Sorafenib after combination therapy with gemcitabine plus doxorubicine in patients with sarcomatoid renal cell Carcinoma: a prospective evaluation

Staehler M, Haseke N, Roosen A, Stadler T, Bader M, Siebels M, Karla, Stief, Stief Cg

Description

Sarcomatoid renal cell cancer (RCC) is a distinct histological variant of RCC that is associated with rapid progression and a poor prognosis. The optimal treatment for patients with sarcomatoid RCC remains to be defined. Gemcitabine plus doxorubicine (GD) has shown some efficacy, however durability of response is limited. We carried out a prospective, open-label study to investigate the efficacy and safety of sorafenib in patients after GD failure in sarcomatoid RCC. Methods Fifteen patients with pure sarcomatoid RCC and objective progressive disease were treated with GD (gemcitabine 1500 mg/m 2 , doxorubicine 50 mg/m 2 administered by weekly intravenous infusion) until progression of disease. Subsequently 9 patients were switched to sorafenib (400 mg twice daily). Tumor response was measured by physical examination and computerized tomography scans and evaluated according to Response Evaluation Criteria in Solid Tumors criteria. Results Median time to progression (TTP) under GD was 6.6 months (range 0.8 - 8 months). During GD treatment there were no remissions and 6 patients died from progressive disease. Median TTP for the 9 patients switched to sorafenib was 10.9 months (range 0.6 - 25.5 months). During sorafenib therapy one patient had a partial remission lasting for 3 months and 4 patients experienced stable disease with a duration of 3 to 9 months. Four patients immediately progressed on sorafenib treatment but had a slower dynamic of tumor progression than under GD. Dosing in both treatment phases was generally well tolerated with manageable toxicities and no requirement for dose reduction. Conclusions Chemotherapy with GD was ineffective in our patients with pure sarcomatoid RCC. Subsequent anti-angiogenic treatment using the multi-tyrosine kinase inhibitor sorafenib resulted in additional progression-free survival in 5 of 9 patients. Further evaluation of targeted anti-angiogenic agents for the treatment of sarcomatoid RCC is warranted.

Sujets

• Renal cell carcinoma
• Chemotherapy
• Sorafenib
• Survival
• Angiogénesis

Informations

• Publié par: biomed
• Publié le: 01 janvier 2010
• Nombre de lectures: 18
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

JULY 26, 2010

EUr J Med Res (2010) 14: 287-291

EuRoPEan JouRnal of MEDICal RESEaRCH

287 © I. HOLzàpFeL PUBLishers 2010

S oRafEnIb aftER C oMbInatIon t HERaPy wItH G EMCItabInE PluS D oxoRubICInE In P atIEntS wItH S aRCoMatoID R Enal C Ell C aRCInoMa : a P RoSPECtIvE E valuatIon

M. STàehLer, n. Hàseke, a. ROOseN, t. STàdLer, M. bàder, M. SieBeLs, a. KàrL, C. G. STieF

DepàrTmeNT OF urOLOgY, uNiVersiTY OF MUNich, KLiNikUm GrOsshàderN, MUNich, GermàNY

Abstract b aCKGRounD Backgr ound:SàrcOmàTOid reNàL ceLL càNcer (RCC) is à disTiNcT hisTOLOgicàL VàriàNT OFRCC ThàT is àssOciàTed SàrcOmàTOid reNàL ceLL càrciNOmà (RCC) is à disTiNcT WiTh ràpid prOgressiON àNd à pOOr prOgNOsis. the Op- RCC OBserVed iN àrOUNd 0.7%hisTOLOgicàL VàriàNT OF TimàL TreàTmeNT FOr pàTieNTs WiTh sàrcOmàTOid RCC re- reNàL pàreNchYmàL càrciNOmàs [1-4]. thisTO 13.2% OF màiNs TO Be deFiNed. GemciTàBiNe pLUs dOXOrUBiciNe FOrm OFThe diseàse is àssOciàTed WiTh ràpid prOgres- (GD) hàs shOWN sOme eFFicàcY, hOWeVer dUràBiLiTY OF siON àNd à VerY pOOr prOgNOsis àNd There is cUrreNTLY respONse is LimiTed. we càrried OUT à prOspecTiVe, pà-NO UNiFOrm cONseNsUs regàrdiNg The TreàTmeNT OF OpeN-LàBeL sTUdY TO iNVesTigàTe The eFFicàcY àNd sàFeTY TieNTs WiTh meTàsTàTic sàrcOmàTOid RCC [5]. becàUse OF sOràFeNiBiN pàTieNTs àFTer GD FàiLUre iN sàrcOmà- RCC àre cONsidered TOmOsT hisTOLOgicàL sUBTYpes OF TOid RCC. Be highLY resisTàNT TO cYTOTOXic chemOTheràpY [6-8], Methods:fiFTeeN pàTieNTs WiTh pUre sàrcOmàTOid RCC sYsTemic TheràpY OFRCC hàs, UNTiL receNTLY, BeeN Bàsed àNd OBjecTiVe prOgressiVe diseàse Were TreàTed WiTh màiNLY ON immUNOTheràpY WiTh iNTerFerON (Ifn) àNd 2 GD (gemciTàBiNe 1500mg/m, dOXOrUBiciNe 50 Or iNTerLekiN-2 (Il-2). HOWeVer, respONse ràTes àre cON- 2 mg/m àdmiNisTeredBY WeekLY iNTràVeNOUs iNFUsiON) sisTeNTLY LOW àNd OFLimiTed dUràBiLiTY [9]. wiTh sàrcO- UNTiL prOgressiON OFdiseàse. SUBseqUeNTLY 9 pàTieNTs màTOid RCC, The VerY FàsT àNd àggressiVe grOWTh OF Were sWiTched TO sOràFeNiB (400 mg TWice dàiLY). tU- The TUmOr prOVides mOre OFà ràTiONàLe FOr The Use OF mOr respONse Wàs meàsUred BY phYsicàL eXàmiNàTiON The dis-chemOTheràpY iN pàTieNTs WiTh This sUB-TYpe OF àNd cOmpUTerized TOmOgràphY scàNs àNd eVàLUàTed àc- sàrcOmà-eàse. SeVeràL àpprOàches TO The TreàTmeNT OF cOrdiNg TO RespONse EVàLUàTiON CriTerià iN SOLid tU- TOid RCC WiTh chemOTheràpeUTic àgeNTs hàVe BeeN iN- mOrs criTerià. VesTigàTed WiTh VàrYiNg degrees OFsUccess. Regimes Results:MediàN Time TO prOgressiON (ttP) UNder GD gemciTàBiNe, dOceTàXeLBàsed ON The cOmBiNàTiON OF Wàs 6.6 mONThs (ràNge 0.8 – 8 mONThs). DUriNg GD àNd càrBOpLàTiN hàVe shOWN sOme eFFecT iN iNdiVidUàL TreàTmeNT There Were NO remissiONs àNd 6 pàTieNTs died càse sTUdies àNd sUB-àNàLY-càses [10, 11]. a NUmBer OF FrOm prOgressiVe diseàse. MediàN ttP FOr The 9 pà- ses hàVe repOrTed cOmpLeTe respONses iN pàTieNTs TreàT- TieNTs sWiTched TO sOràFeNiB Wàs 10.9 mONThs (ràNge ed WiTh cOmBiNàTiONs iNcLUdiNg dOXOrUBiciN [12-14], 0.6 – 25.5 mONThs). DUriNg sOràFeNiB TheràpY ONe pà- àLThOUgh ONe Làrger sTUdY, iN 23 pàTieNTs, repOrTed The TieNT hàd à pàrTiàL remissiON LàsTiNg FOr 3 mONThs àNd 4 iFOsFàmide àNd dOXOrUBiciN TO Be iNeF-cOmBiNàTiON OF pàTieNTs eXperieNced sTàBLe diseàse WiTh à dUràTiON OF FecTiVe [15]. IN cONTràsT, nàNUs eT àL. cONFirmed The eF- 3 TO 9 mONThs. fOUr pàTieNTs immediàTeLY prOgressed FecTiVeNess OFdOXOrUBiciNe iN 18 pàTieNTs WiTh ràpidLY ON sOràFeNiB TreàTmeNT BUT hàd à sLOWer dYNàmic OF grOWiNg meTàsTàTic RCC Or sàrcOmàTOid RCC TreàTed TUmOr prOgressiON ThàN UNder GD. DOsiNg iN BOTh WiTh dOXOrUBiciNe àNd gemciTàBiNe [16]. wiTh This regi- TreàTmeNT phàses Wàs geNeràLLY WeLL TOLeràTed WiTh meN à cOmpLeTe respONse Wàs OBserVed iN TWO pàTieNTs, màNàgeàBLe TOXiciTies àNd NO reqUiremeNT FOr dOse re- à pàrTiàL respONse iN FiVe pàTieNTs, à miXed respONse iN dUcTiON. Three pàTieNTs àNd sTàBLe diseàse iN ONe pàTieNT. the Conclusions:ChemOTheràpY WiTh GD Wàs iNeFFecTiVe respONse Wàs 5 mONThs.mediàN dUràTiON OF iN OUr pàTieNTs WiTh pUre sàrcOmàTOid RCC. SUBse-the iNTrOdUcTiON OFmULTi-kiNàse iNhiBiTOrs TàrgeT- qUeNT àNTi-àNgiOgeNic TreàTmeNT UsiNg The mULTi-TYrO-iNg The vEGf-R àNd PDGf-R pàThWàY, sUch às sO- siNe kiNàse iNhiBiTOr sOràFeNiB resULTed iN àddiTiONàLràFeNiB àNd sUNiTiNiB, hàs TràNsFOrmed The TreàTmeNT prOgressiON-Free sUrViVàL iN 5 OF9 pàTieNTs. fUrTherOF meTàsTàTicOr àdVàNced RCC [17, 18]. IN pàTieNTs eVàLUàTiON OFTàrgeTed àNTi-àNgiOgeNic àgeNTs FOr ThepreViOUsLY TreàTed WiTh immUNOTheràpY sOràFeNiB dOU- TreàTmeNT OFsàrcOmàTOid RCC is WàrràNTed.BLed prOgressiON Free sUrViVàL FrOm 12 TO 24 Weeks WiTh à màNàgeàBLe TOXiciTY prOFiLe [17]. IT is NOT YeT Key words:kNOW WheTher These NeW iNhiBiTOrs WiLL shOW simiLàrreNàL ceLL càrciNOmà, sàrcOmàTOid, chemO- TheràpY, sOràFeNiB, mULTi-kiNàse iNhiBiTOr, sUrViVàL,àcTiViTY iN pàTieNTs WiTh sàrcOmàTOid RCC. uNFOrTU- àNgiOgeNesis NàTeLY,dàTà FrOm The phàse III cLiNicàL TriàLs OFTàrgeT-