乳腺癌术后淋巴水肿的多因素研究

Clinical Investigation:Breast CancerA 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 Myungsoo Kim,MD,Seok Won Kim,MD,Sung Uk Lee,MD,Nam Kwon Lee,MD, So-Youn Jung,MD,Tae Hyun Kim,MD,Eun Sook Lee,MD,Han-Sung Kang,MD, and Kyung Hwan Shin,MDResearch Institute and Hospital,National Cancer Center,Goyang,KoreaReceived Nov22,2012,and in revised form Jan22,2013.Accepted for publication Feb15,2013SummaryIn our patients with breast cancer,the risk factors asso-ciated with breast cancer-related lymphedema were the number of dissected axillary lymph nodes, adjuvant chemotherapy,and supraclavicular radiation therapy.We proposeda model to estimate the5-year lymphedema proba-bility using combinations of these risk factors and this simple model may help clinicians predict the risk of lymphedema.Purpose:The 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:A total of772patients with breast cancer,who underwent primary surgery with axillary lymph node dissection from2004to2009,were retrospectively analyzed. Adjuvant chemotherapy(ACT)was performed in677patients(88%).Among patients who received radiation therapy(n Z675),274(35%)received supraclavicular radiation therapy (SCRT).Results:At a median follow-up of5.1years(range,3.0-8.3years),127patients had developed LE.The overall5-year cumulative incidence of LE was17%.Among the127affected patients, LE occurred within2years after surgery in97(76%)and within3years in115(91%)patients. Multivariate analysis showed that N-ALN(hazard ratio[HR],2.81;P<.001),ACT(HR,4.14; P Z.048),and SCRT(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 or1risk factor showed a significantly lower5-year probability of LE(3%)than patients with2(19%)or3risk factors(38%)(P<.001).Conclusions:The 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.Ó2013Elsevier Inc.Reprint requests to:Kyung Hwan Shin,MD,Research Institute and Hospital,National Cancer Center,323Ilsan-ro,Ilsandong-gu,Goyang-si, Gyeonggi-do,410-769,Republic of Korea.Tel:þ82-31-920-1722;E-mail:shin.kyunghwan@M.Kim and S.W.Kim contributed equally to this work.This research was supported by National Cancer Center Grant NCC-1210181-1.Conflict of interest:none.Int J Radiation Oncol Biol Phys,V ol.86,No.3,pp.498e503,2013 0360-3016/$-see front matterÓ2013Elsevier Inc.All rights reserved. /10.1016/j.ijrobp.2013.02.018Radiation Oncology International Journal of biology physicsIntroductionBreast cancer-related lymphedema(LE)is one of the unpleasant complications of breast cancer surgery with axillary lymph node dissection(ALND).As the survival rate among breast cancer patients has increased,LE has emerged as an important long-term morbidity that can cause functional,cosmetic,and psychological problems and which can impair survivors’quality of life.The reported incidence of LE after breast cancer treatment varies widely,from less than5%with lumpectomy alone to more than60% when treatment includes mastectomy with ALND and radiation therapy(RT)(1).In addition to these therapeutic modalities, nonstandard diagnostic methods of LE and variation in the follow-up period also contribute to the large variation in LE incidence.The origins of and risk factors associated with LE are multi-factorial and are still not fully understood.Three categories of treatment-related,disease-related,and patient-related risk factors have been reported to increase the incidence of LE in several series(2-4).Although sentinel lymph node biopsy(SLNB)has replaced ALND for staging of patients in whom axillary nodes are clinically negative,and it is well known that LE after SLNB is less common or severe than after ALND,ALND remains the standard of care in the management of invasive breast carcinoma when patients have clinically positive lymph nodes or metastatic spread to the sentinel nodes(5,6).Approximately one-third of patients undergo ALND,and treatment-related factors for ALND, chemotherapy,and RT are assumed to be closely related to LE development(7,8).For this subset of patients,a tool for predicting the risk of LE should be created to help physicians and breast cancer patients control such patient-related factors as obesity, infection,injury,and arm overuse.In the present study,we analyzed the probability of LE by using grading scales that combined objective and subjective methods with a relatively long follow-up period.The main purpose was to create a model for use in estimating the risk of LE based on combinations of treatment-or disease-related risk factors,which can be used easily and effectively in a busy clinical setting.Methods and MaterialsPatientsThe study population consisted of1254consecutive patients with breast cancer who underwent modified radical mastectomy(MRM) or breast-conserving surgery(BCS)with ALND at the National Cancer Center,Korea between May2004and April2009.Among these,375women who were treated with neoadjuvant chemo-therapy followed by surgery were excluded from the study.Patients with synchronous or metachronous contralateral breast cancer (n Z4)and male patients(n Z2)were excluded.Patients whose follow-up periods were less than3years(n Z101)were also excluded.The remaining772patients were included in the analysis, which was performed in accordance with the guidelines of our Institutional Review Board.TreatmentSurgery consisted of either MRM or BCS,as necessary,based on the surgeon’s recommendations and tumor characteristics.The general criteria for patient selection for BCS included a lack of initial extensive skin or chest wall involvement,an absence of extensive microcalcifications or multifocal disease,the anticipated adequacy of residual breast tissue following BCS,and an absolute contraindication against breast irradiation.Standard ALND was performed with or without SLNB in all patients.RT was delivered to all BCS and MRM patients with pT3,pN2 to pN3,or pN1with extracapsular invasion of the involved nodes. Planning computed tomography(CT)scans were obtained in all patients,and RT was performed using conventional technique. Typically,50.4Gy was delivered in28fractions to the ipsilateral breast or chest wall with tangentialfields,using6-MV photons. After BCS,all patients received an electron boost(median10Gy) to the lumpectomy cavity.The ipsilateral axillary apex and supraclavicular RT(SCRT)were delivered to patients with a pN2 to pN3status(median,45Gy).The supraclavicular and axillary lymph nodes were contoured in planning CT scans,and the dose was prescribed to a supraclavicular target volume to encompass with95%minimum.Internal mammary nodal RT was adminis-tered to only4patients with clinically-positive internal mammary nodes.The initial planned dose of RT was completed in all cases.ACT consisted of6to8courses of a non-taxane containing (n Z268)or taxane-containing(n Z409)regimen.Adjuvant hormonal suppression therapy using tamoxifen or an aromatase inhibitor was offered to patients with estrogen receptor-positive or progesterone receptor-positive tumors.Trastuzumab(Herceptin) was administered for1year in44patients with c-erbB2-overexpressing tumors.Measurement and assessment of LEDetermination of LE was based on both objective(circumference measurement)and subjective(patient perception of arm edema) assessment methods.The measurement and assessment of LE was done with all patients as a part of a prospective database since 2004,and this was done by a single physician(K.H.S).At each follow-up visit,patients were asked whether they were currently experiencing swelling,heaviness,thickness,tiredness,or pain in their affected arms,regardless of reported arm size differences. Circumference measurements of the ipsilateral and contralateral arms at10cm above the antecubital fold were taken regularly from at least6months postoperatively until the last follow-up at every6 months.Ipsilateral arm swelling of more than5%of the circum-ferential difference without special conditions such as a previous accident or injury to the contralateral arm was considered objec-tive LE.Grading scales combining the subjective symptoms of the patients and Common Terminology Criteria for Adverse Events, version4.0,were used as an LE scoring system.The difference of 5%to10%in arm measurement or only subjective self-perception of arm edema difference less than5%was scored as grade1.A 10%to30%difference and difference greater than30%were scored as grades2and3,respectively,regardless of the presence of subjective LE.LE was defined only when arm swelling was persistent at2consecutive follow-up examinations. Statistical analysisThe actuarial rates of LE were calculated using the Kaplan-Meier method.All statistics were measured from the date of surgery. Univariate Cox proportional hazards models were used to evaluate risk factors associated with the incidence of LE,including age, BMI,pathologic stage,type of surgery,N-ALNs,ACT,and RTVolume86 Number3 2013Breast cancer-related lymphedema499field.Only significant variables after univariate analysis were included in the multivariate parisons between risk groups were performed using log d rank tests.P values less than .05were deemed statistically significance.All statistical tests were 2-sided and performed using SPSS,version17.0,software(SPSS Inc,Chicago,IL).ResultsPatient and treatment characteristics are summarized in Table1. The median age at the time of surgery was47years old(range,26-83years old).BCS was performed in606(79%)and MRM in166 (21%)patients.Median N-ALN was11(range,5-41).ACT was administered to677patients(88%).In total,RT was administered to674patients(87%),among whom400(52%)received breast or chest wall irradiation alone.SCRT was delivered to274patients (35%).Among98patients(13%)who did not receive RT,94who underwent MRM and had no postoperative indications for RT,and 4who underwent BCS refused RT.Incidence and time course of LEThe median follow-up duration after surgery was5.1years(range, 3.0-8.3years).Initially,201patients(26%)had been reported to have episodes of subjective or objective LE during follow-up. Among these201patients,74patients whose arm edema resolved spontaneously at the next follow-up after6months were defined as having transient LE.These74patients,who were diagnosed with initial subjective LE(36patients)or objective LE only(38 patients),thereafter showed no more LE episodes at regular follow-up.Only127patients(16%)who showed persistent arm swelling at2consecutive follow-up examinations were classified as having LE:106(14%)were grade1,and21(2.7%)were grade 2according to our grading scales.No grade3patient was observed.The initial grade at thefirst swelling episode was grade 1in119(15%)and grade2in8(1.0%)patients.A total of14of 119patients who were initially grade1progressed to grade2,and 1of8patients who were initially grade2showed improvement to grade1at the subsequent follow-up examination.Of106grade1 patients,54had only a subjective self-perception of arm edema with a difference of less than5%.The median interval from surgery to initial swelling in patients with permanent LE was1.2 years(range,0.1-5.6years).The overall5-year cumulative inci-dence of LE was16.8%(Fig.1).Among127affected patients,LE first occurred within2years of the diagnosis in76%and within3 years in91%of patients.Risk factors correlated with LEHigher rates of LE development correlated with the following variables by univariate analysis:pathologic stage(II or III), N-ALN(>10),ACT,and RT(breast with SCRT)(Table2).For RT,the LE rate of33%in patients who received breast and SCRT was significantly higher than that of7%in patients who received no RT or breast RT only(P<.001).However,breast or chest wall RT itself did not incur a higher risk of LE development compared to no RT(P Z.65).The LE rates in patients with N-ALN10and >10were6%and27%,respectively(P<.001).Age,BMI,and type of surgery did not significantly correlate with LE.In multivariate analysis of the patients,the following treatment-related factors were significantly correlated with increased LE development:N-ALN>10(hazard ratio[HR],2.81;P<.001),ACT (HR,4.14;P Z.048),and breast with SCRT(HR,3.24;P<.001) (Table3).The HR of pathologic stage II or III was1.60without significance(P Z.25).Risk groups for LE based on combinations of3 treatment-related factorsThe5-year LE rates according to the3treatment-related risk factors(N-ALN,ACT,and SCRT)that showed asignificantFig. 1.Kaplan-Meier plots of the cumulative incidence ofbreast cancer-related lymphedema.Kim et al.International Journal of Radiation Oncology Biology Physics 500difference by both univariate and multivariate analyses are presented in Table4.The5-year LE rate in patients with no risk factor(N-ALN10,ACT not done,and SCRT not done)was 1.4%,and it was not significantly different from patients with1 risk factor(3.8%;N-ALN10,ACT done or SCRT not done) (P Z.3).Fifteen patients treated with N-ALN>10showed no incidence of LE when they received neither ACT nor SCRT (P Z.7).The5-year LE rates in patients with2risk factors were 24%(N-ALN10,ACT done and SCRT done)and17%(N-ALN >10,ACT done and SCRT not done).Patients with all3 treatment-related risk factors showed an LE rate as high as38%at 5years.There was no patient who met the criteria of1risk factor (N-ALN10,ACT not done and SCRT done)or2risk factors(N-ALN>10,ACT not done and SCRT done).We divided the patients into low-,intermediate-,and high-risk groups based on the number of treatment-related risk factors.The low-risk group(1risk factor)consisted of343 patients(44%)and demonstrated a3.1%LE rate at5years.The intermediate-risk group(2risk factors)consisted of220 patients(29%)and showed a19%LE rate at5years.The high-risk group(all3risk factors)consisted of209patients(27%) and displayed a38%LE probability at5years(P<.001) (Fig.2).DiscussionThe incidence of LE is difficult to compare among studies because of a lack of standardization of follow-up periods and definitions. Several reports with long-term follow-up have shown that the risk of lymphedema increases persistently until20years after surgery, although most cases occurred within3years(6,7).Therefore, studies reporting the incidence of LE with less than5years of follow-up would underestimate the true incidence.We followed our patients for at least3years(median,5.1years),supporting the acquisition of the long-term incidence of LE.Most patients(91%) developed arm lymphedema within3years in the present study, consistent with other reports(6).Petrek et al(7)however,reported that the onset of lymphedema symptoms occurred after3years in approximately25%of patients.Circumferential arm measurements have been widely used to detect lymphedema;however,they could underestimate the inci-dence of lymphedema because,for example,those patients with isolated hand edema could be omitted.Therefore,the influence of self-perception is also important to detect LE.McLaughlin et al (6)argued that both symptom assessment and objective measurements are needed to determine the true incidence of clinically significant lymphedema.We used grading scales combining both the objective method of circumference measure-ment and subjective method of patient perception of arm edema. Additionally,another definition of LE was used in the present study:persistent arm edema at2consecutive follow-up exami-nations.Among201patients(26%)with initial LE,74(10%) showed normalization of arm edema at the subsequent consecutive follow-up visit.In another report,this transient arm edema was defined as mild LE(9).We mainly tested treatment-and disease-related factors. Among patient-related factors,age and BMI were investigated.In the literature,increased age(>60years)and obesity have been reported to be important risk factors for LE(10,11).We found no correlation between those factors and LE,possibly because BMIsVolume86 Number3 2013Breast cancer-related lymphedema501of our patients were mostly in the normal range or <25kg/m 2(67%).Only 42patients had BMI >30kg/m 2.It is generally accepted that more extensive ALND results in more extensive surgical disruption of lymphatic vessels and,consequently,is associated with an increased risk of LE.In conventional ALND,where most lymph nodes in the axilla are removed,LE rates vary from 12%to 49%(12).Several authors have reported that N-ALN is one of the most significant predictors of LE development (5,13).However,other series reporting no relation between lymphedema and N-ALN,suggest that this relationship is complex,and other factors likely play an important role in LE development (3,7).In our study,the mean N-ALN was 11(range,5-41),and multivariate analyses showed N-ALN results to be significant for LE.In addition to N-ALN,an association between the level of ALND and LE was rson et al (14)reported that the risk of LE was 37%when full ALND was per-formed compared with 8%when a partial ALND was performed.However,in many studies,N-ALN rather than the level of ALND has been analyzed in LE,and we also used N-ALN to represent the extent of ALND.RT has been found to be a major independent risk factor for the development of LE in many studies,and regional irradiation is considered to be the strongest contributing factor,with a 2-to 4.5-fold increase in the risk of LE (15).Additionally,the combi-nation of ALND and radiation is known to have a synergistic effect on the development of LE,being associated with 8-to 10-fold higher risk of LE.In an evaluation of 727patients who were treated with BCS and breast irradiation with or without SCRT,Coen et al (2)reported that the LE rate at 10years was 1.8%for breast irradiation alone and 8.9%for breast and SCRT.Nodal irradiation was the only significant risk factor for LE.Our study also found that SCRT was significantly associated with LEwith a HR of 3.24(P <.001).Irradiation of the breast or chest wall only was not significantly associated with LE (P Z .65).Chemotherapy as a risk factor for the development of LE remains controversial.The mechanism by which chemotherapy would increase the risk of LE is unknown,and chemotherapy might be a marker for more aggressive disease.An evaluation by Norman et al (11)found that patients receiving anthracycline-based chemotherapy had an increased risk of developing LE,with an HR of 1.46compared with no chemotherapy.They also reported that treatment combinations involving ALND or chemotherapy resulted in approximately 4-to 5-fold increases in the HR compared with no treatment.In our study,ACT led to a 4.1-fold increase in HR compared with no treatment.Two studies recently reported predictive models for LE.Soran et al (16)investigated a predictive tool for LE using combinations of three modifiable,patient-related risk factors,including an upper extremity infection on the surgery side,level of hand use,and BMI !25kg/m 2.This model showed that it is possible to decrease the risk of LE by avoiding these 3risk factors;however,the model was limited by the small number of patients and its exclusion of any treatment-related factors.Bevilacqua et al (17)proposed nomograms to estimate the probability of LE after ALND based on data collected from a large prospective cohort comprising 1054patients.They used patient-,disease-,and treatment-related risk factors to predict the 5-year LE probability,and the nomograms were validated by concordance indices of >70%.However,the follow-up period was relatively short,and the nomograms were somewhat complicated for clinicians to use easily.Our model to estimate the risk of LE using the combination of N-ALN,ACT,and SCRT is effective and would be simple to use in a busy clinical setting.Clinicians may remember the 3treatment-related factors and predict the 5-year LE probability by memorizing the 3risk numbers for each risk group.As depicted in Figure 2,the 5-year LE probabilities were <5%for patients with no or 1risk factor,20%for 2factors,and 40%for all 3factors.The arm conditions for the intermediate-to high-risk patient groups could be followed more carefully,and patient-related factors such as obesity,hand use,injury,and infection could be modified to reduce the risk.In this retrospective analysis,patient-related factors (arm infection,injury,and excessive hand use)could neither be tested nor be included in the risk groups because we did not use questionnaires including those factors.Although they seem to be significant risk factors,this risk-estimating model is considered valuable to predict the risk of LE and modify those factors for high-risk group patients.Another limitation is the accuracy of the subjective and objective definitions of LE.For the subjective patient perception of arm edema,this was dependent on patient recall or swelling sense at the time of the outpatient clinic visit.For objective measurement,we measured only the upper arm circumference;hence,localized forearm or hand edema could be neglected,although the subjective method might complement it.ConclusionsIn conclusion,the results of the current analysis show that N-ALN,ACT,and SCRT are independent risk factors for the development of LE.The number of risk factors was well corre-lated with the LE risk.A simple model to estimate the 5-year LE probability using combinations of risk factors wasproposed,Fig.2.Kaplan-Meier plots of the cumulative rates of breast cancer-related lymphedema according to risk groups,defined on the basis of the number of treatment-related risk factors (number of dissected axillary nodes,adjuvant chemotherapy,and supra-clavicular radiation therapy).Low-risk group, 1factor;intermediate-risk group,2factors;high-risk group,all 3factors.Kim et al.International Journal of Radiation Oncology Biology Physics 502which might be useful for identifying patients at risk for LE and in creating a management plan for these patients. 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