements in women with lymphedema: A comparison of measures obtained via water displacement with geometrically determined volume. J APTA 82:1201-1212, 2002
13. Casley-Smith J: Measuring and representing peripheral oedema and bioimpedance. Lymphology 27:56-70, 1994 14. Stanton AW, Northfield JW, Holroyd B, et al: Validation of an optoelectronic limb volumeter (Perometer). Lymphology 30:77-97, 1997 15. Segerstrom K, Bjerle P, Nystrom A: Importance of time in assessing arm and hand function after treatment of breast cancer. Scand J Plast Reconstr Hand Surg 25:241244, 1991 16. Loprinzi CL, Kugler JW, Sloan JA, et al: Lack of effect of coumarin in women with lymphedema after treatment for breast cancer. N Engl J Med 340:346-350, 1999 17. Casley-Smith JR, Morgan RG, Piller NB: Treatment of lymphedema of the arms and legs with 5,6-benzo-[␣]pyrone. N Engl J Med 329:1158-1163, 1993 18. Goltner E, Fischbach JU, Monter B, et al: Objective measurement of lymphedema after mastectomy. Dtsch Med Wochenschr 110:949-952, 1985 19. Common Toxicity Criteria (CTC) v.2.0. Available at. website: ctep.cancer.gov/reporting/ctc.html. Accessed March 30, 2003 20. Petrek JA, Senie RT, Peters M, et al: Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer 92:1368-1377, 2001 21. Gerber L, Lampert M, Wood C, et al: Comparison of pain, motion, and edema after modified radical mastectomy vs. local excision with axillary dissection and radiation. Breast Cancer Res Treat 21:139-145, 1992 22. Lin PP, Allison DC, Wainstock J, et al: Impact of axillary lymph node dissection on the therapy of breast cancer patients. J Clin Oncol 11:1536-544, 1993 23. Werner RS, McCormick B, Petrek J, et al: Arm edema in conservatively managed breast cancer: Obesity is a major predictive factor. Radiology 180:177-184, 1991 24. Keramopoulos A, Tsionou C, Minaretzis D, et al: Arm morbidity following treatment of breast cancer with total axillary dissection: A multivariated approach. Oncology 50:445-449, 1993 25. Kiel KD, Rademacker AW: Early-stage breast cancer: Arm edema after wide excision and breast irradiation. Radiology 198:279-283, 1996 26. Paci E, Cariddi A, Barchelli A, et al: Long-term sequelae of breast cancer surgery. Tumori 82:321-324, 1996 27. Casley-Smith JR: Alterations of untreated lymphedema and its grades over time. Lymphology 28:174-185, 1995 28. American Physical Therapy Association: Impaired circulation and anthropometric dimensions associate with lymphatic system disorders: evaluation, diagnosis, and prognosis. Guide to Physical Therapist Practice (ed 2). Alexandria, VA, American Physical Therapy Association, 2001 29. Pavy JJ, Denekamp J, Letschert J, et al: EORTC Late Effects Working Group. Late effects toxicity scoring: The SOMA scale. Radiother Oncol 35:11-15, 1995 30. Pavy JJ, Denekamp J, Letschert J, et al: EORTC Late Effects Working Group. Late Effects toxicity scoring: The SOMA scale. Int J Radiat Oncol Biol Phys 31:1043-1047, 1995 31. Senofsky GM, Moffat FL Jr, Davis K, et al: Total axillary lymphadenectomy in the management of breast cancer. Arch Surg 126:1336-1341, 1991
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32. Cheville A, Shults J, Dugan N, et al: Predicting lymphedema outcomes: inadequacy of current parameters. Academy of Physical Medicine and Rehabilitation Annual Assembly, Poster Presentation, Orlando, FL, 2002 33. Norman SA, Miller LT, Erikson HB, et al: Development and validation of a telephone questionnaire to characterize lymphedema in women treated for breast cancer. Phys Ther 6:1192-1205, 1981 34. Doldi SB, Lattuada E, Zappa MA, et al: Ultrasonography of extremity lymphedema. Lymphology 25:129-133, 1992 35. Balzarini A, Milella M, Civelli E, et al: Ultrasonography of arm edema after axillary dissection for breast cancer: A preliminary study. Lymphology 34:152-155, 2001 36. Gniadecka M, Quistorff B: Assessment of dermal water by high-frequency ultrasound: Comparative studies with nuclear magnetic resonance. Br J Dermatol 135:218-224, 1996 37. Case TC, Witte CL, Witte MH, et al: Magnetic resonance imaging in human lymphedema: Comparison with lymphangioscintigraphy. Magn Reson Imaging 10:549-558, 1992 38. Duewell S, Hagspiel KD, Zuber J, et al: Swollen lower extremity: Role of MR imaging. Radiology 184:227-231, 1992 39. Huang A, Fruauff A, Dicarmine F, et al: Case report 861. Skeletal Radiol 23:483-485, 1994 40. Fuji K: MR imaging of edematous limbs in lymphatic and nonlymphatic edema. Acta Radiol 35:262-269, 1994 41. Astrom KGO, Abdsaleh S, Brenning GC, et al: MR imaging of primary, secondary, and mixed forms of lymphedema. Acta Radiol 42:409-416, 2001
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42. Liu NF, Wang CG: The role of magnetic resonance imaging in diagnosis of peripheral lymphatic disorders. Lymphology 31:119-127, 1998 43. Misselwitz B, Schmitt-Willich H, Michaelis M, et al: Interstitial magnetic resonance lymphography using a polymeric t1 contrast agent: Initial experience with Gadomer-17. Invest Radiol 37:146-151, 2002 44. Ward LC, Bunce IH, Cornish BH, et al: Multi-frequency bioelectrical impedance augments the diagnosis and management of lymphoedema in post-mastectomy patients. Eur J Clin Invest 22:751-754, 1992 45. Cornish BH, Ward LC, Thomas BJ, et al: Quantification of lymphedema using multi-frequency bioimpedance. Appl Radiat Isot 49:651-652, 1998 46. Cornish BH, Bunce IH, Ward LC, et al: Bioelectrical impedance for monitoring the efficacy of lymphoedema treatment programmes. Breast Cancer Res Treat 38:169176, 1996 47. Cornish BH, Chapman M, Hirst C, et al: Early diagnosis of lymphedema using multiple frequency bioimpedance. Lymphology 34:2-11, 2001 48. Clodius L, Deak L, Piller NB: A new instrument for the evaluation of tissue tonicity in lymphoedema. Lymphology 9:1-5, 1996 49. Bates DO, Levick JR, Mortimer PS: Quantification of rate and depth of pitting in human edema using an electronic tonometer. Lymphology 27:159-172, 1994 50. Lindahl OA: The evaluation of a biexponential model for description of intercompartmental fluid shifts in compressed oedematous tissue. Physiol Measurement 16:1728, 1995
tively quantifying lymphedema have been developed and validated. Although these are briefly reviewed, it is recognized that cost and access issues limit their widespread clinical utility and, as such, were not considered in developing the CTC v3.0 criteria. The CTC v3.0 lymphedema criteria adopted several innovations. Principle among these was the decision to generate separate criteria for volumetric increase, dermal changes, and subcutaneous fibrosis. We anticipate the use of the new CTC v3.0 lymphedema criteria to begin in mid-2003 for grading the key clinical features of this disorder in oncology clinical trials. The purpose of this article is to familiarize the reader with (1) background on the clinical features of lymphedema, (2) information on established lymphedema rating systems, (3) the consensus process and rationale of the Lymphedema Working Group, (4) the new CTC v3.0, and (5) quantitative techniques for assessment of lymphedema. © 2003 Elsevier Inc. All rights reserved.
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multiple lymphatic structures leading to truncal lymph stasis. Lymphedema may be described as primary or secondary based on its presumed etiology. Primary lymphedema describes cases for which no source of lymphatic compromise can be identified. Secondary lymphedema is the most common cause of lymphedema both in the United States and worldwide. It arises from lymphatic obstruction, obliteration, or functional insufficiency because of a pathological process exogenous to the lymphatic system. Such processes are commonly iatrogenic (eg, surgery or radiation therapy). Infection, traumatic injury, cancerous invasion or compression, and inflammation are frequent noniatrogenic causes of secondary lymphedema. Cancer patients are subject to a variety of clinical factors that can induce lymphedema. Lymphatic injury may occur through surgical disruption of lymph nodes or vessels. External-beam radiation therapy extrinsically damages the lymphatic system leading to fibrosis and compromise of lymph transport.2,3 Any patient who has undergone lymphadenectomy or received radiation to lymph nodes or vessels is at risk for the eventual development of lymphedema. This risk may be compounded by comorbid conditions including
ymphedema is defined as an abnormal accumulation of protein-rich fluid in a body part secondary to insufficiency of the lymphatic system. Lymphatic compromise occurs when the lymphatic system is unable to adequately sequester and/or transport lymph.1 This may arise from an iatrogenic or infectious injury to the system or to congenital hypoplasia or aplasia of the lymphatic structures. Generally limbs are affected, although viscera and axial structures may be subject to lymphedema as well. This is particularly true of cancer patients who often sustain injury to
From the Department of Rehabilitation Medicine, University of Pennsylvania Health System, Philadelphia, PA; Rehabilitation Medicine Department, Warren Magnuson Clinical Center, National Institutes of Health, Bethesda, MD; Evelyn H. Lauder Breast Center, Memorial Sloan-Kettering Cancer Center, New York, NY; Department of Radiation Oncology, Columbia Presbyterian Medical Center, New York, NY; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO; and National Lymphedema Network, Oakland, CA. Address reprint requests to Andrea L. Cheville, MD, Department of Rehabilitation Medicine, University of Pennsylvania Health System, 5 West Gates, 3400 Spruce Street, Philadelphia, PA 19104. © 2003 Elsevier Inc. All rights reserved. 1053-4296/03/1303-0006$30.00/0 doi:10.1016/S1053-4296(03)00038-9
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venous or arterial insuffiency, diabetes, neurogenic motor deficits, and hypoproteinemia, which are commonly seen in oncology populations. Lymphedema may manifest in any area of the body. The extremities are most commonly affected. This is explained by the limited opportunity for development of collateral lymphatic drainage. Limb edema may extend to involve the associated truncal quadrant (eg, anterior and posterior aspects of the ipsilateral lower truncal quadrant and external genitalia in cases of lowerextremity lymphedema). Although the extremities are most commonly involves the extremities, lymphedema may also develop in the craniocervical region, abdomen, breast, trunk, and genitals. The distribution of all secondary lymphedema is determined by the nature and location of the lymphatic disruption, as well as by the resilience of patients’ baseline lymphatic function. When the lymphatic system fails to transport the lymph produced by a body part, congestion results. The solid and fluid constituents of lymph accumulate in the interstitial space. Increased density of solid debris (eg, large proteins, long chain fatty acids, nonfunctional erythrocytes, and leukocytes) leads to the recruitment of neutrophils, macrophages, and fibroblasts. The resultant chronic, low-grade inflammation triggers the deposition of disorganized collagen fibers. Fibrosis may engulf any residual functioning lymph collectors, further aggravating lymph stasis. As histopathologic tissue changes progress, metaplasia may develop in the overlying skin. Dermal keratinification and papillomas are the stigmata of advanced lymphedema or lymphostatic elephantiasis. Their presence indicates that significant subcutaneous fibrosis has occurred. With soft-tissue changes, bacterial and fungal infections may become increasingly frequent. Cellulitic infections further injure superficial lymphatics and hasten hyperkeratotic changes. The presence and degree of subdermal fibrosis and dermal metaplasia are important reflections of lymphedema severity. The adverse functional consequences of lymphedema have not been adequately characterized in either a qualitative or quantitative fashion. In cancer patients, lymphedema is often associated with other function-compromising toxicities such as fibrosis, skin breakdown, pain, neuropathy, arthropathy, and myopathy. It therefore becomes challenging to ascribe particular deficits
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exclusively to lymphedema. Light is shed on this problem by the functional impairments noted in primary lymphedema patients. The vast majority of these patients have lower-extremity lymphedema. When advanced, impaired mobility and capacity for self-care are common.4 Negotiating the weight and bulk of a lymphedematous limb can lead patients to adopt dysfunctional biomechanical patterns. These often increase energy expenditure and lead to abnormal joint forces, which may accelerate degeneration. Significant psychosocial morbidity has been associated with breast cancer–related lymphedema.5-7 Breast cancer patients with lymphedema are more likely to experience vocational, familial, and sexual dysfunction.5,6 A recent study reported that 11% of a large cohort of lymphedema patients (the majority related to cancer treatment) were receiving disability compensation.8
Clinician- and Patient-Rated Measures of Lymphedema Measures of pathological conditions generally detect or quantify deviation from a “norm.” The absence of a universally accepted “norm” has been an impediment to the development of lymphedema metrics. In the case of cancer-related lymphedema, the “norm” that defines pathology is either an uninvolved contralateral extremity or the patient’s hypothetical baseline. Baseline interlimb volume discrepancy because of arm dominance, neurogenic atrophy, or differential muscle hypertrophy is a problem inherent in the first approach. Assessment of bilateral limb or truncal lymphedema must rely on the second approach, each patient’s hypothetical baseline. This is a generated from patient recollection and clinician interpretation. Problems arise in the absence of premorbid photographs or measurements because of the highly subjective nature of this “norm.” Additionally, many factors can influence soft-tissue volume and texture (eg, weight gain and muscle hypertrophy) other than lymphedema. A variety of subjective and objective parameters have been used to grade the severity of lymphedema. These are listed in Table 1. Subjectively, many patients describe sensations of heaviness, tightness, and aching in their affected limbs. The specificity of these sensations to lymphedema has not been determined, nor has
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Table 1. Subjective and Objective Parameters Used to Rate Lymphedema
Parameter Subjective Sensations Objective Volume
Limb circumference Deviation from “normal” appearance Tissue texture Tissue reponse to pressure Tissue response to gravity Presence of Dermal change
Measurement Strategy/Descriptor
Level of Measurement
Used in Clinical Trials/Scales (Reference)
Heavy, numb, tingly, achey
Categorical
Water displacement Calculation from serial circumferential measurements Optoelectrial volumetry Clinician rated scale None-mildmoderate-severe Patient rated scale None-mildmoderate-severe Loss of limb contour, Obscuration of anatomic architecture Spongy, fatty, fibrotic Pitting 1⫹ to 3⫹ Resolution with elevation, Exacerbation with dependency Presence of keratinification/ papillomas
Used in Staging Systems
Formally Validated
Utility in Nonlimb Lymphedema
Yes9,10
No
No
Yes
Interval Interval
Yes15 Yes10
No No
Yes Yes
No No
Interval
Yes18
No
Yes
No
Ordinal
Yes19
Yes
No
Yes
Ordinal
Yes9
No
No
Yes
Interval Ordinal
Yes20-26,28,29,30 No
Yes No
No No
No Yes
Categorical Ordinal
No No
No No
No No
Yes Yes
Categorical
Yes27
Yes
Yes
Yes
Categorical
Yes27
Yes
Yes
Yes
their prognostic significance. Nonetheless, they have been the basis of lymphedema detection in several epidemiological studies.9,10 Objective measures are based predominantly on changes in volume and tissue texture/appearance. Volume increase can be precisely quantified through water displacement, serial circumferential measurements, and optoelectric volumetry.11-14 Each of these methods has been widely used in both epidemiological incidence studies and clinical trials of lymphedema.10,15-18 They are not practical for routine clinical use because of time, training, and equipment requirements. These problems can be obviated through the use of a patient- or clinician-rated ordinal scale using none, mild, moderate, or severe classifications.9,19 This approach to rating has not been validated, nor has its reliability been
established. Interlimb circumferential discrepancy has been the most widely used outcome measure and has been incorporated into many formal rating scales.20-26 Measurement taken by patients or clinicians at sites defined by bony landmarks (eg, ulnar styloid and olecranon) are taken to accurately reflect limb volume. This assumption has not been validated, nor has a structured approach (designated measurement sites and degree of tension on the tape measure) to circumferential measurement been formulated. However, because circumferential measurements can be obtained by anyone without special training or equipment, they remain the most common approach to lymphedema measurement. Qualitative descriptors are widely used clinically to characterize soft-tissue changes associated with lymphedema. To date, no formal tax-
The Grading of Lymphedema
Table 2. American Physical Therapy Association Lymphedema Criteria28 Lymphedema Grade
Interlimb Circumference Discrepancy ⬍3 cm 3-5 cm ⬎5 cm
Mild Moderate Severe
onomy has been developed to allow consistent use of descriptors in research or clinical discourse. Many soft-tissue characteristics can be described and some have been incorporated into lymphedema rating scales.27 Alternations in “normal” soft-tissue appearance can be qualitatively detailed including loss of contour and obscuration of anatomic architecture (eg, veins, tendons, and bony landmarks). Soft-tissue texture and its response to pressure or gravity are frequently described because these characteristics presumably reflect the extent to which subdermal fibrosis has occurred.27 The presence of dermal change, generally characterized categorically as present or absent, is an additional clinically relevant softtissue finding. Although ubiquitous in clinical lymphedema practice, the qualitative description of soft tissue has not been used by the oncological community in detecting or rating cancer-related lymphedema. The majority of extant lymphedema rating scales reflect the oncological community’s prevailing and past focus on breast cancer–related lymphedema. Approaches to rating lymphedema have been driven by the anatomy of the involved body part (eg, upper extremity). The availability of an uninvolved arm has led to reliance on comparison interlimb volume or circumference. For compelling reasons of convenience, circumferential comparisons have been the basis of most lymphedema rating scales. Three of the 4 extant rating scales are predominantly volume based. These are as follows:
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1. American Physical Therapy Association (APTA)28: the APTA’s lymphedema rating system is a 3-point scale based exclusively on discrepancy in limb circumference (Table 2). Lymphedema is graded mild, moderate, or severe contingent on the amount of interlimb circumferential discrepancy. No specifications are provided regarding where measurements should be obtained. The scale has been used predominantly as a means of anticipating the number of physical therapy visits that will be required to achieve anticipated goals within an episode of care. The reliability and validity of this scale have not been assessed. 2. The Late Effects of Normal Tissues (LENT)/ SOMA: the LENT/SOMA measure, when LENT denotes late effects of normal tissues, includes 3 lymphedema-related items (Table 3).29,30 The LENT/SOMA measure subdivides items into subjective, objective, management, and analytic components (SOMA). There are no subjective LENT/SOMA items related to lymphedema. The objective, management, and analytic components are rated on a 4-point scale ranging from present to severe dysfunction. The objective and analytical items are based on measurement of arm circumference at an unspecified site. A problem inherent in management-based lymphedema rating is the lack of practice standardization in lymphedema treatment. The LENT/SOMA lymphedema items have not been validated, nor has their reliability been assessed. 3. CTC v2.0: the CTC v2.0 lymphedema criteria19 (Table 4) are based on a 4-point system ranging from normal to severe lymphedema limiting function with ulceration. The rater is provided with no volumetric or circumferential criteria to distinguish between grades of lymphedema. Management requirements (eg, requiring surgery and compression) and the presence of functional impairment are used to
Table 3. LENT/SOMA Lymphedema-Related Items29,30 Objective
Arm Circumference
Management
Analytic
Tape measure
Grade 1 2 cm-4 cm
Grade 2 ⬎4 cm-6 cm
Grade 3 ⬎6 cm
Grade 4 Useless Arm
Elevate arm, elastic stocking
Compression wrapping, intensive physiotherapy
Surgical intervention/ amputation
Assessment of forearm diameter
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Table 4. CTCv2.0 Lymphedema Grades and Criteria19 Grade
0
1
2
3
4
Criteria Normal Mild lymphedema Moderate lymphedema Severe lymphedema Severe lymphedema requiring limiting function, limiting function compression; lymphocyst requiring with ulceration lymphocyst surgery
discriminate between grades 3 and 4. A desirable aspect of the CTC v2.0 stems from the lack of specific volumetric criteria. This allows this system to be used in grading nonlimb edema and bilateral edema. The validity and reliability of this system have not been formally assessed. The APTA, LENT/SOMA, and CTC v2.0 lymphedema rating systems have not been widely used in lymphedema-specific research. Many epidemiological studies have been conducted to determine the incidence of breast cancer–related lymphedema. Most have used independently developed, nonvalidated diagnostic, and rating criteria. The majority is volume based, but several use symptom- and management-based criteria. Table 5 lists 11 reports, all of which used different measurement techniques and diagnostic criteria.9,10,15,20-26,31 The problems inherent in using nonstandardized measurement techniques are illustrated in the wide variance in reported incidences of breast cancer–related lymphedema (11%-56%). The variance persists when samples are substratified by type of primary breast cancer treatment. The marked inconsistency between studies can be explained in part through discrepancies in the number and location of circumferential measurements, the amount of tension on the tape measure, the duration and frequency of patient follow-up, and the criteria for diagnosing lymphedema. An unfortunate consequence of volume- or circumference-based lymphedema grading systems is the inability to use these systems in the assessment of nonlimb edema or bilateral limb edema. This has given rise to an almost complete lack of information on lymphedema incidence after the treatment of nonbreast malignancies, particularly those associated with axial lymphedema (eg, bladder, prostate, ovarian, cervical, endometrial, and colon cancers). Despite inherent limitations in this approach, the validity of circumference- and volume-based measurement is attested by the correlation between treatment intensity and lymphedema risk.
Reported incidences vary, yet more aggressive axillary perturbation (eg, greater numbers of resected lymph nodes, higher dose, and more extensive irradiation volume) has been consistently shown to increase the probability that lymphedema will develop and become severe. For example, Goltner et al18 reported a 25% incidence of lymphedema in breast cancer patients treated with lumpectomy and lymph node dissection, versus a 42% incidence in patients treated with modified radical mastectomy and radiation to axilla and chest wall. These data suggest that volume assessment may be a clinically valid approach reflecting the severity of change, but that lack of standardized assessment procedures undermines the reliability and accuracy of volume-based grading systems. Most epidemiological studies have relied exclusively on interlimb volumetric discrepancy; however, several investigators, recognizing the relevance of other clinical variables, have devised grading systems that use symptom self-report, functional limitations, and/or management criteria to define lymphedema grades. These multidimensional assessment systems differ in the incorporated variables, but all acknowledge the relevance of clinical criteria other than volume. Schrenk et al9 devised the following scale: none ⫽ no arm swelling, tightness, or heaviness; mild ⫽ periods of arm swelling but no constant increase in greatest diameter and clothes fit the same; moderate ⫽ constant arm swelling and heaviness, clothes do not fit the same, physical discomfort but no decrease in functional activity; and severe ⫽ constant arm heaviness, disability, decreased functional activity, huge arm swelling. Liljegren and Holmberg10 similarly emphasized symptom self-report in the diagnosis of lymphedema. He surveyed patients as to the presence of pain, numbness, impaired shoulder mobility, and weakness. Senofsky et al31 used management-based grades in devising the following system: grade 1 ⫽ minimal to mild edema, requiring no intervention or only elevation on 1 or 2 pillows
The Grading of Lymphedema
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Table 5. Epidemiological Trials of Lymphedema Incidence After Primary Breast Cancer Treatment Author, Year Petrek, 2001
20
Schrenk, 20009
Lijegren, 199710 Kiel, 199625
Keramopoulos, 199324
Gerber, 199221
Segerstrom, 199115 Werner, 199123
Lin, 199322
Paci, 199626
Senofsky, 199131
Lymphedema Measurement Method Self-reported arm circumference Measured 2 in and 6 in above, and 4 in below the olecranon
Lymphedema Definition
Inter-limb descrepancy “Mild” lymphedema ⬍ 0.5 in ⫹ self report of “enlargement” or “heaviness” “Moderate” lymphedema 0.5-2.0 in “Severe” ⬎2.0 in Self-reported arm symptoms Subjective self-report of arm and grading of edema as swelling as none, mild, “none, mild, moderate, or moderate, severe severe” Volume calculated from ⬎100 mL inter-limb volume serial circumferencial discrepancy measurements Arm circumference ⬎1 cm change compared to Measured 15 cm above previous measurements and 10 cm below olecranon Arm circumference ⬎2 cm inter-limb Measured 15 cm above discrepancy and 10 cm below lateral epicondyle Arm circumference ⬎2cm inter-limb discrepancy Measured at ulnar styloid, olecranon, and 35 cm proximal to ulnar syloid Volume by water ⬎150 mL inter-limb volume displacement discrepancy Arm circumference ⬎2.5 cm inter-limb Measured 13 cm above discrepancy and 10 cm below olecranon Arm circumference ⬎2.0 cm inter-limb Measured 10 cm above discrepancy and 10 cm below olecranon Arm circumference Inter-limb discrepancy Measured at 6 points “light” edema ⬎4 cm “moderate” edema 4-8 cm “heavy” edema ⬎8 cm Grade I-IV, ordinal scale ⬎ “minimal to mild” based on management lymphedema requirements
at night, grade 2 ⫽ required an external compression stocking for satisfactory control, grade 3 ⫽ required use of lymphedema pump and stocking for control, grade 4 ⫽ poorly controlled lymphedema or edema complicated by lymphangitis. These multidimensional rating scales have not been validated, nor have they been used in studies other than those of the investigators that generated them.
Reported Incidence “Mild” 19% “Moderate” 17% “Severe” 13%
SLN 0% Axillary dissection: “Mild” edema 40% “Moderate” edema 14% 11.20% 35%
17%
56%
43% 19.50%
24%
46.70%
9.40%
Criteria used by physicians and physical/occupational therapists with specialized training in lymphedema management differ from those used to detect breast cancer–related lymphedema. This reflects a significant shift in clinical focus. Lymphedema specialists are concerned with factors (eg, fibrosis and dermal metaplasia) other than volume, having long recognized that volume is a poor indicator of lymphedema severity, prog-
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nosis, or treatment responsiveness. In addition, specialists frequently manage lymphedema involving axial structures such as the craniocervical region, trunk, and genitalia, as well as bilateral limb edema. In axial lymphedema volumetric measurement is not feasible, whereas for bilateral edema, volume can be used as a means of measuring treatment response but is of little utility in diagnosing lymphedema. The extent of subdermal fibrosis and dermal metaplasia are the primary variables used in conventional lymphedema staging.27 This emphasis is based on current understanding of the pathophysiology, histopathology, and national history of lymphedema outlined previously in this article. Casley-Smith27 proposed a 3-part lymphedema staging system based on the affected region’s response to gravity and whether dermal change has occurred (Table 6). This has been widely adopted by lymphedema specialists. Stage 1 lymphedema (spontaneously reversible) is characterized by a return of the affected body part to its baseline volume with elevation. The capacity of a limb to normalize with elevation suggests that little or no subcutaneous fibrosis has developed. A limb with stage 2 lymphedema (spontaneously irreversible) fails to return to its baseline volume despite protracted elevation. The incomplete reduction of stage 2 limbs is assumed to reflect the presence of subcutaneous fibrosis. Stage 3 lymphedema or lymphostatic elephantiasis is distinguished by the presence of skin changes. Table 6 describes clinical findings typical of each stage of lymphedema. Although widely used, this staging system has not been formally validated, nor has its reliability been determined. A significant drawback is the fact that it offers limited prognostic information because the majority of lymphedema patients present at stage 2. Frequently, lymphedema stage does not meaningfully influence management. A recent study found that volume discrepancy and lymphedema stage predicted only 7% of treatment response based on regression modeling.32
A single multidimensional clinician administered, self-report measure for detecting the presence and degree of lymphedema has been validated and reported in the literature.33 For the diagnosis of moderate lymphedema (difference in upper-extremity circumference ⬎2.0 cm.), sensitivity of the questionnaire ranged from 0.93 to 0.96, and the specificity was 0.90. The results of the survey were validated against the assessment of 2 experienced lymphedema therapists. This instrument represents a valuable resource for clinical investigation; however, its length makes it unfeasible for routine clinical assessment.
CTCAE v3.0 The National Cancer Institute Common Toxicity Criteria (NCI-CTC) are a collection of grading scales designed for the ranking of severity of adverse events (treatment- or tumor-related or comorbidity events), which patients may experience while participating in NCI-sponsored oncology clinical trials. Adverse events are considered important secondary endpoints (primary endpoints are usually survival, tumor response/control). Adverse event data are intended to allow clinicians and investigators to evaluate the toxicity profile of a new treatment approach. The NCI-CTC was first created in 1988 and revised in 1998 (CTC v2.0).19 The most recent revision, Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0) includes a significant revision and expansion of radiotherapy, surgical, and pediatric criteria. There is a particular emphasis on the chronic and delayed effects of cancer treatment. Electronic dissemination by NCI via web site of CTCAE v3.0 is anticipated to occur in spring 2003. Development of CTCAE v3.0 Criteria for Lymphedema In April, 2002, the National Cancer Institute sponsored the LENT IV in St Petersburg, Florida. More than 90 international, multidisciplinary investigators participated in presentations and
Table 6. Casley-Smith’s Proposed 3-Part Lymphedema Staging System27
Stage 1 Stage 2 Stage 3
Fibrosis
Pitting
Elevation
Skin
None or minimal Moderate Substantial
Pits on pressure May be present May be present
Reduces edema Minimal to no reduction No reduction
No change No change Trophic changes
The Grading of Lymphedema
working groups to address the measurement and reporting of late effects. The overarching goal of the LENT Lymphedema Working Group at this workshop was to devise a clear, user-friendly grading system that could be readily applied in the oncology clinical trials setting by clinicians unfamiliar with traditional lymphedema metrics and that required no special equipment. The new criteria developed by the group are intended to replace existing lymphedema criteria in CTC v2.0. The Lymphedema Working Group comprised an interdisciplinary team of clinicians: Andrea L. Cheville, MD (rehabilitation medicine); Charles McGarvey, PT (physical therapy); Jeanne Petrek, MD (surgical oncology); Sandra Russo, MD (radiation oncology); Marie Taylor, MD (radiation oncology); and Saskia Thiadens (lymphedema nursing). Because the validity and reliability of all extant lymphedema staging systems has yet to be established, the Working Group did not believe it was appropriate to use these systems as a basis for revising the CTC v2.0. Group consensus was established regarding the following principles in developing a novel lymphedema staging system: (1) avoid exclusive reliance on volume-based measurement, (2) avoid use of managementbased criteria given the absence of a widely acknowledged standard of care, (3) use language and physical examination findings familiar to all medical disciplines, (4) include symptom grading and language reflecting indication for the level of medical intervention, (5) limit function-based criteria given the potential for other sources of impairment to confound accurate grading, (6) ensure that the grading system were applicable to any body part, (7) establish clear intergrade distinctions, (8) separate lymphedema characteristics (eg, volume, fibrosis, and dermal change) that might be inadvertently under- or overemphasized with a summed score, and (9) ensure that a significant distinction in morbidity occurred between grades 2 and 3. CTCAE v3.0 lymphedema criteria are presented in Table 7. A concerted effort was made by the working group to avoid using specific (eg, ⱖ2 cm) differences in interlimb circumference as the basis for detecting or grading lymphedema. This has been a common past approach that is of limited clinical relevance because 2 cm may produce a visibly undetectable difference in a large arm but marked asymmetry in a small arm. Many individ-
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uals without lymphedema may display inherent anatomic variations or baseline differences between dominant and nondominant limbs related to differences in muscle mass. In addition, the utilization of anatomic landmarks to determine where measurements are taken can lead clinicians to inadvertently overlook lymphedema if it occurs outside of a measurement site. For patients with an uninvolved limb, the lymphedema working group incorporated quantitative volumetric criteria. However, rather than choosing an arbitrary, absolute value (eg, 2 cm), the percent difference in total limb volume and in limb circumference at the point of greatest visible discrepancy were used as the basis for determining lymphedema grade. The group developed vocabulary describing volumetric change that could be applied with equal ease to limb, truncal, and head and neck lymphedema. Obscuration of anatomic architecture (eg, blood vessels, tendons, and bony landmarks), obliteration of skin folds, deviation from normal anatomic contour, and the presence of pitting were incorporated into the criteria as a basis for detecting and grading lymphedema in all body parts. Lymphorrhea (exudation of lymph fluid through intact skin) was incorporated into the CTCAE v3.0 criteria as a means of clearly distinguishing severe, grade 3 lymphedema. Group consensus established that volume, soft-tissue change, and dermal change would be graded separately. This represented a marked departure from CTC v2.0. Another significant change from CTC v2.0 arose from the group’s acknowledgment that appendicular and axial lymphedema were distinct phenomena and should be measured and described separately. Hence, the group generated specific criteria for head/neck edema, limb edema, and truncal/genital edema. Criteria and descriptors from established lymphedema staging systems (eg, circumferential measurement and presence of dermal change) were selectively incorporated into the CTC v2.0 revisions to produce a more comprehensive grading system. Although these criteria will be immediately introduced and used for toxicity grading in NCI-sponsored clinical trials, the validity, accuracy, and reliability of the CTCAE v3.0 should be tested in future studies. Lymphatic toxicities were restricted to somatic lymphedema in the CTC v2.0. These were expanded in the CTCAE v3.0 to include lympho-
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Table 7. CTC v.3.0 Lymphedema Criteria Lymphatics Grade Adverse Event Chyle or lymph leakage
Short Name Chyle or lymph leakage
1
2
3
Asymptomatic; clinical or radiographic findings
Symptomatic; medical intervention indicated
Symptomatic and interventional radiology or operative intervention indicated
Trace thickening or faint discoloration
Marked discoloration — or leathery skin texture or papillary formation
4 Life-threatening complications
Also consider: Chylothorax. Dermal change lymphedema, phlebolymphed ema
Dermal change
—
Remarks: Dermal change lymphedema, phlebolymphedema refers to changes due to venous stasis. Also consider: Ulceration. Edema-head and neck
Edema-head and neck
Localized to Localized facial or dependent areas neck edema with and no disability or functional functional impairment impairment
Edema-limb
Edema-limb
5%-10% inter-limb discrepancy in volume or circumference at point of greatest visible difference; swelling or obscuration of anatomic architecture on close inspection; pitting edema
Edema-trunk/genital
Edema-trunk/genital
Swelling or obscuration of anatomic architecture on close inspection; pitting edema
Edema-viscera
Edema-viscera
Asymptomatic; clinical or radiographic findings only
⬎10-30% inter-limb discrepancy in volume or circumference at point of greatest visible difference; readily apparent obscuration of anatomic architecture; obliteration of skin folds; readily apparent deviation from normal anatomic contour Readily apparent obscuration of anatomic architecture; obliteration of skin folds; readily apparent deviation from normal anatomic contour Symptomatic; medical intervention indicated
Lymphedema-related Lymphedema-related Minimal to moderate Marked increase in fibrosis fibrosis redundant soft density and tissue unresponsive firmness, with or to elevation or without tethering compression with moderately firm texture or spongy feel Lymphocele Lymphocele Asymptomatic, Symptomatic; clinical or medical radiographic intervention findings only indicated Phlebolymphatic cording
Phlebolymphatic cording
Asymptomatic, clinical findings only
Symptomatic; medical intervention indicated
Lymphatics-other (Specify)
Lymphatics-other (Specify)
Mild
Moderate
Generalized facial or Severe with neck edema with ulceration or functional cerebral edema; impairment (e.g., tracheotomy or difficulty in turning feeding tube neck or opening indicated mouth compared to baseline) ⬎30% inter-limb Progression to discrepancy in malignancy (i.e., volume; lymphangiosarcoma); lymphorrhea; gross amputation deviation from indicated; disabling normal anatomic contour; interfering with ADL
Lymphorrhea; interfering with ADL; gross deviation from normal anatomic contour
Progression to malignancy (ie lymphangiosarcoma); disabling
Symptomatic and unable to aliment adequately orally; interventional radiology or operative intervention indicated Very marked density and firmness with tethering affecting ⱖ40% of the edematous area
Life-threatening consequences
Symptomatic and interventional radiology or operative intervention indicated Symptomatic and leading to contracture or reduced range of motion Severe
—
—
—
Life-threatening; disabling
The Grading of Lymphedema
coele, chyle/lymph leak, and visceral edema. No previous systems have been formulated to grade any of these complications. Therefore, the group incorporated standard language widely used throughout CTCAE v3.0 for visceral complications. For each of these, the following grading system was adopted: grade 1: asymptomatic, clinical or radiographic findings only; grade 2: symptomatic, medical intervention indicated; grade 3: symptomatic and interventional radiology or operative intervention indicated. This approach offers the opportunity to capture the key features of treatment-related lymphatic morbidity. Criteria on phlebolymphatic cording were also added to CTCAE v3.0. This is a relatively common phenomenon arising predominantly in the axilla from the clipping of small axillary veins and the removal of lymph nodes. Phlebolymphatic cording is noted very soon after surgery and therefore has not been attributed to venous collapse and clotting secondary to intravenous therapy or irritating chemotherapeutic agents. Veins and lymphatics whose proximal termini are occluded will eventually sclerose and be reabsorbed. Until this occurs, they can be a source of significant discomfort and limit shoulder mobility. The criteria for phlebitis, including superficial venous thrombosis, are graded separately in CTCAE v3.0 as a vascular event. Quantitative Measures of Lymphedema Various quantitative approaches have been adopted to characterize soft-tissue changes in lymphedema. These may be useful to validate clinical grading systems and to provide more objective endpoints in toxicity intervention studies. They can be divided into 3 distinct approaches: (1) soft-tissue imaging, (2) quantification of changes in electrical conductance, and (3) quantification of changes in biomechanical properties. Conventional imaging modalities have been used to characterize soft-tissue changes in lymphedema. Low-frequency ultrasound (3.5-10 MHz), despite its capacity to detect subcutaneous fibrosclerosis, has thus far proved to be of limited utility.34,35 In contrast, high-frequency ultrasound may offer a useful means of discriminating between lymphedema and edema arising from venous insufficiency or cardiac failure. Changes in dermal echogenicity measured by high-frequency ultrasonography are a valid surrogate measure for changes in dermal water content.36 Magnetic
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resonance imaging (MRI) soft-tissue changes in lymphedema include dermal and subcutaneous thickening, increased subcutaneous fat, and trabecular structures in the subcutis.37-42 The anatomic, pathophysiologic, and prognostic relevance of these structures has yet to be determined. High resolution MRI of skin and subcutis by using a specialized surface gradient coil is able to precisely quantify increases in the water content and size of dermal structures. It may provide a means of tracking change in lymphedema over time. The development of MRI contrast agents of sufficient molecular size to be sequestered and transported by the lymphatics has been the focus of several investigations.43 Computed tomography scanning offers little advantage over MRI aside from cost. Cornish and colleagues have pioneered the use of electrical impedance to assess soft-tissue change in lymphedema.44 The information provided by bioimpedance is confined to changes in soft-tissue water content. Nonetheless, bioimpedance was shown to reproducibly detect increased water content in progressive stages of lymphedema.45 With decongestive therapy, bioimpedance measures decreases in water content that correlate with limb volume reduction.46 Perhaps most significantly, bioimpedance was recently shown to detect subclinical lymphedema after axillary dissection in breast cancer patients.47 Tissue texture, elasticity, and compressibility change in response to fluid and fibrosis in the interstitial space. Biomechanical measurements have been used to characterize these alterations in lymphedema. Objective determination the depth of tissue pitting can be obtained with the tonometer,48 a device that measures the depth of compression by an applied mass after a fixed time period. Alternate approaches to biomechanical characterization involve the generation of indentation and impression force curves.49,50 These techniques capitalize on the fact that edematous and fibrotic tissues respond very differently over time to sustained compression. They have yet to be validated for the assessment of lymphedema or widely integrated into clinical practice.
Summary Lymphedema is an important adverse effect of cancer and its treatment. Because of its diffuse
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nature, clinical recognition and severity ranking can be difficult for even trained observers. The lymphedema criteria generated by the LENT Lymphedema Working Group, and subsequently incorporated in CTCAE v3.0, include key clinical descriptive elements available for assessment and grading in clinical trials. Further work is needed to establish their validity and reliability, including correlation with quantitative technologies and patient-rated instruments.
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