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tiinifice cu caracter interdisciplinar pentru a contribui astfel la susinerea i dezvoltarea

profesionitilor din domeniul medical din Romnia.

V ateptm, de asemenea, s ne fii alturi pe 5 decembrie 2014, la Bucureti, la Crystal Palace

Ballroom, n cadrul evenimentului tiinific interdisciplinar i translaional Health Meeting,

ediia a II-a, unde sunt invitai specialiti din domeniile oncologie, ginecologie, dermatologie,

terapia durerii, paliaie i medicin de familie, mpreun cu lectori de renume din Romnia

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detalii despre eveniment, putei afla de pe site-nostru, www.msc-ro.com, la Seciunea Events.

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Titlul articoluluiInternational articles

115

Nume autori

September 2014

Issue 3 I Volume 2 I September 2014

R o m a n i a n J o u r n a l o f

Oncology & Hematology

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ef LucrriDr. Simona Mihuiu (Universitatea de Medicin i Farmacie Oradea, Oradea, Romnia)Cerc. St. Gr. I. Dr. Grigorescu Alexandru (Institutul oncologic Prof. Dr. Alexandru Trestiorean, Bucureti, Romnia)

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Romanian Editorial BoardProf. Dr. Oltean Galafteon (Universitatea of Medicin i Farmacie Trgu Mure, Trgu Mure, Romnia)

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Oncology & Hematology

EVENTSOncogenetica i terapiile intite: O ans sporit la prelungirea duratei de via

ORIGINAL ARTICLEPrevention of coronary heart disease (CHD) in prostate cancer patients undergoing androgen deprivation therapy (ADT)Mazilu L, Parepa IR, Suceveanu AI, Catrinoiu D, Tofolean DE

Castration-resistant prostate cancerGrigorescu AC

INTERNATIONAL ARTICLESBevacizumab in Association With deGramont 5-Fluorouracil/Folinic Acid in Patients With Oxaliplatin-, Irinotecan-, and Cetuximab-Refractory Colorectal CancerA Single-Center Phase 2 TrialVincenzi B, Santini D, Russo A, Spoto C, Venditti O, Gasparro S, Rizzo S, Beomonte B, Caricato M, Valeri S, Coppola R, Tonini G

Intratumoral steroidogenesis in castration-resistant prostate cancer: a target for therapy Armandari I, Hamid AR, Verhaegh G, Schalken J

Angiotensin (1-7) Antagonist Diminished the Anti-Tumor Effect of Olmesartan in Tumor Cell Lines Grown In-vitro and In-vivoAbd-Alhaseeb MM, Zaitone SA, Abou-El-Ela SH, Moustafa YM

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Events

Concluziile evenimentului au artat c medicina personalizat poate fi definit ca tratamentul potri-vit pentru pacientul potrivit, la momentul potrivit. Dac s-ar adopta pe scar larg principiile medi-cinei personalizate, bazat pe nelegerea i inte-grarea informaiei genetice, atunci am beneficia de o medicin preventiv, nu de una reactiv, cum se ntmpl n prezent. Tratamentul optim ar fi mult mai bine selectat i s-ar reduce prescrierea medica-mentelor de tipul ncercare-eroare. Cunoscnd pro-filul genetic al pacientului, medicamentele ar fi mai sigure n administrare, datorit evitrii efectelor ad-verse. n consecin, ar crete aderena la tratament a pacienilor i ar crete durata i calitatea vieii, dar s-ar controla mult mai bine costurile n sistemul sanitar.

Progresele din ultimii ani, n domeniul on-cologiei, au fost extraordinare. Att ca mod de

nelegere a bolilor maligne, ct i din punctul de vedere al tratamentului. Informaiile sunt din ce n ce mai ample deoarece medicina evolueaz, oncogenetica este un pas pentru pa-cientul cu cancer, duce ctre un tratament intit care ofer o ans n plus pacientului i reacii adverse minore. Aici s-a vorbit i de o abor-dare holistic a pacientului cu cancer, ceea ce ne-a bucurat cel mai mult este c exist o uni-tate fireasc ntre medic-pacient, vine mai mult informaie direct de la specialist, vine i din me-diul privat informaia i mna ntins ctre noi pacienii, a declarat Cezar Irimia, preedinte al FABC. Aducem n Romnia cel mai avansat sistem informaional de depistare a mutaiilor genetice i identificare a celei mai eficiente terapii n can-cer la nivel mondial, aadar prezena noastr la

La Poiana Braov, a avut loc ediia a VI-a a Conferinei Naionale a Federaiei Asociaiilor Bolnavilor de Cancer din Romnia, ce a avut ca tem principal Oncogenetica, o ans la via?, scopul evenimentului fiind creterea nivelului de informare i educare asupra oportunitilor aduse de testrile genetice i de tratamentele personalizate.

ONCOGENETICA I TERAPIILE INTITE: O ANS SPORIT LA PRELUNGIREA DURATEI DE VIA

Andreea Banea

121September 2014

ediia din anul acesta a conferinei FABC, dedicat anselor crescute la via pe care oncogenetica le ofer pacienilor romni, a fost un demers firesc. Este important ca medicii curani i specialitii oncologi, alturi de pacienii romni, s aib aceeai nelegere n ceea ce privete medicina personalizat i genetica molecular; acestea le ofer anse reale de a detecta i iniia schema de terapie cea mai adecvat tipului lor de tumoare, cu anse reale de mbuntire a vieii i prelungire a acesteia. n contextul standardelor medicinei con-temporane, importana diagnosticului molecular este esenial pentru un prognostic cu acuratee al bolii, au declarat reprezentanii ONCOMPASS, cel mai avansat sistem informaional la nivel mondial de identificare a celei mai eficiente terapii person-alizate a cancerului.

ONCOMPASS este disponibil i n Romnia i cu ajutorul acestui test inovator pacienii cu cancer pot obine informaii referitoare la posibilitile de tratament intite disponibile la nivel mondial, personalizate tipului de tumoare, att din cadrul medicamentelor existente pe pia, ct i din cadrul celor aflate n curs de nregistrare n diverse studii clinice n Europa i n alte regiuni ale globului. KPS, compania care deine licena ONCOMPASS, intermediaz includerea acestor pacieni n aceste studii, uti-

liznd o baz de date actualizat n permanen, referitoare la testele clinice la nivel mondial.

Testrile farmaco-genetice/genomice repre zint calea spre o medicin personalizat, dare nevoie de multrigurozitate n recoman-darea lor. Astfel, sunt testri obligatorii, acolo unde rezultatele pot fi urmate de o terapie intit cu medicamente nregistrate i cuprinse n ghidurile internaionale/naionale de di-agnostic i tratament oncologic, dar i testri orientative, pentru cazuri selecionate care nu rspund la terapia standard i care pot fi ur-mate de ajustri terapeutice cu medicamente nregistrate, sau n curs de evaluare n studii clinice. Concluzionnd, exist testri farmaco-genetice/genomice a cror valoare n manage-mentul cazului oncologic este deja o certitudi-ne i testri de la care deocamdat avem doar ateptri i care nu trebuie prescrise de rutin, ci doar pentru cazuri atent selecionate, pen-tru a nu induce sperane false i n acelai timp pentru a nu genera o imagine defavorabil unui trend medical cu mare potenial de vi-itor, i anume individualizarea terapiilor on-cologice, a declarat dr. Delia Mateescu, din cadrul Medicover, care a susinut prezentarea cu tema Farmaco-genetica - certitudini i ateptri.

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Original article PREVENTION OF CORONARY HEART DISEASE (CHD) IN PROSTATE CANCER PATIENTS UNDERGOING ANDROGEN DEPRIVATION THERAPY (ADT)

PREVENTION OF CORONARY HEART DISEASE (CHD) IN PROSTATE CANCER PATIENTS UNDERGOING ANDROGEN DEPRIVATION THERAPY (ADT)

PREVENIA BOLII CORONARIENE (CHD) LA PACIENII CU CANCER DE PROSTAT N CURS DE TERAPIE DE DEPRIVARE ANDROGENIC (ADT)

Mazilu Laura, Parepa Irinel-Raluca, Suceveanu Andra-Iulia, Catrinoiu Doina, Tofolean Doina-EcaterinaFaculty of Medicine, Ovidius University, Clinical Emergency Hospital St. Apostle Andrew of Constana

Cite this article: Mazilu L, Parepa IR, Suceveanu AI, Catrinoiu D, Tofolean DE. Preven-tion of coronary heart disease (CHD) in prostate cancer patients undergo-ing androgen depriva-tion therapy (ADT). Rom J Oncol Hematol. 2014; 2(3):122-126.

Received: 13 April 2014Reviewed: 05 May 2014Accepted: 10 May 2014

Open Access Article

Corresponding author: Laura Mazilu Oncology Department, Clinical Emergency Hospital of Constana, Tomis Blvd. no. 145, Constana, Romania, 900591

Tel: 0241503485e-mail: lauragrigorov@gmail.com

Keywords:

Statins, prostate cancer, coronary heart disease

AbstractIntroduction: In addition to risk factors for coronary heart disease (CHD) that are applicable to the general population, men with prostate cancer are at increased risk for CHD due to the use of androgen deprivation therapy (ADT). Hyperlipidemia, insulin resistance, metabolic syndrome, and CHD are all reported consequences of ADT. The aim of this study was to evaluate strategies to prevent cardiovascular events in newly diagnosed prostate cancer patients undergoing ADT. Methods: We prospectively analyzed 23 patients with prostate cancer, undergoing ADT with a luteinizing hormone-releasing hormone (LHRH/GnRH) agonist. All patients were evaluated and monitored by a mixed team oncologist and cardiologist. Patients were assigned to an interventional arm (n=12) which received prophylactic statin therapy with simvastatin or rosuvastatin, and an observational arm (n=11) with no associated statin treatment. Results: After 12 months of ADT treatment, the lipid profile was normal in the prophylactic statin therapy arm (n=11) in comparison with the non-interventional arm, in which the lipid profile was normal in 3 cases (95% CI, 4.49-7.67; p

123September 2014

Mazilu L, Parepa IR, Suceveanu AI, Catrinoiu D, Tofolean DE

Introducere

Avnd n vedere prevalena crescut a canceru-lui de prostat la brbaii cu vrste de peste 50 de ani, brbaii cu risc pentru cancerul de prostat reprezint aceeai populaie de pacieni cu risc de sindrom metabolic, diabet zaharat i boal coronarian (CHD) (1).

Factorii majori de risc pentru CHD includ vrsta >45 ani, sexul masculin, istoricul familial pozitiv, nivelul crescut al LDL-colesterolului, nivelul sczut al HDL-colesterolului, hipertensiunea arterial, di-abetul zaharat i consumul de tutun. n plus fa de aceti factori de risc pentru CHD, factori aplicabili populaiei generale, brbaii cu cancer de prostat prezint risc crescut pentru CHD ca urmare a utilizrii terapiei de deprivare androgenic (ADT) (1). Hiperlipidemia, rezistena la insulin, sindro-mul metabolic i sindromul coronarian acut, toate reprezint consecine raportate ale ADT.

Studiile clinice prospective au demonstrat c ADT poate crete riscul bolilor cardiovasculare prin creterea greutii corporale, reducerea sensibilitii la insulin i/sau ca urmare a dislipid-emiei secundare (2). ADT scade semnificativ masa

muscular i crete esutul adipos (2-7). Aceste modificri ale masei musculare i ale esutului adipos par a fi n primul rnd un efect negativ pre-coce, majoritatea lor devenind aparente n primele luni de terapie (2,8,9).

ADT crete, de asemenea, nivelurile serice ale colesterolului i trigliceridelor, iar majoritatea modificrilor observate pe termen lung ale lipid-elor serice sunt evidente n primele 3 luni de trata-ment (2,5,10,11).

Rezistena la insulin este o anomalie metabolic frecvent, care st la baza diabetului zaharat tip 2 i este prevalent la aproximativ 1/4 din pacienii de sex masculin non-diabetici (2,12). Unele stu-dii au raportat hiperinsulinemia ca i factor de risc independent pentru boala cardiovascular (2,13,14). ADT crete nivelurile plasmatice ale insu-linei jeun, niveluri care reprezint un marker de rezisten la insulin la pacienii cu cancer de prostat (2,4,15). Un studiu prospectiv efectuat pe pacieni de sex masculin nediabetici a evideniat faptul c ADT crete semnificativ (26%) nivelurile plasmatice ale insulinei jeun, i scade sensibili-tatea la insulin (13%) (2,11).

Cuvinte-cheie:

Statine, cancer de prostat, boal coronarian

RezumatIntroducere: n plus fa de factorii de risc pentru boala coronarian (CHD), factori care sunt aplicabili populaiei generale, pacienii cu can-cer de prostat prezint un risc crescut pentru CHD din cauza utilizrii terapiei de deprivare androgenic (ADT). Hiperlipidemia, rezistena la insulin, sindromul metabolic i CHD sunt toate consecine ale utilizrii ADT. Scopul studiului nostru a fost de a evalua strategiile de prevenire a CHD la pacienii cu cancer de prostat nou diagnosticat, n curs de ADT. Metode: Am analizat prospectiv 23 de pacieni cu cancer de prostat, n curs de ADT cu un agonist LHRH/GnRH. Toi pacienii au fost evaluai i monitorizai de ctre o echip mixt oncolog i cardiolog, pe parcursul unui an de tratament. Pacienii au fost repartizai ntr-un bra intervenional (n=12), care au primit tratament profilactic cu statine i un bra observaional (n=11), fr tratament cu statine. Rezultate: Dup 12 luni de tratament ADT, profilul lipidic a fost normal n braul intervenional (n=11), comparativ cu braul observaional, n care profilul lipidic a fost normal n doar 3 cazuri (95% CI, 4,49-7,67; p

124

Mai multe studii recente au sugerat o aso-ciere a ADT cu analogii LHRH (cu sau fr antiandrogen) sau orhiectomie bilateral i creterea incidenei i mortalitii prin boli car-diovasculare (2,16-20).

Scopul acestui studiu a fost de a evalua strategi-ile de prevenire a evenimentelor cardiovasculare la pacienii cu cancer de prostat nou diagnosticat, n curs de ADT.

MetodeAm analizat prospectiv 23 de pacieni cu can-

cer de prostat n curs de ADT cu un agonist LHRH/GnRH. Pacienii cu diabet preexistent sau cu profil lipidic/glicemic anormal au fost exclui din studiu. Toi pacienii au fost evaluai i monitorizai de ctre o echip mixt medic oncolog i cardiolog.

Profilul lipidic (colesterol total, LDL-colesterol, HDL-colesterol i trigliceride), profilul glicemic, val-orile tensiunii arteriale (TA) i greutatea corporal

au fost evaluate la nceputul studiului i apoi anali-zate la fiecare 3 luni.

Pacienii au fost repartizai ntr-un bra intervenional (n=12), care a primit tratament pro-filactic cu statine simvastatin 20-40mg/zi sau rosuvastatin 10 mg/zi i un bra observaional (n=11), fr tratament cu statine. Pacienii din braul intervenional au fost testai pentru nive-lurile serice ale transaminazelor dup 1 lun de tratament cu statine (pentru a evidenia nivelul crescut al transaminazelor secundar tratamentu-lui cu statine).

De asemenea, toi pacienii au fost consiliai cu privire la modificrile stilului de via diet, scdere n greutate, activitate fizic, iar cei care au continuat s fumeze au fost consiliai pentru a opri fumatul i au fost ndrumai ctre programe de renunare la fumat.

Toi pacienii cu hipertensiune arterial (HTA) preexistent sau nou diagnosticai au prim-it medicaie anti-hipertensiv (ACEis/ARBs,

Figura 1. Profilul lipidic dup 12 luni de ADT

Figura 2. Incidena CHD dup 12 luni de ADT

PREVENTION OF CORONARY HEART DISEASE (CHD) IN PROSTATE CANCER PATIENTS UNDERGOING ANDROGEN DEPRIVATION THERAPY (ADT)Original article

125September 2014

Mazilu L, Parepa IR, Suceveanu AI, Catrinoiu D, Tofolean DE

blocante ale canalelor de Ca), pentru a menine valorile TA n limitele recomandate de ghiduri.

Datele au fost analizate cu ajutorul Graph Pad InStat si Graph Prism 5.

RezultateTratamentul profilactic cu statine a fost ntrerupt

dup 6 luni de tratament ntr-un singur caz, ca ur-mare a nivelului crescut al transaminazelor serice (8,33%).

Dup 12 luni de tratament ADT, profilul lipidic a fost normal n braul de terapie profilactic cu statine (n=11), comparativ cu braul observaional, n care profilul lipidic a fost normal n 3 cazuri (95% CI, 4.49-7.67, r2=0,86, p

126

versus 5 cazuri, p=0,1587) i toi pacienii au primit terapie antihipertensiv pentru a reduce TA la valori

127

Nume autori

September 2014

128

Original article Castration-resistant prostate cancer

CASTRATION-RESISTANT PROSTATE CANCER

CANCERUL DE PROSTAT REZISTENT LA CASTRARE

Alexandru C. GrigorescuCercettor tiinific gradul I, mdic primar oncologie medical, Institutul Oncologic Bucureti

Corresponding author:CSI Dr. Alexandru C. Grigorescu

e-mail: alexgrigorescu2004@yahoo.com

Cite this article: Grigorescu AC. Castration-resistant prostate cancer. Rom J Oncol Hematol. 2014; 2(3):128-130.

Received: 05 Sept 2014Reviewed: 10 Sept 2014Accepted: 15 Sept 2014

Open Access Article

Keywords:

Cuvinte-cheie:

Prostate cancer, treatment, metastasis

cancer de prostat, tratament, metastaze

Abstract

Rezumat

Prostate cancer is the most common cancer in men in the United States and in the world compete for first place with lung cancer. The incidence and mortality of prostate cancer is high, especially with an aging population. We intend to discuss about some aspect of diagnosis, staging and treatment of prostate cancer, emphasizing the castration-resistant prostate cancer (CRPC). Definition of castration-resistant prostate cancer is important to diagnose this clinical entity and to initiate appropriate treatment. Thus CRPC is defined as an evolution of PSA or metastasis, most frequent bone localized, patient having the corresponding values of testosterone castration. CRPC is complex treatment including radiotherapy (radium 223), immunotherapy (Sipuleucel-T), hormonal manipulation and chemotherapy. Hormonal manipulation is already classic but the new treatment compounds: abiraterone and enzalutamide bring an increase in survival and a positive impact on symptoms. CRPC benefit from classical chemotherapy plus a new efficient cytostatic Cabazitaxel used today after developing resistance to docetaxel.

Cancerul de prostat este cel mai frecvent cancer la brbat n Statele Unite, iar n lume i disput locul nti cu cancerul bronhopulmonar. Incidena i mortalitatea prin cancer de prostat este ridicat mai ales prin mbtrnirea populaiei. Ne propunem s discutm despre cte-va aspecte ale diagnosticului, stadializrii i tratamentului cancerului de prostat, accentund asupra cancerului de prostat rezistent la castrare (CRPC). Definiia cancerului de prostat rezistent la castrare este important pentru a putea diagnostica aceast entitate clinic i pentru a iniia un tratament adecvat. Astfel, CRPC se definete ca o evoluie a PSA sau a metastazelor, cel mai frecvent osoase, la valori ale testosteronului corespunznd castrrii. Tratamentul CRPC este com-plex cuprinznd radioterapia (radium 223), manipularea hormonal i chimioterapia, imunoterapia (Sipuleucel-T). Manipularea hormonal este deja un tratament clasic, dar noii compui - abiraterona i enzalu-tamida - aduc o cretere n supravieuire i un impact pozitiv asupra simptomatologiei. La chimioterapia clasic se adaug astzi i cabazi-taxelul, un citostatic eficient dup apariia rezistenei la docetaxel.

129September 2014

Grigorescu AC

Introducere

La nivel mondial, neoplasmul de prostat reprezint al doilea cel mai frecvent tip de cancer diagnosticat la brbai, n timp ce n Europa este cel mai frecvent diagnostic de cancer la brbai. Prevalena global a cancerului de prostat n 2008 a fost 21,1 la 100.000 de persoane, cu o rat de deces de 4,6 la 100.000 (echivalentul a 258.000 de decese); iar n Europa, incidena acestui tip de can-cer n 2008 a fost de 110,5 la 100.000. Prevalena cancerului de prostat va crete n continuare, o dat cu mbtrnirea populaiei din rile euro-pene. Dei rata de supravieuire la 5 ani n cance-rul de prostat este 87,2%, se estimeaz c 10-20% dintre pacieni vor progresa ctre stadiul rezistent la castrare ntr-o perioad de 5 ani. Dintre acetia, mai mult de 84% vor avea metastaze la momentul diagnosticului(1).

DiagnosticulDiagnosticul cancerului de prostat se pune prin

biopsie de prostat. Decizia pentru a face biopsia se ia pe baza creterii valorilor PSA i a tueului rectal care relev semnele clinice ale unei tumori de prostat. Este important a se corela valoarea global a PSA cu free PSA, velocitatea PSA i den-sitatea PSA.

Cancerul de prostat poate fi stadializat dup gradul de risc. Pacienii care au comorbiditi importante sau nu se ncadreaz pentru un tratament cu intenie de radicalitate nu trebuie investigai complet n vederea stadializrii. Stadi-alizarea clinic se face prin tueu rectal, ecografie,

RMN i prin analiza PSA. Categoriile de risc sunt urmtoarele: risc sczut la cei cu T1-2a, Gleason mai mic dect 7 i PSA mai mic dect 10, risc cres-cut cnd exist T3-4, Gleason mai mare dect 7 i PSA peste 20 i riscul intermediar ntre cele dou.

Definiia noiunii de cancer de prostat rezistent la castrare

Cancerul de prostat rezistent la castrare (CRPC) este definit de progresia bolii n ciuda terapiei de deprivare androgenic (ADT) i poate s se mani-feste printr-o cretere continu a concentraiilor serice ale antigenului specific prostatic (PSA), pro-gresia bolii preexistente, apariia de noi metastaze, sau combinaia acestor aspecte evolutive.

Cancerul de prostat avansat a fost cunoscut sub mai multe denumiri de-a lungul anilor, inclu-siv cancer de prostat hormono-rezistent (HRPC) sau androgen insensibil. Cel mai recent, termenii castrat-rezistent sau castrat recurent au fost introdui cu realizarea c producia de androgeni intracrin i paracrin joac un rol important n rezistena celulelor cancerului de prostat la trata-mentul de supresie a testosteronului(2).

Grupul de studiu al cancerului de prostat (PCWG2) a definit CRPC n baza metastazelor de-tectabile (clinic sau prin imagistic) i dac testos-teronului seric este n intervalul de castrare prin orhiectomie chirurgical sau terapia medical(3).

Cancerul de prostat rezistent la castrare prezint un spectru de boli variind de la creterea nivelului PSA fr metastaze sau simptome n ciuda ADT, pn la prezena metastazelor i a

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Castration-resistant prostate cancer

deteriorrii semnificative simptomatice. Prog-nosticul este asociat cu mai multi factori, printre care starea de performan, prezena de dureri osoase, gradul de extindere a metastazelor osoase, precum i nivelurile serice ale fosfatazei alcaline. Metastaze osoase apar la 90% dintre brbaii cu CRPC i pot produce morbiditate semnificativ, inclusiv durere, fracturi patologice, compresie medular i insuficien medular. Efectele paraneoplazice sunt, de asemenea, comune, inclusiv anemie, scdere n greutate, oboseal, hipercoagulabilitate i susceptibilitate crescute la infecii(4).

TratamentSunt multiple mijloace terapeutice incluznd te-

rapia imun ( Sipuleucel-T) radioterapia (radium 223), terapia hormonal.

Vom discuta mai mult despre terapia hormonal care este apanajul oncologului medical.

La pacienii tratai cu monoterapie, utiliznd agoniti LH-RH sau la cei la care s-a practicat orhi-ectomia, se poate recomanda blocada total de androgeni cu antagoniti de testosteron, cum ar fi bicalutamida.Acest tratament poate avea o rat de rspuns de 30-35%.

Pentru pacienii care au suferit blocada total androgenic i prezint semne de progresie, an-ti-androgenul poate fi ntrerupt n ncercarea de a obine un rspuns de retragere antiandrogenic. Rspunsul la aceast manipulare hormonal apare la 20%-30% dintre pacieni. Alte opiuni ar putea include o schimbare cu un antiandrogen diferit, cum ar fi nilutamida sau flutamida, sau utilizarea de ketoconazol 7. Pentru toate aceste modaliti, au fost raportate reduceri tranzitorii ale PSA la aproximativ 30% dintre pacieni.

Pentru c receptorul androgenic rmane activ la majoritatea pacienilor care au dezvoltat boala rezistent la castrare, grupuri cum ar fi Ameri-can Society of Clinical Oncology (ASCO), Com-prehensive National Cancer Network (NCCN) recomand ca ADT ar trebui s fie continuat.

ChimioterapiaSocietatea European de Oncologie Medical

(ESMO) recomand ca prim linie de chimiotera-pie, monochimioterapia cu docetaxel care poate fi administrat n doze la 2 sau la 3 sptmni.

n linia a doua de chimioterapie se poate folosi mitoxantronul sau recentul citostatic cu aciune la nivelul tubulinei, cabazitaxelul asociat cu predni-son, care n studii clinice s-a dovedit mai eficient dect mitoxantronul asociat cu prednison(5).

Noi ageni terapeuticin ultimii ani s-au dezvoltati mai muli ageni tera-

peutici noi care acioneaz specific asupra recep-torilor androgenici sau a produciei de androgeni. Compuii care s-au impus n practica clinic sunt abiraterona i enzalutamida.

AbirateronaA fost aprobata n urma rezultatelor obinute n

studiul COU-AA-301, un studiu de faz III- versus placebo.

Acest produs este indicat pentru utilizare n aso-ciere cu prednison ca un tratament pentru cance-rul de prostata metastatic rezistent la castrare. A primit aprobare din partea FDA i EMA n 2011(6).

Abiraterona se administreaz n asociere cu prednisonul.

EnzalutamidaEnzalutamida este un antagonist al receptorilor

androgenici, care inhib proliferarea celulelor neo-plazice ale cancerului de prostat, cu inducerea apoptozei celulelor neoplazice i regresie tumoral. Nu prezint activitate agonist asupra receptorilor androgenici.

Studiul AFFIRM a demonstrat c, n comparaie cu BSC (best standard of care), enzalutamida a determi-nat creterea semnificativ a supravieuirii generale (valoare median) cu 4,8 luni i a perioadei fr pro-gresia bolii (confirmat radiologic) cu 5,4 luni, cu reducerea semnificativ a rspunsului PSA cu 54%, n condiiile n care au fost raportate mai puine eve-nimente adverse grave comparativ cu BSC i sem-nificativ mai puine cazuri de deteriorare a calitii vieii pacienilor. Enzalutamida este de asemenea aprobat de FDA i EMA pentru tratamentul canc-erului de prostat rezistent la castrare(7).

Bibliografie

1. Ferlay J et al, Cancer incidence and mortality patterns in Europe: incidence for 40 countries in 2012. European Journal of Cancer (2013) 49, 1374 1403.2. Mostaghel EA, Page ST, Lin DW, et al. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res.2007;67:503341. 3. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26:114859) .

4. Curr Oncol. Sep 2010; 17(Suppl 2): S72S79., 5.5. PMCID: PMC2935714,Current management of castrate-resistant prostate cancer, S.J. Hotte, MD MSc* and F. Saad, MD6. http://www.esmo.org/Guidelines/Genitourinary-Cancers/Prostate-Cancer ZYTIGA (abiraterone acetate) tablet [Janssen Biotech, Inc.]. DailyMed. Janssen Biotech, Inc. September 2013. Retrieved 24 January 2014.7. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002321/WC500112858.pd

This work is licensed under a Creative Commons Attribution 4 .0 Unported License. The images or other third party material in this article are included in the articles Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/

Conflict of Interests: None.

Original article

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132

International articles Bevacizumab in Association With de Gramont 5-Fluorouracil/Folinic Acid in Patients With Oxaliplatin-, Irinotecan-, and Cetuximab-Refractory Colorectal Cancer

BEVACIZUMAB IN ASSOCIATION WITH DEGRAMONT 5-FLUOROURACIL/FOLINIC ACID IN PATIENTS WITH OXALIPLATIN-, IRINOTECAN-, AND CETUXIMAB-REFRACTORY COLORECTAL CANCERA SINGLE-CENTER PHASE 2 TRIAL

Bruno Vincenzi, MD1; Daniele Santini, MD1; Antonio Russo, MD2; Chiara Spoto, MD1; Olga Venditti, MD1; Simona Gasparro, MD1; Sergio Rizzo, MD2; Bruno Beomonte Zobel, MD3; Marco Caricato, MD4;

Sergio Valeri, MD4; Roberto Coppola, MD4; and Giuseppe Tonini, MD1

Corresponding author: Antonio Russo, MD, Section of Medical Oncology, Department of Surgery and Oncology, Universita` di Palermo, Via del

Vespro 129, 90127 Palermo, Italy; Fax: (011) 39-091-6554529; lab-oncobiologia@usa.net1Department of Medical Oncology, Campus Bio-Medico University, Rome, Italy; 2Section of Medical Oncology, Department of Surgery and

Oncology, University of Palermo, Palermo, Italy; 3Department of Radiology, Campus Bio-Medico University, Rome, Italy; 4Department of General Surgery, Campus Bio-Medico University, Rome, Italy

Open Access Article

Keywords:

bevacizumab, de Gramont, colorectal cancer, 5-fluorouracil, folinic acid

AbstractBACKGROUND: The aim of the current study was the investigation of the value of bevacizumab 5-fluo- rouracil(5FU)/folinic acid in patients with advanced colorectal cancers who have exhausted standard chemotherapy options. METHODS: The authors included 48 heavily pretreated patients (colon:rectum, 33:15; men:women, 23:25; median age, 63 years; range, 27-79 years) whose disease had progressed during or within an oxaliplatin-based first-line chemotherapy, an irinotecan-based second-line regimen, and a third-line treatment with cetuximab plus weekly irinotecan. Bevacizumab was given at a dose of 5 mg/kg.5-FU/folinic acid was administered according to the de Gramont schedule. RESULTS: The response rate was 6.25%, and 30.4% of patients demonstrated stable disease as the best response. The median time to disease progression was 3.5 months (95% confidence interval [95% CI], 2.3-6.9 months), and the median survival time was 7.7 months (95% CI, 3.9-11.9 months). The most common grade 3 to 4 side toxicities (graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) were: diarrhea (20.8%), fatigue (14.5%), and stomatitis (12.5%). Grade 3 to 4 hemorrhage occurred in 8 patients (16.6%), including 4 cases of bleeding in the gastrointestinal tract. Other relatively common adverse events such as hypertension, thrombosis, and bowel perforation were reported in 50%, 18.7%, and 4.16%, of patients respectively. CONCLUSIONS: The data from the current study suggest a modest but significant clinical benefit of bevacizumab de Gramont schedule in heavily pretreated colorectal cancer patients. Cancer 2009;115:484956. VC 2009 American Cancer Society.

Cite this article: Vincenzi B, Santini D, Russo A, Spoto C, Venditti O, Gasparro S, Rizzo S, Beomonte B, Caricato M, Valeri S, Coppola R, Tonini G.Bevacizumab in Association With deGramont 5-Fluorouracil/Folinic Acid in Patients With Oxaliplatin-, Irinotecan-, and Cetuximab-Refractory Colorectal Cancer. Rom J Oncol Hematol. 2014; 2(3):132-138.

Published online July 22, 2009 in Wiley InterScienceDOI: 10.1002/cncr.24540, www.interscience.wiley.comPublished 15 October 2009 in Cancer

Received: 11 Nov 2008Reviewed: 25 March 2009Accepted: 27 March 2009

133September 2014

Vincenzi B, Santini D, Russo A, Spoto C, Venditti O, Gasparro S, Rizzo S, Beomonte B, Caricato M, Valeri S, Coppola R, Tonini G

Bevacizumab is a humanized immunoglobulin G1 murine antibody directed against all isoforms of vascular endothelial growth factor (VEGF)-A.1 To our knowledge to date, it is the most clinically advanced monoclonal antibody (MoAb) target-ing the VEGF signaling pathway and the only 1 currently approved for use in the treatment of metastatic colorectal cancer (MCRC).

A randomized phase 2 trial (AVF0780) investi-gated the safety and efficacy of 2 dose levels of bevacizumab in combination with 5-fluorouracil (5FU)/leucovorin in patients with MCRC.2

The 2 treatment arms that included bevaci-zumab (at doses of 5 mg/kg or 10 mg/kg, re-spectively) resulted in higher risk ratios (40% and 24%, respectively) and a longer median time to disease progression (9 months and 7.2 months, respectively) and median overall surviv-al (OS) (21.5 months and 16.1 months, respec-tively) compared with the control arm comprised of 5-FU/leucovorin alone (5.2 months and 13.6 months, respectively).

However, because higher clinical efficacy was noted in the 5-mg/kg arm compared with the 10-mg/kg arm, the 5-mg/kg dose of bevacizumab was chosen for further clinical study. Although bevacizumab was generally well tolerated, this trial identified several important safety signals, including an increased incidence of thromboem-bolic complications, hypertension, proteinuria, bleeding complications in the form of epistaxis, headache, fever, and rash. In general, however, these adverse events were either clinically insig-nificant or were easily managed.

Some phase 3 trials have confirmed the pre-liminary efficacy data published by Kabbinavar et al.2

In a pivotal randomized phase 3 study, previ-ously untreated patients with advanced colorec-tal cancer (CRC) who received bevacizumab and weekly irinotecan plus bolus 5-fluorouracil/leu-covorin (IFL) regimen had longer progression-free survival (PFS) (10.6 months vs 6.2 months; P < .00001) and survived significantly longer (20.3 months vs 15.6 months; P .00003) than those receiving IFL chemotherapy alone plus place-bo.3 The only adverse event that occurred with greater frequency with the anti-VEGF regimen was grade 3 (graded according to the National Cancer Institute Common Toxicity Criteria [ver-sion 2.0]) hypertension, which was managed ef-fectively with oral medications.

In addition to being combined with either 5-FU/ leucovorin or the bolus weekly IFL sched-ule, bevacizumab has been studied with oxali-platin-based chemotherapy in the second-line setting. In the study published by Giantonio et al, patients with advanced CRC, who were pre-viously treated with 5-FUbased therapy and

irinotecan for advanced or recurrent disease after adjuvant chemotherapy, were randomized to 1 of 3 treatment arms, including FOLFOX-4, FOLFOX-4 and bevacizumab, and bevacizumab alone.4

The results of this trial demonstrated that the addition of bevacizumab to oxaliplatin, 5FU, and leucovorin improves the duration of survival for patients with previously treated MCRC that was refractory to irinotecan-based chemothera-py. In contrast to the randomized first-line trial, Chen et al failed to demonstrate any benefit in terms of response rate, finding that the associa-tion of bevacizumab and 5-FU/ leucovorin was associated with rare objective responses.5

The main purpose of the current study was to evaluate the efficacy and safety of the associa-tion of bevacizumab and 5-FU/folinic acid in an extremely pretreated but homogeneous popula-tion of CRC patients.

MATERIALS AND METHODS

Patients We considered patients eligible if they were

aged >18 years and had stage IV, histologically confirmed, colorectal adenocarcinoma (grad-ing determined according to the American Joint Committee on Cancer staging system).

Other criteria for eligibility were: an Eastern Collaborative Oncology Group (ECOG) perfor-mance staus of 9 g/dL, neutrophil count of >1500/mm3, and platelet count of >100,000/mm3), renal function (serum creati-nine

134

International articlesFOLFOX IV consisted of leucovorin (200 mg/

m2/ d) followed by a 5-FU bolus (400 mg/m2/d) and 22-hour infusion (600 mg/m2/d) for 2 con-secutive days every 2 weeks with oxaliplatin at a dose of 85 mg/m2 as a 2-hour infusion on Day 1.7

FOLFIRI consisted of irinotecan at a dose of 180 mg/m2 as a 90-minute infusion on Day 1 and leucovorin at a dose of 400 mg/m2 as a 2-hour infusion during irinotecan therapy, immediately followed by a 5-FU bolus of 400 mg/m2 and 46-hour continuous infusion of 2.4 to 3 g/m2 every 2 weeks.8

Three-weekly irinotecan was comprised of iri-notecan at a dose of 350 mg/m2. Finally, after progression to and an oxaliplatin-based and iri-notecan-based chemotherapy, all patients were treated with cetuximab plus weekly irinotecan according to the following schedule: cetuximab was given at an initial dose of 400 mg/m2, fol-lowed by weekly infusions of 250 mg/m2, and irinotecan was administered weekly at the dose of 90 mg/m2.9

Disease progression was documented by com-puted tomography (CT) or magnetic resonance imaging (MRI). At least 1 unidimensionally mea-surable lesion was required. Epidermal growth factor receptor (EGFR) expression in the primary tumor or in at least 1 metastatic lesion was per-formed. All the patients signed a consent form.

Study Design and Treatment The current study was a single-center, phase

2 trial conducted from March 2004 to February 2006. Bevacizumab was given at the dose of 5 mg/kg. De Gramont chemotherapy was com-prised of folinic acid (200 mg/m2/d) followed by a 5-FU bolus (400 mg/m2/d) and 22-hour infu-sion (600 mg/m2/d) for 2 consecutive days every 2 weeks.

Dexamethasone was given at the dose of 16 mg before each course. A standard antiemetic drug was always given in the premedication and in the following days, at the physicians discre-tion.

All the patients were to be treated until disease progression or unacceptable toxic Bevacizumab de Gramont in CRC Patients/Vincenzi et al effects occurred. In the case of disease progression, further anticancer treat-ments were allowed.

Tumor response was evaluated every 8 weeks with the use of consistent imaging techniques (CT or MRI). Assessment was performed by the investigators, who used Response Evaluation Criteria in Solid Tumors (RECIST).10

Toxic effects were assessed according to the National Cancer Institute Common Toxicity Cri-teria (version 2.0).

Modifications of bevacizumab dose were not planned, and the drug was stopped if grade 3 to 4 adverse events possibly related to bevacizum-ab were recorded. Modifications in the doses of the de Gramont regimen were made in cases of hematologic or nonhematologic toxic effects.

The present trial was approved by the institu-tional review board of our institution, and written informed consent was obtained from all partici-pating patients.

Statistical Plan and Analysis This study used Simons Minimax 2-stage de-

sign11 to test the null hypothesis that the true overall response rate was 5% (which would not be clinically meaningful), as opposed to the alter-native hypothesis that the true overall response rate was 10%. Up to 33 patients were planned for each cohort to assess the overall response rate with 85% power and a .05. If 2 objective tumor responses were observed in the cohort, an ad-ditional 15 patients would be enrolled onto that cohort in stage 2.

The primary endpoint was the rate of con-firmed radiologic tumor response, as assessed by a local committee, in the intent-to-treat popu-lation. Secondary endpoints were the evaluation of time to disease progression, OS, safety pro-file, and the median time to response. All analy-ses were performed following an intenttotreat analysis method. The time to disease progres-sion was calculated as the period from the date of the initiation of treatment to the first observa-tion of disease progression or to death from any cause within 60 days after the initiation of treat-ment or the most recent tumor assessment. The OS time was calculated as the period from the date treatment was initiated until death from any cause or until the date of the last follow-up, at which point data were censored. Time to disease progression and OS were both determined by the Kaplan-Meier product-limit method.12

The difference in terms of time to disease pro-gression and OS according to anticancer treat-ment delays or termination was evaluated by the log-rank test.13

The cutoff point for survival data was July 2007; for safety data, it was July 2006. SPSS statistical software (version 14.00; SPSS, Chicago, Ill) was used for statistical analysis. A P value of

135September 2014

Vincenzi B, Santini D, Russo A, Spoto C, Venditti O, Gasparro S, Rizzo S, Beomonte B, Caricato M, Valeri S, Coppola R, Tonini G

were evaluated for the declared study efficacy endpoints and 48 for the safety analysis.

Efficacy Analysis For the intent-to-treat analysis, 46 patients

were evaluated for efficacy (2 patients were re-moved from the study early because the patients refused to continue anticancer therapy and were not evaluable for both time to disease progres-sion and OS). The best objective responses were achieved as follows: 0 (0%) complete responses, 3 (6.5%; 95% confidence interval [95% CI], 1.9-6.5%) partial responses, 14 (30.4%; 95% CI, 22.5-41.7%) cases of stable disease, and 30 (65.2%; 95% CI, 44.7-71.8%) instances of disease pro-gression. Therefore, the overall response rate was 6.5% (95% CI, 4.3-10.4%), and the disease control rate (partial response stable disease) was 36.9% (95% CI, 25.8-44.8%). The median time to disease progression was 3.5 months (95% CI, 2.3-6.9 months), and the median OS time was 7.7 months (95% CI, 3.9-11.9 months).

No patients received any further anticancer treatment after they withdrew from therapy for disease progression.

Comparing patients with an ECOG perfor-mance status of 2 (25% of the total study popu-lation) with the others revealed no differences in terms of response rate. However, a slight but significant difference in terms of time to disease progression (2.6 months vs 3.8 months; P .03) and OS (6.0 months vs 8.9 months; P .007) was noted.

Moreover, we compared patients defined as responders to at least 1 (firstline, secondline, or third line) anticancer treatment (39 patients) with nonresponders (7 patients), and did not identify any differences with regard to response rate, time to disease progression, or OS (data not shown).

Adverse Events All patients were evaluated for safety analy-

sis. Leukopenia and neutropenia were the most common hematologic toxicities, with an inci-dence of 54.1% and 64.5%, respectively. How-ever, grade 3 to 4 neutropenia was recorded only in 6 patients (12.5%), and it did not cause any dose reductions or treatment discontinua-tion. No patients required the administration of granulocytecolony-stimulating factor to recover after a neutropenic event. In 2 patients, neutro-penic fever required hospitalization and infusion of antibiotics.

The most common nonhematologic toxicities were diarrhea (grade 3-4 in 20.8% of patients), fatigue (grade 3-4 in 14.5% of patients), and oral mucositis (grade 3-4 in 12.5% of patients). Safety results are summarized in Table 2.

Overall, 21 patients experienced a delay or change in dosing (of 5-FU) as a result of adverse events during the study. In particular, treatment was delayed in 10 patients because of bevaci-zumab-related toxicities, and the 5-FU dose was reduced or treatment delayed in 11 patients be-cause of 5-FUrelated toxicities.

Because of nonhematologic toxicities, the 5-FU dose was reduced (25% dose reduction) in 9 patients (18.7%). Because of the persis-tence of diarrhea in 2 of the 9 patients, 5-FU was discontinued, and treatment was contin-ued with bevacizumab only. In only 2 patients, the 5-FU dose was reduced for neutropenic fever. Grade 3 to 4 hemorrhage was reported

ECOG indicates Eastern Cooperative Oncology Group; XELOX, capecitabine plus oxaliplatin; FOLFOX, leucovorin followed by a 5-fluorouracil bolus; FOLFIRI, leucovorin, 5-fluorouracil, and irinotecan.

Table 1. Baseline Characteristics of the Patients

Patient Characteristics No. of Patients

Total 48 (100%)

Men/women 23/25 (47.2%/52.08%)

Age, y

Median 68

Range 31-74

ECOG performance status

0 19 (39.5%)

1 17 (35.4%)

2 12 (25%)

Primary tumor site

Colon 33 (68.7%)

Rectum 15 (31.2%)

No. of metastatic sites

1 12 (25%)

2 23 (47.9%)

3 13 (27.08%)

First-line regimen

XELOX 26 (54.1%)

FOLFOX 22 (45.8%)

Second-line regimen

FOLFIRI 38 (79.1%)

Three-weekly irinotecan 10 (20.8%)

Third-line regimen

Cetuximab plus weekly irinotecan 48 (100%)

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International articles

in 8 patients (16.6%), with 4 events (8.3%) oc-curring in the gastrointestinal tract. The rate of venous thrombosis was 18.7%, with 3 (6.2%) cases of pulmonary thromboembolism report-ed; in all 3 cases, hospitalization was required with- Bevacizumab de Gramont in CRC Pa-tients/Vincenzi et al out a fatal event. Data regarding adverse events possibly related to bevacizumab are summarized in Table 3.

Bowel perforation was rare (2 patients). In 1 pa-tient, bowel perforation was diagnosed by a leak of oral contrast into the pelvis after a standard CT scan performed to restage disease after 2 months of treatment, but the perforation appeared to be contained and treated with intravenous antibiotics. In 3 cases, grade 3 to 4 fistulas were identified, with 1 fatal outcome after a surgical procedure needed to evacuate a local abdominal abscess (because of the urgency of the intervention, the interval be-tween the last bevacizumab administration and surgery was inadequate: only 2 weeks). In the other 2 cases, surgery for the drainage of a pelvic abscess was required, with complete resolution of the clinical presentation after 35 days and 45 days, respectively.

Other than the previously mentioned 2 patients who decided to withdraw from therapy, only 4 patients were excluded from the study because of toxicity (the 2 patients who developed bowel

perforations and 2 patients who developed fistu-las). Comparing patients with an ECOG perfor-mance status of2 (25% of our total population) with the remaining patient population revealed no significant differences with regard to the inci-dence of adverse events.

Influence of Dose Reduction/ Delay of Treatment on Anticancer Efficacy

As stated earlier, a reduction of dose or a de-lay was required in 21 patients during treatment. We analyzed the efficacy of treatment in this sub-group, comparing it with the efficacy in the group of patients who better tolerated treatment. The response rate in the group with a treatment de-lay or change in dosing was lower than in the group without (19.04% vs 50%, respectively). This difference was statistically significant, with a P value of .046. Furthermore, a statistically sig-nificant difference also was recorded in terms of time to disease progression, with a median time to disease progression in the group of patients who required a treatment delay or change in dosing of 2 months versus 4 months in the group that did not (P .03) (Table 4).

DISCUSSION The efficacy of oncology drug regimens tradi-

tionally has been assessed by their potency to

Table 2. Adverse Events Related to Treatment Recorded in 48 Patients* Side Effects No. of Patients With Toxicity

* Toxicity was according to the National Cancer Institute Common Toxicity Criteria (version 2.0).

Table 3. Adverse Events Possibly Related to Bevacizumab Recorded in 48 Patients* Side Effects No. of Patients With Toxicity

All Grades Grade 3-4

Hematologic

Anemia 12 (25%) 5 (10.4%)

Leukopenia 26 (54.1%) 2 (4.1%)

Neutropenic 31 (64.5%) 6 (12.5%)

Thrombocytopenia 13 (27.08%) 3 (6.2%)

Nonhematologic

Diarrhea 29 (60.4%) 10 (20.8%)

Fatigue 28 (58.3%) 7 (14.5%)

Oral mucositis 18 (37.5%) 6 (12.5%)

Nausea/vomiting 6 (12.5%) 0 (0%)

Liver toxicity 8 (16.6%) 2 (4.1%)

Hypersensitivity reaction 1 (2.08%) 0 (0%)

All Grades Grade 3-4

Hemorrhage

Gastrointestinal 8 (16.6%) 4 (8.3%)

Nose 13 (27%) 3 (6.2%)

Other 4 (8.3%) 1 (2%)

Cardiovascular events

Hypertension 24 (50%) 6 (12.5%)

Thrombosis/embolism 9 (18.7%) 3 (6.2%)

Arterial events

Cardiac ischemia 0 (0%) 0 (0%)

Cerebral vascular events 1 (2%) 1 (2%)

Other adverse events

Gastrointestinal perforation 2 (4.1%) 2 (4.1%)

Gastrointestinal fistula 5 (10.4%) 3 (6.2%)

* Toxicity was according to the National Cancer Institute Common Toxicity Criteria (version 2.0).

Bevacizumab in Association With de Gramont 5-Fluorouracil/Folinic Acid in Patients With Oxaliplatin-, Irinotecan-, and Cetuximab-Refractory Colorectal Cancer

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shrink existing tumors and, ideally, to prolong PFS and OS. Tumor response can be easily evaluated in small trials, and data from small trials may pro-vide early evidence that an investigational agent warrants further testing. In clinical practice, the observation of a tumor response reassures the patient and the oncologist that the selected ther-apy is active in the malignant disease. The com-mon use of tumor response criteria as a measure of efficacy in CRC has persisted despite multiple analyses demonstrating a weak correlation be-tween tumor response and OS.14

This concept is supported even more by the in-troduction into oncology of novel drugs without intrinsic direct cytotoxic activity, such as antian-giogenic agents, suggesting that tumor response could be re-evaluated as a key marker of efficacy in patients with CRC.15

This theory is supported by the recent article by Grothey et al,15 in which the authors evaluated the survival benefit, both in terms of PFS and OS, associated with tumor response in 2 clinical trials, 1 containing bevacizumab in the experimental arm3 and 1 that did not.16

By this analysis, the authors clearly demonstra ted that even patients with advanced CRC who did not achieve a response according to traditional criteria significantly benefited from being treated with the superior regimen and had the same magnitude of benefit as responders, regardless of whether this regimen was chemotherapy alone or included the antiangiogenic agent bevacizumab.

All these data support the hypothesis that dis-ease control may be translated into survival bene-fit, even if patients in an experimental arm do not demonstrate an increase in response rate.

The data presented in the current trial indi-cate that treating heavily resistant CRC patients

may be possible without severe toxicities, even if some secondary effects possibly related to beva-cizumab have been recorded. This result is very interesting in particular because, to the best of our knowledge, the current study is the first to be performed in a population of patients treated with irinotecan-based, oxaliplatin-based, and ce-tuximab-based anticancer agents. Moreover, the identification of a disease control rate of 36.9% appears to suggest some anticancer activity in this very heavily pretreated population. However, we must note that, to the best of our knowledge, no data from randomized clinical trials are actual-ly available regarding the potential role of bevaci-zumab-based anticancer therapy in such a popu-lation and, most likely even more important, there are no data regarding quality of life in patients receiving this treatment versus patients who do not. The key finding in this trial is that introducing a bevacizumab-based therapy in a very late phase of therapy in CRC patients may yet play a role in contributing to tumor control.

Moreover, the use of bevacizumab plus the de Gramont schedule as fourth-line therapy (as first bevacizumab use) could be reserved for patients for whom anti-angiogenic therapy has previously been contraindicated for different reasons (such as instable blood hypertension, a recent episode of arterial thromboembolism, recent episode of bleeding, or recent bowel perforation).Once these contraindications have been resolved or stabilized, these patients may yet benefit from bevacizumab-based therapy. Moreover, there is a substantial difference reported by Chen et al5; in the current study, all patients had been previ-ously treated with an additional third-line therapy (cetuximab-based therapy). This is a clear dem-onstration that bevacizumab-based therapy can

Table 4. Influence of Treatment Delay or Change in Dosing on Disease Control*

Disease Control PR1SD/Total (%) P

No treatment delay or change in dosing 13/25 (52%) .046

Treatment delay or change in dosing 4/21 (19.04%)

TTP, median mo (95% CI)

No treatment delay or change in dosing 4.00 (3.6-6.7) .03

Treatment delay or change in dosing 2.00 (1.3-3.4)

OS, median mo (95% CI)

No treatment delay or change in dosing 9.0 (8.3-10.5) .07

Treatment delay or change in dosing 4.5 (4.0-9.1)

PR indicates partial response; SD, stable disease; TTP, time to disease progression; 95% CI, 95% confidence interval; OS, overall survival. * Efficacy evaluated in 46 patients.

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International articlesproduce an interesting rate of disease control, time to disease progression, and OS when admi-nistered to patients refractory to anti-EGFR MoAb therapy.

Preclinical studies have demonstrated that a murine MoAb against VEGF can inhibit the growth of human tumor xenografts when given alone or with chemotherapy.17,18 A humanized variant of this antibody (bevacizumab) has clinical acti vity in human cancer and increases survival when added to standard chemotherapy in patients with MCRC.3

Mice who received active antibody demonstra-ted a 90% reduction in tumor volume at the highest dose. These findings correspond well with the paradigm that tumors require neovascu-larization for growth.19

A consequence of this biologic action of VEGF in vivo could be that the blockage of VEGF-de-pendent angiogenesis leads to prolonged dis-ease control in cancers of different histologies. On this basis, we found the rationale to propose to our heavily treated patients a palliative

Bevacizumab b de Gramont in CRC Patients/Vincenzi et al therapy containing bevacizumab. Clearly, we understand that such treatment may be related to a significant increase in cost in this patient population. Therefore, a detailed cost analysis of bevacizumab-based anticancer treat-ment in heavily pretreated CRC patients could be very useful for understanding the economic im-pact of this treatment. Moreover, the safety pro-file also needs to be considered. The incidence of grade 3 to 4 hypertension in the phase 3 study of

patients receiving bevacizumab plus chemother-apy as first-line anticancer therapy for advanced CRC by Hurwitz et al was 11%.3 Consequently, the incidence of this side effect overlapped the incidence reported in previous first-line clinical trials. The incidence of grade 3 to 4 hemorrhage was noted in 16% of patients in the current study versus 5% for the study by Chen et al5; this dis-crepancy could be, at least partially, ascribed to the finding that patients in the current study were more heavily pretreated.

One of the main concerns in this trial is repre-sented by the percentage of patients who went on to receive fourth-line chemotherapy. According the results of the Medical Research Council FO-CUS trial, approximately 24% to 27% of patients with metastatic CRC receive third or further lines of chemotherapy.20 Considering the relatively re-cent introduction of biologic agents in the treat-ment of this patient population, this percentage is destined to increase in the coming years.

In conclusion, to our knowledge, the current study is the first to demonstrate some anticancer activity of bevacizumab de Gramont schedule in patients who had received all other anticancer drugs available for the treatment of MCRC, with an acceptable safety profile.

Bevacizumab in Association With de Gramont 5-Fluorouracil/Folinic Acid in Patients With Oxaliplatin-, Irinotecan-, and Cetuximab-Refractory Colorectal Cancer

References

1. Presta LG, Chen H, OConnor SJ, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997;5:4593-4599. 2. Kabbinavar FF, Schulz J, McCleod M, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005;23:3697-3705. 3. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:23352342. 4. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25:15391544. 5. Chen HX, Mooney M, Boron M, et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center trial TRC-0301. J Clin Oncol. 2006;24:3354-3360. 6. Santini D, Vincenzi B, La Cesa A, et al. Continuous infusion of oxaliplatin plus chronomodulated capecitabine in 5fluorouracil-and irinotecan-resistant advanced colorectal cancer patients. Oncology. 2005;69:27-34. 7. Andre T, Bensmaine MA, Louvet C, et al. Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen. J Clin Oncol. 1999;17:3560-3568. 8. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000;343:905-914. 9. Vincenzi B, Santini D, Rabitti C, et al. Cetuximab and irinotecan as third-line therapy in advanced colorectal cancer patients: a single centre phase II trial. Br J Cancer. 2006;94:792-797. 10. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and

Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205-216. 11. Simon R. Optimal 2-stage designs for phase II clinical trials. Control Clin Trials. 1989;10:1-10. 12. Kaplan E, Meier P. Non parametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481. 13. Peto R, Pike MC,ArmitageP,etal. Design andanalysisof randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer. 1977;35:1-39. 14. Buyse M, Thirion P, Carlson RW, Burzykowski T, Molenberghs G, Piedbois P. Re: A model to select chemotherapy regimens for phase III trials for extensive-stage small-cell lung cancer. J Natl Cancer Inst. 2001;93:399-401. 15. Grothey A, Hedrick EE, Mass RD, et al. Response-independent survival benefit in metastatic colorectal cancer: a comparative analysis of N9741 and AVF2107. J Clin Oncol. 2008;26:183-189. 16. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22:23-30. 17. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669-676. 18. Dickson PV, Hamner JB, Sims TL, et al. Bevacizumabinduced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin Cancer Res. 2007;13:3942-3950. 19. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182-1186. 20. Seymour MT, Maughan TS, Ledermann JA, et al. Colorectal Clinical Studies Group. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007;370:143-152.

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Conflict of Interests: None.

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International articles Intratumoral Steroidogenesis in Castration-Resistant Prostate Cancer: A Target for Therapy

INTRATUMORAL STEROIDOGENESIS IN CASTRATION-RESISTANT PROSTATE CANCER: A TARGET FOR THERAPY

Inna Armandari1, Agus Rizal Hamid1,2, Gerald Verhaegh1,3, Jack Schalken1,3

Corresponding author: Jack Schalken

Department of Urology, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands E-mail: Jack.Schalken@radboudumc.nl / Tel: +31-24-3614146 / Fax: +31-24-3541222

INTRODUCTION

Prostate cancer (PCa) is rated to be the second most prevalent malignancy in males worldwide. According to GLOBOCAN, in 2008 there were about 903,500 new cases of PCa and 258,400 deaths of PCa worldwide (1). he dependence of PCa on androgens, such as testosterone (T) and

dihydrotestosterone (DHT), during early carcino-genesis and progression to metastatic disease has been broadly reported, and therefore androgen deprivation therapy (ADT) is given to reduce T and DHT levels (2). During ADT, a reduction of serum T levels up to 90% is achieved after 2 to 4 weeks of treatment. However, most of the patients will de-velop a recurrence under low androgen levels,

Open Access Article

Keywords:

Castration-resistant prostatic neoplasms, Enzyme inhibitors, Steroidogenesis, Molecular targeted therapy

AbstractDevelopment of castration-resistant prostate cancer (CRPC) in a low androgen environment, arising from androgen deprivation therapy (ADT), is a major problem in patients with advanced prostate cancer (PCa). Several mechanisms have been hypothesized to explain the progression of PCa to CRPC during ADT, one of them is so called persistent intratumoral steroidogenesis. The existence of intratumoral steroidogenesis was hinted based on the residual levels of intraprostatic testosterone (T) and dihydrotestosterone (DHT) after ADT. Accumulating evidence has shown that the intraprostatic androgen levels after ADT are suicient to induce cancer progression. Several studies now have demonstrated that PCa cells are able to produce T and DHT from diferent androgen precursors, such as cholesterol and the adrenal androgen, dehydroepiandrosterone (DHEA). Furthermore, up-regulation of genes encoding key steroidogenic enzymes in PCa cells seems to be an indicator for active intratumoral steroidogenesis in CRPC cells. Currently, several drugs are being developed targeting those steroidogenic enzymes, some of which are now in clinical trials or are being used as standard care for CRPC patients. In the future, novel agents that target steroidogenesis may add to the arsenal of drugs for CRPC therapy.

1Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands 2Department of Urology, Ciptomangunkusumo Hospital, University of Indonesia Faculty of Medicine, Jakarta, Indonesia

3Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands

Cite this article: Armandari I, Hamid AR, Verhaegh G, Schalken J.Intratumoral steroidogenesis in castration-resistant prostate cancer: a target for therapy . Rom J Oncol Hematol. 2014; 2(3):140-149.

Received: 26 July 2014 Accepted after revision: 21 August 2014

Published in Prostate Int 2014;2(3):105-113 http://p-international.org/pISSN: 2287-8882 eISSN: 2287-903Xhttp://dx.doi. org/10.12954/ PI.14063Copyright 2014 Asian Pacific Prostate Society (APPS)

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that is called castration-resistant prostate cancer (CRPC) (3).

Several mechanisms have been suggested to cause the progression of PCa to CRPC under ADT conditions, including hypersensitivity of the androgen receptor (AR) signaling pathway to an-drogens, enrichment or accumulation of andro-gen-insensitive stem cells, and activation of in-tratumoral steroidogenesis (4). Among these, the intratumoral steroidogenesis pathway has recently gained much attention and support. Although se-rum T levels decrease during ADT, it was shown that the intraprostatic androgen levels in CRPC pa-tients was equal before and after ADT (5-8). Based on this fact, it was hypothesized, and later shown, that PCa cells are able to produce androgens it-self via steroidogenesis (9), either by producing T and DHT from weak adrenal androgens (e.g., de-hydroepiandrosterone (DHEA)) (10) or by de novo androgen synthesis starting from cholesterol (11). It was also shown that several enzymes responsible for androgen synthesis are up regulated in CRPC tissue (12-14). Due to the importance of intratumoral steroidogenesis to support the progression PCa to CRPC, new drugs are being developed that target the steroidogenic process, and hence may become new treatment options for CRPC. In this review, we will highlight the role of intratumoral steroidogenesis in CRPC and the status quo of de-veloping novel targeted therapies for CRPC.

Intratumoral Steroidogenesis in CRPC Tissue T and DHT are the main androgens for prostate

cell diferentiation and homeostasis (15). T is synthe-sized in Leydig cells, while DHT is mainly produced in prostate tissue. In primary and metastatic PCa, the dependence of prostate cells on androgens persists, and androgens now directly support tu-mor cell proliferation, and hence tumor growth (16). It was hypothesized that diminishing serum androgen levels should lead to inhibition of PCa cell growth, and thus ADT was recommended for advanced or metastatic PCa (17). Unfortunately, the lower serum androgen levels obtained during ADT were not accompanied by a reduction of intrapros-tatic androgen levels within the tumor. In many studies, serum and intraprostatic T and DHT levels prior and after ADT have been measured (Table 1) (5-8,18,19).

Serum T levels are reduced signiicantly from 410465 ng/dL to 11.513.4 ng/dL after ADT (7). In contrast, intraprostatic T levels after ADT (0.741.44 ng/g tissue) (6,8) were equal to that prior to ADT (0.071.3 ng/g tissue) (18,19). A decline in both serum and prostatic DHT levels were reported after ADT (7). Prior to ADT, serum DHT levels ranged from 43.555.68 ng/dL, and after ADT, the serum DHT levels were dropped to 3.483.98 ng/dL (7). Prior to ADT, intraprostatic DHT levels ranged from 4.66.4

ng/g tissue (7), and after ADT, prostatic DHT levels were reduced approximately 75% (1.01.9 ng/g tissue) (7). Still, in vitro and in vivo data indicate that these low intraprostatic DHT levels are sufficient to stimulate expression of androgen-regulated genes, and to support AR-mediated tumor-cell growth and survival (20). In conclusion, current ADT strategies are not suicient to reduce intraprostatic T and DHT to levels that can no longer activate AR signaling in prostate cancer cells (21).

Although serum T and DHT levels are suppressed after ADT, serum levels of adrenal androgen pre-cursors, such as DHEA (Table 1), remain constant after ADT (60211 ng/dL vs. 90203 ng/dL before ADT) and was found to be the most abundant ad-renal androgen in PCa tissue (5,22,23). Measurement of intraprostatic DHEA levels are ~35 ng/g tissue in untreated PCa patients, while in ADT treated pa-tients, intraprostatic DHEA levels are even slightly increased to ~48 ng/g tissue (24). In the later study, androstenedione (AD) and androstenediol levels in PCa tissue after ADT were also shown to be simi-lar to those in untreated PCa. AD and androstene-diol levels in untreated PCa versus after ADT are ~0.125 ng/g tissue versus ~0.06 ng/g tissue and ~2.5 ng/g tissue versus ~3.5 ng/g tissue, respec-tively (24). In summary, after ADT, the total androgen pool in the circulation is reduced by only 59% (25). he remaining 41% of androgens, including DHEA, are still available in the prostate for the synthesis of T and DHT, which can stimulate prostate cancer after castration.

THE MECHANISM OF INTRATUMORAL STEROIDOGENESIS IN CRPC

Many studies have unraveled that intratumoral steroidogenesis could be initiated from weak ad-renal androgens, such as DHEA or even by de novo androgen synthesis starting from cholesterol (10,11). hese androgen precursors are then convert-ed to androgens, T and DHT. In the next part, we will discuss the possible mechanism of CRPC cells to synthesize androgens.

Cholesterol is the natural precursor for andro-gen synthesis. It was reported that cholesterol levels could influence PCa progression. Xenograft tumors (derived from the LNCaP PCa cell line) in mice on a hypercholesterolemic diet were big-ger and contained higher intratumoral T levels, compared to xenograft tumors in mice on a low fat/no cholesterol diet (11). he enzymes required for de novo steroidogenesis from cholesterol, such as cytochrome P (CYP) 11A, CYP17A, and 3b-hydroxysteroid dehydrogenase (3bHSD) 1 were detected in LNCaP tumors in these mice fed on a hypercholesterol diet. A high expression of CYP17A, the key enzyme for de novo androgen synthesis, in tumor tissue was also correlated sig-niicantly with cholesterol levels (11). In a study using

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International articles Intratumoral Steroidogenesis in Castration-Resistant Prostate Cancer: A Target for Therapy

patient tissue samples, metastatic CRPC exhibited signiicant increases in the expression levels of the FASN, CYP17A1, 3bHSD1, and 3bHSD2 genes when compared to primary PCa (8). Also, immuno-histochemical staining for the CYP11A1, CYP17A1, and 17b-hydroxysteroid dehydrogenase (17bHSD) 3 enzymes in lymph node metastasis showed a moderately higher staining intensity compared to primary PCa samples, indicating that all these en-zymes are up-regulated in metastatic CRPC tissue (26). he results above support the existence of intra-tumoral de novo steroidogenesis from cholesterol.

Subsequently, de novo synthesized androgen precursors need to be converted into active andro-gens. In PCa, the mechanism or pathway, by which androgen precursors are converted into T and DHT is under extensive investigation. Many stud-ies have shown that in CRPC cells the androgens, T and DHT, can be synthesized via the classical and/or the backdoor pathways (27). Figure 1 illustrates the mechanism of intratumoral steroidogenesis in CRPC tissue and the steroidogenic enzymes that are involved in each particular pathway.

In the classical pathway, DHT, as a final androgen product, is produced by reduction of T, a reaction catalyzed by the 5-reductase (SRD5A) enzyme (Figure 1; blue arrow). he classical pathway plays an essential role in intratumoral steroidogenesis and can be initiated from DHEA. In one of our stud-ies (10), we have shown that DuCaP cells, a CRPC cell line model, are able to use DHEA as an andro-gen precursor. DuCaP cells were able to prolifer-ate in DHEA-supplemented medium, an environ-ment that resembles ADT. Furthermore, T and DHT were detected in the medium soon after DHEA addition. hese results suggested that these CRPC cells were able to convert DHEA into T and DHT, at levels suicient to support cell growth.

Several studies reported the up-regulation of key steroidogenic enzymes involved in DHT synthesis via the classical pathway in prostate cancer tissue. In an in vivo study using LN-CaP xenograft, examination of tumor homogenate of castrated mice revealed an increased expres-sion of SRD5A1, an enzyme involved in the con-version of T into DHT (28). In clinical CRPC sam-ples, expression of aldo-keto reductase family 1 (AKR1) C3 and 17bHSD3 was increased, but SRD5A2 expression was decreased (13). Similar results were found in metastatic CRPC samples that displayed up-regulation of AKR1C3 tran-

script levels, and down-regulation of SRD5A2 expression (8). In line with these indings in tissue samples, higher transcript expression levels of AKR1C3, SRD5A1, and SRD5A3 were found in circulating tumor cells (CTC) derived from pri-mary PCa. In CTC derived from CRPC patients, up-regulation of AKR1C3 and SRD5A1 transcript was detected. However, in both CTC samples, SRD5A2 transcript levels were decreased (12). Since the SRD5A isoforms all possess similar SR-D5A activity, elevated SRD5A1 and/or SRD5A3 transcript levels suggest that PCa and CRPC cells actively convert T into DHT (12).

Beside the classical pathway, the backdoor path-way provides an alternative production of DHT that bypasses the need of T as an intermediate (Figure 1; red arrow). he backdoor pathway is primarily ac-tive during organogenesis in the fetus to produce suicient amounts of DHT for male sex develop-ment, whereas it is less active in the adult male (29). Active intratumoral steroidogenesis via the back-door pathway was demonstrated by the high con-version rate of androstenedione (AD) into DHT in CRPC cell lines and tissues from CRPC patients (30). By treating CRPC cell lines with (

3

H)-AD and (3

H)-T, followed by HPLC analysis, the conversion path-way, either AD androstanedione (5-dione) DHT or AD T DHT, could be measured. he outcome of these studies showed that AD is more rapidly and uniformly converted into DHT via the backdoor pathway (i.e., via 5-dione) than via the classical pathway (i.e., via T). Similarly, fresh CRPC metastases exhibited robust conversion of AD 5-dione DHT (30). In the same study, the es-sential role of SRD5A1 in the backdoor pathway synthesis of DHT was shown by knockdown of the SRD5A1 gene in LNCaP and LAPC4 cells. Accumu-lation of AD after SRD5A1 knockdown suggested that the conversion of AD into DHT was blocked (30). In an in vivo study, high DHT levels up to 28 folds compared to control levels, were detected in tumors of CWR22R-bearing athymic mice af-ter androstanediol dipropionate injection at the tumor site (31). High conversion of androstanediol into DHT was correlated with increased mRNA and protein levels of 17bHSD6, an enzyme required for DHT synthesis. hese studies suggest that the back-door pathway is remarkably active in PCa, and may be responsible for PCa progression to CRPC (31).

In summary, multiple studies have shown that in-tratumoral steroidogenesis in CRPC cells is active.

Table 1. Levels of T and DHT in serum and prostate tissue

Conditions)eussit g/gn( eussit etatsorP)Ld/gn( mureS

T DHT DHEA T DHT DHEA

Before ADT 410465 43.555.68 90203 0.071.34 4.66.4 ~35After ADT 11.513.4 3.483.98 60211 0.741.44 1.01.9 ~48

T, testosterone; DHT, dihydrotestosterone; DHEA, dehidroepiandroseterone; ADT, androgen deprivation therapy.

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International articles Intratumoral Steroidogenesis in Castration-Resistant Prostate Cancer: A Target for Therapy

Figure 1. The illustration of intratumoral steroidogenesis pathway in castration-resistant prostate cancer tissue. T and DHT can be produced from cholesterol or DHEA via either the classical pathway, indicated by blue arrows or using the backdoor pathway, indicated by red arrows. The conversion of cholesterol into intermediate products is indicated by black arrows. Steroidogenic enzymes involved in each conversion are indicated in blue capital letters. T, testosterone; DHT, dihydrotestosterone; DHEA, dehidroepiandroseterone

Both cholesterol and adrenal androgens, such as DHEA, are potential sources for the intratumoral synthesis of DHT. Albeit the possibility of using multiple routes for androgen synthesis, the con-version of DHEA via the backdoor pathway seems to be the major route to produce DHT. Regardless the pathway used for DHT synthesis, the same set of genes/enzymes are needed for the conversion of androgen precursors into DHT, and all of these genes, AKR1C3, 17bHSD3, and SRD5A1/3, were found up-regulated in PCa cells.

THERAPEUTIC IMPLICATION AND TARGETED THERAPY

The up-regulation of steroidogenic enzymes as shown in previous section is essential to main-tain persistent intratumoral steroidogenesis and

become attractive targets for therapy. Numerous compounds have been and are being developed to inhibit steroidogenic enzyme activity, yet only few of them accepted by the U.S. Food and Drug Administration (FDA) for clinical application. One of the approved steroidogenic enzyme inhibitors for the treatment of CRPC is the CYP17A inhibitor, abiraterone, while some other inhibitors are still under intensive development, such as inhibitors of AKR1C3, 17bHSD3, and SRD5A. he current status of development of these inhibitors is discussed below.

1. CYP17A inhibitors he CYP17A enzyme plays an important role in an-

drogen biosynthesis. It possesses 17-hydroxylase

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and C17,20-lyase activities, with the C17,20-lyase being the key enzyme that involves in DHEA biosynthe-sis by the adrenal glands and the testes as well as several conversions during intratumoral steroido-genesis. Because of the central role of CYP17A in androgen synthesis (Figure 1), it was hypothesized that speciic inhibition of CYP17A enzyme activity may lead to clinical antitumor responses (32).

Abiraterone is the only CYP17A inhibitor ap-proved by the FDA (April 2011) for the treat-ment of metastatic CRPC that previously received docetaxel-based chemotherapy (32). It is formulat-ed as the prodrug of abiraterone acetate, a non-steroid, highly selective, and irreversible CYP17A inhibitor (33). Strikingly, its nonspecific CYP17A inhibition leads to rise in mineralocorticoids (34). herefore, addition of prednisone or prednisolone as mineralocorticoid receptor antagonist during abiraterone therapy is needed to prevent miner-alocorticoid excess syndrome (i.e., hypertension, hypokalemia, and lower-limb edema) (35).

In preclinical studies, intraperitoneal adminis-tration of abiraterone acetate in a rodent model resulted in inhibition of CYP17A activity as shown by reduced weight of the ventral prostate (36). Ap-proval of abiraterone by the FDA was based on the outcome of a multinational phase III clinical trial that included 1,195 CRPC patients who previously received chemotherapy. In this study, oral admin-istration of 1,000 mg abiraterone with 5-mg pred-nisone prolonged the patient overall survival by an average of 14.8 months and increased the pros-tate-speciic antigen (PSA) response rate by 29% (37). Nowadays, oral abiraterone acetate (Zytiga, Janssen Biotech Inc., Horsham, PA, USA) is used in combination with prednisone or prednisolone in Europe and the United States for metastatic CRPC previously treated with docetaxel-containing che-motherapy (38).

Recently, a novel selective CYP17A inhibitor with more potent inhibition of C17,20-lyase over 17-hydroxylase activities was developed, namely TAK-700 (Orteronel, Takeda Ltd., Osaka, Japan) (39). It is a nonsteroidal, reversible 17,20-lyase inhibitor that is five-fold more selective to inhibit C17,20-lyase activity than 17-hydroxylase activity (40). By selectively inhibiting C17,20-lyase activity, the need of prednisone supplementation would be reduced because of less inluence on minera