British Journl of Cncer (2000) 83(5), 583 587 doi: 10.1054/ bjoc.2000.1340, vilble online t http://www.idelibrry.com on Cpecitbine in the tretment of metsttic renl cell crcinom K Oevermnn 1, J Buer 1, R Hoffmnn 1, A Frnzke 1, A Schrder 1, T Ptzelt 2, H Kirchner 1 nd J Atzpodien 1,2,3 1 Medizinische Hochshule Hnnover, Deprtment of Hemtology nd Oncology, Crl-Neuberg-Strsse 1, 30625 Hnnover, Germny 2 Europen Institute for Tumor Immunology nd Prevention (EUTIP), Gotenstr. 152, 53175 Bonn, Germny 3 Robert Jnker Cncer Center, Villenstr. 4, 53129 Bonn, Germny Summry To evlute the therpeutic effects nd systemic toxicities of cpecitbine-bsed home therpy regimen in ptients with metsttic renl cell crcinom, 30 ptients were enrolled in phse II clinicl tril. Tretment consisted of orl cpecitbine combined with subcutneous recombinnt humn interferon-α 2, recombinnt humn interleukin-2 nd orl 13-cis-retinoic cid. There were two (7%) complete responses (CRs) nd eight (27%) prtil remissions (PRs), for n overll objective response rte of 34% (95% CI 17 53%). Except one, ll responses re ongoing, with medin durtion of 9+ nd 8+ months for CRs nd PRs, respectively. Additionlly, 12 ptients (40%) reched stble disese. Eight ptients (27%) showed continued disese progression despite tretment. Therpy ws well tolerted nd ws given in the outptient setting. Cpecitbine-relted World Helth Orgniztion (WHO) grde 2 nd 3 toxicities were observed in five nd two ptients respectively, nd were limited to ftigue, nuse/vomiting, dirrhoe, stomtitis, dermtitis nd hnd-nd-foot syndrome. The substitution of cpecitbine for 5-FU in the pre-existing biochemotherpy regimen did not result in reduced therpeutic efficcy nd showed significnt nti-tumour ctivity in ptients with dvnced renl cell crcinom. Keywords: renl cell crcinom; cpecitbine; 13-cis-retinoic cid; lph-interferon Renl cell crcinom is known to be mostly chemotherpy-resistnt (Hrusshesky nd Murphy, 1977; Duensing et l, 1994; Ygod et l, 1995). While the prognosis of ptients with metsttic renl cell crcinom remins poor, objective nd durble remissions cn be reched in pproximtely one third of ptients using pllitive biochemotherpies, especilly employing combined cytokines nd 5-fluorourcil (Lopez et l, 1996; Ellerhorst et l, 1997). Cpecitbine is n orlly dministered fluoropyrimidine crbmte, ctivted by three-step converstion process to the cytotoxic gent 5-FU. After orl dministrtion, cpecitbine is first metbolized in the liver to 5 -DFCR. Second, 5 -DFCR is converted to 5 -DFUR by cytidine deminse, locted in high concentrtions in the liver nd tumour tissues (Tkebyshi et l, 1996; Miw et l, 1998). Finlly, converstion of 5 -DFUR to 5- FU occurs by thymidine phosphorylse, which is present t higher concentrtions in tumour thn in norml tissue, thus minimizing the exposure of helthy body tissues to 5-FU (Tkebyshi et l, 1996; Ishikw et l, 1998; 1998b). The efficcy nd fvourble sfety profiles of cpecitbine hve been demonstrted in ptients with common solid tumours such s colorectl nd brest cncer (Blum et l, 1999; Mcken et l, 1998; Schüller et l, 1997). So fr, no results hve been reported in dvnced renl crcinom. Here we report phse II clinicl tril of p.o. cpecitbine combined with s.c. interferon-α2, s.c. interleukin-2 nd p.o. 13- cis-retinoic cid. Systemic toxicity nd therpeutic response were evluted in 30 ptients with progressive metsttic renl cell crcinom. The results of this study re presented. Received 9 June 1999 Revised 10 My 2000 Accepted 17 My 2000 Correspondence to: J Atzpodien PATIENTS AND METHODS The study protocol ws pproved by the Clinicl Institutionl Ethicl Review Bord of the University of Hnnover. Between June 1998 nd December 1998 we entered 30 ptients in phse II clinicl tril, (Tble 1). All ptients presented with histologiclly confirmed metsttic renl cell crcinom in dvnced stte, ged 18 75 yers, expected survivl of more thn 3 months, Krnofsky sttus of 70%, nd signed informed consent. Ptients received the following cpecitbine-bsed outptient chemo-immunotherpy regimen. Interferon-α ws dministered subcutneously t 5 MIU m 2 on dy 1 of weeks 5 8. Interleukin-2 ws dministered subcutneously t 10 MIU m 2 on dys 3, 4 nd 5 of weeks 1 nd 4, nd t 5 MIU m 2 on dys 1, 3 nd 5 of weeks 2 nd 3. Cpecitbine ws dministered orlly on dys 1 5 of weeks 5 8 t 1000 mg m 2 twice dily. In ddition, orl 13-cisretinoic cid ws given t 34 mg m 2 dily during weeks 1 8. Concomitnt mediction ws given s needed to control dverse effects of immunotherpy. Ptients were treted on n outptient bsis. Tble 2 summrizes the therpy regimen used in this study. 8-week tretment cycles were repeted for up to three courses. Number of tretment cycles vried exclusively bsed on progressive disese of the ptients. Re-evlution of the ptients tumour sttus ws performed between tretment cycles. Response to therpy ws evluted ccording to World Helth Orgniztion (WHO) criteri: complete response = disppernce of ll signs of disese for minimum of 8 weeks; prtil response = 50% or more reduction in sum of products of the gretest perpendiculr dimeters of mesurble lesions, no increse in lesion size nd no new lesions; stble disese = less thn prtil response with no disese progression for t lest 8 weeks; progressive disese = 25% nd more increse in sum of the products in the 583
584 K Oevermnn et l Tble 1 Chrcteristics longest perpendiculr dimeters of mesurble lesions, or development of new lesions. Systemic toxicity ws evluted t weekly intervls using grding system dpted from the World Helth Orgniztion (WHO). Tretment efficcy ws ssessed on intent-to-tret bsis. RESULTS Ptients chrcteristics Ptients Entered 30 Sex mle 24 femle 6 Age (yers) medin 60 rnge 38 73 Tumour nephrectomy yes 29 no 1 Metstses lung 23 bone 14 lymph nodes 12 liver 9 pleur 4 renl 4 drenl glnd 3 locl relpse 1 other 5 Prognosis b good 5 poor 25 No. of tretment cycles 46 (rnge 1 3) Tumour thrombus, soft tissue, pericrdium, myelon (n = 2); b Good prognosis ws defined by the presence of lung metstses nd the bsence of bone metstses, ESR < 70 mm fter 1 h, serum lctic dehydrogense < 280 units l 1, neutrophilic grnulocytes < 6000 µl 1 nd hemoglobin > 100 gm l 1 poor prognosis ptients included ll others Medin follow-up nd survivl Medin follow-up of ll ptients is 8 months; except for three ptients, ll ptients re still live. Tretment response Out of 30 ptients, two (7%) chieved complete response, nd eight (27%) hd prtil remission (Tble 3). The overll response rte in this study ws 34% (95% CI 17 53%). Complete responses (CRs) occurred in lung (n = 1), liver (n = 1), pleur (n = 1) nd kidney (n = 1), while prtil remissions (PRs) were seen in lung (n = 4), liver (n = 3) (Figure 1), bone (n = 1), pleur (n = 1) nd locl relpse (n = 1). The medin response durtion for CRs nd PRs were 9+ nd 8+ months, respectively, with rnge from 4 10+ months (Tble 4). Except for one ptient who developed brin metstses, ll ptients re in sustined remission. In ddition, 12 ptients (40%) chieved stble disese upon chemoimmunotherpy (medin durtion of 8+ months). Eight ptients (27%) hd continued disese progression despite tretment. Toxicity In ll ptients, cpecitbine therpy ws completed without modifiction of dosge or chnge of time-intervl. 25 of 30 ptients reported cpecitbine-ssocited, mostly mild sideeffects (Tble 5). No grde 4 toxicity ws observed nd only two ptients reported grde 3 mlise, one of them with concomitnt grde 3 nuse/vomiting nd stomtitis. Grde 2 stomtitis, dermtitis, hnd-nd-foot syndrome, norexi, dirrhoe nd mlise were observed in four, two, two, two, one nd one ptients, respectively. Mild grde 1 gstrointestinl side-effects were reported in 16, nd mild norexi in nine ptients with moderte dermtitis, five showed erly stges of hnd-nd-foot syndrome in the upper extremity nd/or nil disorders. Few ptients (n = 9) developed grde 1 neurologicl symptoms including trnsient presthesisis, hedche nd dizziness; eight ptients reported mild mylgi. Grde 1 neutropeni ws seen in one ptient. No crdic toxicity ws noted; one ptient with history of severe ortic stenosis tolerted cpecitbine without tretment-ssocited crdic symptoms. In ll ptients tretmentrelted toxicities resolved fter cesstion of therpy. No toxic deth occurred. DISCUSSION The use of biologic therpies hs n estblished role in the tretment of metsttic renl cell crcinom (Quesd, 1988; Belldegrun et l, 1991; Atzpodien et l, 1995; Hofmockel et l, 1997). Potentilly better results cn be obtined using combintion therpies with cytokines nd 5-fluorourcil (Lopez et l, 1996; Hofmockel et l, 1997). Retinoids re known to control mny importnt biologicl processes, including differenttion, morphogenesis, growth nd tissue homeostsis (Wrrel, 1994). Clinicl nd pre-clinicl results provide evidence for n ntiprolifertive effect of 13-cis-retinoic cid in IFN-α-treted ptients with renl cell crcinom (Buer et l, 1995; Motzer et l, 1995). Furthermore, it seems to hve fvourble effect in the tretment of renl Tble 2 Home therpy regimen Therpeutic gent Dose Regimen Recombinnt interferon-α2 5 Million IU m 2 s.c. Once dily, dy 1, weeks 1 nd 4; dys 1,3,5, week 2 nd 3 10 Million IU m 2 s.c. Once dily, dys 1,3,5, weeks 5 8 Recombinnt interleukin-2 10 Million IU m 2 s.c. Twice dily, dys 3,4,5, weeks 1 nd 4 5 Million IU m 2 s.c. Once dily, dys 1,3,5, weeks 2 nd 3 Cpecitbine 1000 mg m 2 p.o. Twice dily, dys 1 5, weeks 5 8 13-cis-retinoic cid 35 mg m 2 p.o. Dily, dys 1 7, weeks 1 8 Ptients were entered between June 1998 nd December 1998. Ptients received cytokines nd chemotherpy t home. Tretment cycles were repeted every 2 months for n verge of 1.5 cycles (rnge 1 3) unless disese progression occurred British Journl of Cncer (2000) 83(5), 583 587
Cpecitbine in metsttic renl cell crcinom 585 Tble 3 Response to therpy Tumour site Response Complete Prtil Stble Progressive Totl remission remission disese disese Lung 1 6 10 6 23 Bone 1 3 7 3 14 Lymph nodes 2 4 6 12 Liver 4 2 3 9 Pleur 1 1 1 1 4 Kidney 1 1 2 4 Adrenl glnd 2 1 3 Locl relpse 1 1 Other 1 b 3 c 1 d 5 Ptients 2 8 12 8 30 Risk e Good/Poor 1/1 2/6 2/10 0/8 5/25 Ptients my hve hd more thn one tumour site; b Soft tissue; c tumor thrombus, pericrdium, myelon; d myelon; e Good Prognosis ws defined by the presence of lung metstses nd the bsence of bone metstses, ESR < 70 mm fter 1 h, serum lctic dehydrogense < 280 units l 1 neutrophilic grnulocytes < 6000 µl 1 nd hemoglobin > 100 gm l 1, poor prognosis ptients included ll others Tble 4 Remissions Age Sex Intervl between first Sites of metsttic Prognosis Mximl response Remission durtion Sttus (yers) dignosis nd ppernce disese upon cpecitbine, upon strt to cpecitbine, αinf, (months) from strt of metstses (months) αinf, IL2, 13-cis-RA of therpy IL2, 13-cis-RA of cpecitbine, αinf, IL2, 13-cis-RA 64 m 11 Lung Good CR 9+ live 71 f 14 Kidney, pleur, bone Poor CR 9+ live 41 f 0 Lung, lymph nodes, liver, bone Poor PR 4 b live 50 m 0 Lung Good PR 9+ live 57 m 10 Lung, liver, locl relpse Poor PR 8+ live 57 m 25 Bone, soft tissue Poor PR 10+ live 58 m 8 Liver, lymph nodes Poor PR 7+ live 58 m 19 Lung, liver, pleur Good PR 8+ live 64 m 23 Lung Poor PR 5+ live 69 m 12 Lung, bone Poor PR 8+ live Good prognosis ws defined by the presence of lung metstses nd the bsence of bone metstses, ESR < 70 mm fter 1 h, serum lctic dehydrogense < 280 units l 1 neutrophilic grnulocytes < 6000 µ l 1 nd hemoglobin > 100 gm l 1, poor prognosis ptients included ll others; b This ptient developed brin metstses cncer, when dded to immuno-chemotherpy regimens (Atzpodien et l, 1995b). Cpecitbine, s novel fluoropyrimidine crbmte which is converted to 5-fluorourcil by three enzymes locted in the liver nd in tumours, shows promising response rtes nd remission durtions while being very well tolerted in ptients with metsttic renl cell crcinom. Due to four-fold higher thymidine phosphorylse (5-DFUR to 5-FU) ctivity in tumour compred to djcent helthy tissue (Frings, 1998), cpecitbine llows for more specific nti-tumour therpy thn conventionl i.v. fluorourcil. In the present home-therpy tril, we treted 30 ptients with progressive metsttic renl cell crcinom with combintion of p.o. cpecitbine, s.c. IFN-α, s.c. IL-2 nd 13-cis-RA. The dose of cpecitbine ws dpted on n empiricl bsis from the recommend dose (Roche Lbortories Inc, 1998). The continued dministrtion over n extended tretment intervl of 4 weeks in combintion with s.c. IFN-α, s opposed to n dministrtion for 2 weeks followed by 1-week rest period, required both reduction in the dily dose of cpecitbine nd > 50% reduction in cumultive 8-week cpecitbine dosges. Cpecitbine shows promising objective response rtes in vrious solid tumours (Frings, 1998). We report first clinicl results of cpecitbine in the tretment of dvnced renl cncer. Tumour regressions occurred in 34% of ptients evluted, with 7% CRs, nd medin response durtion of 8+ months. These results were comprble to other 5-FU-bsed therpy regimens in renl cell crcinom (Sell et l, 1994; Joffe et l, 1996; Hofmockel et l, 1997; Tourni et l, 1998). In the ptients reported here, the rte of cpecitbine-relted toxicity ws low, nd side-effects were moderte overll. Predominnt side-effects included gstrointestinl toxicities with dirrhoe, nuse/vomiting, dyspepsi nd stomtitis, nd cutneous symptoms including dermtitis nd erly stges of hndnd-foot syndrome. A few ptients experienced mild mlise nd mild neurologicl/musculoskeletl side-effects. Cpecitbine-ssocited systemic toxicities were mostly limited to WHO grde 1, rrely grde 2. Only two ptients experienced WHO grde 3 effects. It should be noted tht in ddition to cpecitbine ll ptients were simultneously treted with s.c. IFN-α nd p.o. 13-cis-RA. This confirmed the excellent tolerbility reported in other mlignncies t vrious dosges nd tretment intervls of British Journl of Cncer (2000) 83(5), 583 587
586 K Oevermnn et l Tble 5 Systemic toxicity of cpecitbine A Side-effects b (WHO criteri) No. of ptients Grde 1 Grde 2 Grde 3 Grde 4 Gstrointestinl 16 4 1 Dirrhoe 6 1 Nuse 15 1 Vomiting 7 1 1 2 Stomtits 7 4 1 Abdominl pin 7 Constiption 6 Dyspepsi 9 Skin nd subcutneous 17 2 Hnd-nd-foot syndrome 5 2 Dermtitis 17 2 Nil disorder 4 Generl 14 1 2 Ftigue 14 1 2 Pyrexi 7 Neurologicl 9 Presthesi 1 Hedche 5 Dizziness 6 Insomni Metbolism 9 2 Anorexi 9 2 Dehydrtion 2 Eye 1 Eye irrittion 1 Muscoloskeletl 8 Mylgi 8 Crdic Oedem Blood 1 Neutropeni 1 Thrombocytopeni Anemi Lymphopeni Heptobiliry Hyperbilirubinemi B C Cpecitbine ssocited toxicities were evluted during weeks 5 8 of ech tretment cycle ccording to WHO criteri nd were observed in 25 of 30 ptients. Grde 2 toxicity ws seen in five ptients nd grde 3 toxicity occured in two ptients; b Ptients my hve hd severl side-effects. cpecitbine (Budmn et l, 1998; Mcken et l, 1998). Per orl dministrtion of cpecitbine, in contrst to most chemotherpeutic gents tht re pplied intrvenously, llows tretment in n outptient or home therpy setting. This dvntge will reduce expenses nd could enhnce qulity of life in the pllitive setting. Unless rndomized dt become vilble, the contribution of cpecitbine nd its potentil therpeutic fesibility cnnot be definitively ssessed. Therefore, we hve initited prospectively controlled rndomized clinicl tril to investigte the role of cpecitbine in ptients with dvnced renl cell crcinom. Figure 1 Liver CT scns of 58-yer-old ptient with history of dvnced renl cell crcinom, post-surgicl of tumour nephrectomy nd prtil liver resection who (A) subsequently developed extensive metsttic lesions in his liver. (B) Prtil remission of metsttic liver disese fter the first 8-week tretment cycle with p.o. cpecitbine, s.c. INF-α; s.c. IL-2 nd p.o. 13-cisRA. (C) Further tumour regression upon completion of the third consecutive tretment cycle. ACKNOWLEDGEMENT Jens Atzpodien nd Jn Buer re supported by the Deutsche Krebshilfe. REFERENCES Atzpodien J, Lopez HE, Kirchner H, Bodenstein H, Pfreundschuh M, Rebmnn U, Metzner B, Illiger HJ, Jkse G nd Niesel T (1995) Multiinstitutionl hometherpy tril of recombinnt humn interleukin-2 nd interferon lf-2 in progressive metsttic renl cell crcinom. J Clin Oncol 13: 497 501 Atzpodien J, Kirchner H, Duensing S, Lopez HE, Frnzke A, Buer J, Probst M, Anton P nd Poliwod H (1995b) Biochemotherpy of dvnced metsttic renl-cell crcinom: results of the combintion of interleukin-2, lphinterferon, 5-fluorourcil, vinblstine, nd 13-cis-retinoic cid. World J Urol 13: 174 177 Belldegrun A, Abi-Ad AS, Figlin RA nd dekernion JB (1991) Renl cell crcinom: bsic biology nd current pproches to therpy. Semin Oncol 18: 96 101 Blum JL, Jones SE, Buzdr AU, LoRusso PM, Kuter I, Vogel C, Osterwlder B, Burger HU, Brown CS nd Griffin T (1999) Multicenter phse II study of British Journl of Cncer (2000) 83(5), 583 587
Cpecitbine in metsttic renl cell crcinom 587 cpecitbine in pclitxel-refrctory metsttic brest cncer. J Clin Oncol 17: 485 493 Budmn DR, Meropol NJ, Reigner B, Creven PJ, Lichtmn SM, Berghorn E, Behr J, Gordon RJ, Osterwlder B nd Griffin T (1998) Preliminry studies of novel orl fluoropyrimidine crbmte: cpecitbine. J Clin Oncol 16: 1795 1802 Buer J, Probst M, Gnser A nd Atzpodien J (1995) Response to 13-cis-retinoic cid plus interferon lph2 in two ptients with therpy refrctory dvnced renl cell crcinom. J Clin Oncol 13: 2679 2680 Duensing S, Dllmnn I, Grosse J, Buer J, Lopez HE, Deckert M, Storkel S, Kirchner H, Poliwod H nd Atzpodien J (1994) Immunocytochemicl detection of P-glycoprotein: initil expression correltes with survivl in renl cell crcinom ptients. Oncology 51: 309 313 Ellerhorst JA, Sell A, Amto RJ, Tu SM, Millikn RE, Finn LD, Bnks M nd Logothetis CJ (1997) Phse II tril of 5-fluorourcil, interferon-lph nd continuous infusion interleukin-2 for ptients with metsttic renl cell crcinom. Cncer 80: 2128 2132 Frings S (1998) Cpecitbine novel orl tumor ctivted fluoropyrimidine. Onkologie 21: 451 458 Hofmockel G, Theiss M, Gruss A, Lnger W nd Frohmuller H (1997) Immunochemotherpy of metsttic renl cell crcinom with interleukin 2, interferon-lph nd 5-fluorourcil. Urologe A 36: 45 49 Hrusshesky WJ nd Murphy GP (1977) Currents sttus of the therpy of dvnced renl cell crcinom. J Surg Oncol 9: 277 288 Ishikw T, Fukse Y, Ymmoto T, Sekiguchi F nd Ishitsuk H (1998) Antitumor ctivities of novel fluoropyrimidine, N4-pentyloxycrbonyl-5 -deoxy-5- fluorocytidine (cpecitbine). Biol Phrm Bull 21: 713 717 Ishikw T, Sekiguchi F, Fukse Y, Swd N nd Ishitsuk H (1998b) Positive correltion between the efficcy of cpecitbine nd doxifluridine nd the rtio of thymidine phosphorylse to dihydropyrimidine dehydrogense ctivities in tumors in humn cncer xenogrfts. Cncer Res 58: 685 690 Joffe JK, Bnks RE, Forbes MA, Hllm S, Jenkins A, Ptel PM, Hll GD, Velikov G, Adms J, Crossley A, Johnson PW, Whicher JT, nd Selby PJ (1996) A phse II study of interferon-lph, interleukin-2 nd 5-fluorourcil in dvnced renl crcinom: clinicl dt nd lbortory evidence of protese ctivtion. Br J Urol 77: 638 649 Lopez HE, Kirchner H nd Atzpodien J (1996) Interleukin-2 bsed home therpy of metsttic renl cell crcinom: risks nd benefits in 215 consecutive single institution ptients. J Urol 155: 19 25 Mcken M, Plnting A, Twelves C, Schellens J, Allmn D, Osterwlder B, Reigner B, Griffin T, Kye S nd Verweij J (1998) Phse I nd phrmcologic study of intermittent twice-dily orl therpy with cpecitbine in ptients with dvnced nd/or metsttic cncer. J Clin Oncol 16: 2977 2985 Miw M, Ur M, Nishid M, Swd N, Ishikw T, Mori K, Shimm N, Umed I nd Ishitsuk H (1998) Design of novel orl fluoropyrimidine crbmte, cpecitbine, which genertes 5-fluorourcil selectively in tumours by enzymes concentrted in humn liver nd cncer tissue. Eur J Cncer 34: 1274 1281 Motzer RJ, Schwrtz L, Murry-Lw T, Murphy BA, Hoffmn AD, Albino AP, Vlmis V nd Nnus DM (1995) Interferon lph2 nd cis-retinoic cid in renl cell crcinom: Antitumor ctivity in phse II tril nd interctions in vitro. J Clin Oncol 13: 1950 1957 Quesd JR (1988) Biologic response modifiers in the therpy of metsttic renl cell crcinom. Semin Oncol 15: 396 407 Roche Lbortories Inc. (1998) Xelod (cpecitbine) prescribing informtion Roche Lbortories: USA Schüller J, Cssidy J nd Reigner B (1997) Tumor selective ctivtion of Cpecitbine in colorectl cncer ptients. Onkologie 20: 189 Sell A, Kilbourn RG, Gry I, Finn L, Zukiwski AA, Ellerhorst J, Amto RJ nd Logothetis CJ (1994) Phse I study of interleukin-2 combined with interferonlph nd 5-fluorourcil in ptients with metsttic renl cell cncer. Cncer Biother 9: 103 111 Tkebyshi Y, Akiym S, Akib S, Ymd K, Miyder K, Sumizw T, Ymd Y, Murt F nd Aikou T (1996) Clinicopthologic nd prognostic significnce of n ngiogenic fctor, thymidine phosphorylse, in humn colorectl crcinom [see comments]. J Ntl Cncer Inst 88: 1110 1117 Tourni JM, Pfister C, Berdh JF, Benhmmoud A, Slze P, Monnier A, Pule B, Guillet P, Chretien Y, Brewer Y, Di Plm M, Untereiner M, Mlurie E, Tdrist Z, Pvlovitch JM, Huteville D, Mejen A, Azgury M, Myeur D, Lucs V, Krkowski I, Lrregin-Fournier D, Abourchid H, Andrieu JM nd Chstng C Subcutneous Administrtion Propeukin Progrm Coopertive Group. (1998) Outptient tretment with subcutneous interleukin-2 nd interferon lf dministrtion in combintion with fluorourcil in ptients with metsttic renl cell crcinom: results of sequentil nonrndomized phse II study. J Clin Oncol 16: 2505 2513 Wrrel RP (1994) Applictions for retinoids in cncer therpy. Semin Hemtol 31(Suppl.): 1 13 Ygod A, Abi-Rched B nd Petrylk D (1995) Chemotherpy for dvnced renlcell crcinom: 1983 1993. Semin Oncol 22: 42 60 British Journl of Cncer (2000) 83(5), 583 587