Is there a relation between hematological toxicity and response to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer?

www.toxsee2023.com 1st TOX SEE REGIONAL CONFERENCE 13th INTERNATIONAL CONGRESS OF THE SERBIAN SOCIETY OF TOXICOLOGY 10 - 12 May, 2023 Belgrade Present and Future of toxicology: Challenges and opportunities A B S T R A C T electronic www.hbisserbia.rs www.super-lab.com www.analysisdoo.comwww.esensa.rs/en www.goodwillpharma.com/srb www.dsp-c.co.rs www.novonordisk.com www.hemofarm.com 198 CLINICAL TOXICOLOGY POSTOJI LI VEZA IZMEĐU HEMATOLOŠKE TOKSIČNOSTI I ODGOVORA NA NEOADJUVANTNU HEMORADIOTERAPIJU KOD PACIJENATA SA LOKALNO UZNAPREDOVALIM KARCINOMOM REKTUMA? Mladen Marinković 1 , Suzana Stojanović-Rundić 1,2 , Ana Đurić 3 , Aleksandra Stanojević 3 , Dušica Gavrilović 4 , Radmila Janković 3 , Jerome Zoidakis 5 , Sergi Castellvi-Bel 6 , Remond Fijneman 7 , Milena Čavić 3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1 Institut za onkologiju i radiologiju Srbije, Klinika za radijacionu onkologiju i dijagnostiku, Odeljenje za radijacionu onkologiju, Beograd, Srbija 2 Univerzitet u Beogradu - Medicinski fakultet, Beograd, Srbija 3 Institut za onkologiju i radiologiju Srbije, Odeljenje za eksperimentalnu onkologiju, Beograd, Srbija 4 Institut za onkologiju i radiologiju Srbije, Data centar, Beograd, Srbija 5 Akademija u Atini, Fondacija za biomedicinska istraživanja, Departmant za biotehnologiju, Atina, Grčka 6 Univerzitet u Barseloni - Fondacija za klinička istraživanja BarseloneInstitut za biomedicinska istraživanja August Pi i Sunier (FRCB-IDIBAPS), Centar za biomedicinska istraživanja u mreži hepatičkih i digestivnih bolesti (CIBERehd), Bolnička klinika, Odeljenje za gastroenterologiju, Barselona, Španija 7 Holandski institut za istraživanje karcinoma, Odeljenje za patofiziologiju, Amsterdam, Holandija ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Standardni tretman lokalno uznapredovalog karcinoma rektuma (LARC) je neoadjuvantna hemioradioterapija (nCRT), nakon čega sledi operacija. Cilj ove studije bio je da se proceni povezanost između hematološke toksičnosti i odgovora tumora na terapiju (TR). U periodu od juna 2020. do januara 2022. godine, u studije je prospektivno uključeno 75 pacijenata sa LARC-om koji su lečeni dugotrajnim režimom CRT-a. RT je isporučena korišćenjem volumnog rotacionog planiranja zračne terapije i simultanog integrisanog boost-a. Istovremena hemioterapija (5-FU, leukovorin) je primenjivana tokom prve i pete nedelje RT. TR je procenjen u 8. nedelji, nakon završetka nCRT. Za pacijente sa potpunim kliničkim odgovorom (cCR) nije predložena neposredna radikalna operacija. 199 CLINICAL TOXICOLOGY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Grupa pacijenata koja je dobro odgovorila na sprovedeno lečenje (eng. responders, R) je definisana sa cCR i TRG1 i TRG2 postoperativnim kategorijama, prema Mandardovoj klasifikaciji. Grupa koja je lošije odgovorila (eng. non-responders, NR) definisana je kao TRG3-5. Akutna toksičnost je procenjivana nedeljno u skladu sa zajedničkim terminološkim kriterijumima za neželjene događaje (CTCAE) v.5.0. R su obuhvatali 46,6% pacijenata. Tokom nCRT, javili su se ukupni hematološki neželjeni efekti: anemija 40,0%, leukopenija 32,0% i neutropenija 21,3%. Anemija 3. stepena, leukopenija i neutropenija su se javile kod 6,7%, 2,7% i 4% pacijenata, respektivno. Nije prijavljena toksičnost 4. stepena. Limfopenija je primećena kod 94,7% pacijenata; 50,7% njih imalo je stepen toksičnosti 3/4. Značajna povezanost između hematološke toksičnosti i TR nije dokazana. Negativan trend je primećen kod anemije; pacijenti bez anemije tokom nCRT bolje su reagovali na lečenje (p=0,05). Ova povezanost može biti dovedena u vezu sa hipoksijom tumora i posledičnom radiorezistentnošću. Limfopenija izazvana zračenjem i njena potencijalna povezanost sa TR biće ispitana u nastavku ove studije. Dalje analize će biti usmerene na ispitivanje subpopulacija zahvaćenih limfocita korišćenjem CyTOF metodologije masene citometrije. KLJUČNE REČI: lokalno uznapredovali karcinom rektuma, neoadjuvantna hemioradioterapija, hematološka toksičnost. ZAHVALNICA: Ovu studiju finansirali su: Horizon Europe Twinning projekat STEPUPIORS (br. 101079217 i Ministarstvo prosvete i nauke Republike Srbije (br. 451-03-68/2022-14/200043). 200 CLINICAL TOXICOLOGY IS THERE A RELATION BETWEEN HEMATOLOGICAL TOXICITY AND RESPONSE TO NEOADJUVANT CHEMORADIOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED RECTAL CANCER? Mladen Marinković 1 , Suzana Stojanović-Rundić 1,2 , Ana Đurić 3 , Aleksandra Stanojević 3 , Dušica Gavrilović 4 , Radmila Janković 3 , Jerome Zoidakis 5 , Sergi Castellvi-Bel 6 , Remond Fijneman 7 , Milena Čavić 3 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 1 Institute for oncology and radiology of Serbia, Clinic for radiation oncology and diagnostics, Department of radiation oncology, Belgrade, Serbia 2 University of Belgrade - Faculty of medicine, Belgrade, Serbia 3 Institute for oncology and radiology of Serbia, Department of experimental oncology, Belgrade, Serbia 4 Institute for oncology and radiology of Serbia, Data Center, Belgrade, Serbia 5 Academy of Athens, Biomedical research foundation, Department of biotechnology, Athens, Greece 6 University of Barcelona, Fundació de recerca clínic Barcelona - Institut d'investigacions biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Centro de investigación biomédica en red de enfermedades hepáticas y digestivas (CIBERehd), Hospital clínic, Gastroenterology department, Barcelona, Spain 7 The Netherlands cancer institute, Department of pathology, Amsterdam, Netherlands ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (nCRT) followed by surgery. The aim of this study was to evaluate the association between different hematological toxicity and tumor response (TR). We prospectively included 75 LARC patients treated with long-course CRT between June 2020 and January 2022. RT was delivered using volumetric modulated arc therapy-simultaneous integrated boost. Concomitant chemotherapy (5FU, Leucovorine) was given during the first and fifth week of RT. TR was assessed in week 8, after nCRT completion. No immediate radical surgery was suggested for patients with complete clinical response (cCR). Responders were defined as patients with cCR and TRG1 and TRG2 postoperative categories, according to the classification by Mandard. Non-responders were classified as TRG3-5. Acute toxicity was evaluated weekly according to common terminology criteria for adverse events (CTCAE) v.5.0. 201 CLINICAL TOXICOLOGY ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Responders group comprised 46.6% of patients. During nCRT, all-grade hematological adverse effects occurred: anemia 40.0%, leukopenia 32% and neutropenia 21.3%. Grade 3 anemia, leukopenia and neutropenia occurred in 6.7%, 2.7% and 4% of patients, respectively. No grade 4 toxicity was reported. Lymphopenia was observed in 94.7% of patients; 50.7% of them had grade 3/4 toxicity. No significant association was found between hematological toxicities and TR. A negative trend was observed for anemia; patients without anemia during nCRT responded better to treatment (p=0.05). This association might be connected to tumor hypoxia and consequent radioresistance. Radiation-induced lymphopenia and its potential association with TR remain to be understood. Further analyses will be directed to the investigation of the affected lymphocytes subpopulations using a CyTOF mass cytometry methodology. KEY WORDS: locally advanced rectal cancer, neoadjuvant chemoradiotherapy, hematological toxicities. ACKNOWLEDGMENTS: This study was funded by the Horizon Europe Twinning Project STEPUPIORS (Agreement No. 101079217) and the Ministry of Education and Science of the Republic of Serbia (Agreement No. 451-03-68/2022-14/200043).