californium-252 brachytherapy combined with external-beam radiotherapy for cervical cancer long-term

CLINICAL INVESTIGATIONCALIFORNIUM-252BRACHYTHERAPY COMBINED WITH EXTERNAL-BEAM RADIOTHERAPY FOR CERVICAL CANCER:LONG-TERM TREATMENT RESULTS X IN L EI,M.D.,P H.D.,C HENG-Y UAN Q IAN,M.S C.,Y I Q ING,M.D.,K E-W EI Z HAO,M.D., Z HENG-Z HOU Y ANG,M.D.,P H.D.,N AN D AI,M.D.,Z HAO-Y ANG Z HONG,M.D.,C HENG T ANG,M.S C., Z HENG L I,M.S C.,X IAN-Q ING G U,M.S C.,Q IAN Z HOU,M.S C.,Y AN F ENG,M.S C.,Y AN-L I X IONG,M.S C.,J IN-L U S HAN,M.D.,AND D ONG W ANG,M.D.,P H.D.Cancer Center,Research Institute of Surgery and Daping Hospital,Third Military Medical University,Chongqing,ChinaPurpose:To observe,by retrospective analysis,the curative effects and complications due to californium-252(252Cf)neutron intracavitary brachytherapy(ICBT)combined with external-beam radiotherapy(EBRT)in the treatmentof cervical cancer.Methods and Materials:From February1999to December2007,696patients with cervical cancer(Stages IB toIIIB)were treated with252Cf-ICBT in combination of EBRT.Of all,31patients were at Stage IB,104at IIA,363atIIB,64at IIIA,and134at IIIB.Californium-252ICBTwas delivered at7–12Gy per insertion per week,with a totaldose of29–45Gy to reference point A in three tofive insertions.The whole pelvic cavity was treated with8-MVX-ray external irradiation at2Gy per fraction,four times per week.After16–38Gy of external irradiation,the center of the whole pelvicfield was blocked with a4-cm-wide lead shield,with a total external irradiationdose of44–56Gy.The total treatment course was5to6weeks.Results:Overall survival rate at3and5years for all patients was76.0%and64.9%,respectively.Disease-free3-and5-year survival rates of patients were71.2%and58.4%,te complications included vaginalcontracture and adhesion,radiation proctitis,radiation cystitis,and inflammatory bowel,which accounted for5.8%,7.1%,6.2%,and4.9%,respectively.Univariate analysis results showed significant correlation of stage,age,histopathologic grade,and lymph node status with overall survival.Cox multiple regression analysis showedthat the independent variables were stage,histopathologic grade,tumor size,and lymphatic metastasis in allpatients.Conclusion:Results of this series suggest that the combined use of252Cf-ICBTwith EBRT is an effective method fortreatment of cervical cancer.Ó2011Elsevier Inc.Cervical cancer,Brachytherapy,Californium-252,Treatment results.INTRODUCTIONCervical cancer ranks as the third leading cause of cancer death among women.It was estimated that in2008,75,400 women were diagnosed with cervical cancer and33,900 died of this disease in China(1,2).Radiotherapy,in the form of a combination of intracavitary brachytherapy (ICBT)with external-beam radiotherapy(EBRT),is consid-ered one treatment option for advanced cervical cancer. Gamma-radiation-emitting isotopes,such as60Co,137Cs, and192Ir,are often used in ICBT.Despite progress in after-loading techniques and computer technology,the survival rate of cervical cancer patients shows little improvement.Sev-eral groups have reported that g-brachytherapy-based concur-rent chemoradiation improves the survival of patients with locally advanced cervical carcer(3–7).In addition to theabove-mentioned g sources,neutron sources,especiallycalifornium-252,may play an important role in brachytherapy.Californium-252(252Cf),discovered in1950(8),emitsa mixedflux of2.1–2.3-MeV neutrons and0.5–1.0MeV g-rays with a half-life of2.65years.Neutrons are high linear energy transfer(LET)radiation resulting in radiobiologicaleffects.These effects include a high relative biological effec-tiveness(RBE)value,low oxygen enhancement ratio,inhi-bition of cell damage repair,and minimal dependence ofradiation sensitivity on the cell cycle.In the late1960s 252Cf was applied as a new radiation source in ICBT for treating gynecologic malignant tumors in the United States,the former Soviet Union,and Japan(9).Reprint requests to:Dong Wang,M.D.,Ph.D.Cancer Center, Research Institute of Surgery and Daping Hospital,Third Military Medical University,No.10Changjiang Zhilu,Yuzhong District,Chongqing400042,China’’Tel:+86-23-68894062, Fax:+86-23-68894062;E-mail:dongwang64@ Supported by the National Natural Science Foundation of China (30970761).C.-y.Q.and X.L.contributed equally to this work.Conflict of interest:none.Received April23,2010,and in revised form July29,2010. Accepted for publication Aug4,2010.1Int.J.Radiation Oncology Biol.Phys.,V ol.-,No.-,pp.1–7,2011CopyrightÓ2011Elsevier Inc.Printed in the USA.All rights reserved0360-3016/$-see front matterdoi:10.1016/j.ijrobp.2010.08.039Although252Cf is not widely used worldwide,and no stan-dard treatment regimen exists,there have been a number of pilot studies demonstrating that252Cf-ICBT is an effective method in the treatment of cervical cancer(10–12). Maruyama et al.(12,13)applied252Cf-ICBT combined with EBRT to treat cervical cancer patients in Stages IB, II,III,and IV A,and the5-year overall survival(OS)rates were87%,62%,33%,and20%,respectively.Marjina(14) studied345patients with cervical cancer in Stages II–III treated with252Cf-ICBT and EBRT.The5-year survival rate for Stages II and III was72.3%.Zhao et al.(15)reported that for Stage II,the3-year and5-year survival rates were 90.9%and76.2%,respectively.For Stage III,the3-year and5-year survival rates were81.5%and61%,respectively. The3-year and5-year OS rates were87.5%and70%,re-spectively.By comparison,it was reported that the5-year survival rates for cervical cancer patients in Stages IIB and IIIB who received g-brachytherapy were65–75%and35–50%for Stages IIB and IIIB,respectively(16–19).In a French Cooperative Group study of1875patients who received g-brachytherapy,Barillot et al.(20)reported5-year survival rates of83.5%,81%,71%,69%,and47.5% for Stages IB,IIA,IIB,IIIA,and IIIB,respectively.Tacev et al.(11)compared252Cf and conventional g-radiation in the brachytherapy of advanced cervical cancer.They found that the overall5-year survival rate of patients treated with252Cf neutron brachytherapy for Stage IIB was better by 18.9%than that of those receiving g-radiation(75.2%vs.56.3%,p<0.001).For IIIB,the improvement was22.8% (66.1%vs.43.3%,p<0.003).Recently we analyzed the current status of brachytherapy on cervical cancer in China by reviewing published articles from1990to2009.The results showed3-year OS rates of 95.3%and75.0%for Stage II and Stage III,respectively, and5-year OS rates of89.2%and75.0%in553patients with252Cf brachytherapy.The3-year OS rates of Stages II and III were83.3%and65.7%,respectively,and5-year OS rates were66.4%and58.4%in1613patients with g-bra-chytherapy(21).Until now,a large portion of cervical cancer patients were still treated with radiation therapy alone in China.Among other factors,the‘‘cost increase’’has argued against com-bined chemoradiation treatment.However,in1999,we im-plemented thefirst252Cf neutron remote afterloading system in China to treat cervical cancers.The afterloading unit is remotely controlled.The dose equivalent rate from the neutrons,for occupational exposures,does not exceed 10m Sv/h on the afterloader shielding surface,which is the limit recommended by the International Commission on Ra-diological Protection(22).Presently18252Cf afterloading systems have been installed in China,with more than3000 cervical cancer patients treated by252Cf-ICBT.In this article, the follow-up data of696cervical cancer patients treated with252Cf neutron brachytherapy and EBRT at our depart-ment are retrospectively analyzed,and the survival rate and cure rates of252Cf neutron brachytherapy for cervical cancer are presented.METHODS AND MATERIALSPatient populationFrom February1999to December2007,696previously un-treated patients with biopsy-proven cervical cancer were treated with252Cf-ICBT and concurrent EBRT at the Cancer Center,Re-search Institute of Surgery and Daping Hospital,Third Military Medical University.All patients had complete medical records and received physical examinations including staging at pelvic ex-amination by a gynecologic oncologist,radiation oncologist,or both.All carcinomas were definitively diagnosed by pathologic as-sessment,which showed normal hemogram and liver and kidney functions.Patients were examined by chest radiograpy,abdominal B-type ultrasonography,computed tomography(CT),positron emission tomography,or magnetic resonance imaging scan of the pelvic cavity to evaluate abdominal,visceral,osseous,nodal,and genitourinary puted tomography facilitated measure-ment of tumor diameter for cervical,especially endocervical tu-mors.The staging of the illness was determined according to the International Federation of Gynecology and Obstetrics(1997)rec-ommendations.Blood transfusions were given to anemic patients and those with severe bleeding to a minimum hemoglobin level of10g/dL.Patient characteristics are listed in Table1.252Cf-ICBTCalifornium-252-ICBT was applied by an LZH-1000afterload-ing system(Lin Den Science and Technology,Shenzhen,China; Fig.1),which contained a526-m g252Cf source.The following for-mula is used to convert252Cf dose to Gy equivalent(Gy-eq):D Gy-eq¼DnÂRBEnþD gÂRBE g;where Dn=252Cf neutron component dose,D g=252Cf g-compo-nent dose,RBEn=relative biological effectiveness of neutrons, Table1.Characteristics of696patients with cervical cancer Characteristics Patients% Total patients696Age(y),median,range46.3(16–81)Follow-up(mo),median(range)44(24–129)Stage(FIGO)IB31 4.5 IIA10414.9 IIB36352.1 IIIA649.2 IIIB13419.3 HistopathologySquamous cell carcinoma67897.4 Adenocarcinoma15 2.2 Others30.4 Histopathologic grade(G)G1(well differentiated)29842.8 G2(moderately differentiated)31244.8 G3(poorly or undifferentiated)8612.4 Tumor size(cm)<424435.0 4–625837.1 >619427.9 Lymph node statusPostive15221.8 Negative33047.4 Unknown21430.8 Abbreviation:FIGO=international federation of gynecology and obstetrics.2I.J.Radiation Oncology d Biology d Physics V olume-,Number-,2011and RBE g =relative biological effectiveness of g -radiation.The RBE value of the 252Cf neutron component is 2–3(23,24).During each applicator insertion,the uterus was first dilated with a dilater.A tricavity applicator (Fig.2)without 252Cf was inserted into the uterine cavity.Rectal barium enema was given to each pa-tient to visualize the rectum.The barium was pulled out as much as possible after radiography.A urine catheter was inserted into the bladder,and 7mL contrast media was injected into a Foley cath-eter.Anterior and posterior vaginal packing was performed after the insertion to fix the applicators and to maximize the distance between the source and the anterior rectal wall and posterior bladder wall.Then,orthogonal radiographs of the pelvic cavity were taken to show the extent and size of the tumor.These radiographs were the basis on which an individualized treatment plan was developed by the treatment planning software of the afterloading system.The dose was prescribed to point A,defined by the Manchester system as 2cm superior (along the tandem)to the flange abutting external cervical os and 2cm lateral from the axis of the tandem.The Inter-national Commision on Radiation Units and Measurements rectal reference point was defined along a lead wire on the rectum wall.The reference dose point of Foley in the bladder was the lowest point of contrast medium in the supine position film.The dose to point A for each patient was 7–12Gy per fraction,administered once per week.Californium-252-ICBT was delieverd in 2to 3h per insertion and performed three to five times in total.The ICBT treatment sched-ules for different tumor stages are listed in Table 2.The total 252Cf-ICBT dose to point A was 29–45Gy-eq in 3to 5fractions.The dose to bladder and rectum was less than 60%of point A,and the dose ra-tio of cervix and vagina was 1:1(Fig.3).Median calculated doses at International Commision on Radiation Units and Measurements ref-erence points from single ICBT were 7.1Gy (range,3.8–9.3Gy)for the rectum and 6.5Gy (range,5.1–8.3Gy)for the bladder.External-beam radiotherapyExternal-beam radiotherapy was given by 8-MV X-ray beams from an Elekta Precise linear accelerator (Elekta,Stockholm,Swe-den)with the position of the tumor target determined by CT scan.The linear accelerator is equipped with multileaf collimators to form conformal radiation fields.The EBRT dose was delivered to the pelvis through anterior and posterior parallel-opposed portals.The fields extended superiorly to the L4–5interspace and inferiorly to the middle part of the lower margin of the obturator t-erally,the fields extended at least 1.5cm beyond the bony margin of the pelvis at the widest point.The total dose of EBRT to the whole pelvis was 44–56Gy (2Gy per fraction per day).The composite dose of ERBT plus 252Cf-ICBT is shown in Table 2.Center shield-ing,with the placement of a 4-cm rectangular midline lead block of 5half value layer in both fields,was applied after 16–38Gy pelvic radiotherapy.The goal of the midline block technique was to spare the bladder and rectum (thereby reducing toxicity)while permitting increased doses to the cervix from the ICBT (thereby improving lo-cal tumor control).The total time of 8-MV X-ray EBRT combined with 252Cf brachytherapy was 5to 6weeks (Table 2).Follow-upFollow-up was performed for each patient every 3months in the first 2years after treatment and every 6monthsthereafter.Fig.1.Californium-252afterloading system.(a)Afterloading application module;(b)treatment control system;(c)treat-ment planningsystem.Fig.2.Tricavity applicator.Table 2.Treatment schedules Stage EBRT (Gy)252Cf-ICBT (Gy fr.)Treatment time (d)WP WP with MB IB 162829/3–40/432–36IIA 20–2422–2840/4–45/532–39IIB 24–2820–2838/4–42/434–41IIIA 30–3418–3238/4–42/434–42IIIB34–3816–2038/4–45/535–42Abbreviations:EBRT =external-beam radiotherapy;ICBT =in-tracavitary brachytherapy;WP =whole-pelvic irradiation;MB =midline block;fr.=fraction.252Cf brachytherapy for cervical cancer–>252Cf brachytherapy for cervical cancer d X.L EI et al .3Checkups included a physical examination,routine blood cell counts,chest radiograpy,intravenous urography,and cystoscopy.If clinical suspicion of recurrence was present,additional investiga-tions including biopsy and CT,positron emission tomography,or magnetic resonance imaging scan of the abdomen and pelvis were to be done.Treatment failures were classified as pelvic recur-rences or distant metastases.Patients who died of causes other than cervical cancer but showed no evidence of other diseases at the last checkup were included in the OS rate.The follow-up examinations ended in December 2009.Late complications were graded according to the Radiation Ther-apy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC)late radiation morbidity scoring scheme.Statistical analysisA Statistical Package for Social Sciences software package (SPSS 13.0for Windows;SPSS,Chicago,IL)was used for analy-sis.The Kaplan-Meier actuarial method was used to analyze OS and disease-free survival (DFS).Durations of survival were calcu-lated from the start of treatment.Endpoint was any death for OS and local recurrence or metastasis for DFS (including deaths observed during treatment).The patients lost to follow-up were considered censored observations.Patients alive without recurrence were cen-sored on the date of the last follow-up.The log–rank test was used to determine any significant differences.Cox multiple regression analysis was used to detect the impact of factors on DFS and OS.Tumor stage,patient age,histopathologic grade,tumor size,and lymph node status were the variable factors for analyzing actuarial OS and DFS at 5years.A statistical result was regarded as signif-icant with p values <0.05or with a 95%confidence level.RESULTSGeneral outcomeMedian follow-up time for all patients was 44months (range,24–130months),65patients (9.3%)were lost to follow-up.Of all alive patients at the time of this analysis,477patients (68.5%)had no evidence of disease,and 28(4.0%)were with cancer,including 7(1.0%)with local re-lapse and 21(3.0%)with distant metastasis.Among expired patients,173(24.9%)died from cancer,15(2.2%)from clin-ical causes,and 3(0.4%)from late complications.The pat-terns of failure included local relapse in only 50patients (7.2%),distant metastasis in 109(16.0%),and local relapse with distant metastasis in 14(2.0%).Distribution of sites of distant metastases for all patients was as follows:bone =32,lung =28,para-aortic lymph nodes =27,left supraclavic-ular lymph nodes =18,and inguinal nodes =12.During follow-up a second malignant primary tumor was detected in 11patients (1.6%),including 3patients with cancer in the lung,3in the breast,3in the ovary,1in the liver,and 1in the bone.Survival ratesSurvival of each patient was calculated from the first ther-apy to the last follow-up examination.Overall survival at 3and 5years for all patients was 76.0%and 64.9%,respec-tively.Actuarial OS rates at 3and 5years for Stages IB,IIA,IIB,IIIA,and IIIB patients were 95.0%and 84.4%,85.3%and 77.7%,76.2%and 66.1%,68.3%and 54.2%,Fig.3.Isodose distribution for a typical 252Cf treatmentplan.Fig.4.Kaplan-Meier overall survival curves for all patients treated by 252Cf intracavitary brachytherapy with external-beam radiother-apy.4I.J.Radiation Oncology d Biology d Physics V olume -,Number -,2011and 68.5%and 55.9%,respectively (p =0.0003)(Fig.4).Disease-free 3-year and 5-year survival rates were 71.2%and 58.4%,respectively.Actuarial DFS rates at 3and 5years for Stages IB,IIA,IIB,IIIA,and IIIB patients were 86.8%and 77.2%,80.0%and 74.1%,71.9%and 60.5%,59.1%and 46.9%,and 65.5%and 42.5%,respectively (p =0.001)(Fig.5).There was no significant difference in survival rates between IB and IIA (p =0.681)or between IIIA and IIIB (p =0.608),whereas there were statistically significant dif-ferences among IB/IIA,IIB,and IIIA/IIIB using the log–rank test (p <0.05).Analysis of factors related to prognosis of cervical cancer The results of univariate analysis of factors related to prognosis in cervical cancer showed that stage,age,histopa-thology,histopathologic grade,and lymphatic metastasis were factors that influenced patient prognosis (Table 3).However,Cox multiple regression analysis showed that stage,histopathologic grade,tumor size,and lymphatic me-tastasis,but not age,were independently sigificant prognos-tic factors (Table 4).In addition,there was no significant difference between squamous cell carcinoma and adenocar-cinoma in our analysis.Late complicationsLate complications in our series were observed in the va-gina,rectum,urinary tract,and bowel and graded accord-ing to RTOG/EORTC scoring criteria.Of all,161patients (23.1%)developed late complications due to te radiation complications are shown in Table 5.The majority of late complications were at Grades 1and 2,and the most common late radiation complications were vaginal contracture and adhesion.The most common Grade 3complications were proctitis (1.1%)and hematuria (1.0%).The most common Grade 4complications were rectovaginal fistula (1.1%)and vesicovaginal fistula (0.6%).Two patients died of uncontrolled rectal bleeding,and 1patient died of rectovaginal fistula.Radiation procti-tis often occurred at 9months,and vaginal contracture and adhesion usually occurred 1year after completion of radio-therapy.Fig.5.Kaplan-Meier disease-free survival curves for all patients treated by 252Cf intracavitary brachytherapy with external-beam radiotherapy.Table 3.Factors relating to 3-year and 5-year overallsurvival Parametern 3-y (%)5-y (%)p Stage 0.0003IB 3195.084.4IIA 10485.377.7IIB 36376.266.1IIIA 6468.354.2IIIB 13468.555.9Age (y)0.011#5045878.268.6>5023871.957.5Histopathology0.452Squamous cell carcinoma 67876.165.8Adenocarcinoma1577.053.9Histopathologic grade (G)0.000G129848.934.4G231274.761.8G38685.077.0Tumor size (cm)0.003<424482.073.64–625876.764.8>619468.155.5Lymph node status 0.000Postive 15262.954.2Negative 33083.371.8Unknown21474.363.1Table 4.Multivariate analysis results for overall survival byCox multiple regression method Variables B Sig.Exp(B)95%CI for Exp(B)Stage 0.1930.006 1.213 1.056–1.393Age0.2870.051 1.3330.999–1.778Histopathologic grade À0.6710.0000.5110.419–0.624Tumor Size0.2640.004 1.302 1.090–1.557Lymph node status0.1880.0181.2071.032–1.411Abbrevaitions:Sig.=significance;CI =confidence interval.Table te radiation complications according to RTOG/EORTC scoring Late complication Grade 1Grade 2Grade 3Grade 4Grade 5Vaginal contracture and adhesion 22(3.2)10(1.4)6(0.9)2(0.3)Proctitis 19(2.7)11(1.6)8(1.1)9(1.3)3(0.4)Cystitis18(2.6)12(1.7)7(1.0)6(0.9)Inflammatory bowel 15(2.1)10(1.4)14(2.0)3(0.4)Total74(10.6)43(6.1)35(5.0)20(2.9)3(0.4)Abbreviation:RTOG/EORTC =radiation therapy oncology group/european organization for research and treatment of cancer.Values are number (percentage).252Cf brachytherapy for cervical cancer d X.L EI et al .5DISCUSSIONIonizing radiation can be divided into high-LET and low-LET.High-LET radiation involves particles,such as neu-trons,that are more effective in killing cells.The resistance of a tumor cell population to low-LET radiation might be one of the factors that cause failure of conventional radiotherapy in treatment of cervical cancer.The studies focusing on the cellular level of biological effects of252Cf demonstrated that the neutron component in the overall biological effect sur-passed that of g-radiation(25–27).The RBE value of neutrons is several times higher than that of photons.To achieve an equivalent biological effect to that of photons, clinicians may prescribe a lower total dose of neutrons in fewer fractions.Additionally,the results of clinical research on252Cf brachytherapy demonstrated that it is able to eliminate tumor cells resistant to conventional g-radiation(11,12).The procedure of252Cf-ICBT combined with EBRT ap-plied in our study was based on Maruyama’s empiricalfind-ings in an early application of the252Cf source in the initial phase of radiotherapy(26).In our series,252Cf-ICBT was started in the initial phase of radiotherapy(within1week of the initial EBRT).It then continued once per week,with the EBRT given on the other4days of the week.Thus the overall treatment time in our study was usually within6weeks be-cause of early application of the252Cf source in the initial phase of radiotherapy.Several studies have demonstrated that overall treatment time was a significant prognostic factor for patients with cervical cancer treated with radiotherapy (28–31).The American Brachytherapy Society also recommends keeping the total treatment duration to less than8weeks(32).In conventional photon brachytherapy (such as with192Ir or60Co),the ICBTwas started immediately or2weeks after the completion of EBRT,and the overall treatment time is usually7–9weeks(32–36).In addition,Maruyama et al.’s study(37)showed that higher fraction dose and lower fequency of252Cf-ICBT can attain better curative effects but have fewer complica-tions.Californium-252neutron therapy is suited to higher fractions and a shorter course of treatment,because a suffi-cient dose administered over a short time can kill hypoxic and radioresistant tumor cells and reduce tumor repopulation and radioresistant pared with higher-fraction dos-ing,lower-fraction dosing has a higher RBE value and may cause more complications.In our practice,patients were treated with252Cf brachytherapy,7–12Gy per insertion once per week.In contrast,the optimal dose for192Ir brachy-thepy was usually<7.5Gy per insertion(32).An important issue in the treatment of cervical cancer is reducing the incidence rate of late te com-plications in our series were observed in the vagina,rectum, bladder,and small bowel,as described and graded in Table5 according to RTOG/EORTC scoring criteria.Severe late rec-tal and bladder complications were relatively low,with crude incidence rates of2.8%and1.9%,respectively.Ferrigno et al.(38)reported that the5-year incidence rates of late complications in the rectum,bladder,and small bowel were16%,11%,and14%,respectively,whereas incidence rates of late complications were17.4%for Grade1/2, 10.9%for Grade3/4,and1.4%for Grade5(fatal)in patients treated with high-dose-rate192Ir ICBT.Considering these data,the incidence of late complications in our study was much lower(i.e.,7.1%for radiation proctitis,6.2%for radi-ation cystitis and4.9%for inflammatory bowel).The use of252Cf-ICBT for cervical cancer has distinct ad-vantages.However,252Cf has only been used for a short time,and further studies are needed to examine the best frac-tion dose and the suitable time of therapy as well as252Cf neutron brachytherapy-based concurrent chemoradiation. 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