Experience with concurrent chemoradiotherapy treatment in advanced cervical : results from a hospital in Argentina

María Eugenia Giavedoni1, Lucas Staringer2, Rosa Garrido1, Cintia Bertoncini2, Mabel Sardi2, Myriam Perrotta1

1Department of , Hospital Italiano of Buenos Aires, Buenos Aires C1199 ABH, Argentina 2Department of Radiation , Hospital Italiano of Buenos Aires, Buenos Aires C1199 ABH, Argentina

Abstract

Objective: To describe our experience with concurrent chemoradiotherapy using three-dimensional conformal radiotherapy (3D-CRT) and high-dose-rate intracavitary brachytherapy with weekly cisplatin in the treatment of patients with locally advanced cervical cancer.

Methods: Forty-three patients were identified between January 2009 and December 2015. Their medical records were retrospectively reviewed, and data on patient charac- teristics, tumour, treatment and toxicities were collected and analysed.

Results: The median age was 45 years (interquartile range (IQR): 26) The median tumour Research size was 45 mm (IQR: 20). Thirty-eight patients (88%) had a cervical tumour with a size of ≥ 40 mm. The median cervical tumour size evaluated by magnetic resonance imaging (MRI) was 52 mm (IQR: 17). Twenty-two patients (51%) had enlarged lymph nodes on MRI (≥ 10 mm). MRI demonstrated the involvement of the parametrium in 29 patients (67%). Fifteen patients had positive para-aortic nodes (36%). The median total treatment time was 58 days (IQR: 20). Sixteen patients (39%) received extended-field radiotherapy. Cisplatin was administered simultaneously for a median of five courses. The median fol- low-up period was 32 months (IQR: 28 months). Grade 3 acute toxicity was observed at the gastrointestinal level in seven patients (16%). Late grade 3/4 toxicity was observed Correspondence to: Maria Eugenia Giavedoni in 14 patients (33%). Seven patients (16%) persisted with the disease and five died. The Email: [email protected] local relapse rate was 9%. Eleven patients underwent a hysterectomy after treatment. The disease-free interval was 24.2 months. The 2-year global survival rate was 82.9%. ecancer 2019, 13:919 https://doi.org/10.3332/ecancer.2019.919 Conclusion: Concurrent chemo-radiotherapy appears to be an effective regimen, with Published: 02/04/2019 acceptable toxicity, for patients with locally advanced cervical cancer. Received: 19/12/2018 Keywords: carcinoma of the cervix, radiotherapy, concurrent , brachytherapy Publication costs for this article were supported by the ecancer Global Foundation. Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access article distributed under the terms of the Introduction Creative Commons Attribution License (http:// creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and In 2012, 528,000 new cases of women with cervical cancer were diagnosed worldwide reproduction in any medium, provided the original [1]. In Argentina, 4,956 women are diagnosed each year with the same disease and 2,127 work is properly cited.

ecancer 2019, 13:919; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2019.919 1 high-rate brachytherapy inlocally advanced stages of cervical cancer through theanalysis of aretrospective cohort from 2009to 2015. this paper, we aimto describetheexperience of theHospital Italiano deBuenos Aires inthetreatment of concurrent chemo-radiation and the treatment of cervical cancer inour region andencourage theprospective registration anddissemination of itsresults inLatin America. In [16–22] and which examine thebenefits andmorbidity of thetreatment. Therefore, thisresearch would provide greater knowledge regarding There is very littlecommunication aboutthistypeof treatment inSouth America [15] , themajority of theliterature coming from other regions, to light questionsaboutthequality of life for patients, dueto itstoxicity. of30%–50% patients inStage IIIBandforof 10%–15% patients inStage IVA. However, radiation treatment for gynaecological brings treatment time improvesdecades in thelast option,use the facilitating practicethe for theoperator andimproving tolerance for patients andshortening use of brachytherapy. Althoughthe different forms of delivery produce thesameglobalsurvival rates, high-rate brachytherapy incorporated opmentand improvement in radiotherapy techniques,is notit possibleto reach thedoseof radiation required by thepathology the without radio-chemo-concurrencemaking thus use, standard the treatment for cervical cancer inlocally advanced stages [13].In spite of thedevel- sive radiotherapy, or hydroxyurea.with Becauseof in1999,theNational thesestudies, Cancer Institute (NCI)issuedtherecommendation for significant improvement inoverall survival andprogression-free survival radio-chemo-concurrencewith platinum,with respectwith to exclu - In thetreatmentof locally advanced cervicalcancer, five randomised Phase IIIclinicalstudies[6–10]andtwo meta-analyses[11, 12]showed Stage IB2isconsidered to belocally advanced cervical cancer [5].Local, regional anddistant relapses are more likely inthisgroupof patients. the staging cancer. This was confirmedin the recent staging publishedin2018, FIGO where the imaging and pathological findings are incorporated into whenever possible,anassessment with magneticnuclear resonance since method itisthebestdiagnostic for locoregional staging of this lished byCommittee the of theInternationalFederation of Gynecology andObstetrics (FIGO) [3].Since hasrecommended, 2009,FIGO Cervical cancer isstaged by clinicalgynaecological examination. In 2009,themostup-to-date version of cervical cancer staging was pub- ond mostfrequent among women aged 14–44 years old[2]. die each year. Cervical cancer isthethirdfrequent most cancer in Argentina among women (after breast andcolorectal cancer) andthesec as tumour size, involvement andlocation ofnodes, involvement lymph of parametria, involvement of septums andinvasion of other adjacent We reviewed theimages of theMRIperformed onthepatients inthecontext of pretreatment stagingto evaluate prognostic factors, such variables interms of oncological follow-up, toxicities, persistence, recurrence (with histological confirmation) anddeath. nodestagingbylymph in theMRI, images or , characteristics of theradiant treatment, characteristics of concurrent chemotherapy, treatment haemoglobin value, pretreatment creatinine clearance, histological tumour tumour type, size, FIGOstage, tumour characteristics that purpose. The following variables were evaluated for eachpatient: age, performance status, body massindex, previous , lastpre- Thehistories clinical corresponding toselected the patients were reviewed andtheinformation was collected inadatabase constructed for Field work patients with ahistological diagnosisof neuroendocrine carcinoma were excluded. of concomitantcancer, history ofor partial total hysterectomy, patients who hadbeguntheir treatmentin another healthcare centre and brachytherapy andconcurrence cisplatinwith as primary treatment. Patients with previous pelvicradiotherapy, presence of another type origin inlocally advanced stages who hadreceived external radiotherapy pelvic three-dimensionalwith shapedtechnique (3D) plushigh-rate The study population consisted of patients intheregistries duringtheperiod 2009–2015 adiagnosisofwith cervical cancer of epithelial Italiano deBuenos Aires. A descriptive andobservationalstudy wasGynecologyin the out carried andRadiation Oncology Department (Mevaterapia) of theHospital Objectives andmethods ecancer 2019, 13:919; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.919 [4]. [14]. Radiotherapy iscurative for locally advanced cervical cancer for approximately 65%–75%of patients inStage IIB,for 2 -

Research 75,000/mm ecancer 2019, 13:919; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.919 forcauses of suspension chemotherapy were asfollows: (1)fever over 38°C,(2)neutropenia under 1,500/mm five cycles duringtheperiodof radiation . Ouris coincident scheme with what isdescribedinthecurrent literature [7,9,30,31].The Patients received indications for concurrent chemotherapy with cisplatin at adoseof 40 mg/m2 (maximum doseof 70mg)once a week for was per fraction Groupe the applicators and guidelines fractions. pelvic in fields the lateral and posterior anterior, with and area pelvic the in technique box four-field the as known fields lateral both and posterior CT External radiation was administered3D. using Ascan pelvic was performed oralwith contrast in CT or through lumbar aorticlaparoscopic stagingsurgery. The latter beganat our under institution aresearch protocol startingin2012. Stagingof lumbar the area aortic to defineradiationthe treatment was performed intwo ways: through positron emissiontomography (PET) clinical history, aphysical evaluation andpelvicexamination, abiopsy of theuterine cervix andanMRIof theabdomenandpelvis. All patients were regularly examined by gynecologists,oncologists andradiant oncologists. Pretreatment evaluation consisted of takingthe Standard evaluation and treatment the investigators madeto patients whose lastcontrol was not at out carried theinstitution. Oncological monitoring data were obtained from medical visits stored inthehospital’s electronic clinicalhistory or from telephone callsthat variables inthiscategory were identified usingthedescription inEifel’s published study [27]. considered to be inadequate to classify someof themore common complications of radiation treatment for cervical cancer; therefore, more Oncology Group andtheEuropean Organization for Research and Treatment of Cancer (EORTC) [26]scores. However, thislastscalemay be Score, andnon-haematological acute toxicities andchronic toxicities were classifiedusingthe Toxicity Criteria of theRadiation Therapy Acute haematological toxicities wereaccording classified toNCI Common the Terminology Criteria for Adverse Events, version 3.0[25] Major toxicity was reported asGrades 3,4and5. Acceptable toxicity was classifiedasGrades 1and2. beginning of treatment. Althoughthere are differentcriteria foracute [23]or classifying chronic[24] toxicity, inthisstudy, we definedas 90days thelimit from the infiltration. ruptionparacervicalin the fibrous ring or parametrium-tumour irregularity and(3)signsof septum involvement: anterior or posterior fatty node morphology,lymph altered signalat T2 or heterogeneous image andrestricted (2)signsof diffusion, parametrial involvement: inter organs. The following were considered to be(1)signsofnode involvement: lymph diameter greater than1cmontheminor axis,changes in and that required anew control after aprudent periodof time(more than3months). and doubtfulfindings intheimages were described. We consider doubtful findingsto beinflammatory changes that could not beclassified 2 years andevery 6monthsuntil end of the 5 the years. After treatment, acontrol study with images was requested. The negative, positive repeated at3 weeks. A weeklycheck-up clinical was performedduring treatment. Then, patients were monitored every 3months for thefirst Laboratory tests blood count,with livertests, functionelectrolytes andcreatinine clearance were requested at theinitialevaluation and solution, ranitidine 50mgIV, dexamethasone 8mgIV andondansetron 8mgIV. Chemotherapy was resumed when toxicityGrade became 1. In premedication, patients received hydration mannitolwith saline solution, 16-slice). The images were into imported theplanningsystem (Blue Frame Shell, Version 14.05.00).Planning was organised usinganterior, lumbar aortic area. aortic lumbar area and 45 Gy in 25 fractions in the lumbar aortic region. Some patients received a parametrial boost of 5.4 Gy in three additional three in Gy 5.4 of boost parametrial a received patients Some region. aortic lumbar the in fractions 25 in Gy 45 and area Regarding brachytherapy—until July 2015, iridium 192 was used as a radioactive source using 2D, following the international the following 2D, using source radioactive a as used was 192 iridium 2015, July brachytherapy—until Regarding (International Commission on Radiation Units and Measurements (ICRU) 38) (ICRU) Measurements and Units Radiation on Commission (International 3 , (4) vomiting,(5) diarrhoea,(6)creatinine clearance dropping to under 50mL/minute and(7)performance status 2or more. Européen de Curietherapie and the European Society for Radiotherapy and Oncology and Radiotherapy for Society European the and Curietherapie de Européen compatible with computed axial tomography. The volumes to be treated were delineated according to the consensus of consensus the to according delineated were treated be to volumes The tomography. axial computed with compatible used foratotaldoseof24Gy.Twofractionsperweekweregiven,makingfourfractions. Photon energy of energy Photon 6, 10 and 15 MV were used. Patients received a dose of 50–50.4 Gy in 25–28 fractions in the in fractions 25–28 in Gy 50–50.4 of dose a received Patients used. were MV 15 and 10 6,

[28] . Then, it was replaced by cobalt 60 using 3D using 60 cobalt by replaced was it Then, . the institutional institutional the [29] . In both 2D and 3D, a 6-Gy design 6-Gy a 3D, and 2D both In . 3 , (3)thrombocytopenia under scanner (PhilipsBrilliance 3 -

Research ecancer 2019, 13:919; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.919 creatinine clearance under 70mL/minute. level of lessthan10g/dL. Of thetotal, five patients (11%)required abloodtransfusion prior to treatment. Seven (16%)patients began with A total of 43patients were included. The patients’ characteristicsare listed in Results The clinicalstudy was approved by theEthics Committee of theHospital Italiano deBuenos Aires, Argentina. Statistical analysis was performed usingtheSTATA 13program. The percentage of tumour persistence anddeath was calculated for thetotal cohort. andinterqua median inmonths pe Fo followed 95%. Patients years 2 at survival person 100 per patients deceased of number the as estimated was rate fatality the event, death the For final the of date the and diagnosis of date the between difference the control as calculated was time follow-up the analysis, follow-up the In variables were summarisedasabsoluteandrelative frequencies. In thedescriptive statisticalanalysis, thecontinuous variables were expressed asmedianandinterquartile range (IQR),and the categorical Statistical analysis spite of treatment) and relapse(reappearanceoftheillnessinpatientswhorespondedtotreatment). of treatment) spite r r i relapse, the rate was estima was rate the relapse, od free of illness as the time from diagnosis of the illness until th until illness the of diagnosis from time the as illness of free od or death. Three patient conditions were analysed: death by illness, persistence (patients who remained actively ill actively remained who (patients persistence illness, by death analysed: were conditions patient Three death. or as a percentage of living patients per 100 patients with cervical cancer, with their respective confidence intervals of intervals confidence respective their with cancer, cervical with patients 100 per patients living of percentage a as for lessthan2yearswereexcludedfromtheanalysis( r til te e d to be the number of relapsed cases per 100 person-years, with a confidence interval of 95%, and the and 95%, of interval confidence a with person-years, 100 per cases relapsed of number the be to d range. Patients with lesstha with range.Patients ▵ Interquartile range Table 1.Baseline characteristics of cervical cancer patients ( Creatinine clearance inmL/min, median(IQR) Haemoglobin pretreatment ing/dL, median(IQR) Yes No Patient with history of prior surgeries (n/%) Body Mass Index inkg/m2, median(IQR) 2 1 0 Performance status ( Age (years), median(IQR) Patients (n) n/%) Details ▵ n

2 years of follow-up were excl were follow-up 2 yearsof e

date of the first r first the of date ▵ Table 1.Six patients (14%)begantreatment with ahaemoglobin n =35). ▵ ▵ Measurement e 23.8 (7.5) 97 (47.7) 13/30.2 30/69.8 10/23.3 32/74.4 12 (2.1) laps 45 (26) 1/2.3 43 n =43). e , uded las medi t

fr om the calculation (n=3 calculation om the cal control or dea or control cal s with cervical cancer cervical with s th, expressed as expressed th, with cancer with 2). and overall and in 4

Research ecancer 2019, 13:919; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.919 chemotherapy. The principalcauses were diarrhoea,decreased creatinine clearance and vomiting. tile range: 6days). Regarding thechemotherapy, themedianfor cycles completed was five cycles. Only seven (16%)patients hadto suspend and twoPET) patientsfor massivenode involvement.lymph pelvic The medianduration of extended-field radiation was 41days (interquar and three patients had a boost in parametrium.Seventeen patients had extended-field radiation: 15 for lymph node involvement (surgery and (95%), treatment was sequential. One patient required hemostaticflash aspartof thetreatment dueto anaemiaat thetimeof presentation, daysdays).(interquartilerange:20 concurrentcompletedA (67.4%) days.radiochemotherapypatientsofFortotal 63 29 ≤ patientsin most Table 3showsradiation the treatment details. Regarding duration the of radiation treatment(external andbrachytherapy), themedian was 58 In all,only two patients didnot have lumbar aorticstaging. in 23patients(23/43), nine of showedwhich involvement(9/23), andthrough PET in20patients (20/43),of which six were positive (6/20). involvement was observed in12patientsby(28%) Lumbar MRI. aorticlymphnodestaging was accomplished through laparoscopic surgery III andfive patientsin stages parametrialthe cases, in these and IIA; IB involvement was notdetected inthephysical examination. Septum node involvement was shown in both areas in only two patients. Parametrial involvement was detected by MRI in24 patients instages IIand of ≥ 6 cm. Images showed lymph node involvement in the pelvic area in 19 patients and in the lumbar aortic area in only one patient. Lymph Table 2 shows the tumour details. Thirty-eight patients (88.4%) had a cervical tumour size of ≥ 4 cm. Twelve patients (28%) had a tumour size Table 2. Tumour characteristics of cervical cancer patients ( ▵Interquartile range Lumbar aorticlymphnodeinvolvement (PET/surgery) (n/%) Yes No Pretreatment lumbar aorticstaging(surgery) (n/%) Positive Negative Parametrial infiltration inimages (MRI)( Positive Negative Lymph nodeinvolvement inimages (MRI)( Tumour size inimages (MRI)incm,median(IQR) IIIB IIB IIA2 IB2 Tumour stage (FIGO) (n/%) Tumour size incm,median(IQR) Other Adenocarcinoma Squamous Histological type( n/%) Details ▵ n/%) n/%) ▵ n =43). Measurement 23/53.5 20/46.5 29/67.4 14/32.6 22/51.2 21/48.8 10/23.3 15/34.9 12/27.9 52 (17) 45 (20) 6/14.0 15/36 37/86 2/4.7 4/9.3 5 -

Research ecancer 2019, 13:919; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.919 h disorders to patients e Table 4lists precd ct gastrointestina acute xperienced ospitalisation. . In ad In . pyometra experienced Gr experienced ( n the frequencythe = 3), hot flash hot 3), = dition to the tox the to dition ad of acute andch e 4 acute toxicity: one patient wi patient one toxicity: acute 4 e e = 1) a 1) = n ( fractures bone 3), = (n s RT: radiotherapy, BT: brachytherapy, ▵Interquartile range patients (n=43). Table 3.Characteristics of concurrent radiochemotherapy incervical cancer o uiay toxici urinary or l i cities reported cities % 39/90.6 Patients receiving ≥four cycles of chemotherapy (n/%) Patient with total treatment time(<63days) (n/%) External RT +BT + lumbar aorticfield,median(IQR) External RT +BT, median(IQR) External RT, median(IQR) Total treatment time(days) Co60 Ir192 Brachytherapy source (n/%) F15Mv F10Mv Lumbar aorticfield F15Mv F10Mv F6Mv External Radiotherapy energy (n/%) 2 1.8 External radiotherapy dosefraction (cGy) (n/%) 55.8 50.4 50 48.6 46 External Radiotherapy dose(cGy) (n/%) External RT +BT +lumbar aorticfield(group 2) External RT andBT Radiation treatment (n/%)  F6Mv ronic toxiciti in the table, 12 patients (28%) patients 12 table, the in y ol 1% exper 16% only ty, e s selected fo Details th debilitating se debilitating th ▵ n d hydroelectrol d ▵ r thisstudy,

ecd eee toxi severe ienced nsitive neuro nsitive according to theh yte changes ( changes yte ex ▵ perienced so perienced Measurements pa thy and one pati one and thy ci 29/67.4 10/23.3 33/76.7 10/23.3 10/23.3 23/53.5 21/48.8 22/51.2 17/39.5 20/46.5 17/39.5 26/60.5 = n 84 (19) 58 (20) 4/23.5 5/29.4 8/47.1 40 (7) 3/7.0 2/4.7 1/2.3 y Gae ) in 3) (Grade ty ighest gradighest 4). Of the total, the Of 4). = (n pain pelvic toxicity: acute me e

e reached. Altho h d the nt with septic shock seconda shock septic with nt only five pa five only gsie tract. igestive ugh most patientsugh most tien ts required ts Only two two Only 1), vaginal 1), ry 6

Research ecancer 2019, 13:919; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.919 c for positive prob gia, metrorrha were treatment, After positive findingsin23%and doubtful findingsin26%. Thetofirsttime the median control imageswith was 2.7 months.Forty-one patients hadMRIs (95%)andnegative findings were seenin51%, In two patients, thefistula was dueto tumour persistence. Four patients experienced fistulas:two rectovaginal andtwo vesicovaginorectal. Median timeto onset of fistula the was 9.5months (IQR:1.6). pyometra/hematometrea, pelvicpainandedema. other ment rectosigmoidtomsin the area and urgency.pain with Intestinaland urinary When we grouptoxicities by patient, we seethat 14patients (33%)experienced someGrade 3/4chronic toxicity. Ofhad symp- these, most oiie o th for positive of 10.8 (IQR: 4.9) and 10.8 (IQR: 14.7) months, respectively. Of the total, only 11 patients required hospitalisation. There were There hospitalisation. required patients 11 only total, the Of respectively. months, 14.7) (IQR: 10.8 and 4.9) (IQR: 10.8 of chronic toxicities not reported in reported not toxicities chronic ancer (3/11). ten patients (23%) received (23%) patients ten able or clearly clinically persi clinically clearly or able dsae El disease. e Table 4. Acute andchronic toxicities profile incervical cancer patients ( Urinary abnormalities Vaginal abnormalities Diarrhoea Rectosigmoid abnormalities Hematochezia Extremities/Neuromuscular bomlcetnn laac 067—— — 7 6 30 Abnormal creatinine clearance Hyponatremia Abnormal bilirubin Abnormal transaminases Sensory neuropathy Motor neuropathy Infectious Thrombocytopenia Neutropenia Leukopenia Anaemia (haemoglobin) Vomiting Dermatological Asthenia Urinary Lower gastrointestinal vn ains 2% hd a had (26%) patients even Chronic adverse effect Acute adverse effect = 2), bone marrow depression, marrow bone 2), = n ( thrombosis 8), = ( n menopause 1), = (n fracture bone 4: Table a cervical biopsy for suspe for biopsy cervical a s tence, persiste tence, ece hyster rescue n ce confirmed by pa by confirmed ce 623—2 — — — — 4 3 3 1 9 5 1 2 7 4 6 11 — 36 4 12 28 2 2 29 5 21 1 21 39 64—3— — 3 — 1 — — — — — 1 1 4 2 1 — — 2 — — 36 1 — — — 43 — 3 — 40 — — — — 4 39 — 6 42 — — 4 — 6 39 4 11 — 39 1 19 33 19 2 14 3 13 23 39 18 4 3 2 1 0 12 — — — 1 4 — 7 20 3 25 21 30 2 17 1 5 1 1 1 0

cted persistence cted e toxicitiesappeared fromtime a median with end of the treat- tm wt te olwn idctos pyome indications: following the with ctomy Grades ( Grades ( thology. Of the hys the Of thology. n) n) of the diseas the of n =43). terectomies perfor terectomies e (clinical or MRI), of which four four which of MRI), or (clinical med, three were three med, r, persisten tra, 7 t

Research ecancer 2019, 13:919; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.919 grade 3/4diarrhoea;thiscoincides with what hasbeenreported. Al Asiri observed 5%grade 3/4nauseaand vomiting ity beinggrade 1/2andonly 9%grade 3leukopenia. Toita reported 28%grade 3/4nauseaand vomiting and15%grade 3/4diarrhoea[21]. reportedgrade 5% 3/4leukopenia [22].Unlike previously results, published our work showed lessacute haematological toxicity, themajor 3/4 toxicity inplatelets. [21]Potter found 4% grade 3anaemia, 23%grade 3/4leukopenia and10%grade 3thrombocytopenia [33].Al Asiri Regarding acute toxicity, Toita observed that grade 3/4leukopenia was themostfrequent adverse effect andfound a25%incidence ingrade the patients treated. intotreatment the of cervicalcancer. It be interestingwill to know inthefuture how thistechnology influences thesurvival andtoxicity of treated after thisdate. Modulated Intensity Radiotherapy andModulated Intensity Volumetric Arcotherapy are currently beingincorporated binationof two the radianttreatments, improving therapeutic times. This practice provided areduction inthetoxicity observed inpatients On theother hand,in July 2015,theradiotherapy department acquired abrachytherapy device with 3Dplanner, which improved thecom- situations onthepartof patients, suchasnon-medicalsituations andpatients residing longdistances from theradiation centre. than recommended. This was probably dueto theavailability of brachytherapy equipment, to delays dueto non-working days andto special exceeds6 weeks radiotherapy. Insense, two this have studies showna significant decrease inpelviccontrol andtheoverall survival rate when thetreatment Itis well knownthat totalthe oftime treatmentis oneof most important the prognostic factors inpatients with cervical cancer treated with tion andevaluation of toxicities which hinder thecomparative analysis. Table 6isacomparison otherwith available studies fromcurrentthe literature. There were wide differences intreatment, recording, defini- in 33%. With amedianfollow-up timeof 32months, grade 3acute gastrointestinal toxicity was observed in16%andgrade 3/4chronic toxicity advanced cervical cancer. At 2 years, theglobalsurvival rate was 82.9%, with atumour persistence rate of 16%andlocalrecurrence of 9%. In thispaper, we report theexperience of 43patients with pelvic3D-CRT andhigh-rate brachytherapy with concurrent chemotherapy in Discussion (due to death from thedisease) andamaximumof 78months. The oncologicalresults are shown in [21, 32].Instudy, this patientsall the although completed theproposed radiant treatment,14 of in alonger themdidit time ▵Interquartile range Table 5.Results of oncological follow-up of cervical cancer patients ( Deaths (n/total) Persistence (n/total) Disease-free interval inmonths, median(IQR) Time to relapse inmonths, median(IQR) Local recurrence rate (%) Recurrence (n) Relapse rate (person-years) Global survival at 2 years (%) Fatality rate (person-years) Follow-up timeinmonths, median(IQR) Table 5.Oftotal, the 29 patients (67%)hadafollow-up oftime > 2 years, of aminimum with 6months [22]. Our work yields almostzero toxicity at thelevel of nauseaand vomiting and16% Follow-up ▵ ▵ ▵ Measurement 20.9 (9.26) 24,2(24,2) 5.7/100 32 (28) 5/100 6/43 7/43 6/35 82.9 9 n =43). 8 -

Research ecancer 2019, 13:919; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.919 Table 6. Comparison of studies available in current literature. Souhami et al Toita et al Pötter et al Atahan et al Parker et al Kato et al Al Asiri et al Giavedoni, Study, year [17], 1993 [21], 2005 [33], 2006 [16], 2007 [18], 2009 [20], 2010 [22], 2013 2016 QT/RT concurrency (n) 50 40 48 89/183 92 120 74 43 Country Canada Japan Austria Turkey UK South-east Asia Saudi Arabia Argentina FIGO stage (I, II, III, IV) (%) 0, 40, 54, 6 2, 33, 65, 0 4, 50, 42, 4 10, 64, 26, 0 8, 63, 26, 3 0, 0, 50, 50 0, 66, 26, 8 28, 49, 23, 0 Conventional Conventional Conventional CT based 3D Conventional Conventional CT based 3D CT based 3D Technique (2D) with 18 (2D) ALE/60 (2D) conformal (2D) (2D) conformal conformal MV CO EBRT (DT) Gy 46 50 50 50 45 50 45–50.4 50 four-field box o four-field box Radiant Fields four-field box APPA four-field box four-field box APPA four- field box treatment APPA or APPA used Boost — yes — — — yes — yes Dose Boost (Gy) — 6–10 — — — 10-15 — 5.4 MRI- based 3D HDR-BT/ TAC- HDR-BT 30 HDR-BT 18 HDR-BT 28 Gy HDR-BT 24 Gy LDR-BT or HDR-BT 28 Gy Brachytherapy (BT) HDR-BT based 3D 24 Gy (3 × 10 Gy) Gy (3 × 6 Gy) (4 × 7 Gy) (4 × 6 Gy) HDR-BT (4–6 ×7 Gy) (5–6 o 7 ×7 Gy) Gy (4 × 6 Gy) Survival rate Early 65% to 44 79% to 36 61% to 36 — 72% to 24 79.6% to 24 — 82.9% to 24 global (months) Rate of SG to 5 — — — 55 55 — 64.5 — years (%) Follow-up Median of Follow- 27 37 33 45 26 27.3 60 32 up (months) Rate of Local 7 (16%) 3 (7%) 10 (21%) 48 (26%) — 14 (12%) 8 (11%) 3 (9%) relapse (%) NCI-CTC Classification of NCI-CTC RTOG/ NCI-CTC NCI-CTC version 3.0 RTOG// NCI// LENT // NCI-CTC toxicity (acute// version 2.0// EORTG// version 3.0// version 2.0// y RTOG/ Pilepich% SOMA score version 3.0 chronic) RTOG/EORTG RTOG/ EORTG RTOG/ EORTG RTOG/ EORTG EORTG// RTOG/ EORTG Toxicity Late toxicity G3 or 13/50 (26) 1/40 (2.5) 2 (4) 8/183 (8) 4/92 (4) 3/120 (4) 3 (4) 14/43 (32.5) G4 (%) urinary tract, vagina, bladder, vagina, bladder, Areas evaluated - vagina, bladder, bowel, bladder, bowel bladder, bowel bladder, bowel bowel, bladder, bowel bowel, Chronic toxicity bowel neuropathy, neuromusc/ ext neuromusc/ ext hearing loss QT/RT: chemoradioconcurrence, FIGO: International Federation of Gynecologists and , CT: computed tomography, 3D: three dimensional, ALE: linear accelerator, 60CO: cobalt 60, Gy: grey, APPA: anterior-posterior, HDR- BT: high rate brachytherapy, LDR- BT: low rate brachytherapy, MRI: magnetic resonance imaging, SG: global survival, RTOG: Oncology Group, NCI-CTC: Common Toxicity Criteria of the National Cancer Institute, RTOG/EORTG: European Organization for Research and Treatment of Cancer, LENT SOMA: Late Effects Normal Tissue Task Force- Subjective, Objective, Management, Analytic scales, Neuromuscular/ext: neuromuscular/extremities % Pilepich, M. International Journal of Radiation Oncology, Biology, Physics. 1987; 13 (3):351–357, EBRT: External Beam Radiation Therapy, DT: Total dose, TAC/TC/CT: computed axial tomography 9

Research quality been reported that vasomotor and genitourinary symptoms (atrophy anddysfunction) ofaffect menopause 80%of patients and worsen their Pelvicradiotherapy is especially toxicfor the ovaries in premenopausalpatients and can leadthemto experience earlyIt menopause. has was therefore not possibleto know anddocument if there are differences inradiotherapy treatment results. Examining histological tumour our type, study found that most were epidermoid(N=37), and very few were of other histological types.It morbidity for patients. Reducing thenumber of post-radiation surgeries isthusdesirable. pleteand radiological clinical response [36].In our study, 11patients hadsurgery after treatment, which involves greater surgery-associated Results of the GYNECO 02 study suggest that performing a post-radiation hysterectomy has no therapeutic impact on patients with a com- Somesurgeons complete hysterectomiesafter radiotherapy inselected patients (large initialtumour size, residual post-treatmentdisease). treatment-associated adverse effects. siderable percentage of patients were instages 1Bor 2(N=12). This fact contributed to better oncological results andalower possibility of For study treatments, dose prescription andplanning were adjusted basedontheaforementioned principles.Last,itisnotable that acon- compliance andgood adherence by patients. that limited treatment volume,and careful planning of monitoring clinical between treatments. These factors allcontribute to treatment factors: rigorous patientin aninterdisciplinary selection context,the firmbelief of themedicalteam inthetreatment, following guidelines Follow-uptime was short, butthisstudy found a high overall early survival rate and a low local relapse rate. This finding is likely due to several follow-up of patients after radiotherapy to detect includinguncommon possiblesequelae, adverse effects. The frequency of delayed toxicity observed inour study was higher thaninother studies. This findingcould resultfrom careful, systematic adequate achieve consistently influence toxicity rates, causingthemtorise. to interrogation direct In thecontext of toxicities,it isnotable that 39%of a patients hadextended-field radiation and26%has post-radiation surgery. Both factors with systematization, requires and the search evaluate to difficult very understanding. is toxicity this because ing. These osteonecrosis of thesymphysis pubisandasacral fracture that improved with medicaltreatment. [24]. We found two asymptomatic casesin our series, the first was an L4 vertebral fracture that required vertebroplasty. The second was fracture, maywhich beasymptomaticbe diagnosed and can images.with The meantimeto theevent is6–20months after radiation ends Theof impact radiation the therapy onbonesisrecognised andcanmanifestitself indifferent ways. The mostcommon eventis apelvic reported by Potter [33]. In our study, chronic toxicity at theurinary level was 16%andonly two patients hadsevere toxicity (grade 4),inthesameproportion as quency over Nakano time. reported major urologicalcomplications at 5,10and20 years at rates of 0.8%,0.9%and1.3%,respectively [35]. The urologicaleffects are commonthe most mild; are narrowing the of theurethra andactiniccystitis [24].However, they increase infre- of 3.8%,4.4%and5.3%,respectively [35]. These results warn of thepossibility of long-term toxicity. other hand,Nakano conducted along-termfollow-up (22 years) andreported major colorectal complications at5, 10and20 years at arate gastrointestinalwith complications (all grades) [21].Potter didnot report any late toxicity at thegastrointestinal level grade 3/4 [33]. On the tine (n=2)andrecto-vaginal (n=2)[17].Other fistula authors reported lesschronic intestinal toxicity. Toita observed eight patients (20%) respectively.and 9.3%, 11.6% Likewise,Souhami reported severe toxicity after treatment: rectal ulcer of (n=10),obstruction intes thesmall - complication rate for grades 1,2, 3 and4of 5.6%,31.7%,6.8%and8.1%,respectively [34].Our study yields similar results: 4.7%,25.6%, of patientsexperienced form some of this. The averageof time presentation is8–10months after treatment [24].Ogino reported alate rectal As for chronic toxicity, gastrointestinal symptoms arecommonly themost observed adverse effects after pelvicradiotherapy. More than50% ecancer 2019, 13:919; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.919 of life [24]. Eleven patientsin our study reported hotflashes and vaginal drynessandnine conditions are related to treatment and to theresultingdisorder. hormonal We believe that these values are of symptoms and the interrogation of the patient very important very patient the of interrogation the and symptoms of This is not yet incorporated into our usual practice. Due to the to Due practice. usual our into incorporated yet not is This

inthefollow-upandtreatment. for patient quality of life, we consider we life, of quality patient for has it importance presented dyspareunia or vaginal shorten- underrepresented 10

Research ecancer 2019, 13:919; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2019.919 Italiano deBuenos Aires. Department;Dr Chacon Carolina, DiagnosticImaging Department; andDr María Guadalupe Patrono, Gynaecology Department; Hospital The authors would like to thankDr Vicens Jimena, Research Department; Dr Díaz Federico andDr Krakobsky Vanesa, Radiation Oncology Acknowledgments No financialfunding was provided to supportthisproject. Funding statement The authors do not have any conflicts to disclose. Conflict of interest fewer radical surgeries, with lower morbidity. We believe that we benefitwill from new advances andtreatcancer more effectively usingmulti-modal treatments, molecular and tions. advanced stages. This concurrent treatment showed good localcontrol, was well tolerated, andhadanacceptable percentage of complica- In conclusion, we report favourable resultsregarding radiochemotherapy concurrent high ratewith brachytherapy incervical cancer inlocally With our follow upperiod,theoverall early survival rate ishigher than what isreported inother internationally studies. published current situation of patients andavailable treatments intheregion. interesting to comparefindings these resultsthe with of other inLatin studies America. This study contributes to our understanding of the on thepartof thepatients, ofpurpose the with anaccurate diagnosisandprecise handlingof thesequelaof radiant treatment. It would be lower than expected, while therate of chronic toxicity was higher due to a correct and adequate follow-up of our patients and knowledge The delayed adverse effectscommonlymost observed inour population were gastrointestinal symptoms. The rate of acute toxicity was stages atHospitalItalianodeBuenosAires. study This Conclusion patients to follow-up. fromin asingleinstitution Argentina. That facility usedmodernradiation technology andcollected information by telephone, not losingany However, we canalsohighlight thestrengths of thisstudy. They includeahomogeneous population with areasonable number of patients have containedincomplete records. Finally,follow-up the in thestudytime was shortfor evaluating oncological results anddelayed toxicities. to experience delayed complications of radiation. Another limitation of this study is that it was retrospective and patient case histories may nising related post-treatment symptoms.Moreover, delayed toxicities may notbe represented assomepatients didnot survive longenough grade 1and2toxicitiesmay have beenunderreportedstudy. inthis Underreporting may have resulted from problems following andrecog- late thoseresultsto other centres. However, it would beinteresting to conduct anational, multi-centre study. Conversely, complications and This study hasseveral limitations. It describesresultsin asingle,private centre with asmallnumber of patients, makingitdifficultto extrapo- provides us with us an initial updated approach of primary radiotherapy in in cervical cancer patients with locally advanced locally with patients cancer cervical in in radiotherapy primary of approach updated initial an us

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