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A Model to Estimate the Risk of Breast Cancer-Related Lymphedema: Combinations of Treatment-Related Factors of the Number of Dissected Axillary Nodes, Adjuvant Chemotherapy, and Radiation Therapy
component or extensive intraductal disease within a close margin. (However, the consensus guideline clearly states that there is no evidence of an increased ipsilateral breast tumor recurrence rate associated with an extensive intraductal component when margins are negative.) Worth noting in this study by Jaffre´ and colleagues is that only margin involvement by intraductal carcinoma was significantly predictive of residual disease on multivariate analysis. Their residual disease rate of 41% for patients undergoing reexcision for ductal carcinoma in situ at the margin is in keeping with the 45% reported by others, and this finding does highlight that intraductal carcinoma at the margin, particularly when diffuse, may be highly predictive for residual disease.3 The authors further demonstrated that for patients with positive margins, only diffuse involvement was associated with an increase in LIR on multivariate analysis; focally involved
margins were not associated with an increase in LIR, despite the authors’ report of a 25% incidence of residual disease on reexcision for margins focally involved with carcinoma. This argument may have been more compelling had there been a comparison of LIR rates with and without reexcision for patients with focally involved margins. The odds ratios for LIR were 3.3 for patients with diffuse infiltrative disease at the margin and 13.4 for those with diffuse intraductal disease. In the aforementioned meta-analysis by Houssami and colleagues, inbreast recurrences were 2-fold higher for patients with positive margins than for those with negative margins. The effect of tumor extent at the margin was not reported. Although thoughtprovoking, the results from the current study are not compelling enough to warrant reconsideration of the current practice standard of reexcising margins when there is any amount of tumor on ink. As we continue to see a decline in local recurrence rates with
breast-conserving therapy, this practice may warrant further research.
A Model to Estimate the Risk of Breast Cancer-Related Lymphedema: Combinations of Treatment-Related Factors of the Number of Dissected Axillary Nodes, Adjuvant Chemotherapy, and Radiation Therapy
nodes, adjuvant chemotherapy, and supraclavicular radiation therapy. We proposed a model to estimate the 5year lymphedema probability using combinations of these risk factors and this simple model may help clinicians predict the risk of lymphedema. Purpose.dThe development of breast cancer-related lymphedema (LE) is closely related to the number of dissected axillary lymph nodes (N-ALNs), chemotherapy, and radiation therapy. In this study, we attempted to estimate the risk of LE based on combinations of these treatment-related factors. Methods and Materials.dA total of 772 patients with breast cancer, who underwent primary surgery with axillary
lymph node dissection from 2004 to 2009, were retrospectively analyzed. Adjuvant chemotherapy (ACT) was performed in 677 patients (88%). Among patients who received radiation therapy (n ¼ 675), 274 (35%) received supraclavicular radiation therapy (SCRT). Results.dAt a median follow-up of 5.1 years (range, 3.0-8.3 years), 127 patients had developed LE. The overall 5-year cumulative incidence of LE was 17%. Among the 127 affected patients, LE occurred within 2 years after surgery in 97 (76%) and within 3 years in 115 (91%) patients. Multivariate analysis showed that N-ALN (hazard ratio [HR], 2.81; P < .001), ACT (HR, 4.14; P ¼ .048), and SCRT
Kim M, Kim SW, Lee SU, et al (Natl Cancer Ctr, Goyang, Korea) Int J Radiat Oncol Biol Phys 86:498-503, 2013
In our patients with breast cancer, the risk factors associated with breast cancer-related lymphedema were the number of dissected axillary lymph
246
Breast Diseases: A Year BookÒ Quarterly Vol 25 No 3 2014
C. L. Akay, MD
References 1. Moran MS, Schnitt SJ, Giuliano AE, et al. Society of Surgical OncologyAmerican Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. Ann Surg Oncol. 2014;21:704-716. 2. Houssami N, Macaskill P, Marinovich ML, Morrow M. The association of surgical margins and local recurrence in women with earlystage invasive breast cancer treated with breast-conserving therapy: a meta-analysis. Ann Surg Oncol. 2014; 21:717-730. 3. Sabel MS, Rogers K, Griffith K, et al. Residual disease after re-excision lumpectomy for close margins. J Surg Oncol. 2009;99:99-103.
(HR, 3.24; P < .001) were independent risk factors for LE. The total number of risk factors correlated well with the incidence of LE. Patients with no risk or 1 risk factor showed a significantly lower 5-year probability of LE (3%) than patients with 2 (19%) or 3 risk factors (38%) (P < .001). Conclusions.dThe risk factors associated with LE were N-ALN, ACT, and SCRT. A simple model using combinations of these factors may help clinicians predict the risk of LE. As reported in this article, Kim and colleagues developed a model to predict the incidence of breast cancere related upper extremity LE according to various treatment parameters by examining prospectively collected data from 772 patients over 5 years. They found that SCRT, the removal of more than 10 axillary lymph nodes, and ACT correlated with the development of LE. Patients with one of these risk factors had approximately the same incidence of LE as those whose treatment had none of these risk factors. The risk of LE in these patients was approximately 4% and 1%, respectively. Patients with 2 risk factors had an LE incidence of approximately 20%, and those with all 3 risk factors had an incidence of up to 40%. This predictive model will be very useful to caregivers and patients alike. It is likely that Kim and colleagues underestimated the incidence of LE in their patient population by using only a single upper arm measurement for surveillance, ignoring the forearm and hand in their objective assessment. While a single circumferential measurement is a simple, quick, and inexpensive tool, a formal LE assessment should include at least tape measurements at multiple prede-
fined levels and/or other volumetric measurements. The same measures should be applied to the contralateral extremity, as a mounting body of evidence suggests a systemic effect that may lead to symptomatic swelling on the noncancer side.1 The standardized questions about patient selfperception of their affected limb are also an important part of the diagnosis of LE. More frequent assessments at 3-month intervals, especially during the first 18 months after cancer therapy, the steepest part of the LE development curve, may identify affected individuals earlier and should be considered. The dissemination of this simple model proposed by the authors will allow breast cancer care providers to closely observe and initiate early referrals to certified LE therapists, especially for high-risk patients. If LE persists for 6 months or beyond the second measurement in the current study, affected patients should be referred to plastic surgeons performing LE surgeries, as earlier surgical intervention has been shown to be more effective and more likely to preserve intrinsic lymphatic function. While the number of axillary nodes removed correlated with the development of LE, a more important factor may actually be the anatomic locations of the nodes that are removed, a difficult parameter to study retrospectively. Work done by Suami and colleagues2 suggests that there may be a “lymphosome” for the upper extremity that is separate from that of the breast in most individuals. These channels are located more superiorly, parallel to the course of the cephalic vein; this anatomic concept may also explain the higher
incidence of LE with SCRT than with breast irradiation. Boneti and colleagues3 have explored this concept clinically for the prevention of breast cancererelated LE. More studies like the current one are needed to define the true incidence of breast cancererelated LE, allow validation of the presented risk factors for other populations, and possibly establish other risk factors that may have been absent in this particular population, such as obesity,4 which has been associated with LE by other authors. A. Ibrahim, MD R. Skoracki, MD
References 1. Aldrich MB, Sevick-Muraca EM. Cytokines are systemic effectors of lymphatic function in acute inflammation. Cytokine. 2013;64: 362-369. 2. Suami H, Pan WR, Taylor GI. Changes in the lymph structure of the upper limb after axillary dissection: radiographic and anatomical study in a human cadaver. Plast Reconstr Surg. 2007;120:982-991. 3. Boneti C, Badgwell B, Robertson Y, Korourian S, Adkins L, Klimberg V. Axillary reverse mapping (ARM): initial results of phase II trial in preventing lymphedema after lymphadenectomy. Minerva Ginecol. 2012;64:421-430. 4. Miller CL, Specht MC, Horick N, et al. A novel, validated method to quantify breast cancer-related lymphedema (BCRL) following bilateral breast surgery. Lymphology. 2013;46:64-74.
Breast Diseases: A Year BookÒ Quarterly Vol 25 No 3 2014
247
margins were not associated with an increase in LIR, despite the authors’ report of a 25% incidence of residual disease on reexcision for margins focally involved with carcinoma. This argument may have been more compelling had there been a comparison of LIR rates with and without reexcision for patients with focally involved margins. The odds ratios for LIR were 3.3 for patients with diffuse infiltrative disease at the margin and 13.4 for those with diffuse intraductal disease. In the aforementioned meta-analysis by Houssami and colleagues, inbreast recurrences were 2-fold higher for patients with positive margins than for those with negative margins. The effect of tumor extent at the margin was not reported. Although thoughtprovoking, the results from the current study are not compelling enough to warrant reconsideration of the current practice standard of reexcising margins when there is any amount of tumor on ink. As we continue to see a decline in local recurrence rates with
breast-conserving therapy, this practice may warrant further research.
A Model to Estimate the Risk of Breast Cancer-Related Lymphedema: Combinations of Treatment-Related Factors of the Number of Dissected Axillary Nodes, Adjuvant Chemotherapy, and Radiation Therapy
nodes, adjuvant chemotherapy, and supraclavicular radiation therapy. We proposed a model to estimate the 5year lymphedema probability using combinations of these risk factors and this simple model may help clinicians predict the risk of lymphedema. Purpose.dThe development of breast cancer-related lymphedema (LE) is closely related to the number of dissected axillary lymph nodes (N-ALNs), chemotherapy, and radiation therapy. In this study, we attempted to estimate the risk of LE based on combinations of these treatment-related factors. Methods and Materials.dA total of 772 patients with breast cancer, who underwent primary surgery with axillary
lymph node dissection from 2004 to 2009, were retrospectively analyzed. Adjuvant chemotherapy (ACT) was performed in 677 patients (88%). Among patients who received radiation therapy (n ¼ 675), 274 (35%) received supraclavicular radiation therapy (SCRT). Results.dAt a median follow-up of 5.1 years (range, 3.0-8.3 years), 127 patients had developed LE. The overall 5-year cumulative incidence of LE was 17%. Among the 127 affected patients, LE occurred within 2 years after surgery in 97 (76%) and within 3 years in 115 (91%) patients. Multivariate analysis showed that N-ALN (hazard ratio [HR], 2.81; P < .001), ACT (HR, 4.14; P ¼ .048), and SCRT
Kim M, Kim SW, Lee SU, et al (Natl Cancer Ctr, Goyang, Korea) Int J Radiat Oncol Biol Phys 86:498-503, 2013
In our patients with breast cancer, the risk factors associated with breast cancer-related lymphedema were the number of dissected axillary lymph
246
Breast Diseases: A Year BookÒ Quarterly Vol 25 No 3 2014
C. L. Akay, MD
References 1. Moran MS, Schnitt SJ, Giuliano AE, et al. Society of Surgical OncologyAmerican Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. Ann Surg Oncol. 2014;21:704-716. 2. Houssami N, Macaskill P, Marinovich ML, Morrow M. The association of surgical margins and local recurrence in women with earlystage invasive breast cancer treated with breast-conserving therapy: a meta-analysis. Ann Surg Oncol. 2014; 21:717-730. 3. Sabel MS, Rogers K, Griffith K, et al. Residual disease after re-excision lumpectomy for close margins. J Surg Oncol. 2009;99:99-103.
(HR, 3.24; P < .001) were independent risk factors for LE. The total number of risk factors correlated well with the incidence of LE. Patients with no risk or 1 risk factor showed a significantly lower 5-year probability of LE (3%) than patients with 2 (19%) or 3 risk factors (38%) (P < .001). Conclusions.dThe risk factors associated with LE were N-ALN, ACT, and SCRT. A simple model using combinations of these factors may help clinicians predict the risk of LE. As reported in this article, Kim and colleagues developed a model to predict the incidence of breast cancere related upper extremity LE according to various treatment parameters by examining prospectively collected data from 772 patients over 5 years. They found that SCRT, the removal of more than 10 axillary lymph nodes, and ACT correlated with the development of LE. Patients with one of these risk factors had approximately the same incidence of LE as those whose treatment had none of these risk factors. The risk of LE in these patients was approximately 4% and 1%, respectively. Patients with 2 risk factors had an LE incidence of approximately 20%, and those with all 3 risk factors had an incidence of up to 40%. This predictive model will be very useful to caregivers and patients alike. It is likely that Kim and colleagues underestimated the incidence of LE in their patient population by using only a single upper arm measurement for surveillance, ignoring the forearm and hand in their objective assessment. While a single circumferential measurement is a simple, quick, and inexpensive tool, a formal LE assessment should include at least tape measurements at multiple prede-
fined levels and/or other volumetric measurements. The same measures should be applied to the contralateral extremity, as a mounting body of evidence suggests a systemic effect that may lead to symptomatic swelling on the noncancer side.1 The standardized questions about patient selfperception of their affected limb are also an important part of the diagnosis of LE. More frequent assessments at 3-month intervals, especially during the first 18 months after cancer therapy, the steepest part of the LE development curve, may identify affected individuals earlier and should be considered. The dissemination of this simple model proposed by the authors will allow breast cancer care providers to closely observe and initiate early referrals to certified LE therapists, especially for high-risk patients. If LE persists for 6 months or beyond the second measurement in the current study, affected patients should be referred to plastic surgeons performing LE surgeries, as earlier surgical intervention has been shown to be more effective and more likely to preserve intrinsic lymphatic function. While the number of axillary nodes removed correlated with the development of LE, a more important factor may actually be the anatomic locations of the nodes that are removed, a difficult parameter to study retrospectively. Work done by Suami and colleagues2 suggests that there may be a “lymphosome” for the upper extremity that is separate from that of the breast in most individuals. These channels are located more superiorly, parallel to the course of the cephalic vein; this anatomic concept may also explain the higher
incidence of LE with SCRT than with breast irradiation. Boneti and colleagues3 have explored this concept clinically for the prevention of breast cancererelated LE. More studies like the current one are needed to define the true incidence of breast cancererelated LE, allow validation of the presented risk factors for other populations, and possibly establish other risk factors that may have been absent in this particular population, such as obesity,4 which has been associated with LE by other authors. A. Ibrahim, MD R. Skoracki, MD
References 1. Aldrich MB, Sevick-Muraca EM. Cytokines are systemic effectors of lymphatic function in acute inflammation. Cytokine. 2013;64: 362-369. 2. Suami H, Pan WR, Taylor GI. Changes in the lymph structure of the upper limb after axillary dissection: radiographic and anatomical study in a human cadaver. Plast Reconstr Surg. 2007;120:982-991. 3. Boneti C, Badgwell B, Robertson Y, Korourian S, Adkins L, Klimberg V. Axillary reverse mapping (ARM): initial results of phase II trial in preventing lymphedema after lymphadenectomy. Minerva Ginecol. 2012;64:421-430. 4. Miller CL, Specht MC, Horick N, et al. A novel, validated method to quantify breast cancer-related lymphedema (BCRL) following bilateral breast surgery. Lymphology. 2013;46:64-74.
Breast Diseases: A Year BookÒ Quarterly Vol 25 No 3 2014
247