Posted on Authorea 20 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160315275.50122866/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. iniBisogno Gianni Sarcomas pediatric High-Risk dose novel for combination a density chemotherapy: standard in Irinotecan Integrating nteotoeo hlrnwt ihrs acmsmyas eprudb piiigteueo already- of use the optimizing by pursued prognosis be poor improvement also An for may (5). approach sarcomas (4) attractive limited high-risk still an with is agents is children new alterations of these of molecular outcome data activity the specific the in target time, be this to have to at However, drugs need who approaches those sarcomas. new treatment with of new (1) together use whom relapse and, for The (3) who group cases high-risk those most a and in form survival prognosis ES, metastases 70-80% and investigated. poor distant a RMS a generally with relapsed carry is or patients still ES treated metastatic DSRCT and for currently with RMS unsatisfactory Patients are localized remains with tumors (2). patients outcome These for the treatment chemother- tumor multi-agent spread. of rate, high-grade intensive outcome metastatic and a the radiotherapy, and is surgery, While invasiveness includes RMS apy. that (DSRCT), local approach tumors multidisciplinary for cell a histotype. tendency using common round most strong small the desmoplastic charac- a is biological and (RMS) with and (ES) rhabdomyosarcoma histological age, sarcoma of pediatric variety Ewing a In Like with prognosis. tumors different rare and of teristics group heterogeneous a represent Sarcomas pediatric European the INTRODUCTION with by irinotecan coordinated combining trial strategy next density the dose in A investigated Group. Study be Conclusions: had sarcoma will patients disease. approach tissue 13 170-231), the This Soft (range with cycles. feasible. days 3 the delay is 195 chemotherapy remissions, of was a treatment standard complete 62.4% with the 9 or in complete alive, time occurred to are on neutropenia time patients round administered median 4 desmoplastic were The patients Grade terms cycles 2 cycles. relapsed in 2-10). of sarcomas, 14 Two assessed (range 83.4% in Ewing 1, was cycles occurred 4 8). day Feasibility Diarrhea 181 rhabdomyosarcomas, day on of 17 ifosfamide). neutropenia. on RESULTS: mg/m2 total febrile of starting a treatment. instead 1.5 days received the 1 vincristine consecutive tumors complete day 5 2, cell to on for time and g/m2 mg/m2 and 1.5 1 toxicity 20 (cyclophosphamide days of IrVAC irinotecan on 10 1, and 3g/m2 day IrIVA on (ifosfamide received IrIVA mg/m2 in 1.5 received irinotecan D patients integrating actinomycin newly-diagnosed strategy for 2020, All dose-density allows January and a theoretically 2013 cycles. of November that Between feasibility profile METHODS: the toxicity sarcomas. patients examined high-risk a 23 with We patients with for drugs. sarcomas regimens chemotherapy myelotoxic pediatric standard more against with active association drug its a is Irinotecan BACKGROUND: Abstract 2020 20, October 3 2 1 Affinita Carmen Poli Elena siuoOclgc eeoIttt iRcvr uaaCrteeScientifico Carattere a Cura e Ricovero di Istituto Veneto Tumori Oncologico dei Istituto Nazionale Istituto IRCCS Fondazione Hospital University Padua < 1 1yasodwt eattc(1cide)o eurn 1 hlrn acmswr rae ih9IrIVA/IrVAC 9 with treated were sarcomas children) (12 recurrent or children) (11 metastatic with old years 21 ivniScarzello Giovanni , 1 1 nraFerrari Andrea , 3 eeiaD Corti De Federica , 2 ran Tagarelli Arianna , < ek ihamda olwu f26yas(ag .-.) 12 0.2-5.0), (range years 2.6 of follow-up median a With week. 1 1 1 ihl Casanova Michela , 1 ivaSorbara Silvia , 1 tfn Chiaravalli Stefano , 2 n Maria and , 2 , Posted on Authorea 20 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160315275.50122866/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. uo ouerdcino oeta w-hrs io epne(R uo ouerdcinof reduction volume tumor a = was (PR) (MR) response primary response response the The partial minor two-thirds; both disease; than visible indicated. of more all site clinically of of the if reduction disappearance at volume possible complete cycles tumor = were 9 a (CR) assessments and = response more 3 complete after and as: not assessed metastases, classified was be any factors to colony-stimulating and scheduled of tumor was use 9 preventive response for Tumor The neutrophils day toxicity. allowed. with a non-hematopoietic days, once of would resolution os 21 trial following every per I mg/kg administered phase 8 were formal cefixime Cycles mg/m subsequent 6. of (20 day a administration on used whether irinotecan the starting was include included ascertain days irinotecan to prophylaxis consecutive and of attempt Diarrhea (preferably information dose first counts, days possible. gather the cell reduced 5 be to was fixed, blood for this days) a of given Since consecutive combination, irrespective and 5 conditions. multidrug setting), patients 8 clinical dose-density outpatient to day good the a administered on in in in was started was VAC administration was patient USA. its Irinotecan the the enable providing line. in to Friday first (COG) to the Group Monday in Oncology ifosfamide Children’s mg/m received 1.5 the mg/m (vincristine that by 1.5 VAC of and injection, intravenous dose Europe, by a dose in bolus at a single actinomycin mg/m at a injection; 1.5 intravenous as ifosfamide by D given ( dose 1 IVA Day bolus of on single 2mg) a consisted as investigated given regimen g/m 1 Day the 3 of of part dose first a the 1, 3g/m of Figure in detailed As optional. radionuclide was scan, PET CT 18F-fluorodeoxyglucose chest tumor, biopsy. TREATMENT primary and the aspirate, of patients marrow scans from bone MRI and/or obtained scan, CT was bone of consent consisted informed workup diagnostic and The committee, ethical appropriate. local as the parents, by neutrophil or approved (absolute was function study marrow The bone adequate an age); patients of (for > years 70-100% [?]12 of [?]1000/mm patients status count (for performance 70-100% be Karnofsky to of had a Score patients metastasis eligible, have: with be DSRCT To and or ES, disease. old, RMS, trial relapsed/refractory of with multicenter diagnosis or confirmed diagnosis next histologically at a the with patients in included study investigated This (EpSSG). further Group be Study soft-tissue will sarcoma high-risk that tissue alkylating METHOD with on Soft concept based pediatric patients of is regimen European for standard proof it the strategy more by a a As dose-density coordinated represents with a irinotecan This of (8). of combination feasibility agents. sarcomas novel drugs. myelotoxic the a other involved more explored that other and we sarcomas with RMS study, associated this including be might In dose-density tumors, can it so-called intensity that pediatric the treatment hypothesized various to we Higher according non-myelotoxic, against relatively time, (7). active of RMS is unit metastatic per Irinotecan for drugs degree, of dosage some effective the to and increasing feasible approach. and, by proved (6) achieved has ES be treatment the also of intensify resistance treatment to a the cycles develop that chemotherapy in between and be currently time cycles may the is chemotherapy It Reducing between sarcomas interval weeks. pediatric the administered. three of drugs during every treatment the again drugs The to growing multiple start containing disease. cells cycles this cancer chemotherapy against administering active on be based to known drugs available irhao notoldinfection. uncontrolled or diarrhea 2 2 nDy n sa3hu nrvnu nuin(v wt oimmratehnsloaeat mercaptoethanesulfonate sodium (with (iv) infusion intravenous 3-hour a as 2 and 1 Days on 2 v n ylpopaie15mg/m 1.5 cyclophosphamide and iv, 2 e a n yehdain;vnrsiea oeo . mg/m 1.5 of dose a at vincristine hyperhydration); and day per 3 ltltcut[?]100,000/mm count platelet , 3 2 ;aeut ea n ie ucin n oatv grade active no and function; liver and renal adequate ); l ndy1 urnl sdrsetvl yteEpSSG the by respectively used currently 1) day on all , 2 > . 10 x 1.0 9 ladpaeesto platelets and /l > 2yasod raLnk Play Lansky a or old) years 12 > otsad[]2 years 21 [?] and months 6 2 aiu,2m)on mg) 2 maximum, ( > 2 0 10 x 100 v actinomycin iv, 2 (maximum, 2 dyfor /day 9 land /l Posted on Authorea 20 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160315275.50122866/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. lo utrswr oiiei ae,btwtotaysgso etcsok n ain a nepisode an had patient One shock. and septic patients, of transfusions 13 signs appendicitis. 14 any in platelet for with without cycles) receiving surgery but patients had of (23.1%), se- cases, one 4 (20.2% cycles less and 4 and neutropenia was 40 typhlitis, in (4.0%), during of positive in Thrombocytopenia fever cycles were evident of 7 of cultures reported). episodes only was (72% blood was 33 in IrVAC anemia were anemia observed receiving 3 toxicity There 4 patients (Table1S-2S-3S). Grade 4 grade in neu- grade (no frequent 4 with (56.1%). transfusions more Grade vere, IrIVA was blood myelosuppression. given and requiring was those (62.4%) toxicity patients in significant cycles most than 108 given the in cycles) was expected, progression, patient observed Another As tumor was to decision. tropenia occurred. parents’ due or deaths cycles 68 clinician’s toxic 7 and the No IrIVA to and due (105 2 cycles toxicity after 5 for patients and evaluable chemotherapy. two 3 were high-dose after in two 173 stopped another and was in administered, and treatment were The 2-10) (range cycles). 2 IrVAC cycles patients, 181 relapsed total, of In group the patients in peritoneal All Toxicity while had DSRCT). combination, IrVAC. DSRCT 1 IrIVA 10 and with the and IrIVA ES, patients received received metastatic 4 patients The newly-diagnosed RMS, newly-diagnosed 11 (7 All diffusion. included tumors metastatic population relapsed important 12 1). study (Table had and The dissemination disease years DSRCT) 25 1 metastatic male. to and with were 1.3 RMS from 15 aged (10 and patients sarcomas 23 years), enrolled 10.9 study this (median 2020, January to 2013 comparison. November our Between of purposes (9). the D) for patients actinomycin this considered RESULTS These but vincristine, not vinorelbine, was (ifosfamide, and treatment IVA protocol. cyclophosphamide the the of with MTS-2008 of compared vincristine, therapy cycles (ifosfamide, part Italy maintenance EpSSG also 5 regimen received in IVADo We by the subsequently the treated followed patients of than in week. RMS These cycles doxorubicin) more 4 one included metastatic and intervals: than with that and D, 3-week patients less at actinomycin established 2020 chemotherapy of of of we January series cycles delay 9 regimen, historical to a received a new 2013 with with this November administered treatment of from be the feasibility to of for have the duration 33% would overall evaluating or cycles 50% for by of criterion reduced 70% then general area, respectively. a surface old, body As months by 12 calculated reduced or be further 6 to be be under had to to patients children had had younger dose irinotecan for the of doses episodes, dose Drug further the were III), there grade If CTC omitted. Criteria course. Toxicity even ([?] subsequent Common diarrhea or the Institute’s significant for Cancer of 25% event National by weekly, the the reduced baseline, In using the graded 5.0. at was version obtained Toxicity were (CTC), chemistry cycle. each blood and before counts and cell blood chemotherapy complete chemotherapy, possible, to During If changes for sarcomas. recommendations metastatic also and newly-diagnosed Radiotherapy population. monitoring in Toxicity study patients. sites feasible. relapsed the metastatic if in and of recommended metastases, primary heterogeneity as was for with/without the classified re-irradiation 4 considered tumors of was the be primary because after to lesions for had given considered new recommended were be of was recommendations to detection Resection general had the recorded surgery only was or and/or but one-third apy, radiotherapy size than with tumor less treatment in of Local volume increase in an (PD) reduction disease while A of (SD), progression two-thirds. disease than stable less as but one-third, than more 3 th yl fchemother- of cycle Posted on Authorea 20 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160315275.50122866/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. h O rtclAS03suywsbsdo h ocp fds-opeso:tecce fchemotherapy of in cycles the included RMS dose-compression: of metastatic concept with the the patients on reduce based in to was beneficial, attempt ARST0431study An protocol possibly COG and previous sarcoma. the received feasible, pediatric proved against already approach cycles had dose-density between expected. they noted the interval in of been so be experience have tumor, reported should limited might relapsed It were is a toxicity a There infections (10). significant within had respectively more 3-4 study treatment 8%, a present grade and their our that where 2% in meaning complete in patients treatments, protocol, worse toxicity to the RMS2005 gastrointestinal significantly of able and the 47.8% not renal were that in was and IVA patients toxicity patients, with the of combinations, treated 57% of intensive patients Most are IrIVA/IrVAC in than Although study. our time. in reasonable toxicity. increase confirmed of an allow was risk theoretically with the 1 This profiles scheme increasing toxicity IVA/VAC for different without standard days their intensity the and 5 chemotherapy of drugs the over the combinations of of (i.e., rational activity schedule therefore, the continuous are, because low. irinotecan regimens a is IrVAC myelotoxicity with or while IrIVA administered diarrhea, The when is effect and, Irinotecan side RMS significant administration. worst against their most its following The active week), weeks 2-3 regimen. drug VAC the RMS. the a in non-metastatic myelotoxicity in is is for ifosfamide combinations trials of two instead European these used of sarcoma, in toxicity is chemotherapy with cyclophosphamide standard patients America, the North treat considered In now to is used regimen IVA currently that The combination regimens chemotherapy chemotherapy a the using RMS. approach in especially density irinotecan and dose a include of disease. in to feasibility with 9 the aimed evaluated alive writing, we were of study, 3 time this the and In at disease) alive relapsing still the were with patients 6 and 12 DISCUSSION and -5.0), ES diagnosis 0.2 relapsed at (range the with metastatic years with alone, treated 2.6 (3 patients patients of CR PR 2/4 the for follow-up and in (7/10) in median CR 70% a evident evident and With was the was (11/13) SD Considering PR 84.6% 1. were RMS. respectively. sarcoma. in rates IrVAC, of Ewing response MR and cases IrIVA The with and DSRCT. in 15, patients with in (15/17) 2 patients PR 88.2% 1/2 in patients, was PD 3 rate and in response evident RMS was with CR children cycles, 2 three therapies. initial local the to After due mainly days, median chemotherapy. 30 of same this than cycles the more comparing Outcome 9 precisely of On complete that delay to found a 170-231). taken we had was (range patients protocol, – days Nine MTS2008 169-270) 195 the (range was treatment), days in cycles the 195 enrolled - ninth concluded patients admin- time and 40 prematurely (83.4%) the first that cycles with patients the 181 outcome between 4 of ( interval the out delay median excluding 151 significant the with (i.e., any treatment 19-51), without cycles. chemotherapy (range and 7 or days whole fever in cyclophos- 23 time radiotherapy to with was on during due replaced cycles withdrawn istered was administered between was Ifosfamide interval not Actinomycin median reduced. and The seizures. never The cycles, from cycles. was 7 suffering irinotecan 15 child in of in a week dose vincristine in The one of phamide than cycles. dose 2 more the in for in neutropenia delayed reduction IrVAC. were a or cycles prompted for IrIVA irinotecan neuropathy given positive them patients peripheral of was between and one test emerged Constipation patients, toxicity stool two in a in difference case diarrhea meaningful 3 one No grade (in rapidly. of neutropenia episodes febrile were 3 episodes difficilis during with 4 episodes grade cycles, no two 14 2); (Table in experienced toxicity occurred non-hematological 3 Diarrhea grade of recorded.. episodes 19 experienced patients Six .Teds fiioea a o eue naysbeun ylsbcueteptet recovered patients the because cycles subsequent any in reduced not was irinotecan of dose The ). < ek.Cnieigteptet h opee the completed who patients the Considering week). 1 4 Clostridium Posted on Authorea 20 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160315275.50122866/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. cioyi ,addxrbcni hlrnwt eattcsf isesroa io td nbhl of behalf 15;103(8):1719-24. on Apr study 2005 pilot 9. Cancer. A 28;5:20 group. vincristine, sarcoma: study Aug ifosfamide, tissue sarcoma with 2015 soft study tissue Res. metastatic pilot soft A Sarcoma with pediatric - children Clin European regimen in IVADo next? the The doxorubicin to al. and Fifteen et where D, L.M. C.; Wagner, sarcoma: actinomycin Bergeron, 8. A.; pediatric 10;34(2):117-22. Ferrari, Jan for G.; 2016 Bisogno, therapy Oncol. Clin irinotecan J of group. vincristi- oncology J.R.; years rhabdomyosarcoma: of children’s and Anderson, high-risk the ifosfamide/etoposide trial E.; from patientswith child- of Lyden, report controlled in A B.J.; cycles the radiation, Randomized Weigel, dose-compressed from and 7. al. including irinotecan, report 20;30(33):4148-54 therapy, et ne/doxorubicin/cyclophosphamide, Nov A Tyrosine multiagent 2012 M.D.; Intensive sarcoma: of Oncol. Dev al. Krailo, ewing Role Clin Cell et D.C.; localized Front J The West, group. Sarcoma. of W. oncology Ewing treatment R.B.; Jin, ren’s in Womer, the tis- 5. Therapies for 6. Targeted soft Sep;83:177-184. chemotherapy 9;8:613. Its metastatic interval-compressed 2017 and Jul the with Cancer. Parameter evaluating 2020 patients Prognostic J ITCC Biol. adolescent Critical Eur the a and Casanova, and study). as J.H.M.; EpSSG childhood BERNIE Kinases Merks, the in (the J.C.; of chemotherapy we sarcoma Chisholm, study to Can sue 4. II multicen- bevacizumab al. Jun;29:107-112. phase retrospective of et 2019 randomised, a addition multicentre, of E. Oncol Results Open-label, Surg Nassif, Tumor? al. patients. J.B.; Cell M.;et 100 Re- regi- Delhorme, Round on Topotecan/carboplatin Honor´e, Small C.; Sarcoma study rhabdomyosarcomas: Desmoplastic Tissue May tric al. 3. abdominal metastatic Soft 2008 with AIEOP et Oncol. in patients the Apr;105(2):138-143. Clin M.; factors from cure 2019 J Casanova, Report Prognostic Tumori. M.C.; Groups. children: Cooperative in Affinita, Committee. al. rhabdomyosarcoma European A.; refractory/recurrent and et for Compostella, States men E.; United 2. from Lyden, analysis A.; 10;26(14):2384-9. pooled Rey, a of O.; sults Oberlin, 1. ONLUS Terrani Valentini management Lucia data Fondazione REFERENCES with the help by their supported was for work Coppadoro This Beatrice and Scagnellato Angela analysis. thank and to like would We disclose. to interest Acknowledgments of one conflicts be no will have This authors The investigation. further statement deserves interest setting chemotherapy study. of this standard EpSSG Conflict in the next in use the novel irinotecan its of this include goals and within to the sarcoma, irinotecan feasible of treat is of to it dose that used tolerated demonstrates regimens maximum study mg/m our the conclusion, (20 establish In irinotecan to mg/m 50 of needed is dose is vincristine, one with study or only I regime. alone tested phase used is we IrVAC proper it that or a when IrIVA irinotecan, is of the study have dose that our recommended some unfavorable of indicate although less (11). with limitation writing, reported, patients (6) of A toxicity of patients group time ES limited homogenous the for the more done at a and already CR in result, features-as possibly in testing, This alive further New were deserve follow-up. combinations patients (6). short of interval a 52% standard after only the population, administered (11). high-risk to chemotherapy approach our according same with chemotherapy In randomized the same treated using A the study patients given under weeks. in are those 2 outcome combinations in to than better high-risk cycles intervals The significantly with between shorter treatment. those a interval standard for reported the the not in study reducing but used RMS, and is embryonal it approach as with chemotherapy-intensifying 21 patients score the for of (Oberlin improvement instead features possible days a 14 showed of interval results an with administered were > )() oepoiigrslswr civdi oaie Sb dpigtesame the adopting by ES localized in achieved were results promising More (7). 1) 5 2 dyfr5dy) The days). 5 for /day 2 o as Therefore days. 5 for Posted on Authorea 20 Oct 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.160315275.50122866/v1 — This a preprint and has not been peer reviewed. Data may be preliminary. combination-for-high-risk-pediatric-sarcomas toxicity.pdf Non-hematological articles/487603-integrating-irinotecan-in-standard-chemotherapy-a-novel-dose-density- - 2 Table file Hosted standard-chemotherapy-a-novel-dose-density-combination-for-high-risk-pediatric-sarcomas at characteristics.pdf Patients\selectlanguage{english}’ available \selectlanguage{english}-- 1 Table file Hosted 68) cycles: of 105) number IrVAC(Total . : with cycles treated of -Patients number toxicity (Total IrIVA Hematologic with Table3S: treated -Patients toxicity Hematologic cycles) 2S: (173 Table population -Whole toxicity Hematologic 1S: Table Information Supporting regimen IrIVA The 1. Figure toxicity Non-hematological 2: Table characteristics Patients’ – 1 Table legends figure and Oncology Table Children’s the From Report A Sarcoma: Mar;63(3):493-8 2016 Ewing al. Cancer. Localized et Blood With Chemothera- M.C.; Pediatr Interval-Compressed Patients Bond, to Group. Diagnosed J.L.; Cyclophosphamide Newly Felgenhauer, and L.; Topotecan, in Vincristine, Mascarenhas, py Adding 11. of chemo- phase Aug;19(8):1061-1071. controlled, Study standard 2018 randomised Pilot to Oncol. doxorubicin open-label, Lancet multicentre, dose-intensified a of trial 2005): Addition 3 RMS al. (EpSSG et rhabdomyosarcoma C.; for Bergeron, therapy M.; Jenney, G.; Bisogno, 10. https://authorea.com/users/338247/articles/487603-integrating-irinotecan-in- vial at available 6 https://authorea.com/users/338247/ Posted on Authorea 20 Oct 2020 — The copyright holder is the author/funder. All rights reserved. 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