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Impact of adjuvant taxane-based chemotherapy on development of breast cancer-related lymphedema: results from a large prospective cohort

Impact of adjuvant taxane-based chemotherapy on development of breast cancer-related lymphedema:... Breast Cancer Res Treat (2015) 151:393–403 DOI 10.1007/s10549-015-3408-1 CLINICAL TRIAL Impact of adjuvant taxane-based chemotherapy on development of breast cancer-related lymphedema: results from a large prospective cohort 1 1 2 1 • • • • Meyha N. Swaroop Chantal M. Ferguson Nora K. Horick Melissa N. Skolny 1 1 3 3 • • • • Cynthia L. Miller Lauren S. Jammallo Cheryl L. Brunelle Jean A. O’Toole 4 5 1 • • Steven J. Isakoff Michelle C. Specht Alphonse G. Taghian Received: 22 April 2015 / Accepted: 24 April 2015 / Published online: 5 May 2015 The Author(s) 2015. This article is published with open access at Springerlink.com Abstract Taxane-based chemotherapy for the treatment risk of lymphedema; however, taxane chemotherapy was of breast cancer is associated with fluid retention in the not significant when compared to no chemotherapy and extremities; however, its association with development of non-taxane chemotherapy (HR 1.14, p = 0.62; HR 1.56, breast cancer-related lymphedema is unclear. We sought to p = 0.40, respectively). Chemotherapy with docetaxel was determine if adjuvant taxane-based chemotherapy in- significantly associated with mild swelling on multivariate creased risk of lymphedema or mild swelling of the upper analysis in comparison to both no chemotherapy and non- extremity. 1121 patients with unilateral breast cancer were taxane chemotherapy groups (HR 1.63, p = 0.0098; HR prospectively screened for lymphedema with perometer 2.15, p = 0.02, respectively). Patients who receive taxane- measurements. Lymphedema was defined as a relative based chemotherapy are not at an increased risk of lym- volume change (RVC) of C10 % from preoperative base- phedema compared to patients receiving no chemotherapy line. Mild swelling was defined as RVC 5- \10 %. or non-taxane adjuvant chemotherapy. Those treated with Clinicopathologic characteristics were obtained via medi- docetaxel may experience mild swelling, but this does not cal record review. Kaplan–Meier and Cox proportional translate into subsequent lymphedema. hazard analyses were performed to determine lymphedema rates and risk factors. 29 % (324/1121) of patients were Keywords Lymphedema  Breast cancer  Taxane treated with adjuvant taxane-based chemotherapy. The chemotherapy  Arm swelling  Quality of life 2-year cumulative incidence of lymphedema in the overall cohort was 5.27 %. By multivariate analysis, axillary lymph node dissection (ALND) (p \ 0.0001), higher body Introduction mass index (p = 0.0007), and older age at surgery (p = 0.04) were significantly associated with increased As the survival from early breast cancer continues to im- prove, the effects of post-treatment-related complications & Alphonse G. Taghian on long-term quality of life (QOL) have become increas- ataghian@partners.org ingly important. Women treated for breast cancer face a 1 lifetime risk of developing lymphedema, which is a chronic Department of Radiation Oncology, Massachusetts General Hospital, 100 Blossom Street, Boston, MA 02114, USA swelling of the arms, breast, or trunk due to an accumulation 2 of lymphatic fluid in the interstitial tissues along with tissue Department of Biostatistics, Massachusetts General Hospital, Boston, USA remodeling and increased fibrosis. This condition is one of 3 the most feared side effects of breast cancer treatment and is Department of Physical and Occupational Therapy, known to have a profoundly negative impact on QOL [1–6]. Massachusetts General Hospital, Boston, USA 4 According to a recent meta-analysis, approximately one in Division of Hematology and Oncology, Massachusetts five survivors will develop lymphedema [7]. General Hospital, Boston, USA 5 Axillary lymph node dissection (ALND), regional Division of Surgical Oncology, Massachusetts General lymph node radiation (RLNR), and higher body mass index Hospital, Boston, USA 123 394 Breast Cancer Res Treat (2015) 151:393–403 (BMI) at time of diagnosis are well-established risk factors chemotherapy and/or radiation, and at regular follow-up for development of lymphedema [1, 3, 8–20]. Some studies oncology visits. This screening protocol was approved by have reported increased incidence of lymphedema after the Partners Healthcare Institutional Review Board and has chemotherapy [1, 7, 8, 13, 21–27]; however, other studies been previously published [47] [Clinicaltrials.gov Identi- have not supported these findings [12, 28–30].These results fication number NCT01521741]. warrant further investigation regarding the relationship between adjuvant chemotherapy and lymphedema. Patient population Taxane-based chemotherapy is routinely used in the treatment of high-risk breast cancer and has been shown to We identified 1121 women diagnosed with unilateral breast improve both disease-free survival and overall survival. cancer between 2005 and 2012 who underwent surgery and [31–35]. A common side effect of taxane-based che- prospective screening for lymphedema at our institution. motherapy, specifically docetaxel, is increased extracellu- All patients had a baseline arm volume measurement lar fluid (ECF) which often presents as fluid retention in the and C18 months of post-operative follow-up. Clinico- extremities [36–39]. Patients typically receive premedica- pathologic characteristics, patient demographics, and tion with corticosteroids to prevent or delay onset of tax- treatment data were collected via medical record review. ane-induced fluid retention while receiving treatment [36, Arm measurements obtained after bilateral breast surgery 40]. However, it is unclear if taxane chemotherapy causes or diagnosis of metastasis were excluded. long-term arm swelling after completion of treatment. Little data exists regarding the association between Lymphedema definition and measurement taxane-based chemotherapy and lymphedema development in breast cancer survivors. To date, only three studies have Arm volume was quantified using the previously validated examined this relationship and all report that taxane-based relative volume change (RVC) equation, which calculates chemotherapy increases the risk of lymphedema [41–43]. change in volume compared to a pre-operative measure- However, these studies are limited by lack of pre-operative ment [47]. Briefly, RVC = [(A(2)U(1)/U(2)A(1)) - 1], arm volume measurement, varying definitions of lym- where A(1), A(2) are the preoperative (1) and postoperative phedema, small sample size, and limited long-term follow- (2) arm volumes on the surgical side and U(1), U(2) are up. arm volumes on the contralateral side at corresponding Since generalized fluid retention is common following time points. The RVC equation accounts for asymmetry taxane chemotherapy, we postulated that adjuvant taxane- between the arms prior to surgery and utilizes the con- based chemotherapy may overwhelm the compromised tralateral arm as a control to account for factors unrelated lymphatic vessels from breast and/or axillary surgery and to lymphedema that may cause change in arm size such as therefore increase risk of lymphedema. We sought to de- weight gain or loss. Lymphedema was defined as a C 10 % termine whether taxane-based chemotherapy for the treat- RVC occurring [3 months post-operatively. This defini- ment of breast cancer is associated with increased risk of tion was based on the scientific consensus in the literature lymphedema in a large cohort of patients prospectively which commonly utilizes a C 10 % increase in the affected screened for arm volume changes. Additionally, we sought limb as criteria for diagnosing lymphedema [7, 12, 48, 49]. to investigate the relationship between taxane-based che- For the present study, we also investigated the risk of motherapy with mild arm swelling versus chronic arm mild swelling as defined by RVC C 5to \10 %. swelling, and determine if type of taxane (paclitaxel vs. docetaxel) affected lymphedema risk. Chemotherapy Taxane-based chemotherapy was classified as regimens Materials and methods containing docetaxel (Taxotere), paclitaxel (Taxol), or al- bumin-bound paclitaxel (Abraxane). Dexamethasone Study design premedication was administered per institutional standard for each regimen. Patients who received neoadjuvant che- Per standard of care at our institution, all newly diagnosed motherapy were excluded from this analysis. breast cancer patients undergo routine screening for lym- phedema with serial perometer arm volume measurements. Statistical analysis The perometer is an optoelectronic device that uses in- frared beams to measure and calculate overall limb volume Patient characteristics were summarized and compared [44–46]. Bilateral arm volume measurements are obtained between patients who did and did not receive taxane-based pre-operatively, post-operatively, after completion of chemotherapy via Chi square and Wilcoxon tests. Two- 123 Breast Cancer Res Treat (2015) 151:393–403 395 year cumulative incidence of lymphedema, defined as 29 % (324/1121) of the cohort received adjuvant taxane RVC C 10 % measured at least 3 months after surgery, chemotherapy, 6 % (62/1121) received non-taxane che- was calculated within each taxane group using the Kaplan– motherapy, and the remaining 66 % (735/1121) received Meier method. Median time from surgery to onset of no chemotherapy. Out of the 324 patients who received lymphedema was calculated among patients who devel- taxane-based chemotherapy, 56 % (181/324) were treated oped lymphedema. Univariate and multivariate Cox pro- with paclitaxel, 40 % (131/324) with docetaxel, and 3 % portional hazard models were used to evaluate the (9/324) with albumin-bound paclitaxel. 3 patients received association between lymphedema risk and use of taxane- a combination of the above types of taxane-containing based chemotherapy, as well as other risk factors. Time- regimens due to intolerance of initial taxane administered. dependent covariates were included for use of systemic therapies and radiation fields such that cases were included Cumulative incidence of lymphedema in the unexposed group prior to initiation of a given treatment and then were included in the exposed group The two-year cumulative incidence of lymphedema was after treatment began. The effects of treatment with pa- 5.27 % (95 % CI 4.10–6.76 %) for the overall cohort. By clitaxel and docetaxel were evaluated both combined (i.e. chemotherapy group, the cumulative incidence of lym- receiving either agent versus neither) and separately (pa- phedema was 10.29 % (95 % CI 7.43–14.18 %) for those clitaxel versus docetaxel versus no taxane treatment). receiving taxane chemotherapy compared to 4.87 % (95 % Multivariate models were derived using backwards selec- CI 1.60–14.33) for those receiving non-taxane che- tion, starting with a model that included all variables that motherapy and 3.07 % (95 % CI 2.03–4.63 %) for those were significant (p \ 0.1) in the univariate analysis, and who did not receiving chemotherapy (Table 2). removing non-significant variables one at a time until only significant variables (p \ 0.05) remained. Two-way inter- actions were evaluated for all covariates included in the Cumulative incidence of mild swelling resulting model. An additional analysis was conducted to assess the relationship between taxane use and risk of low The two-year cumulative incidence of mild swelling was level swelling, defined as 5 % B RVC \ 10 % measured 16.37 % for the overall cohort. For patients receiving tax- at least 3 months after surgery. Patients with RVC C 10 % ane chemotherapy, the cumulative incidence of mild swel- were excluded from this analysis. ling was 22.76 % (95 % CI 18.19–28.28 %) compared to 7.05 % (95 % CI 2.71–17.71 %) for the non-taxane che- motherapy group and 14.64 % (95 % CI 12.20–17.53 %) Results for those who did not receive any chemotherapy (Table 3). Patient population Timing of swelling Arm volume measurements from 1121 patients were in- cluded with a median post-operative follow-up of Among patients who developed lymphedema, median time 39.7 months (range 7.7–103.3). All patients underwent from final surgery to onset of lymphedema was unilateral breast surgery with 76 % (854/1121) lumpec- 19.97 months in the no chemotherapy group, 20.72 months tomy and 24 % (267/1121) mastectomy. 66 % (738/ in the non-taxane chemotherapy group, and 19.41 months 1121) underwent sentinel lymph node biopsy (SLNB) in the taxane chemotherapy group. Among those who de- and 20 % (219/1121) had axillary lymph node dissection veloped mild swelling, median time from final surgery to (ALND). 14 % (164/1121) did not have any nodal sur- onset of mild swelling was 19.28 months in the no che- gery, largely due to diagnosis of ductal carcinoma in situ. motherapy group, 44.21 months in the non-taxane che- Of the 219 patients treated with ALND, 73 % (159/219) motherapy group and 14.54 months in the taxane subsequently received taxane chemotherapy compared to chemotherapy group (Fig. 1). 7 % (16/219) treated with non-taxane chemotherapy and 20 % (44/219) did not receive adjuvant chemotherapy. Univariate analysis Out of 738 patients who had SLNB, 22 % (165/738) received taxane chemotherapy, 6 % (46/738) received By univariate analysis, adjuvant taxane-based chemother- non-taxane chemotherapy, and 71 % (527/738) received apy was associated with a significantly increased risk of no chemotherapy. Clinicopathologic factors of patients lymphedema, as defined by RVC C 10 %, compared to no with and without taxane-based chemotherapy are listed in chemotherapy (HR 2.61, p \ 0.0001) as well as non-taxane Table 1. chemotherapy (HR 2.90, p = 0.0412). In addition, an 123 396 Breast Cancer Res Treat (2015) 151:393–403 Table 1 Clinicopathologic characteristics of study population (n = 1121), adjuvant taxane patients (n = 324) compared with patients who received either adjuvant chemotherapy without taxane or no chemotherapy (n = 797) Entire cohort Adjuvant taxane No adjuvant taxane p value n = 1121 n = 324 n = 797 Patient characteristics Median age at surgery (months) 57 53 (24–78) 59 (30–89) \0.0001 b 2 Median pre-operative body mass index (BMI) (kg/m ) 26.3 26.6 (16.8–50.4) 26.2 (16.5–55.7) 0.75 Median post-operative follow up (months) 39.7 42.0 (18–100.4) 38.5 (7.7–103.3) 0.05 Breast surgery \0.0001 Lumpectomy 854 (76 %) 207 (64 %) 647 (81 %) Mastectomy 267 (24 %) 117 (36 %) 150 (19 %) Axillary surgery \0.0001 None 164 (14 %) 0 (0 %) 164 (21 %) Sentinel lymph node biopsy (SLNB) 738 (66 %) 165 (51 %) 573 (72 %) Axillary lymph node dissection (ALND) 219 (20 %) 159 (49 %) 60 (8 %) Tumor type \0.0001 Invasive Carcinoma 925 (83 %) 320 (99 %) 605 (76 %) Ductal Carcinoma in Situ (DCIS) 196 (17 %) 4 (1 %) 192 (24 %) Pathologic characteristics Median invasive tumor size, cm 1.4 (0.05–12.5) 1.9 (0.2–12.5) 1.1 (0.05–10.5) \0.0001 Median number lymph nodes dissected 2 (0–43) 6 (1–43) 1 (0–26) \0.0001 Median number positive lymph nodes 0 (0–39) 1 (0–39) 0 (0–26) \0.0001 Radiation therapy \0.0001 None 216 (19 %) 40 (12 %) 176 (22 %) Partial Breast Irradiation (PBI) 96 (9 %) 1 (0.3 %) 95 (12 %) Breast ? Chest Wall only 640 (57 %) 148 (46 %) 492 (62 %) Breast ? Chest Wall ? Nodal Radiation (RLNR) 167 (15 %) 133 (41 %) 34 (4 %) Adjuvant chemotherapy \0.0001 Yes 386 (34 %) 324 (100 %) 62 (8 %) No 735 (66 %) 0 (0 %) 735 (92 %) Adjuvant hormonal therapy 0.20 Yes 874 (78 %) 79 (24 %) 167 (21 %) No 246 (22 %) 244 (76 %) 630 (79 %) Herceptin-based chemotherapy \0.0001 Yes 87 (8 %) 75 (23 %) 12 (2 %) No 1031 (92 %) 248 (77 %) 783 (98 %) P value for test of association between characteristic and receipt of taxane 17 values missing for BMI Table 2 Two-year cumulative N 2-Year cumulative incidence (%) 95 % Confidence interval incidence of lymphedema (RVC C 10 %) overall and by Entire cohort 1121 5.27 4.10–6.76 chemotherapy group No chemotherapy 735 3.07 2.03–4.63 Non-taxane chemotherapy 62 4.87 1.60–14.33 Taxane-based chemotherapy 324 10.29 7.43–14.18 analysis of paclitaxel and docetaxel as individual agents chemotherapy (HR 2.00, p = 0.0053; HR 2.54, p = 0.0004, showed that both were significantly associated with lym- respectively). However, when compared to the non-taxane phedma risk compared to those who did not receive chemotherapy group, only docetaxel was significant for 123 Breast Cancer Res Treat (2015) 151:393–403 397 Table 3 Two-year cumulative N 2-Year cumulative 95 % Confidence incidence of mild swelling incidence (%) interval (RVC 5- \ 10 % RVC) overall and by chemotherapy group Entire cohort 1121 16.37 14.22–18.80 No chemotherapy 735 14.64 12.20–17.53 Non-taxane chemotherapy 62 7.05 2.71–17.71 Taxane-based chemotherapy 324 22.76 18.19–28.28 multivariate analysis. Neither paclitaxel nor docetaxel was No chemotherapy Non-taxane chemotherapy Taxane-based chemotherapy significantly associated with increased lymphedema risk when analyzed as individual agents (Table 4). Risk factors 19.97 (n=37) that were associated with lymphedema included ALND 20.72 (n=5) (HR 8.19, p\ 0.0001), higher pre-operative BMI (HR 19.41 (n=53) 1.05, p = 0.0007), and older age at surgery (HR 1.02, p = 0.0433) (Table 4). Adjuvant taxane-based chemotherapy associated with a 0 5 10 15 20 25 30 borderline increase in risk of mild swelling compared to no Median time** from final surgery to onset of lymphedema (months) chemotherapy (HR 1.33, p = 0.0778) and non-taxane che- ** Medians reported among patients who developed lymphedema motherapy (HR 1.74, p = 0.0732). Docetaxel was sig- nificantly associated with increased risk of mild swelling Fig. 1 Median time to onset of lymphedema (RVC C 10 %) by when compared to no chemotherapy (HR 1.63, p = 0.0098) chemotherapy group as well as to non-taxane chemotherapy (HR 2.15, p = 0.0195). Paclitaxel, however, was not associated with increased lymphedema risk (HR 3.12, p = 0.0392). Other risk of mild swelling in comparison to either the no che- significant risk factors included: higher pre-operative BMI, motherapy group or the non-taxane chemotherapy group ALND, greater number of lymph nodes (LNs) removed, (HR 1.13, p = 0.5428; HR 1.49, p = 0.2174, respectively) invasive versus ductal carcinoma in situ pathology, greater (Table 5). Older age at surgery (HR 1.02, p = 0.0003) and number of positive LNs, and RLNR (Table 4). ALND (HR 1.47, p = 0.0266) were also significantly as- Univariate analysis of mild swelling, as defined by sociated with increased risk of mild swelling on multivariate RVC C 5% to \10 %. indicated that taxane chemotherapy analysis. was associated with a borderline significant increase in risk of mild swelling compared to no chemotherapy (HR 1.31, p = 0.0512), and a significant increase in risk of mild Discussion swelling compared to non-taxane chemotherapy (HR 1.86, p = 0.0398). Additionally, comparison of paclitaxel and In this cohort of 1121 patients prospectively screened for docetaxel as individual agents showed docetaxel, but not lymphedema with perometer measurements, adjuvant tax- paclitaxel to be significantly associated with mild swelling ane-based chemotherapy with either paclitaxel or docetaxel when compared to non-taxane chemotherapy (HR 2.31, was not significantly associated with an increased risk of p = 0.0107; HR 1.65, p = 0.1163, respectively). Docetaxel lymphedema (RVC C 10 %) compared to no adjuvant was also associated with a significant increase in risk for chemotherapy as well as non-taxane chemotherapy. How- mild swelling compared to no chemotherapy (HR 1.62, ever, adjuvant chemotherapy with docetaxel was a sig- p = 0.0084), however, paclitaxel was not (HR 1.16, nificant risk factor for mild arm swelling (5 to \10 % RVC) p = 0.3882). Other significant risk factors for mild swelling compared to no chemotherapy as well as non-taxane che- included older age at surgery, ALND, greater number of LNs motherapy (p = 0.0098, p = 0.0195, respectively). Addi- removed, and greater number of positive LNs (Table 5). tional risk factors for mild arm swelling were older age at surgery and ALND. Consistent with the literature, ALND, Multivariate analysis pre-operative BMI C 30, and older age at surgery were in- dependent risk factors for lymphedema (RVC C 10 %). Receipt of taxane-based chemotherapy did not remain Currently, taxane-based chemotherapy is administered significantly associated with increased risk of lymphedema for node-positive and high-risk node-negative breast can- compared to no chemotherapy (HR 1.14, p = 0.6188) and cer, as it has been shown to significantly reduce mortality non-taxane chemotherapy (HR 1.56, p = 0.3988) on [31–35, 38, 50–53]. The use of anthracycline-alone 123 398 Breast Cancer Res Treat (2015) 151:393–403 Table 4 Univariate and multivariate analysis of characteristics associated with risk of lymphedema (RVC C 10 %) Univariate results Multivariate results Hazard ratio (95 % CI) p value Hazard ratio (95 % CI) p value Patient characteristics Age at surgery (years) 1.02 (1.00–1.03) 0.1080 1.02 (1.00–1.04) 0.0433 a 2 Pre-operative BMI (kg/m ) 1.07 (1.04–1.10) \0.0001 1.05 (1.02–1.09) 0.0007 Surgical characteristics Axillary surgery SLNB versus no axillary surgery 0.83 (0.36–1.89) 0.6507 – ALND versus no axillary surgery 6.31 (2.88–13.80) \0.0001 7.32 (3.16–17.01) \0.0001 ALND versus SLNB/no axillary surgery 7.37 (4.86–11.19) \0.0001 8.19 (5.12–13.10) <0.0001 Pathologic characteristics Invasive vs. DCIS 2.20 (1.06–4.53) 0.0335 1.05 (0.49–2.25) 0.9041 Number positive lymph nodes 1.10 (1.07–1.13) \0.0001 1.02 (0.98–1.06) 0.4337 Systemic therapy Adjuvant taxane-based chemotherapy Yes versus no chemo 2.61 (1.73–3.95) \0.0001 1.14 (0.69–1.87) 0.6188 Yes versus non-taxane chemo 2.90 (1.04–8.08) 0.0412 1.56 (0.56–4.37) 0.3988 Paclitaxel Yes versus no chemo 2.00 (1.23–3.24) 0.0053 0.81 (0.46–1.41) 0.4473 Yes versus non-taxane chemo 2.45 (0.85–7.07) 0.0984 1.26 (0.43–3.65) 0.6725 Docetaxel Yes versus no chemo 2.54 (1.52–4.26) 0.0004 1.25 (0.71–2.18) 0.4374 Yes versus non-taxane chemo 3.12 (1.06–9.20) 0.0392 1.95 (0.65–5.85) 0.2334 Non-taxane chemotherapy Yes versus no chemo 0.90 (0.32–2.52) 0.8417 0.64 (0.22–1.83) 0.4056 Hormonal therapy Yes versus no 1.59 (0.90–2.80) 0.1098 – Herceptin-based chemotherapy Yes versus no 1.10 (0.55–2.20) 0.7778 – – Radiation therapy Yes versus no 1.06 (0.65–1.75) 0.8056 – – RLNR versus breast?chest wall/none 4.32 (2.82–6.63) \0.0001 1.29 (0.77– 2.16) 0.3354 CI confidence interval, BMI body mass index, SLNB sentinel lymph node biopsy, ALND axillary lymph node dissection, DCIS ductal carcinoma in situ, RLNR regional lymph node radiation Age at surgery, pre-operative BMI, and number of positive lymph nodes were analyzed as continuous variables such that the hazard ratios reflect the change in lymphedema risk associated with a 1-unit increase in the variable ‘‘–’’ indicates the specified variable/comparison was not analyzed 2 Separate models, each including age at surgery, BMI and ALND were used to estimate the hazard ratios for (1) adjuvant taxane-based chemo and (2) individual effects of paclitaxel and docetaxel regimens in breast cancer treatment has declined [54], similarities between the mechanism of fluid retention and which has resulted in a growing increase of taxane-based development of breast cancer-related lymphedema [55, 56] chemotherapy for early stage breast cancer. Therefore, a the association between taxane-based chemotherapy full understanding of the QOL and long-term implications (specifically docetaxel) and lymphedema warrants further of taxanes is necessary. investigation. A recent review comparing adjuvant che- Docetaxel has relatively greater hematologic toxicity motherapy with and without docetaxel in breast cancer and is more commonly associated with edema than pacli- patients showed that patients receiving docetaxel consis- taxel [53]. To reduce incidence and severity of edema, tently had increased rates of edema compared to patients coticosteroids are routinely administered [40]. Due to receiving docetaxel-free chemotherapy [57]. This review 123 Breast Cancer Res Treat (2015) 151:393–403 399 Table 5 Univariate and multivariate analysis of characteristics associated with risk of mild swelling (5 B 10 % RVC) Univariate results Multivariate results Hazard Ratio (95 % CI) p value Hazard Ratio (95 % CI) p value Patient characteristics Age at surgery (years) 1.02 (1.01–1.03) 0.0011 1.02 (1.01–1.03) 0.0003 a 2 Pre-operative BMI (kg/m ) 1.02 (1.00–1.04) 0.1366 1.01 (0.99–1.03) 0.4157 Surgical characteristics Axillary surgery –b SLNB versus no axillary surgery 0.90 (0.63–1.29) 0.5631 – ALND versus no axillary surgery 1.36 (0.89–2.07) 0.1527 1.35 (0.84–2.18) 0.2188 ALND versus SLNB/no axillary surgery 1.48 (1.10–2.00) 0.0105 1.47 (1.05–2.07) 0.0266 Pathologic characteristics Invasive vs. DCIS 1.42 (0.99–2.04) 0.0572 1.27 (0.87–1.84) 0.2152 Number positive lymph nodes 1.07 (1.03–1.11) 0.0002 1.04 (0.99–1.00) 0.0603 Systemic therapy Adjuvant taxane-based chemo Yes versus no chemo 1.31 (1.00–1.71) 0.0512 1.33 (0.97–1.83) 0.0778 Yes versus non-taxane chemo 1.86 (1.03–3.35) 0.0398 1.74 (0.95–3.13) 0.0732 Paclitaxel Yes versus no-chemo 1.16 (0.83–1.62) 0.3882 1.13 (0.77–1.66) 0.5428 Yes versus non-taxane chemo 1.65 (0.88–3.07) 0.1163 1.49 (0.79–2.80) 0.2174 Docetaxel Yes versus no-chemo 1.62 (1.13–2.32) 0.0084 1.63 (1.13–2.36) 0.0098 Yes versus non-taxane chemo 2.31 (1.21–4.38) 0.0107 2.15 (1.13–4.09) 0.0195 Non-taxane chemotherapy Yes versus no chemo 0.70 (0.40, 1.24) 0.2265 0.75 (0.42–1.35) 0.3473 Hormonal therapy Yes versus no 1.05 (0.78–1.41) 0.7639 – – Herceptin-based chemotherapy Yes versus no 0.80 (0.50–1.30) 0.3644 – – Radiation therapy Yes versus no 1.04 (0.77–1.40) 0.8106 – – RLNR versus breast ? chest wall/none 1.18 (0.80–1.74) 0.4043 0.82 (0.51–1.31) 0.4064 CI confidence interval, BMI body mass index, SLNB sentinel lymph node biopsy, ALND axillary lymph node dissection, DCIS ductal carcinoma in situ, RLNR regional lymph node radiation Age at surgery, pre-operative BMI, and number of positive lymph nodes were analyzed as continuous variables such that the hazard ratios reflect the change in lymphedema risk associated with a 1-unit increase in the variable ‘‘–’’ indicates the specified variable/comparison was not analyzed 2 Separate models, each including age at surgery, BMI and ALND were used to estimate the hazard ratios for (1) adjuvant taxane-based chemo and (2) individual effects of paclitaxel and docetaxel included studies comparing generalized edema in docetaxel women for lymphedema with bioimpedence spectroscopy and docetaxel-free groups, but did not specifically report on (BIS) as part of a larger randomized study which evaluated lymphedema of the arm. The relationship between effect of exercise after breast surgery. Measurements were docetaxel and upper extremity lymphedema is unclear, as taken at 1, 3, 9, and 15 months post-operatively and lym- the only studies in the literature examining this are case phedema was defined according to previously established reports [58, 59]. cutoffs. On multivariate analysis, patients who received The association of breast cancer-related lymphedema taxane chemotherapy had a 7-fold greater risk of swelling with taxane-based chemotherapy has been reported, but not in the arm at 9-months after surgery compared to women widely studied. In 2013, Kilbreath et al. analyzed 160 who did not receive taxane chemotherapy (HR 7.4, 123 400 Breast Cancer Res Treat (2015) 151:393–403 p \ 0.001) [42]. However, taxane chemotherapy did not distinguish between minor increases in arm volume versus remain significant at 15 months post-operative, leading to chronic lymphedema. Because of our prospective screening the conclusion that taxanes cause transient swelling in the and quantified method of measuring arm volume, the re- at-risk arm. sults of this study fill a gap in the literature regarding risk A similar study by Jung et al. evaluating patients who of lymphedema after receiving taxane-based chemother- underwent ALND showed that taxane-based chemotherapy apy. Furthermore, our data better informs clinicians of was an independent risk factor for lymphedema on multi- docetaxel-related arm edema, and can help educate patients variate analysis [41]. In 848 patients evaluated post-op- on treatment-related risk factors for lymphedema. eratively for a one-time lymphedema event as well as for Due to the non-randomized selection of patients for persistent lymphedema, taxane-based chemotherapy was taxane-based chemotherapy versus non-taxane-based che- associated with higher incidence of lymphedema motherapy, there are limitations in the present study. At our (HR = 1.69, p = 0.03 for lymphedema event; HR 2.07, institution, few patients receive chemotherapy without a p = 0.04 for persistent lymphedema) [41]. However, pa- taxane (i.e. anthracycline alone); out of 1121 patients tients did not undergo a pre-operative arm measurement and eligible for this analysis, only 62 received adjuvant non- lymphedema was defined using a wide range of both objec- taxane chemotherapy (5.5 %). Although a larger percent- tive and subjective criteria. Interestingly, in our analysis, age of patients receiving non-taxane-based chemotherapy taxane-based chemotherapy was not associated with in- would have allowed for a more accurate analysis on the creased risk of lymphedema. Possible explanations for this effects of taxane, the minimal usage of anthracyclines include low cumulative incidence of lymphedema of the alone in our cohort reflects standard practice and guidelines entire cohort and the impact of multivariable analysis ad- for systemic treatment. The nature of our screening pro- justed for factors known to increase risk of lymphedema such tocol calls for arm volume assessments to be taken before as ALND (Table 3). and after completion of chemotherapy, but not during; Most recently, Lee et al. reported on lymphedema fol- therefore, the data that are reported in this study does not lowing taxane chemotherapy in women with early stage include any arm volume changes that occurred while re- breast cancer. 63 patients were assessed with BIS after ax- ceiving active taxane chemotherapy. Taking these factors illary surgery, before taxane-chemotherapy, and 6 months into account, there are many areas for future research. after completion of chemotherapy. Results showed that The current study also has several strengths. We utilized a taxane chemotherapy increased incidence of lymphedema of large cohort of patients prospectively screened for changes in the ipsilateral arm and persisted for at least 6 months after arm volume with a perometer, a device with demonstrated completion of chemotherapy, whereas generalized edema in validity for lymphedema assessment [44, 45, 60, 61]. This cohort of 1121 patients represents one of the largest in the the legs resolved during this timeframe [43]. This series was limited by small sample size and lack of long-term follow- lymphedema literature, and to our knowledge, the largest in up. In our series the median time to lymphedema in all co- which risk of lymphedema was evaluated for association horts was between 19 and 21 months post-surgery, therefore with adjuvant taxane-based chemotherapy. Of note, patients the increased swelling that this study reports could be related receiving neoadjuvant chemotherapy were excluded in order to transient edema. to solely assess the hypothesis that fluid retention from The results of our study show adjuvant docetaxel in- chemotherapy may overwhelm compromised lymphatic creases risk of mild swelling; however, multivariate analysis vessels after surgery, and could therefore lead to chronic indicates that this does not subsequently lead to increased lymphedema. All patients in our study underwent a pre-op- risk of lymphedema. These findings are consistent with the erative arm volume measurement and regular post-operative reported side effects of docetaxel treatment, and further the screening, with a median follow-up of over 3 years. The understanding of the relationship between docetaxel and importance of obtaining pre-operative assessments to ac- breast cancer-related lymphedema. More importantly, be- count for asymmetry between arms and adjustment for fac- cause docetaxel is not an independent risk factor for lym- tors unrelated to lymphedema has been previously phedema and the median time to onset of lymphedema was demonstrated [47, 62, 63]. In addition, we utilized a similar across chemotherapy groups (Fig. 1), results of this validated formula to measure arm volume differences, ac- study suggest that it is largely ALND that elevates risk of counting for baseline pre-operative differences as well as lymphedema, not receipt of taxane chemotherapy. weight changes [64]. Lymphedema was defined as C10 % As many patients who receive ALND are also subse- RVC, which has been widely used in the literature [7, 12, 48]. quently treated with taxanes due to more advanced disease, Our study also separates paclitaxel and docetaxel for risk these individuals should still be closely monitored for de- of lymphedema due to the well known differences in adverse velopment of lymphedema. The strong association between events related to these therapeutic agents. Additionally, adjuvant docetaxel and mild swelling highlights the need to distinction between mild and chronic edema was evaluated 123 Breast Cancer Res Treat (2015) 151:393–403 401 in both univariate and multivariate models. Mild swelling References was defined as RVC C 5to \10 % based on our previously 1. Paskett ED, Naughton MJ, McCoy TP et al (2007) The epi- published analysis of 1173 patients in which we found that a demiology of arm and hand swelling in premenopausal breast measurement of C5to \10 % RVC at [3 months post-op- cancer survivors. Cancer Epidemiol Biomarkers Prev 16:775–782 erative was significantly associated with an increased risk of 2. Sakorafas GH, Peros G, Cataliotti L et al (2006) Lymphedema progression to C10 % [65]. As the importance of detecting following axillary lymph node dissection for breast cancer. Surg Oncol 15:153–165 sublinical edema has been cited in the literature [63, 66–68], 3. Hayes SC, Janda M, Cornish B et al (2008) Lymphedema after we sought to determine if patients receiving taxane-based breast cancer: incidence, risk factors, and effect on upper body chemotherapy were more likely to exhibit these low level function. J Clin Oncol 26:3536–3542 arm volume increases compared to patients who did not re- 4. 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Norman SA, Localio AR, Kallan MJ et al (2010) Risk factors for lymphedema after breast cancer treatment. Cancer Epidemiol Biomarkers Prev 19:2734–2746 Conclusions 9. Yang EJ, Park WB, Seo KS et al (2010) Longitudinal change of treatment-related upper limb dysfunction and its impact on late dysfunction in breast cancer survivors: a prospective cohort In conclusion, multivariate analysis of 1121 patients study. J Surg Oncol 101:84–91 prospectively screened for lymphedema via perometry 10. Lucci A, McCall LM, Beitsch PD et al (2007) Surgical compli- demonstrated that taxane-based chemotherapy did not in- cations associated with sentinel lymph node dissection (SLND) crease risk of lymphedema. Athough docetaxel was found plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group Trial to be a significant risk factor for mild swelling, it did not Z0011. J Clin Oncol 25:3657–3663 correlate with progressive lymphedema. These findings can 11. Park JH, Lee WH, Chung HS (2008) Incidence and risk factors of be utilized for patient counseling and education regarding breast cancer lymphoedema. J Clin Nurs 17:1450–1459 common side effects while undergoing taxane-based che- 12. Tsai RJ, Dennis LK, Lynch CF et al (2009) The risk of devel- oping arm lymphedema among breast cancer survivors: a meta- motherapy. Although arm volume changes should be analysis of treatment factors. Ann Surg Oncol 16:1959–1972 regularly monitored for early signs of progression, it is 13. Ahmed RL, Schmitz KH, Prizment AE et al (2011) Risk factors important for clinicians to differentiate between treatment- for lymphedema in breast cancer survivors, the Iowa Women’s related risk factors for developing chronic edema versus Health Study. Breast Cancer Res Treat 130:981–991 14. Crosby MA, Card A, Liu J et al (2012) Immediate breast re- mild or transient edema that may resolve without inter- construction and lymphedema incidence. 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Impact of adjuvant taxane-based chemotherapy on development of breast cancer-related lymphedema: results from a large prospective cohort

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0167-6806
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10.1007/s10549-015-3408-1
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Abstract

Breast Cancer Res Treat (2015) 151:393–403 DOI 10.1007/s10549-015-3408-1 CLINICAL TRIAL Impact of adjuvant taxane-based chemotherapy on development of breast cancer-related lymphedema: results from a large prospective cohort 1 1 2 1 • • • • Meyha N. Swaroop Chantal M. Ferguson Nora K. Horick Melissa N. Skolny 1 1 3 3 • • • • Cynthia L. Miller Lauren S. Jammallo Cheryl L. Brunelle Jean A. O’Toole 4 5 1 • • Steven J. Isakoff Michelle C. Specht Alphonse G. Taghian Received: 22 April 2015 / Accepted: 24 April 2015 / Published online: 5 May 2015 The Author(s) 2015. This article is published with open access at Springerlink.com Abstract Taxane-based chemotherapy for the treatment risk of lymphedema; however, taxane chemotherapy was of breast cancer is associated with fluid retention in the not significant when compared to no chemotherapy and extremities; however, its association with development of non-taxane chemotherapy (HR 1.14, p = 0.62; HR 1.56, breast cancer-related lymphedema is unclear. We sought to p = 0.40, respectively). Chemotherapy with docetaxel was determine if adjuvant taxane-based chemotherapy in- significantly associated with mild swelling on multivariate creased risk of lymphedema or mild swelling of the upper analysis in comparison to both no chemotherapy and non- extremity. 1121 patients with unilateral breast cancer were taxane chemotherapy groups (HR 1.63, p = 0.0098; HR prospectively screened for lymphedema with perometer 2.15, p = 0.02, respectively). Patients who receive taxane- measurements. Lymphedema was defined as a relative based chemotherapy are not at an increased risk of lym- volume change (RVC) of C10 % from preoperative base- phedema compared to patients receiving no chemotherapy line. Mild swelling was defined as RVC 5- \10 %. or non-taxane adjuvant chemotherapy. Those treated with Clinicopathologic characteristics were obtained via medi- docetaxel may experience mild swelling, but this does not cal record review. Kaplan–Meier and Cox proportional translate into subsequent lymphedema. hazard analyses were performed to determine lymphedema rates and risk factors. 29 % (324/1121) of patients were Keywords Lymphedema  Breast cancer  Taxane treated with adjuvant taxane-based chemotherapy. The chemotherapy  Arm swelling  Quality of life 2-year cumulative incidence of lymphedema in the overall cohort was 5.27 %. By multivariate analysis, axillary lymph node dissection (ALND) (p \ 0.0001), higher body Introduction mass index (p = 0.0007), and older age at surgery (p = 0.04) were significantly associated with increased As the survival from early breast cancer continues to im- prove, the effects of post-treatment-related complications & Alphonse G. Taghian on long-term quality of life (QOL) have become increas- ataghian@partners.org ingly important. Women treated for breast cancer face a 1 lifetime risk of developing lymphedema, which is a chronic Department of Radiation Oncology, Massachusetts General Hospital, 100 Blossom Street, Boston, MA 02114, USA swelling of the arms, breast, or trunk due to an accumulation 2 of lymphatic fluid in the interstitial tissues along with tissue Department of Biostatistics, Massachusetts General Hospital, Boston, USA remodeling and increased fibrosis. This condition is one of 3 the most feared side effects of breast cancer treatment and is Department of Physical and Occupational Therapy, known to have a profoundly negative impact on QOL [1–6]. Massachusetts General Hospital, Boston, USA 4 According to a recent meta-analysis, approximately one in Division of Hematology and Oncology, Massachusetts five survivors will develop lymphedema [7]. General Hospital, Boston, USA 5 Axillary lymph node dissection (ALND), regional Division of Surgical Oncology, Massachusetts General lymph node radiation (RLNR), and higher body mass index Hospital, Boston, USA 123 394 Breast Cancer Res Treat (2015) 151:393–403 (BMI) at time of diagnosis are well-established risk factors chemotherapy and/or radiation, and at regular follow-up for development of lymphedema [1, 3, 8–20]. Some studies oncology visits. This screening protocol was approved by have reported increased incidence of lymphedema after the Partners Healthcare Institutional Review Board and has chemotherapy [1, 7, 8, 13, 21–27]; however, other studies been previously published [47] [Clinicaltrials.gov Identi- have not supported these findings [12, 28–30].These results fication number NCT01521741]. warrant further investigation regarding the relationship between adjuvant chemotherapy and lymphedema. Patient population Taxane-based chemotherapy is routinely used in the treatment of high-risk breast cancer and has been shown to We identified 1121 women diagnosed with unilateral breast improve both disease-free survival and overall survival. cancer between 2005 and 2012 who underwent surgery and [31–35]. A common side effect of taxane-based che- prospective screening for lymphedema at our institution. motherapy, specifically docetaxel, is increased extracellu- All patients had a baseline arm volume measurement lar fluid (ECF) which often presents as fluid retention in the and C18 months of post-operative follow-up. Clinico- extremities [36–39]. Patients typically receive premedica- pathologic characteristics, patient demographics, and tion with corticosteroids to prevent or delay onset of tax- treatment data were collected via medical record review. ane-induced fluid retention while receiving treatment [36, Arm measurements obtained after bilateral breast surgery 40]. However, it is unclear if taxane chemotherapy causes or diagnosis of metastasis were excluded. long-term arm swelling after completion of treatment. Little data exists regarding the association between Lymphedema definition and measurement taxane-based chemotherapy and lymphedema development in breast cancer survivors. To date, only three studies have Arm volume was quantified using the previously validated examined this relationship and all report that taxane-based relative volume change (RVC) equation, which calculates chemotherapy increases the risk of lymphedema [41–43]. change in volume compared to a pre-operative measure- However, these studies are limited by lack of pre-operative ment [47]. Briefly, RVC = [(A(2)U(1)/U(2)A(1)) - 1], arm volume measurement, varying definitions of lym- where A(1), A(2) are the preoperative (1) and postoperative phedema, small sample size, and limited long-term follow- (2) arm volumes on the surgical side and U(1), U(2) are up. arm volumes on the contralateral side at corresponding Since generalized fluid retention is common following time points. The RVC equation accounts for asymmetry taxane chemotherapy, we postulated that adjuvant taxane- between the arms prior to surgery and utilizes the con- based chemotherapy may overwhelm the compromised tralateral arm as a control to account for factors unrelated lymphatic vessels from breast and/or axillary surgery and to lymphedema that may cause change in arm size such as therefore increase risk of lymphedema. We sought to de- weight gain or loss. Lymphedema was defined as a C 10 % termine whether taxane-based chemotherapy for the treat- RVC occurring [3 months post-operatively. This defini- ment of breast cancer is associated with increased risk of tion was based on the scientific consensus in the literature lymphedema in a large cohort of patients prospectively which commonly utilizes a C 10 % increase in the affected screened for arm volume changes. Additionally, we sought limb as criteria for diagnosing lymphedema [7, 12, 48, 49]. to investigate the relationship between taxane-based che- For the present study, we also investigated the risk of motherapy with mild arm swelling versus chronic arm mild swelling as defined by RVC C 5to \10 %. swelling, and determine if type of taxane (paclitaxel vs. docetaxel) affected lymphedema risk. Chemotherapy Taxane-based chemotherapy was classified as regimens Materials and methods containing docetaxel (Taxotere), paclitaxel (Taxol), or al- bumin-bound paclitaxel (Abraxane). Dexamethasone Study design premedication was administered per institutional standard for each regimen. Patients who received neoadjuvant che- Per standard of care at our institution, all newly diagnosed motherapy were excluded from this analysis. breast cancer patients undergo routine screening for lym- phedema with serial perometer arm volume measurements. Statistical analysis The perometer is an optoelectronic device that uses in- frared beams to measure and calculate overall limb volume Patient characteristics were summarized and compared [44–46]. Bilateral arm volume measurements are obtained between patients who did and did not receive taxane-based pre-operatively, post-operatively, after completion of chemotherapy via Chi square and Wilcoxon tests. Two- 123 Breast Cancer Res Treat (2015) 151:393–403 395 year cumulative incidence of lymphedema, defined as 29 % (324/1121) of the cohort received adjuvant taxane RVC C 10 % measured at least 3 months after surgery, chemotherapy, 6 % (62/1121) received non-taxane che- was calculated within each taxane group using the Kaplan– motherapy, and the remaining 66 % (735/1121) received Meier method. Median time from surgery to onset of no chemotherapy. Out of the 324 patients who received lymphedema was calculated among patients who devel- taxane-based chemotherapy, 56 % (181/324) were treated oped lymphedema. Univariate and multivariate Cox pro- with paclitaxel, 40 % (131/324) with docetaxel, and 3 % portional hazard models were used to evaluate the (9/324) with albumin-bound paclitaxel. 3 patients received association between lymphedema risk and use of taxane- a combination of the above types of taxane-containing based chemotherapy, as well as other risk factors. Time- regimens due to intolerance of initial taxane administered. dependent covariates were included for use of systemic therapies and radiation fields such that cases were included Cumulative incidence of lymphedema in the unexposed group prior to initiation of a given treatment and then were included in the exposed group The two-year cumulative incidence of lymphedema was after treatment began. The effects of treatment with pa- 5.27 % (95 % CI 4.10–6.76 %) for the overall cohort. By clitaxel and docetaxel were evaluated both combined (i.e. chemotherapy group, the cumulative incidence of lym- receiving either agent versus neither) and separately (pa- phedema was 10.29 % (95 % CI 7.43–14.18 %) for those clitaxel versus docetaxel versus no taxane treatment). receiving taxane chemotherapy compared to 4.87 % (95 % Multivariate models were derived using backwards selec- CI 1.60–14.33) for those receiving non-taxane che- tion, starting with a model that included all variables that motherapy and 3.07 % (95 % CI 2.03–4.63 %) for those were significant (p \ 0.1) in the univariate analysis, and who did not receiving chemotherapy (Table 2). removing non-significant variables one at a time until only significant variables (p \ 0.05) remained. Two-way inter- actions were evaluated for all covariates included in the Cumulative incidence of mild swelling resulting model. An additional analysis was conducted to assess the relationship between taxane use and risk of low The two-year cumulative incidence of mild swelling was level swelling, defined as 5 % B RVC \ 10 % measured 16.37 % for the overall cohort. For patients receiving tax- at least 3 months after surgery. Patients with RVC C 10 % ane chemotherapy, the cumulative incidence of mild swel- were excluded from this analysis. ling was 22.76 % (95 % CI 18.19–28.28 %) compared to 7.05 % (95 % CI 2.71–17.71 %) for the non-taxane che- motherapy group and 14.64 % (95 % CI 12.20–17.53 %) Results for those who did not receive any chemotherapy (Table 3). Patient population Timing of swelling Arm volume measurements from 1121 patients were in- cluded with a median post-operative follow-up of Among patients who developed lymphedema, median time 39.7 months (range 7.7–103.3). All patients underwent from final surgery to onset of lymphedema was unilateral breast surgery with 76 % (854/1121) lumpec- 19.97 months in the no chemotherapy group, 20.72 months tomy and 24 % (267/1121) mastectomy. 66 % (738/ in the non-taxane chemotherapy group, and 19.41 months 1121) underwent sentinel lymph node biopsy (SLNB) in the taxane chemotherapy group. Among those who de- and 20 % (219/1121) had axillary lymph node dissection veloped mild swelling, median time from final surgery to (ALND). 14 % (164/1121) did not have any nodal sur- onset of mild swelling was 19.28 months in the no che- gery, largely due to diagnosis of ductal carcinoma in situ. motherapy group, 44.21 months in the non-taxane che- Of the 219 patients treated with ALND, 73 % (159/219) motherapy group and 14.54 months in the taxane subsequently received taxane chemotherapy compared to chemotherapy group (Fig. 1). 7 % (16/219) treated with non-taxane chemotherapy and 20 % (44/219) did not receive adjuvant chemotherapy. Univariate analysis Out of 738 patients who had SLNB, 22 % (165/738) received taxane chemotherapy, 6 % (46/738) received By univariate analysis, adjuvant taxane-based chemother- non-taxane chemotherapy, and 71 % (527/738) received apy was associated with a significantly increased risk of no chemotherapy. Clinicopathologic factors of patients lymphedema, as defined by RVC C 10 %, compared to no with and without taxane-based chemotherapy are listed in chemotherapy (HR 2.61, p \ 0.0001) as well as non-taxane Table 1. chemotherapy (HR 2.90, p = 0.0412). In addition, an 123 396 Breast Cancer Res Treat (2015) 151:393–403 Table 1 Clinicopathologic characteristics of study population (n = 1121), adjuvant taxane patients (n = 324) compared with patients who received either adjuvant chemotherapy without taxane or no chemotherapy (n = 797) Entire cohort Adjuvant taxane No adjuvant taxane p value n = 1121 n = 324 n = 797 Patient characteristics Median age at surgery (months) 57 53 (24–78) 59 (30–89) \0.0001 b 2 Median pre-operative body mass index (BMI) (kg/m ) 26.3 26.6 (16.8–50.4) 26.2 (16.5–55.7) 0.75 Median post-operative follow up (months) 39.7 42.0 (18–100.4) 38.5 (7.7–103.3) 0.05 Breast surgery \0.0001 Lumpectomy 854 (76 %) 207 (64 %) 647 (81 %) Mastectomy 267 (24 %) 117 (36 %) 150 (19 %) Axillary surgery \0.0001 None 164 (14 %) 0 (0 %) 164 (21 %) Sentinel lymph node biopsy (SLNB) 738 (66 %) 165 (51 %) 573 (72 %) Axillary lymph node dissection (ALND) 219 (20 %) 159 (49 %) 60 (8 %) Tumor type \0.0001 Invasive Carcinoma 925 (83 %) 320 (99 %) 605 (76 %) Ductal Carcinoma in Situ (DCIS) 196 (17 %) 4 (1 %) 192 (24 %) Pathologic characteristics Median invasive tumor size, cm 1.4 (0.05–12.5) 1.9 (0.2–12.5) 1.1 (0.05–10.5) \0.0001 Median number lymph nodes dissected 2 (0–43) 6 (1–43) 1 (0–26) \0.0001 Median number positive lymph nodes 0 (0–39) 1 (0–39) 0 (0–26) \0.0001 Radiation therapy \0.0001 None 216 (19 %) 40 (12 %) 176 (22 %) Partial Breast Irradiation (PBI) 96 (9 %) 1 (0.3 %) 95 (12 %) Breast ? Chest Wall only 640 (57 %) 148 (46 %) 492 (62 %) Breast ? Chest Wall ? Nodal Radiation (RLNR) 167 (15 %) 133 (41 %) 34 (4 %) Adjuvant chemotherapy \0.0001 Yes 386 (34 %) 324 (100 %) 62 (8 %) No 735 (66 %) 0 (0 %) 735 (92 %) Adjuvant hormonal therapy 0.20 Yes 874 (78 %) 79 (24 %) 167 (21 %) No 246 (22 %) 244 (76 %) 630 (79 %) Herceptin-based chemotherapy \0.0001 Yes 87 (8 %) 75 (23 %) 12 (2 %) No 1031 (92 %) 248 (77 %) 783 (98 %) P value for test of association between characteristic and receipt of taxane 17 values missing for BMI Table 2 Two-year cumulative N 2-Year cumulative incidence (%) 95 % Confidence interval incidence of lymphedema (RVC C 10 %) overall and by Entire cohort 1121 5.27 4.10–6.76 chemotherapy group No chemotherapy 735 3.07 2.03–4.63 Non-taxane chemotherapy 62 4.87 1.60–14.33 Taxane-based chemotherapy 324 10.29 7.43–14.18 analysis of paclitaxel and docetaxel as individual agents chemotherapy (HR 2.00, p = 0.0053; HR 2.54, p = 0.0004, showed that both were significantly associated with lym- respectively). However, when compared to the non-taxane phedma risk compared to those who did not receive chemotherapy group, only docetaxel was significant for 123 Breast Cancer Res Treat (2015) 151:393–403 397 Table 3 Two-year cumulative N 2-Year cumulative 95 % Confidence incidence of mild swelling incidence (%) interval (RVC 5- \ 10 % RVC) overall and by chemotherapy group Entire cohort 1121 16.37 14.22–18.80 No chemotherapy 735 14.64 12.20–17.53 Non-taxane chemotherapy 62 7.05 2.71–17.71 Taxane-based chemotherapy 324 22.76 18.19–28.28 multivariate analysis. Neither paclitaxel nor docetaxel was No chemotherapy Non-taxane chemotherapy Taxane-based chemotherapy significantly associated with increased lymphedema risk when analyzed as individual agents (Table 4). Risk factors 19.97 (n=37) that were associated with lymphedema included ALND 20.72 (n=5) (HR 8.19, p\ 0.0001), higher pre-operative BMI (HR 19.41 (n=53) 1.05, p = 0.0007), and older age at surgery (HR 1.02, p = 0.0433) (Table 4). Adjuvant taxane-based chemotherapy associated with a 0 5 10 15 20 25 30 borderline increase in risk of mild swelling compared to no Median time** from final surgery to onset of lymphedema (months) chemotherapy (HR 1.33, p = 0.0778) and non-taxane che- ** Medians reported among patients who developed lymphedema motherapy (HR 1.74, p = 0.0732). Docetaxel was sig- nificantly associated with increased risk of mild swelling Fig. 1 Median time to onset of lymphedema (RVC C 10 %) by when compared to no chemotherapy (HR 1.63, p = 0.0098) chemotherapy group as well as to non-taxane chemotherapy (HR 2.15, p = 0.0195). Paclitaxel, however, was not associated with increased lymphedema risk (HR 3.12, p = 0.0392). Other risk of mild swelling in comparison to either the no che- significant risk factors included: higher pre-operative BMI, motherapy group or the non-taxane chemotherapy group ALND, greater number of lymph nodes (LNs) removed, (HR 1.13, p = 0.5428; HR 1.49, p = 0.2174, respectively) invasive versus ductal carcinoma in situ pathology, greater (Table 5). Older age at surgery (HR 1.02, p = 0.0003) and number of positive LNs, and RLNR (Table 4). ALND (HR 1.47, p = 0.0266) were also significantly as- Univariate analysis of mild swelling, as defined by sociated with increased risk of mild swelling on multivariate RVC C 5% to \10 %. indicated that taxane chemotherapy analysis. was associated with a borderline significant increase in risk of mild swelling compared to no chemotherapy (HR 1.31, p = 0.0512), and a significant increase in risk of mild Discussion swelling compared to non-taxane chemotherapy (HR 1.86, p = 0.0398). Additionally, comparison of paclitaxel and In this cohort of 1121 patients prospectively screened for docetaxel as individual agents showed docetaxel, but not lymphedema with perometer measurements, adjuvant tax- paclitaxel to be significantly associated with mild swelling ane-based chemotherapy with either paclitaxel or docetaxel when compared to non-taxane chemotherapy (HR 2.31, was not significantly associated with an increased risk of p = 0.0107; HR 1.65, p = 0.1163, respectively). Docetaxel lymphedema (RVC C 10 %) compared to no adjuvant was also associated with a significant increase in risk for chemotherapy as well as non-taxane chemotherapy. How- mild swelling compared to no chemotherapy (HR 1.62, ever, adjuvant chemotherapy with docetaxel was a sig- p = 0.0084), however, paclitaxel was not (HR 1.16, nificant risk factor for mild arm swelling (5 to \10 % RVC) p = 0.3882). Other significant risk factors for mild swelling compared to no chemotherapy as well as non-taxane che- included older age at surgery, ALND, greater number of LNs motherapy (p = 0.0098, p = 0.0195, respectively). Addi- removed, and greater number of positive LNs (Table 5). tional risk factors for mild arm swelling were older age at surgery and ALND. Consistent with the literature, ALND, Multivariate analysis pre-operative BMI C 30, and older age at surgery were in- dependent risk factors for lymphedema (RVC C 10 %). Receipt of taxane-based chemotherapy did not remain Currently, taxane-based chemotherapy is administered significantly associated with increased risk of lymphedema for node-positive and high-risk node-negative breast can- compared to no chemotherapy (HR 1.14, p = 0.6188) and cer, as it has been shown to significantly reduce mortality non-taxane chemotherapy (HR 1.56, p = 0.3988) on [31–35, 38, 50–53]. The use of anthracycline-alone 123 398 Breast Cancer Res Treat (2015) 151:393–403 Table 4 Univariate and multivariate analysis of characteristics associated with risk of lymphedema (RVC C 10 %) Univariate results Multivariate results Hazard ratio (95 % CI) p value Hazard ratio (95 % CI) p value Patient characteristics Age at surgery (years) 1.02 (1.00–1.03) 0.1080 1.02 (1.00–1.04) 0.0433 a 2 Pre-operative BMI (kg/m ) 1.07 (1.04–1.10) \0.0001 1.05 (1.02–1.09) 0.0007 Surgical characteristics Axillary surgery SLNB versus no axillary surgery 0.83 (0.36–1.89) 0.6507 – ALND versus no axillary surgery 6.31 (2.88–13.80) \0.0001 7.32 (3.16–17.01) \0.0001 ALND versus SLNB/no axillary surgery 7.37 (4.86–11.19) \0.0001 8.19 (5.12–13.10) <0.0001 Pathologic characteristics Invasive vs. DCIS 2.20 (1.06–4.53) 0.0335 1.05 (0.49–2.25) 0.9041 Number positive lymph nodes 1.10 (1.07–1.13) \0.0001 1.02 (0.98–1.06) 0.4337 Systemic therapy Adjuvant taxane-based chemotherapy Yes versus no chemo 2.61 (1.73–3.95) \0.0001 1.14 (0.69–1.87) 0.6188 Yes versus non-taxane chemo 2.90 (1.04–8.08) 0.0412 1.56 (0.56–4.37) 0.3988 Paclitaxel Yes versus no chemo 2.00 (1.23–3.24) 0.0053 0.81 (0.46–1.41) 0.4473 Yes versus non-taxane chemo 2.45 (0.85–7.07) 0.0984 1.26 (0.43–3.65) 0.6725 Docetaxel Yes versus no chemo 2.54 (1.52–4.26) 0.0004 1.25 (0.71–2.18) 0.4374 Yes versus non-taxane chemo 3.12 (1.06–9.20) 0.0392 1.95 (0.65–5.85) 0.2334 Non-taxane chemotherapy Yes versus no chemo 0.90 (0.32–2.52) 0.8417 0.64 (0.22–1.83) 0.4056 Hormonal therapy Yes versus no 1.59 (0.90–2.80) 0.1098 – Herceptin-based chemotherapy Yes versus no 1.10 (0.55–2.20) 0.7778 – – Radiation therapy Yes versus no 1.06 (0.65–1.75) 0.8056 – – RLNR versus breast?chest wall/none 4.32 (2.82–6.63) \0.0001 1.29 (0.77– 2.16) 0.3354 CI confidence interval, BMI body mass index, SLNB sentinel lymph node biopsy, ALND axillary lymph node dissection, DCIS ductal carcinoma in situ, RLNR regional lymph node radiation Age at surgery, pre-operative BMI, and number of positive lymph nodes were analyzed as continuous variables such that the hazard ratios reflect the change in lymphedema risk associated with a 1-unit increase in the variable ‘‘–’’ indicates the specified variable/comparison was not analyzed 2 Separate models, each including age at surgery, BMI and ALND were used to estimate the hazard ratios for (1) adjuvant taxane-based chemo and (2) individual effects of paclitaxel and docetaxel regimens in breast cancer treatment has declined [54], similarities between the mechanism of fluid retention and which has resulted in a growing increase of taxane-based development of breast cancer-related lymphedema [55, 56] chemotherapy for early stage breast cancer. Therefore, a the association between taxane-based chemotherapy full understanding of the QOL and long-term implications (specifically docetaxel) and lymphedema warrants further of taxanes is necessary. investigation. A recent review comparing adjuvant che- Docetaxel has relatively greater hematologic toxicity motherapy with and without docetaxel in breast cancer and is more commonly associated with edema than pacli- patients showed that patients receiving docetaxel consis- taxel [53]. To reduce incidence and severity of edema, tently had increased rates of edema compared to patients coticosteroids are routinely administered [40]. Due to receiving docetaxel-free chemotherapy [57]. This review 123 Breast Cancer Res Treat (2015) 151:393–403 399 Table 5 Univariate and multivariate analysis of characteristics associated with risk of mild swelling (5 B 10 % RVC) Univariate results Multivariate results Hazard Ratio (95 % CI) p value Hazard Ratio (95 % CI) p value Patient characteristics Age at surgery (years) 1.02 (1.01–1.03) 0.0011 1.02 (1.01–1.03) 0.0003 a 2 Pre-operative BMI (kg/m ) 1.02 (1.00–1.04) 0.1366 1.01 (0.99–1.03) 0.4157 Surgical characteristics Axillary surgery –b SLNB versus no axillary surgery 0.90 (0.63–1.29) 0.5631 – ALND versus no axillary surgery 1.36 (0.89–2.07) 0.1527 1.35 (0.84–2.18) 0.2188 ALND versus SLNB/no axillary surgery 1.48 (1.10–2.00) 0.0105 1.47 (1.05–2.07) 0.0266 Pathologic characteristics Invasive vs. DCIS 1.42 (0.99–2.04) 0.0572 1.27 (0.87–1.84) 0.2152 Number positive lymph nodes 1.07 (1.03–1.11) 0.0002 1.04 (0.99–1.00) 0.0603 Systemic therapy Adjuvant taxane-based chemo Yes versus no chemo 1.31 (1.00–1.71) 0.0512 1.33 (0.97–1.83) 0.0778 Yes versus non-taxane chemo 1.86 (1.03–3.35) 0.0398 1.74 (0.95–3.13) 0.0732 Paclitaxel Yes versus no-chemo 1.16 (0.83–1.62) 0.3882 1.13 (0.77–1.66) 0.5428 Yes versus non-taxane chemo 1.65 (0.88–3.07) 0.1163 1.49 (0.79–2.80) 0.2174 Docetaxel Yes versus no-chemo 1.62 (1.13–2.32) 0.0084 1.63 (1.13–2.36) 0.0098 Yes versus non-taxane chemo 2.31 (1.21–4.38) 0.0107 2.15 (1.13–4.09) 0.0195 Non-taxane chemotherapy Yes versus no chemo 0.70 (0.40, 1.24) 0.2265 0.75 (0.42–1.35) 0.3473 Hormonal therapy Yes versus no 1.05 (0.78–1.41) 0.7639 – – Herceptin-based chemotherapy Yes versus no 0.80 (0.50–1.30) 0.3644 – – Radiation therapy Yes versus no 1.04 (0.77–1.40) 0.8106 – – RLNR versus breast ? chest wall/none 1.18 (0.80–1.74) 0.4043 0.82 (0.51–1.31) 0.4064 CI confidence interval, BMI body mass index, SLNB sentinel lymph node biopsy, ALND axillary lymph node dissection, DCIS ductal carcinoma in situ, RLNR regional lymph node radiation Age at surgery, pre-operative BMI, and number of positive lymph nodes were analyzed as continuous variables such that the hazard ratios reflect the change in lymphedema risk associated with a 1-unit increase in the variable ‘‘–’’ indicates the specified variable/comparison was not analyzed 2 Separate models, each including age at surgery, BMI and ALND were used to estimate the hazard ratios for (1) adjuvant taxane-based chemo and (2) individual effects of paclitaxel and docetaxel included studies comparing generalized edema in docetaxel women for lymphedema with bioimpedence spectroscopy and docetaxel-free groups, but did not specifically report on (BIS) as part of a larger randomized study which evaluated lymphedema of the arm. The relationship between effect of exercise after breast surgery. Measurements were docetaxel and upper extremity lymphedema is unclear, as taken at 1, 3, 9, and 15 months post-operatively and lym- the only studies in the literature examining this are case phedema was defined according to previously established reports [58, 59]. cutoffs. On multivariate analysis, patients who received The association of breast cancer-related lymphedema taxane chemotherapy had a 7-fold greater risk of swelling with taxane-based chemotherapy has been reported, but not in the arm at 9-months after surgery compared to women widely studied. In 2013, Kilbreath et al. analyzed 160 who did not receive taxane chemotherapy (HR 7.4, 123 400 Breast Cancer Res Treat (2015) 151:393–403 p \ 0.001) [42]. However, taxane chemotherapy did not distinguish between minor increases in arm volume versus remain significant at 15 months post-operative, leading to chronic lymphedema. Because of our prospective screening the conclusion that taxanes cause transient swelling in the and quantified method of measuring arm volume, the re- at-risk arm. sults of this study fill a gap in the literature regarding risk A similar study by Jung et al. evaluating patients who of lymphedema after receiving taxane-based chemother- underwent ALND showed that taxane-based chemotherapy apy. Furthermore, our data better informs clinicians of was an independent risk factor for lymphedema on multi- docetaxel-related arm edema, and can help educate patients variate analysis [41]. In 848 patients evaluated post-op- on treatment-related risk factors for lymphedema. eratively for a one-time lymphedema event as well as for Due to the non-randomized selection of patients for persistent lymphedema, taxane-based chemotherapy was taxane-based chemotherapy versus non-taxane-based che- associated with higher incidence of lymphedema motherapy, there are limitations in the present study. At our (HR = 1.69, p = 0.03 for lymphedema event; HR 2.07, institution, few patients receive chemotherapy without a p = 0.04 for persistent lymphedema) [41]. However, pa- taxane (i.e. anthracycline alone); out of 1121 patients tients did not undergo a pre-operative arm measurement and eligible for this analysis, only 62 received adjuvant non- lymphedema was defined using a wide range of both objec- taxane chemotherapy (5.5 %). Although a larger percent- tive and subjective criteria. Interestingly, in our analysis, age of patients receiving non-taxane-based chemotherapy taxane-based chemotherapy was not associated with in- would have allowed for a more accurate analysis on the creased risk of lymphedema. Possible explanations for this effects of taxane, the minimal usage of anthracyclines include low cumulative incidence of lymphedema of the alone in our cohort reflects standard practice and guidelines entire cohort and the impact of multivariable analysis ad- for systemic treatment. The nature of our screening pro- justed for factors known to increase risk of lymphedema such tocol calls for arm volume assessments to be taken before as ALND (Table 3). and after completion of chemotherapy, but not during; Most recently, Lee et al. reported on lymphedema fol- therefore, the data that are reported in this study does not lowing taxane chemotherapy in women with early stage include any arm volume changes that occurred while re- breast cancer. 63 patients were assessed with BIS after ax- ceiving active taxane chemotherapy. Taking these factors illary surgery, before taxane-chemotherapy, and 6 months into account, there are many areas for future research. after completion of chemotherapy. Results showed that The current study also has several strengths. We utilized a taxane chemotherapy increased incidence of lymphedema of large cohort of patients prospectively screened for changes in the ipsilateral arm and persisted for at least 6 months after arm volume with a perometer, a device with demonstrated completion of chemotherapy, whereas generalized edema in validity for lymphedema assessment [44, 45, 60, 61]. This cohort of 1121 patients represents one of the largest in the the legs resolved during this timeframe [43]. This series was limited by small sample size and lack of long-term follow- lymphedema literature, and to our knowledge, the largest in up. In our series the median time to lymphedema in all co- which risk of lymphedema was evaluated for association horts was between 19 and 21 months post-surgery, therefore with adjuvant taxane-based chemotherapy. Of note, patients the increased swelling that this study reports could be related receiving neoadjuvant chemotherapy were excluded in order to transient edema. to solely assess the hypothesis that fluid retention from The results of our study show adjuvant docetaxel in- chemotherapy may overwhelm compromised lymphatic creases risk of mild swelling; however, multivariate analysis vessels after surgery, and could therefore lead to chronic indicates that this does not subsequently lead to increased lymphedema. All patients in our study underwent a pre-op- risk of lymphedema. These findings are consistent with the erative arm volume measurement and regular post-operative reported side effects of docetaxel treatment, and further the screening, with a median follow-up of over 3 years. The understanding of the relationship between docetaxel and importance of obtaining pre-operative assessments to ac- breast cancer-related lymphedema. More importantly, be- count for asymmetry between arms and adjustment for fac- cause docetaxel is not an independent risk factor for lym- tors unrelated to lymphedema has been previously phedema and the median time to onset of lymphedema was demonstrated [47, 62, 63]. In addition, we utilized a similar across chemotherapy groups (Fig. 1), results of this validated formula to measure arm volume differences, ac- study suggest that it is largely ALND that elevates risk of counting for baseline pre-operative differences as well as lymphedema, not receipt of taxane chemotherapy. weight changes [64]. Lymphedema was defined as C10 % As many patients who receive ALND are also subse- RVC, which has been widely used in the literature [7, 12, 48]. quently treated with taxanes due to more advanced disease, Our study also separates paclitaxel and docetaxel for risk these individuals should still be closely monitored for de- of lymphedema due to the well known differences in adverse velopment of lymphedema. The strong association between events related to these therapeutic agents. Additionally, adjuvant docetaxel and mild swelling highlights the need to distinction between mild and chronic edema was evaluated 123 Breast Cancer Res Treat (2015) 151:393–403 401 in both univariate and multivariate models. Mild swelling References was defined as RVC C 5to \10 % based on our previously 1. 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These findings can 11. Park JH, Lee WH, Chung HS (2008) Incidence and risk factors of be utilized for patient counseling and education regarding breast cancer lymphoedema. J Clin Nurs 17:1450–1459 common side effects while undergoing taxane-based che- 12. Tsai RJ, Dennis LK, Lynch CF et al (2009) The risk of devel- oping arm lymphedema among breast cancer survivors: a meta- motherapy. Although arm volume changes should be analysis of treatment factors. Ann Surg Oncol 16:1959–1972 regularly monitored for early signs of progression, it is 13. Ahmed RL, Schmitz KH, Prizment AE et al (2011) Risk factors important for clinicians to differentiate between treatment- for lymphedema in breast cancer survivors, the Iowa Women’s related risk factors for developing chronic edema versus Health Study. Breast Cancer Res Treat 130:981–991 14. Crosby MA, Card A, Liu J et al (2012) Immediate breast re- mild or transient edema that may resolve without inter- construction and lymphedema incidence. Plast Reconstr Surg vention. This may help patients avoid costly treatment 129:789e–795e expenses and potentially reduce fear of lymphedema. 15. Swenson KK, Nissen MJ, Leach JW et al (2009) Case-control study to evaluate predictors of lymphedema after breast cancer Acknowledgments The study described was supported by Award surgery. Oncol Nurs Forum 36:185–193 Number R01CA139118 (AGT), Award Number P50CA089393 16. Soran A, D’Angelo G, Begovic M et al (2006) Breast cancer- (AGT) from the National Cancer Institute and the Adele McKinnon related lymphedema—what are the significant predictors and how Research Fund for Breast Cancer-Related Lymphedema. The content they affect the severity of lymphedema? Breast J 12:536–543 is solely the responsibility of the authors and does not necessarily 17. 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Published: May 5, 2015

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