|Year : 2018 | Volume
| Issue : 2 | Page : 184-189
Breast cancer-related lymphedema in postmastectomy patients receiving adjuvant irradiation: A prospective study
Kartick Rastogi1, Sandeep Jain1, Aseem-Rai Bhatnagar2, Shivani Gupta1, Sandeep Bhaskar1, RK Spartacus1
1 Department of Radiotherapy, SMS Medical College and Attached Group of Hospitals, Jaipur, Rajasthan, India
2 Department of Radiation Oncology, Shalby Hospital, Jaipur, Rajasthan, India
|Date of Web Publication||31-Dec-2018|
Dr. Kartick Rastogi
Department of Radiotherapy, SMS Medical College and Attached Group of Hospitals, Jaipur, Rajasthan
Source of Support: None, Conflict of Interest: None
CONTEXT: In India, most breast cancer patients present with advanced stage requiring postmastectomy radiotherapy. Lymphedema is a long-term side effect that causes both physical and psychological distresses. AIMS: The present prospective study was carried out to study various factors affecting breast cancer-related lymphedema (BCRL). SUBJECTS AND METHODS: From January 2015 to March 2016, 100 postmastectomy patients who received adjuvant irradiation to chest wall were selected prospectively. Circumference of both arms was measured before surgery, at start, and at end of radiotherapy followed by 3 monthly intervals till last follow-up. Lymphedema was defined as a difference of ≥2 cm from the baseline in the arm circumference on the side of surgery. RESULTS: At a median follow-up of 24 months, the cumulative incidence of BCRL was 13%. On multivariate analysis, risk of BCRL was significantly associated with higher body mass index (BMI) (P = 0.004), greater number of lymph nodes (LNs) dissected (P = 0.005), higher nodal ratio (P = 0.006), and regional LN radiation (RLNR) (P = 0.048) but not with the type of fractionation (P = 0.094). CONCLUSIONS: Adjuvant RLNR, higher BMI, greater number of LNs dissected, and higher nodal ratio significantly increases the risk of development of BCRL. There was no significant difference in the lymphedema with the type of fractionation. Females receiving RLNR should be prospectively monitored for lymphedema to ensure early detection and possible intervention.
Keywords: Breast cancer-related lymphedema, hypofractionated radiotherapy, lymphedema, postmastectomy radiotherapy, regional lymph node radiation
|How to cite this article:|
Rastogi K, Jain S, Bhatnagar AR, Gupta S, Bhaskar S, Spartacus R K. Breast cancer-related lymphedema in postmastectomy patients receiving adjuvant irradiation: A prospective study. Indian J Cancer 2018;55:184-9
|How to cite this URL:|
Rastogi K, Jain S, Bhatnagar AR, Gupta S, Bhaskar S, Spartacus R K. Breast cancer-related lymphedema in postmastectomy patients receiving adjuvant irradiation: A prospective study. Indian J Cancer [serial online] 2018 [cited 2020 Jul 7];55:184-9. Available from: http://www.indianjcancer.com/text.asp?2018/55/2/184/249209
| » Introduction|| |
Breast cancer is the most commonly diagnosed cancer in females worldwide. In contrast to the western world, most of the females present with locally advanced breast cancer in India requiring modified radical mastectomy (MRM) more often than breast conservative surgery (BCS). Most of these require postmastectomy radiotherapy. With recent advances in technology, patients have good long-term outcomes; hence, long-term side effects assume great importance in patient's quality of life. Breast cancer-related lymphedema (BCRL) is one among them that causes both physical and psychological distresses.,,,,,
| » Subjects and Methods|| |
One hundred females with histologically confirmed infiltrating ductal carcinoma (IDC) of unilateral breast without distant metastasis at diagnosis were included in the study. All patients underwent MRM along with axillary lymph node (LN) dissection (ALND) followed by adjuvant radiotherapy. The average duration between surgery and starting of radiotherapy was 3½ months (range, 2–7 months). Patients with bilateral breast cancer, histology other than IDC, other synchronous malignancies, preexisting lymphedema, or previous surgery in the upper limb on the same side of ALND were excluded from the study. All patients were referred to the department of physiotherapy after surgery for various lymphedema-preventive exercises equivocally.
All patients received radiotherapy on dual-energy Siemens® ONCOR™ Expression linear accelerator machine with three-dimensional conformal radiation therapy technique between January 2015 and March 2016. Fifty patients received the standard conventional fractionated (CF) radiotherapy with a dose of 50 Gy in 25 fractions with 2 Gy/fraction, 1 fraction/day, 5 days a week for 5–6 weeks and 50 patients received hypofractionated (HF) radiotherapy with a dose of 42.72 Gy in 16 fractions with 2.67 Gy/fraction, 1 fraction/day, 5 days/week for 3.5 weeks. Each patient was categorized as per the treatment she received into either chest wall (CW) radiation alone or CW with regional LN radiation (RLNR). RLNR was not prescribed in patients with negative axillary nodes and tumor size >5 cm or margins positive and in patients with negative axillary nodes and tumor ≤5 cm and negative margins but <1 mm. Baring a few cases with extracapsular extension or inadequate ALND, RLNR usually covered supraclavicular fossa only; axilla was not covered for cases with adequate ALND. The targets were contoured according to the Radiation Therapy Oncology Group Atlas More Details. The CW was treated with oblique beams and nodal basins received either CF or HF radiotherapy through an anterior field angled 10–15° to save the spinal cord. The dose was calculated at a depth of mostly 3 cm (range, 2–5 cm). None of the patients in the present study received posterior axillary boost.
The arm circumference was taken at wrist, elbow, upper arm just below the axilla, and 10 cm proximal and 10 cm distal to the lateral epicondyle on both the arms before starting radiotherapy and at the end of radiotherapy followed by 3 monthly intervals till the last follow-up. Lymphedema was defined as a difference of 2 cm or more in the circumference of the arm on the side of ALND pre- and postradiotherapy as opposed to asymmetry between the arm on the side of ALND and the contralateral arm.
Factors evaluated in the analysis were based on the review of literature describing various factors associated with the development of lymphedema. These were age at diagnosis, hand dominance, tumor size, number of LNs removed, number of positive LNs, and region irradiated (CW and CW + RLNR). In addition, we also evaluated nodal ratio defined as the ratio of positive LNs to the LNs dissected and the type of radiotherapy (CF vs HF). All data were prepared and processed on Microsoft Excel 2007 for Windows. In univariate analysis, qualitative data (hand dominance, RLNR, and type of radiotherapy) were analyzed using Chi-square test and quantitative data (age, body mass index [BMI], tumor size, number of LNs dissected, positive number of nodes, and nodal ratio) were analyzed using t-test. Multivariate analysis was performed using Cox proportional hazard methodology defining lymphedema as an event. To identify predictors of lymphedema, hazard ratio, 95% confidence interval, and P value were calculated using the XLSTAT software version 2017 for Windows (Addinsoft, NY, USA). In all calculations, the significance level was taken as 0.05.
| » Results|| |
The baseline patient-, tumor-, and treatment-related characteristics are shown in [Table 1]. At a median follow-up of 24 months (range, 16–30 months), the cumulative incidence (CI) of lymphedema was 13% [Figure 1] and [Table 2]. The results of univariate analysis are shown in [Table 3]. Risk of lymphedema development was significantly associated with higher BMI (P < 0.001), greater number of LNs dissected (P = 0.006), positive LNs (P < 0.001), higher nodal ratio (P < 0.001), and RLNR (P = 0.01). On multivariate analysis, the factors found for significantly increasing the risk of development of lymphedema were higher BMI (P = 0.004), greater number of LNs dissected (P = 0.005), higher nodal ratio (P = 0.006), and RLNR (P = 0.04) [Table 4]. The association was not significant with the type of RT (CF vs HF) in both univariate (P = 0.77) and multivariate (P = 0.09) analyses.
|Table 1: Baseline patient-, tumor-, and treatment-related characteristics of the study cohort|
Click here to view
|Figure 1: Cumulative incidence of lymphedema. CF: Conventional fractionation, HF: Hypofractionation|
Click here to view
|Table 2: Cumulative incidence of lymphedema stratified by various factors|
Click here to view
|Table 3: Univariate analysis for factors associated with risk of lymphedema|
Click here to view
|Table 4: Multivariate analysis for factors associated with risk of lymphedema|
Click here to view
| » Discussion|| |
The present study has utilized a cohort of 100 post-MRM female breast cancer patients prospectively screened for lymphedema at a single institution between January 2015 and March 2016 representing a population treated with modern radiotherapy techniques over a relatively short time period. Most of the studies done till date evaluating risk factors for lymphedema including adjuvant radiotherapy have utilized retrospectively collected data with larger number of cohort and have included both BCS and MRM patients with relatively longer follow-up. However, stratification by the type of radiotherapy and association of development of lymphedema with nodal ratio has not been addressed in any such study.
There is no common consensus regarding the use of method to diagnose BCRL. A large number of methods have been described in the literature [Table 5].,,,,,,,,, The method of measuring lymphedema (circumference measurement) used in the present study is simple, easily reproducible, and the most commonly used method in the medical literature. Moreover, many studies have compared the circumference of two arms for defining lymphedema, which is a wrong method giving rise to false-positive results.
The CI of lymphedema in our study was 13% at a median follow-up of 24 months. This is at par with what has been reported in previous studies utilizing larger cohort [Table 5].,,,,, In our study, the addition of RLNR to CW increased the risk of lymphedema significantly compared to CW radiation alone (P = 0.04). We observed an increased lymphedema incidence for patients who underwent ALND and RLNR (19.6%) compared to those who underwent ALND and CW radiation alone (2.5%), consistent with several prior studies [Table 5].,,,,
The other independent risk factors that have shown statistically significant association with the development of lymphedema in the present study were higher BMI and greater number of LNs dissected, which has also been consistently reported as independent risk factors in many studies [Table 5].,,,,,,,, The present study is one of the few studies that have highlighted the impact of conventional versus HF radiotherapy on the development of lymphedema. In addition, nodal ratio has been found to be an independent risk factor in the development of lymphedema in the present study, which has not been tested in any previous studies to the best of our knowledge.
| » Conclusions|| |
The addition of RLNR to CW significantly increases the risk of developing lymphedema compared to CW radiotherapy alone. Other independent risk factors that significantly increase the risk of developing lymphedema are higher BMI, greater number of LN dissected, and higher nodal ratio. However, HF radiotherapy does not significantly increase the risk of lymphedema compared to CF radiotherapy. Females who receive RLNR should be prospectively monitored for lymphedema to ensure early detection and timely intervention. The limitations of the present study include small sample size and relatively short follow-up period. Most of the patients were referred to our department after surgery followed by completion of adjuvant chemotherapy not only from surgical and medical oncology departments of our institute, but also from different institutes. The median time between surgery and initiation of radiotherapy was 3½ months (range, 2–7 months). Being a prospective study, the impact of postoperative infection and chemotherapy thence could not be assessed, which is also a limitation of the present study.
We would like to thank Dr. Daleep Singh, Junior Specialist, Radiotherapy, SMS Hospital, Jaipur, Rajasthan, India, for his guidance.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Ceilley E, Jagsi R, Goldberg S, Grignon L, Kachnic L, Powell S, et al.
Radiotherapy for invasive breast cancer in North America and Europe: Results of a survey. Int J Radiat Oncol Biol Phys 2005;61:365-73.
Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, et al.
Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish breast cancer cooperative group 82b trial. N Engl J Med 1997;337:949-55.
Ragaz J, Olivotto IA, Spinelli JJ, Phillips N, Jackson SM, Wilson KS, et al.
Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the British Columbia randomized trial. J Natl Cancer Inst 2005;97:116-26.
Whelan TJ, Julian J, Wright J, Jadad AR, Levine ML. Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 2000;18:1220-9.
Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans V, et al.
Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005;366:2087-106.
Miller CL, Specht MC, Horick N, Skolny MN, Jammallo LS, O'Toole J, et al.
A novel, validated method to quantify breast cancer-related lymphedema (BCRL) following bilateral breast surgery. Lymphology 2013;46:64-74.
Ancukiewicz M, Russell TA, Otoole J, Specht M, Singer M, Kelada A, et al.
Standardized method for quantification of developing lymphedema in patients treated for breast cancer. Int J Radiat Oncol Biol Phys 2011;79:1436-43.
Armer JM, Stewart BR. A comparison of four diagnostic criteria for lymphedema in a post-breast cancer population. Lymphat Res Biol 2005;3:208-17.
Ancukiewicz M, Miller CL, Skolny MN, O'Toole J, Warren LE, Jammallo LS, et al.
Comparison of relative versus absolute arm size change as criteria for quantifying breast cancer-related lymphedema: The flaws in current studies and need for universal methodology. Breast Cancer Res Treat 2012;135:145-52.
Smoot BJ, Wong JF, Dodd MJ. Comparison of diagnostic accuracy of clinical measures of breast cancer-related lymphedema: Area under the curve. Arch Phys Med Rehabil 2011;92:603-10.
Svensson BJ, Dylke ES, Ward LC, Kilbreath SL. Segmental bioimpedance informs diagnosis of breast cancer-related lymphedema. Lymphat Res Biol 2017;15:349-55.
Warren LE, Miller CL, Horick N, Skolny MN, Jammallo LS, Sadek BT, et al.
The impact of radiation therapy on the risk of lymphedema after treatment for breast cancer: A prospective cohort study. Int J Radiat Oncol Biol Phys 2014;88:565-71.
Soares EW, Nagai HM, Bredt LC, da Cunha AD Jr., Andrade RJ, Soares GV, et al.
Morbidity after conventional dissection of axillary lymph nodes in breast cancer patients. World J Surg Oncol 2014;12:67.
Coen JJ, Taghian AG, Kachnic LA, Assaad SI, Powell SN. Risk of lymphedema after regional nodal irradiation with breast conservation therapy. Int J Radiat Oncol Biol Phys 2003;55:1209-15.
Norman SA, Localio AR, Kallan MJ, Weber AL, Torpey HA, Potashnik SL, et al.
Risk factors for lymphedema after breast cancer treatment. Cancer Epidemiol Biomarkers Prev 2010;19:2734-46.
DiSipio T, Rye S, Newman B, Hayes S. Incidence of unilateral arm lymphoedema after breast cancer: A systematic review and meta-analysis. Lancet Oncol 2013;14:500-15.
Ribeiro Pereira ACP, Koifman RJ, Bergmann A. Incidence and risk factors of lymphedema after breast cancer treatment: 10 years of follow-up. Breast 2017;36:67-73.
Asdourian MS, Swaroop MN, Sayegh HE, Brunelle CL, Mina AI, Zheng H, et al.
Association between precautionary behaviors and breast cancer-related lymphedema in patients undergoing bilateral surgery. J Clin Oncol 2017;35:3934-41.
Stout Gergich NL, Pfalzer LA, McGarvey C, Springer B, Gerber LH, Soballe P, et al.
Preoperative assessment enables the early diagnosis and successful treatment of lymphedema. Cancer 2008;112:2809-19.
Hayes SB, Freedman GM, Li T, Anderson PR, Ross E. Does axillary boost increase lymphedema compared with supraclavicular radiation alone after breast conservation? Int J Radiat Oncol Biol Phys 2008;72:1449-55.
Shah C, Wilkinson JB, Baschnagel A, Ghilezan M, Riutta J, Dekhne N, et al.
Factors associated with the development of breast cancer-related lymphedema after whole-breast irradiation. Int J Radiat Oncol Biol Phys 2012;83:1095-100.
Whelan TJ, Olivotto IA, Parulekar WR, Ackerman I, Chua BH, Nabid A, et al
.:MA.20 Study Investigators. Regional Nodal Irradiation in Early-Stage Breast Cancer. N Engl J Med 2015;373:307–16.
Tsai RJ, Dennis LK, Lynch CF, Snetselaar LG, Zamba GK, Scott-Conner C, et al.
The risk of developing arm lymphedema among breast cancer survivors: A meta-analysis of treatment factors. Ann Surg Oncol 2009;16:1959-72.
Ahmed RL, Schmitz KH, Prizment AE, Folsom AR. Risk factors for lymphedema in breast cancer survivors, the Iowa women's health study. Breast Cancer Res Treat 2011;130:981-91.
McLaughlin SA, Wright MJ, Morris KT, Giron GL, Sampson MR, Brockway JP, et al.
Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: Objective measurements. J Clin Oncol 2008;26:5213-9.
Sayegh HE, Asdourian MS, Swaroop MN, Brunelle CL, Skolny MN, Salama L, et al.
Diagnostic methods, risk factors, prevention, and management of breast cancer-related lymphedema: Past, present, and future directions. Curr Breast Cancer Rep 2017;9:111-21.
Mahamaneerat WK, Shyu CR, Stewart BR, Armer JM. Breast cancer treatment, BMI, post-op swelling/lymphoedema. J Lymphoedema 2008;3:38-44.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]