Lymphedema: What Causes It and Can It Be Prevented?

1. Lymphedema: What Causes It and Can It Be Prevented? Electra Paskett, PhD The Ohio State University

2. Lymphedema: Definition • Side effect of treatment due to disruption of lymph flow. • Distinguished by swelling and/or pain in affected area. • Estimates of incidence, prevalence, duration of swelling are varied. • Effects on survivors’ quality of life varied. • No prevention strategies have been proven effective.

3. Who Gets Lymphedema? • Cancer patients who receive surgery and/or radiation therapy • Other types of surgeries – e.g., CABG, hip replacement • Lymphedema occurs in upper/lower limbs, head/neck, breast/torso • Why do some people get it and others do not? What do we know about it?

4. Lymphedema: Overview • The accurate incidence and prevalence of lymphedema is “complex,” and the pertinent medical publications are sparse (Williams et al., 2005). • Little has been published about primary, trauma- and iatrogenic-related lymphedema (Rockson & Rivera, 2008). • Leg lymphedema is most often seen in survivors of uterine and prostate cancer, as well as melanoma and lymphoma survivors (Meneses & McNees, 2007). • A majority of the published literature focuses on breast cancer-related arm lymphedema.

5. Background • Early detection and treatments have increased the number of survivors. • In 2012, over 13 million cancer survivors • Focus on quality of life and survivorship. • Issues for cancer survivors: • Fatigue • Nausea • Pain • Depression • Anxiety • Infertility • Sexual dysfunction • Sleep disturbance • Osteoporosis • Lymphedema

6. Data Source: Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2008/, based on November 2010 SEER data submission, posted to the SEER web site, 2011. Prevalence of Cancer Survivors by Site of Malignancy

7. New York Times Article June 5, 2007

8. NCI Cancer Bulletin: Spotlight on Lymphedema After Cancer(May 29, 2007)

9. What We Know about Lymphedema Risk • Increases LE risk • Radiation and chemotherapy (Geller et al., 2003; Todo et al., 2010; Ohba et al., 2011; Helyer et al., 2010) • Axillary (AND) and sentinel node (SND) dissection (Mansel et al., 2006; Del Bianco et al., 2008; Lucci et al., 2007; Ashikaga et al., 2010; Land et al., 2010; Van der Zee et al., 2008; Cormier et al., 2009) • Risk of LE in patients who undergo SND only is lower than AND + SND • Nodes removed (higher number and positivity) (Todo et al., 2010; Graham, 2002; Clark et al., 2005)

10. What We Know about Lymphedema Risk (cont.) • Increases LE risk (cont.) • Overweight and obesity (Werner et al., 1991; Soran et al., 2006; Swenson et al., 2009; Mak et al., 2008) • Little or conflicting evidence for age, air travel, needle sticks, surgery on the dominant arm, mastectomy and hand use • Exercise and physical activity do not increase LE risk (Schmitz et al., 2009; Schmitz et al., 2010)

11. Lymphedema Incidence • Lymphedema can develop days or years after treatment. • Most survivors develop lymphedema within 3 years of treatment, while the remainder develop it at a rate of 1% per year (Petrek et al., 2001). • The overall incidence of arm lymphedema can range from 0% to 65%, depending on diagnostic criteria and method of assessment (Deutsch et al., 2008; Kwan et al., 2010; Paskett et al., 2007; Gartner et al., 2010; Shah & Vicini, 2011).

12. Electra Paskett, Michelle Naughton, Thomas McCoy, L. Douglas Case and Jill Abbott The Epidemiology of Arm and Hand Swelling in PremenopausalBreast Cancer Survivors Funded by U.S. Army Medical Research and Materiel Command grants DAMD17-96-1-6292 and DAMD17-01-1-0447.

13. Purpose • In a cohort of young women, aged 45 or younger, diagnosed with breast cancer to: • Estimate the incidence and prevalence of self-reported swelling; • Explore which patient characteristics were associated with lymphedema; and • Assess impact of lymphedema on quality of life. (Paskett et al. 2007)

14. Eligibility Requirements • Women age 18 to 45 at diagnosis • Stage I – III invasive breast cancerwithin the previous 8 months • Regular menstrual cycles at the time of diagnosis • No prior or concurrent history of any cancer, excluding basal or squamous cell carcinoma and stage 0 cervical cancer

15. Study Design • Prospective cohort with mailed baseline and annual surveys • LE (swelling) questions included (self-reported) • QoL: FACT-B and SF-12 • Assessed factors related to swelling: • Personal • Lifestyle • Tumor • Treatment

16. Demographics (n = 622) • Mean age at diagnosis: 38.5 years (range 20 – 45) • A majority of the participants were: • White (89%) • Married or living as married (75%) • College graduates (66%) • Employed full-time (55%) • A majority of the participants had: • Axillary node dissection (93%) • Chemotherapy (88%) • Radiation (70%)

17. 0.7 0.6 0.5 0.4 Proportion Ever Swelling 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 Time (Months) Lymphedema Incidence among Young Breast Cancer Survivors One to Three Years Post-Surgery (n = 622) Paskett et al., 2007

18. Factors Associated with Persistent Swelling During 1st 3 Years (n=622)* * 32% reported persistent swelling

19. Effect of LE on Quality of Life (n = 622)

20. Health-related Quality of Life (HRQL) in Long-term Breast Cancer Survivors:A CALGB Study (79804) Electra Paskett, Nancy Stark, Eric Winer, Marcy List,Martee Hensley, Alice Kornblith,KarleenHabin, James Herndon II, Jeannette Dowell, Marisa Bittoni, Jill Oliveri, Mira Katz, Catherine Alfano, Michelle Naughton, Gini Fleming, Charles Shapiro, Kathleen Donohue Funded by grants AG16602, CA78983, CA57707 from the NIH

21. Purpose To describe: • Characteristics of arm and hand swelling; and • Effects of swelling upon perceived physical functioning and mental health.

22. Population • Women who participated in CALGB 8541 • CALGB 8541: • Arm 1 - high dose: C/DOX/F at 600/60/600 (n=78) • Arm 2 - low dose: C/DOX/F at 300/30/300 (n=74) • Arm 3 - standard: C/DOX/F at 400/40/400 (n=93)

23. Eligibility Requirements • Patients must have been treated on CALGB clinical trial 8541 (open to accrual from January 1985 to April 1991). • Originally registered to CALGB 8541 by an institution that is still a member of CALGB. • Patient must be free from breast cancer for at least 12 months prior to registration. • No concurrent malignancy. • Must be able to read and complete an English-language questionnaire.

24. Demographics (N = 245) • A majority of the participants: • were 50 – 69 years of age (61%) • were White (93%) • had incomes > $20,000 (68%) • had a high school diploma or greater (94%)

25. Results • 31% of the 245 long-term survivors reported arm/hand swelling since their surgery. • Of these survivors: • 76% reported current swelling; • 49% reported constant swelling; and • Swelling was most often experienced in upper arm.

26. Results (cont.) • Of those who reported swelling since surgery: • 88% perceived swelling was mild or moderate. • Swelling interfered with daily activities • Fit of clothing: 36% • Perceptions about general appearance: 32% • Only 37% sought treatment for swelling. • 43% also experienced pain with swelling.

27. Results (cont.) • Regarding relationship between swelling characteristics, perceived physical functioning and mental health: • Swelling severity was negatively associated with physical functioning. • Swelling showed little association with mental health.

28. Lymphedema Prevalence • Prevalence estimates vary greatly due to: • Lack of standard diagnostic criteria (e.g., % of limb volume change, absolute difference in measurements, etc.) • Method of assessment (e.g., arm circumference, perometry, bioimpedance, etc.). • Deo et al. (2004) reported that 33.5% of breast cancer patients at least 1 year post-treatment had clinically significant lymphedema, with 17.2% reporting severe lymphedema.

29. Lymphedema Prevalence (cont.) • 75.3% of patients with head and neck cancer (at least 3 months post-treatment) had some form of lymphedema (i.e., internal, external or both) (Deng et al., 2011). • 31% of patients undergoing surgical treatment for vulvar cancer were diagnosed with lymphedema 6 months post-surgery (Novackova et al., 2012). • 34% of breast cancer survivors 6 years post-treatment showed clinical evidence of lymphedema at follow-up (Hayes et al., 2011). • 48% reported arm swelling at least once since the baseline assessment. • Lymphedema diagnosed by arm circumference and bioimpedance between 6 and 18 months post-cancer diagnosis predicted mortality (p = 0.04 and 0.08, respectively).

30. Other Considerations • Women relied heavily on healthcare providers for information about treatment and side effects of treatment (Paskett and Stark, 2000). • The negative effect of swelling on quality of life is well-documented (Paskett and Stark, 2000; Paskett et al., 2007; Oliveri et al., 2008; Shih et al., 2009; McWayne & Heiney, 2005; Vassard et al., 2010; Hormes et al., 2010; Ridner et al., 2011).

31. What We Know about Lymphedema Prevention • Current prevention knowledge is based more on clinical observation rather than research. • Exercise can improve body’s ability to respond to infection, trauma, injury and inflammation (Schmitz et al., 2010). • Weight training might prevent LE or reduce swelling (Schmitz et al., 2010). • Physiotherapy (including manual lymph drainage) has been shown to reduce LE incidence (Box et al., 2002; Torres Lacomba et al., 2010). • Effective strategies are needed to prevent LE.

32. CALGB/CTSU 70305: A Randomized Study to Prevent Lymphedema in Women Treated for Breast Cancer Electra Paskett, PhD, Protocol Chair The Ohio State University Comprehensive Cancer Center Funded by Lance Armstrong Foundation, Susan G. Komen Breast Cancer Foundation, the National Cancer Institute and private donors

33. Goals • Test a program to reduce the incidence/severity of lymphedema • Implement and test a program in a group randomized clinical trial (RCT) (intervention vs. education-only) • Assess differences in health-related quality of life (HRQL) • Assess adherence • Assess agreement between self-report and measurement of swelling

34. Design • Group RCT (randomized at institution level) • Women receiving sentinel node (SND) or axillary node dissection (AND) for breast cancer • Test education-only vs. education plus exercise and counseling • Followed for 18 months • Physical and self-report assessments • At least 28 sites needed (currently have 34)

35. Study Schema InstitutionLevel Institution completes questionnaire Lymphedema prevention patient education & tailored exercise intervention Institutional randomization Lymphedema prevention patient education Step 2 Registration Patient Level If patient received SND or AND Step 1 Registration (pre-surgery) Surgery Baseline measures

36. Step 1 Eligibility Criteria • Stage I-III breast cancer • Aged 18 years and older • Able to participate in mild exercise program • Remain in study area • Likelihood of sentinel (SND) or axillary node dissection (AND) • Arm measurements for axilla, elbow and wrist that accommodate a standard size elastic compression garment • No previous history of breast cancer or lymphedema diagnosis (other cancers ≥ 5 years post-treatment are eligible) • Agree conditionally to participate • Patients receiving neoadjuvant chemotherapy or radiation are eligible, provided that pre-surgery measurements are taken prior to neoadjuvant therapy.

37. Step 2 Eligibility Criteria • Sentinel node dissection (SND) only or axillary node dissection (AND) • Patients with double mastectomy, SND/AND and/or radiation on both arms are ineligible.

38. Outcomes • Lymphedema • Self-report • Measurement (4-cm protocol) • HRQL • FACT-B+4 • Adherence • Others: body image, fear of recurrence, self-efficacy, lymphedema knowledge, range of motion

39. Intervention Program (LEAP) • Education (American Cancer Society guidelines for lymphedema preventive care) • PT assessment • Individualized exercise • Breathing exercises • Elastic compression sleeve • Instructional video

40. Lymphedema Prevention Pilot Study Results – Paskett et al. (2005) • 52% performed arm exercises and 39% performed lymph flow exercises • 35% wore elastic sleeve ≥ 75% of time (as indicated) • Forgetfulness and time limitations most common barriers to adherence • Observed some reduction in arm volume compared to pre-surgery measurements

41. Assessment Schedule • Pre-surgery assessment • Up to 6 weeks post-surgery (baseline) • 6 months post-baseline (self-report measures only by mail or phone) • 12 months post-baseline • 18 months post-baseline

42. Clinical Variables (from chart review)* • Stage • Surgery type • Type of dissection • Number of nodes removed • Number of positive nodes • Chemotherapy received • Radiation therapy received • Adjuvant therapy received * at Step 2 registration and end of study

43. Adherence • Questionnaire at each visit (6, 12 and 18 months post-baseline) • Adherence “tips” incorporated into each visit • Reminder calls in Months 9 and 15 • Adherence calendars for each month in study (intervention only) • Incentives (intervention only): refrigerator magnet, hand and body lotion, bookmark

44. Other Study Considerations • $10 gift card to local retailer per patient/per visit • Elastic compression sleeves and gauntlets are provided by the study for intervention women. • Women who show signs or symptoms of lymphedema are referred to a specialist for lymphedema treatment.

45. Accrual To Date • Began December 2006 • Indefinite accrual period with 18-month follow-up period post-surgery • Goal to close study to accrual in early 2013 • Will maintain 18 months of follow-up until Summer 2014 • At least 560 participants across 34 sites* • About 20 participants per site (1-2 per month) • As of 7/31/2012, 456 patients have been registered to Step 2 across all sites.

46. Conclusions • Lymphedema has been understudied. • Lymphedema affects millions of cancer survivors. • Estimates of incidence, prevalence and effects of lymphedema are being reported. • Results suggest the need for effective prevention strategies.

47. Future Directions • Awareness/education – general, patients, providers • Treatment and certification – capacity • Research – prevention, detection, treatment • Dissemination of effective strategies • Policy issues – insurance, legislation, standards of care

48. The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute