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REVIEW – SHAITELMAN (2015)
RECENT PROGRESS IN THE TREATMENT AND PREVENTION OF CANCER-RELATED LYMPHEDEMA

This panoramic survey of the contemporary lymphedema literature brings together discussions of many of the recent developments in the diagnosis, treatment and prevention of lymphedema. Yet with all of the excellent data and evaluation, it suffers from some major omissions and an entire section that is replete with inaccuracies.

Incidence of Breast Cancer-Related Lymphedema (BCRL)

It is well known that estimates of the incidence of lymphedema are diverse for a number of reasons, many of which are dealt with in separate sections of this review, e.g. measurement technique or instrument, stage or severity, body site, etiology and lack of agreement as to the definition of lymphedema. Compounding these individual differences are uncertainties introduced by trial design and patient selection.

Tables 1 and 2 of the reviewed document[1] present summaries of the incidences of upper limb lymphedema among breast cancer patients undergoing sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) respectively. The information summarized on the tables, i.e. Principal Author, Number of Patients, Measurement Technique and Incidence is abstracted from each reviewed reference. A pooled incidence is derived from the averaging of these data.

There are many problems with these tables as published. The first problem is that there are errors in the information abstracted from the cited references as to numbers of patients, measurement method and incidence. If this information is important enough to include in an archival publication and is to be used by other researchers, it must be accurate. Corrections of errors detected by this reviewer include the following:

Table 1 Studies Assessing Upper Limb Lymphedema After SLNB for the Treatment of Breast Cancer
Sackey 2014Subjective
Lucci 2007226 Patients, 6%
RönkäClinical Examination (This incidence is for breast lymphedema, not UL)
Blanchard 2003Survey
Swenson 20023.5% at 12 months (9% and 5% at 1 and 6 months)
Senner 2001Arm measurements
Schrenk 2000Subjective
Table 2 Studies Assessing Upper Limb Lymphedema After ALND for the Treatment of Breast Cancer
Sackey 2014Subjective
Rutgers 2013Arm Circumference
Lucci 2007242 Patients
Blanchard 200391 Patients, Survey, 34%
Swenson 200214% at 12 months (16% and 20% at 1 and 6 months)
Senner 2001Arm Measurements, 17%
Schrenk 2000Subjective, 54%

The second problem is that the incidences recorded in the tables do not represent the same statistic, and it may be misleading and meaningless to combine them until and unless a measurement standard is agreed upon. The studies reviewed use percent excess volume, arm circumference, skin bioelectric impedance, skin thickness, clinical examination, and patient surveys with differing break points to define lymphedema. Criteria for the definition of "lymphedema" differ, as so aptly demonstrated by co-authors Armer and Stewart in their 2005 study[2].

Furthermore the incidence of lymphedema generally increases as a function of time from cancer treatment, and is influenced by interventions during the time of observation. Onset of lymphedema varies as a function of the method of measurement and the causative therapeutic procedure. Toxic effects of radiotherapy may not become fully evident until many years after treatment. Using sensitive lymphoscintigraphic measures of lymphedema, Campisi[3] shows early effects of breast cancer treatment at 3-6 months (range <1 to 24 months). The delayed effects of radiotherapy are demonstrated by Pierquin[4] with median onset at 7 months (range 2-37) with surgery alone, 12 months (1-52) with surgery and radiation and 25 months (6-156) with radiation alone. Other researchers demonstrate medians between 1 and 2 years, with maximum times of onset of 3 to 10 years for cohorts with a mix of treatments. So the incidence at the end of study periods of 6 months, 1 year, 3 years and 5 years (Table 9 of reference 1) cannot simply be averaged without reference to lymphedema life cycle, measurement technique and threshold and intervention.

Incidence of Breast Lymphedema include quote from Meek & Lawenda on importance of breast LE

The protocols for breast cancer diagnosing, staging and treatment frequently involve surgery and radiation to the breast, and less frequently to the axilla and clavicle. The removal of as few as one node in the drainage path of the tumor [sentinel lymph node biopsy (SLNB)] can alter the lymph drainage of the breast and cause breast edema/lymphedema. Subsequent irradiation of the breast alters the regeneration and function of the breast lymphatic drainage network and is responsible for a not insignificant incidence of lymphedema of the breast and chest.

Measurement of breast lymphedema has been a challenging task since the breast is not amenable to volumetric measurements or calculations as are the upper limbs. The result of this difficulty is probably an under-measurement and under-reporting of breast lymphedema. While this review covers upper and lower extremity lymphedema resulting from treatment of breast cancer, melanoma, genitourinary cancers and sarcomas, it neglects the incidence of breast and truncal lymphedema which, according to some researchers, has an incidence as high as that of upper limb lymphedema resulting from breast cancer treatment. Methods used to measure breast lymphedema have included[5]:

Breast lymphedema started to receive attention in 1982 with Kissin[6] reporting clinical rates of 8% and Clarke[7] reporting rates of 41% using skin measurements. More recent reports estimate the rates at 1-9% based on subjective reporting [Fehlauer 2003][Højris 2000], 10-29% based on clinical examination [Fehlauer 2003][Goffman 2004], 20-48% [Rönkä 2004][Senofsky 1991] and 30-70% based on skin thickness measurement [Rönkä 2004] and tissue dielectric constant skin water content [Johansson 2014]. Without knowledge of the measurement method and diagnostic criteria, any statement of lymphedema incidence is meaningless.

Table A. Studies Assessing Breast Lymphedema After Treatment of Breast Cancer

Researcher
First Auth.		Pub.
Date		Number
Breasts		ConditionsAxillary
Treatment		MeasureIncidence %
Mild/Med/Sev
Clarke 198274 CBS + RTx
@1 year		None/SLNB
ALND		 Clinical
Evaluation		6/25
79
Beadle 1984239 @6 months
@5 years		 Clinical
Evaluation		32/3/0
23/0/0
Pezner 198547 Bra Cup Size
A-B/C-DD		 15/48
Senofsky 1991133 50 months (4-180)RTx/NoRTx
ALND		 Clinical
Evaluation		21/5
12
Bosompra 2002148 @2-4 years Patient
survey		14
Goffman 2004240 BCS>1.5 yearsSLNB 5%
ALND 76%		 Clinical
exam		8/0/1
Rönkä 2004160 @1 year,SLNB
ALND		 Skin thickness/
Subcut. Fluid*		*28/17
*70/54-59
Rönkä 2005109 @1 yearSLNB
ALND		 Self-reported16/7/0
41/15/2
Leidenius 2005139 @3 yearsSLNB
ALND		 Self-reported6/1/0
21/4/0
Degnim
Boughey		 2012
2014		78 11 monthsSLNB
ALND		 Clinical exam
QOL Instr.		46/3
Johansson 2014118 @4 weeksBefore/After
RTx		 TDC Ratio**
>1.40		**31/63

CBS = conservative breast surgery (lumpectomy), RTx = Radiotherapy, QOL = quality of life survey ALND = axillary lymph node dissection, SLNB = sentinel lymph node biopsy *Ultrasound imaging, skin thickness >2mm, pools of subcutaneous fluid ** Tissue Dielectric Constant ratio between irradiated and healthy breast

Omissions of Important Topics Relating to BCRL

Omission of some topics and references I believe to be significant because of their future impact on diagnosis, prevention and treatment of lymphedema:

  1. Measurement of early lymphedema by measuring tissue dielectric constant as an objective measure of tissue fluid at any body site, used by Johansson et al. to define breast edema following surgery and radiation for breast cancer[8]. The localized measurements of breast edema at each quadrant of the breast separately, before and after surgery and radiation, enabled conclusions as to the separate causative effects of these modalities;
  2. Ultrasonic measurement of skin thickness as an objective measure of tissue fluid at any body site, used by Rönkä in investigations of early breast lymphedema[8], demonstrates another viable technique for detection of pre-clinical lymphedema (used by Rönkä in Ref. 40, listed as N/R in Table 1);
  3. The discussion of Incidence of Lymphedema among Patients with Breast Cancer (Table 1 and Table 2) is limited to lymphedema of the upper extremity with the exception of one data point at Rönkä 2004[40] which refers to breast lymphedema. Breast lymphedema/delayed breast cellulitis, which may have an incidence equal to upper extremity lymphedema as a sequela of breast cancer treatment[8][9], is afforded no discussion despite there being a dozen publications on the subject since 1982;
  4. Potential utility of manual lymphatic drainage as a lymphedema preventive intervention in breast cancer treatment survivors when given routinely after surgery[10]. No discussion of Zimmermann 2012 which supports the use of MLD as a lymphedema preventive intervention in breast cancer treatment survivors when given routinely after surgery, and which results were not considered by Huang Ref. 159. See http://www.lymphactivist.org/review-zimmermann-2012.php

Errors of Fact in Insurance Coverage Section

The subject paper brings together diverse previously-published materials to synthesize a review of the current status of lymphedema knowledge that will be a valuable reference to researcher, practitioner and patient. There are, however, errors of fact that need correcting in the Insurance Coverage section at the end of the paper.

The insurance coverage errors of fact seem to come about from a misreading of Reference 239[11]. Table 3 of this reference examines the reports of three state health mandate commissions that analyzed the lymphedema treatment bills introduced in California, Massachusetts and Virginia. These reports analyzed the medical, societal and financial impacts of the proposed bills, intended to inform legislators prior to any legislative action. Only the Virginia bill was passed on to the Virginia General Assembly and subsequently enacted. Neither the California nor the Massachusetts bills ever left Committee for a floor vote.

As of 2014 only two states have enacted legislation mandating the diagnosis and treatment of lymphedema, i.e. Virginia in 2004 and North Carolina in 2010. A third state, Louisiana, in 2014, mandated inclusion of coverage for the treatment of lymphedema as an option in certain policies[12]. Effective January 1, 2014,

California includes coverage of "lymphedema wraps and garments" as prosthetic and orthotic services and devices under Essential Health Benefits[13]. New York State funds grants for lymphatic research, and has established a National Lymphatic Disease and Lymphedema Patient Registry and Tissue Bank.

Over the last decade lymphedema bills have been presented, but not passed, in a handful of states and in Congress. They have ranged in scope from educational efforts such as pronouncements of lymphedema awareness days and production of lymphedema brochures (e.g. NY A7398-2007) to comprehensive lymphedema diagnosis and treatment acts (e.g. US H.R.4662-2010, CA AB-213-2006, MA S.586-2007, NY A7077-2007). Many bills have intermediate objectives such as recognition of lymphedema therapist requirements (e.g. US S.3963- 2006 and US H.R.1846-2007), coverage of lymphedema compression items (e.g. US H.R.4154-2002, US H.R.3877-2014, CT HB5303-2007) and pilot programs to evaluate cost of lymphedema treatment (GA HB1011-2007).

H.R.3877-2014 (the Lymphedema Treatment Act) does not mandate that "insurance companies provide coverage for lymphedema treatment on best practice standards, as well as CDT, compression garments, and at home aids". It only provides coverage of "certain compression treatment items". H.R.4662-2010 the Lymphedema Diagnosis and Treatment Cost Saving Act of 2010, which died in Committee, would have provided comprehensive diagnosis and treatment of lymphedema according to best standards, CDT including compression supplies, therapist and fitter qualification standards and patient education.

There are currently comprehensive lymphedema treatment mandate bills in the state legislatures in Massachusetts (S.493 2013) and New York (A08363/S03474A-2014 and A00436/S00252-2015), awaiting action by the Health or Insurance Committee.

With respect to the statement concerning the 2009 meeting of the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) it should be noted that this panel reported that evidence supports an intermediate level of confidence that complex decongestive therapy (CDT) alone, CDT with adjuvant compression devices, compression bandaging/compression garments alone, and pneumatic compression devices alone "produce clinically meaningful improved health outcomes for patients with secondary lymphedema"[14].

REFERENCES

[1] Shaitelman SF, Cromwell KD, Rasmussen JC, Stout NL, Armer JM, Lasinski BB and Cormier JN. Recent progress in the treatment and prevention of cancer-related lymphedema. CA: Cancer J Clin. 2015;65(1):55-81.

[2] Armer JM and Stewart BR. A Comparison of Four Diagnostic Criteria for Lymphedema in a Post-Breast Cancer Population. Lymph Res Biol.2005;3(4):208-217.

[3] Campisi C, Boccardo F, Zilli A, Napoli F, Ferreira Azevedo W Jr, Fulcheri E and Taddei G. Lymphedema secondary to breast cancer treatment: Possibility of diagnostic and therapeutic prevention. Ann Ital Chir. 2002;73(5):493-8.

[4] Pierquin B, Mazeron JJ and Glaubiger D. Conservative treatment of breast cancer in Europe: Report of the Groupe Européan de Curiethérapie. Radiother Oncol. July 1986;6(3):187-98

[5] Weiss R. Breast and truncal lymphedema—Its nature and treatment. July 2014, Pages 10-11. [Accessed March 18, 2015 at http://www.lymphactivist.org/breast_lymphedema_for_therapists.pdf

[6] Kissin MW, Thompson EM, Price AB and Slavin G. The inadequacy of axillary sampling in breast cancer. Lancet May 29, 1982;1(8283):1210-2.

[7] Clarke D, Martinez A, Cox RS and Goffinet DR. Breast edema following staging axillary node dissection in patient with breast carcinoma treated by radical radiotherapy. Cancer Jun 1, 1982;49(11): 2295-9.

[8] Johansson K, Lathinen T and Björk-Eriksson T. "Breast edema following breast conserving surgery and radiotherapy" Euro J Lymphology. 2014 25(70):1-5. See also http://www.lymphactivist.org/review-johansson-2014.php.

[9] Rönkä RH, Pamilo MS, von Smitten KAJ and Leidenius MHK. "Breast lymphedema after breast conserving treatment" Acta Oncol. 2004;43(6):551-7.

[10] Zimmermann A, Wozniewski M, Szklarska A, Lipowicz A and Szuba A. "Efficacy of manual lymphatic drainage in preventing secondary lymphedema after breast cancer surgery" Lymphology 2012;45:103-112. See also http://www.lymphactivist.org/review-zimmermann-2012.php

[11] Stout NL, Weiss R, Feldman JL, et al. "A systematic review of care delivery models and economic analyses in lymphedema: health policy impact (2004-2011)" Lymphology. 2013;46:27-41.

[12] LymphActivist’s Site http://www.lymphactivist.org RESOURCES > STATE LEGISLATION tabs.

[13] California Department of Managed Health Care (DMHC), California Code of Regulations, Title 28, §1300.67.005 Essential Health Benefits, subsection (d)(9)(B)(iii).

[14] MEDCAC Lymphedema Panel Score Sheets, MEDCAC Lymphedema Technical Panel, Question 6 https://www.cms.gov/faca/downloads/id51a.pdf

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