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To determine the incidence of breast cancer-related lymphedema (BCRL) during the early survivorship period, and demographic, lifestyle, and clinical factors associated with BCRL development.
The Pathways Study, a prospective cohort study of breast cancer survivors with a mean follow-up of 20.9 months.
Kaiser Permanente Northern California (KPNC) Medical Care Program.
997 women diagnosed from January 2006 to October 2007 with primary invasive breast cancer and at least 21 years of age at diagnosis, had no prior history of any cancer, and spoke English, Spanish, or Chinese.
Clinical indication of BCRL as determined from outpatient or hospitalization diagnostic codes, outpatient procedural codes, and durable medical equipment orders.
133 women (13.3%) had a clinical indication of BCRL, with a mean time to diagnosis of 8.3 months (range: 0.7–27.3). Being African American (HR = 1.93; 95% CI: 1.00–3.72) or more educated (p trend = 0.03) was associated with an increased risk of BCRL. Removal of at least one lymph node (HR = 1.04; 95% CI: 1.02–1.07) was associated with increased risk, yet no significant association was observed for type of lymph node surgery. Being obese at breast cancer diagnosis was suggestive of an elevated risk (HR = 1.43; 95% CI: 0.88–2.31).
In a large cohort study, BCRL occurs among a substantial proportion of early breast cancer survivors. Our findings agree with previous studies on the increased risk of BCRL with removal of lymph nodes and being obese, yet point to differential risk by race/ethnicity.
Breast cancer survival rates have been increasing over the past decade,1 resulting in more long-term health consequences of having been treated for breast cancer. With incidence rates averaging around 26% two years after surgery, at least 400,000 women may be currently living with breast cancer-related lymphedema (BCRL),2 the disruption of lymph transport leading to constant buildup of protein-rich fluid within the subcutaneous tissue of the arm, hand, and/or chest.3–5 Possible risk factors include degree of axillary dissection, radiation therapy, obesity at diagnosis, older age, post-operative fluid formation, and infection in the arm.6
Reports of BCRL incidence vary widely due to non-standard diagnostic methods, type of cancer therapy, and follow-up since treatment.4 Incidence ranges from 10 to 56% after axillary lymph node dissection (ALND), 0 to 23% after sentinel lymph node biopsy (SLNB), and 21 to 51% after axillary radiation therapy and lymph node surgery,2, 7 while the prevalence increases over time since treatment.8, 9 BCRL can cause functional impairment of the affected arm10, 11 and psychological morbidity,12–14 both of which can lead to overall decreased quality of life.9, 15–18
Given the limited number of prospective studies examining determinants of BCRL, we initiated a prospective cohort study among recently diagnosed breast cancer patients within Kaiser Permanente Northern California (KPNC). The Pathways Study is one of the first to systematically examine the incidence of BCRL, as well as demographic, lifestyle, and clinical factors associated with its development. We present data from the first 997 enrolled participants with an average follow-up time of 20.9 months.
The Pathways Study is an ongoing, prospective cohort study actively recruiting women from the KPNC patient population recently diagnosed with invasive breast cancer. As of January 30, 2009, 2,415 patients have been enrolled since recruitment began in January 2006, with a mean time from breast cancer diagnosis to enrollment of 1.9 months (range: 0.3–7.3 months). Participants are largely representative of the overall KPNC breast cancer population yet are slightly younger and more likely to be diagnosed with earlier stage disease, as described elsewhere.19 Cases are rapidly ascertained on a daily basis by automatic scanning of electronic pathology reports, with subsequent verification of cancer diagnosis and patient notification by a medical record analyst. Eligibility criteria include: current KPNC membership; at least 21 years of age at diagnosis; recent diagnosis of primary invasive breast cancer (all stages); no prior history of any cancer; and ability to speak English, Spanish, Cantonese, or Mandarin. Written informed consent is obtained from participants before commencement of the in-person interview. The study was approved by the institutional review boards of all collaborating institutions.
Diagnosis of lymphedema after breast cancer requires consideration of multiple clinical factors, including post-surgical transient swelling (not considered lymphedema). Lymphedema is classically defined by swelling.20 However, more recent guidelines in the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0)21 acknowledge that lymphedema not only includes swelling but tissue tone and texture as well. Diagnosis requires examination by a specialist trained as recommended by the National Lymphedema Network.22
Using KPNC electronic medical records, a diagnosis of lymphedema was determined from three sources: 1) outpatient or hospitalization ICD-9 diagnostic codes 457.0 (postmastectomy lymphedema syndrome) and 457.1 (other lymphedema, including acquired [chronic]); 2) outpatient procedural codes corresponding to lymphedema treatment and duration of the procedure, such as manual lymph drainage (CPT-4 code 97140 and internal KPNC qualifiers signifying duration) and compression wrap (CPT-4 code 97139 and internal KPNC qualifiers signifying duration); and 3) durable medical equipment (DME) orders associated with BCRL. Relevant events must have occurred after the primary breast cancer diagnosis. Women were excluded if they had a prior history of lymphedema diagnosis, procedures, and DME orders.
For the analysis, three definitions of a BCRL diagnosis were developed: 1) transient and persistent lymphedema: an outpatient clinic or hospitalization diagnosis, BCRL procedure, or DME order anytime after breast cancer diagnosis, 2) persistent lymphedema: an outpatient clinic or hospitalization diagnosis, BCRL procedure, or DME order at least three months after definitive breast cancer surgery, and 3) persistent lymphedema: an outpatient clinic or hospitalization diagnosis anytime after definitive breast cancer surgery followed by a BCRL procedure or DME order.
During the interview, demographic information (age at breast cancer diagnosis, race/ethnicity, education, marital status, and household income) as well as lifestyle factors (body mass index [BMI], smoking, and physical activity) are collected. BMI was calculated from self-reported weight and height, and missing values were supplemented by concurrent data from KPNC electronic medical records. Physical activity in MET (metabolic equivalent)-hours/week was assessed from a previously validated, self-administered questionnaire.23
Using KPNC electronic medical records, data on breast surgery (lumpectomy, mastectomy) and lymph node surgery (ALND, SLNB) were obtained using ICD-9 (85.20–85.23, 85.33–85.48, 40.23, 40.3, 40.51) and CPT-4 (19120–19240, 19301–19307, 19340–19342, 38500–38530, 38740, 38745, 38792) procedural codes. Number of lymph nodes removed during the definitive surgery was abstracted from pathology reports by a trained staff member. Data on number of positive nodes, American Joint Committee on Cancer (AJCC) stage, and chemotherapy and radiation therapy were obtained from the KPNC Cancer Registry (KPNCCR).24 Data are collected, coded, and added to the KPNCCR approximately four months post-diagnosis to allow for the completion of treatment. Radiation therapy data were also supplemented by other electronic sources. Information on adjuvant hormonal therapy was abstracted from outpatient pharmacy records.
The present analysis is based on the first 997 women enrolled in the Pathways Study with complete demographic, lifestyle, and clinical data. Initially, comparisons of relevant characteristics as determined a priori from previous literature and current hypotheses between women who developed BCRL and those who did not were compared using Pearson chi-square tests (categorical variables) and Satterthwaite t-tests (continuous variables). Follow-up began on the date of initial breast cancer diagnosis until BCRL diagnosis or July 31, 2008; women were censored on the date of death or disenrollment from the KP health plan (defined as first occurrence of a gap in coverage greater than 90 days). .
The Kaplan-Meier method was used to generate a cumulative incidence curve25 from initial breast cancer diagnosis to occurrence of BCRL in the cohort by plotting the complement of the survival function estimates. Initially, univariate Cox proportional hazards models26 were constructed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for each selected demographic, lifestyle, and clinical factor and risk of BCRL as defined above. Subsequently, only variables that retained a priori interest and/or statistical significance were included in three final multivariable models, with each model estimating the associations between the selected covariates (adjusted for each other) and one of the three definitions of a BCRL diagnosis. Linear tests of trend were estimated by modeling continuous predictor variables (age, BMI, physical activity) and categorical predictor variables (household income) on an ordinal scale.
All analyses were performed in SAS v. 9.1 (SAS Institute, Carey, NC).
Table 1 shows selected demographic, lifestyle, and clinical characteristics among 133 BCRL and 864 non-BCRL patients in the cohort. Women with BCRL were younger (55.3 years vs. 60.1 years), more educated (58.7% vs. 44.9% had completed college and/or graduate school), and never smoked (63.9% vs. 50.6%) compared to patients without BCRL. BCRL patients had more advanced cancer at diagnosis (AJCC stage II and III), were more likely to have had a mastectomy (58.6% vs. 34.6%), ALND (86.5% vs. 72.1%), and SLNB (84.2% vs. 71.4%), and were more likely to have had radiation therapy (77.4% vs. 70.3%) and chemotherapy (74.4% vs. 39.7%) compared to non-BCRL patients. On average, women with BCRL had more lymph nodes removed (n=12.4 vs. n=6.1) and more positive lymph nodes (n=3.3 vs. n=0.8) compared to women without BCRL. No significant differences were observed between the two groups by race/ethnicity, marital status, household income, BMI, physical activity, and adjuvant hormone therapy.
Among the 997 women followed over a mean of 20.9 months (range: 0.7–31.8 months) since breast cancer diagnosis, 133 women (13.3%) had a clinical indication of BCRL with a mean time to diagnosis of 8.3 months (range: 0.7–27.3 months) (Figure 1). After 12 and 24 months since breast cancer diagnosis, the cumulative incidence of BCRL was 10.4% and 13.5%, respectively.
Table 2 presents the associations between demographic, lifestyle, and clinical characteristics and risk of BCRL, adjusted for all characteristics of interest in three multivariable proportional hazards models.
For Model 1 showing risk of transient and persistent BCRL, compared to white women, African American women had an increased risk of BCRL (HR = 1.93; 95% CI: 1.00–3.72). Risk appeared to be increased in other minority groups as well but were not statistically significant (HR for Asians = 1.65; 95% CI: 0.88–3.10; HR for other races/ethnicities = 1.77; 95% CI: 0.73–4.25). Compared to women with a high school education or less, women with at least a college education also had an increased risk of BCRL (HR for college education = 2.58; 95% CI: 1.18–5.63; HR for post-graduate education = 2.72; 95% CI: 1.21–6.11; p trend = 0.03). Higher BMI was suggestive of an increased risk of BCRL among obese women (HR = 1.43; 95% CI: 0.88–2.31), yet the test for trend was not significant. Overall physical activity and moderate-to-vigorous physical activity were not associated with risk of BCRL.
Among the clinical characteristics, women diagnosed with more advanced cancer stage had an increased risk of BCRL (HR for AJCC Stage II = 2.58; 95% CI: 1.43–4.65; HR for AJCC Stage III = 5.39; 95% CI: 2.47–11.75). In addition, for each lymph node removed, BCRL risk increased by 4.1% (corresponding to a 49.3% increase in risk for every 10 nodes removed). Elevated yet non-significant associations were observed for having a mastectomy (HR = 1.29; 95% CI: 0.77–2.16) and lymph node dissection (HR for axillary = 1.37; 95% CI: 0.44–4.28; HR for sentinel = 1.54; 95% CI: 0.49–4.86; HR for axillary and sentinel = 1.75; 95% CI: 0.62–4.94). Chemotherapy (HR = 1.38; 95% CI: 0.81–2.38) or radiation therapy (HR = 1.25; 95% CI: 0.70–2.25) was associated with modest increased risks of BCRL, while hormone therapy was not associated with risk (HR = 0.96; 95% CI: 0.62–1.47).
Similar associations with generally wider confidence intervals were observed in Models 2 and 3 of risk of persistent BCRL compared to Model 1, although some differences were apparent (Table 2). In Model 2, chemotherapy was significantly associated with risk of BCRL (HR = 2.04; 95% CI: 1.03–4.03) compared to Model 1 (HR = 1.38; 95% CI: 0.81–2.38). For Model 3, being obese was significantly associated with increased risk of BCRL (HR = 2.34; 95% CI: 1.23–4.44) compared to Model 1 (HR = 1.43; 95% CI: 0.88–2.31).
In this prospective cohort study of 997 breast cancer survivors followed for BCRL development over an average of 20.9 months, 133 women (13.3%) developed BCRL as defined by a clinical diagnosis, procedure, or equipment order over an average of 8.3 months. Being African American and more educated was associated with an increased risk of BCRL. Advanced stage breast cancer and number of lymph nodes removed were also associated with an increased risk of BCRL, although no significant association was observed for mastectomy and type of lymph node surgery. Smoking and physical activity were not associated with BCRL risk, but being obese was suggestive of an elevated risk. After restricting BCRL diagnoses to exclude any transient swelling that might be treated as BCRL, all the associations remained, with a stronger association of BCRL with obesity and chemotherapy.
Our results confirm and contrast with findings from two recent studies of BCRL.6, 27 Paskett et al.6 conducted a prospective study of 622 young breast cancer survivors (≤45 years at diagnosis) using semi-annual questionnaires, and assessed factors associated with incidence of arm and/or hand swelling in adjusted Cox proportional hazards models. Similar to our results, the authors found that lymph node removal was associated with an increased risk of swelling (for each node removed, HR = 1.02; 95% CI: 1.01–1.04). They observed that receiving chemotherapy (HR = 1.76; 95% CI: 1.10–2.82), being obese (HR = 1.51; 95% CI: 1.09–2.09), and being married (HR = 1.36; 95% CI: 1.00–1.85) were also associated with an elevated risk, while age at breast cancer diagnosis (HR = 1.00; 95% CI: 0.97–1.03) and radiation therapy (HR = 1.23; 95% CI: 0.86–1.77) were not associated with risk. With the exception of marital status, these findings are similar to those that we observed.
Hayes et al.27 evaluated 287 women between 6 and 18 months after breast cancer treatment for BCRL using bioimpedance spectroscopy, and assessed the associations of personal, treatment, and behavioral characteristics with BCRL risk in adjusted logistic regression models. Similar to our study, they observed that removal of lymph nodes was associated with an increased risk (OR = 3.9; 95% CI: 0.5–28.9) and that radiation therapy was not associated with risk (OR = 0.9; 95% CI: 0.2–4.3). In contrast to our null results, Hayes et al. observed that lower income (less than $52,000 per year) was associated with decreased risk (OR = 0.2; 95% CI: 0.1–0.5) while having a mastectomy (OR = 5.9; 95% CI: 1.4–22.5) and being at least 50 years old at cancer diagnosis (OR = 3.3; 95% CI: 1.0–11.1) were associated with increased risk. They also reported that leading a sedentary lifestyle [OR = 6.1; 95% CI: 1.3–27.6)] was associated with an increased risk of BCRL, thus suggesting, along with several studies observing no increase in symptoms after participating in various exercise programs,28–32 that it is safe for women with BCRL to engage in physical activity.
The generally consistent findings across these studies and ours suggest that factors such as educational attainment, body size, and lymph node removal are risk factors for BCRL. The association of greater BCRL risk with higher education may be due to increased clinical consultation for swelling by more educated women, thereby resulting in additional BCRL diagnoses. Weight status at breast cancer diagnosis might be a predictor of developing BCRL, also suggested by other studies,6, 33–35 as being obese can contribute to increased risk of postoperative complications and reduced muscle-pumping efficiency within loose tissues.33, 36 As for chemotherapy, glucocorticoid agents such as dexamethasone can produce side effects of swelling,37, 38 which may also increase BCRL risk.
Removal of lymph nodes, rather than type of lymph node surgery, may be more germane to risk of BCRL. Observational studies have documented a lower risk of BCRL and other arm morbidity symptoms among patients who underwent SLNB only compared to ALND.39–45 For example, Francis et al.45 observed a 16.8% incidence of BRCL after SLNB using the CTCAE v3.0 criteria for diagnosis, compared to an increased risk of 47.1% after ALND. In contrast, no differences in risk at one year of follow-up were observed between women who underwent SLNB and ALND compared to SLNB alone in the American College of Surgeons Oncology Group (ACOSOG) randomized clinical trial.46 Final results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial of over 5,500 breast cancer patients are still outstanding.47 Although the evidence is suggestive that SLNB compared to ALND is associated with lower risk of BCRL,48 likely due to fewer lymph nodes removed with SLNB, we found that with even one removed node, a woman is at an increased risk (4.1%) for BCRL. Similarly, in a retrospective study of 1,338 older breast cancer patients who were diagnosed with in situ and invasive cancer and self-reported having BCRL, an increased risk of BCRL was observed with successive removal of nodes but not with type of surgery.49
To our knowledge, we are the first study to report an elevated risk of BCRL among minority groups, specifically African Americans, independent of confounding factors such as age at diagnosis, breast cancer stage, and socioeconomic status (education and income). While we cannot completely rule out residual confounding and spurious results due to small sample size in our analysis, one prior retrospective study noted a higher prevalence of BCRL among minority women.50 This racial/ethnic difference is consistent with the hypothesis that, in comparison to white women, minority women may be more likely to do manual labor involving the upper body and to return to work prior to full recovery and/or rehabilitation from their breast cancer surgery for their arms.
Strengths of this study include being one of the few large, prospective cohort studies of BCRL, and being conducted within KPNC, one of the largest HMOs in the United States with electronic medical records, facilitating rapid case ascertainment and participant follow-up, and identification of BCRL. We assessed BCRL by clinical indication using standard diagnostic and procedural codes. Furthermore, as part of a prospective study of breast cancer survivorship, we were able to examine the associations between demographic, lifestyle, and clinical characteristics and risk of BCRL.
Several limitations should be noted. First, we could only examine the effect of overall radiation therapy, rather than radiation therapy to the axilla, due to lack of information on anatomical site of treatment in electronic data sources. Second, considering our outcome ascertainment methods using electronic medical records, we could have missed underlying BCRL cases not brought to the attention of, or not diagnosed by, a clinician, and therefore not documented in the data sources. Conversely, we could have captured BCRL cases diagnosed for preventive or evaluative purposes only, although when we refined our definition of BCRL diagnosis to outcomes of likely persistent BCRL, most of the associations remained.
In summary, our findings confirm results of previous studies, especially those concerning the increased risk of BCRL with removal of lymph nodes and being obese. While we did not examine change in body size, management of body weight may be one avenue for decreasing risk of BCRL. We also observed increased risk among minority groups, including African American women, in comparison to white patients, and reasons for these differences need to be pursued. Considering the functional and psychosocial impact of developing BCRL, instituting educational programs which include a detailed clinical profile of identified risk factors prior to surgery might lead to improved prevention and treatment of this debilitating condition.
We gratefully acknowledge Bruce Fireman, MA, for biostatistical support, Erin Weltzien, BA, and Isaac Joshua Ergas, MPH, for programming assistance, the Pathways Study office and field staff, and most importantly, the Pathways Study participants. This work was supported by the National Cancer Institute [CA105274 to L.H.K]; and the American Cancer Society [RSG-06-209-01-LR to M.L.K.]. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the funding agencies.
Funding Sources: National Cancer Institute (R01 CA105274), American Cancer Society (RSG-06-209-01-LR)