Entertainment

Metastatic colorectal cancer in the elderly: An overview of the systemic treatment modalities (Review)

Description
ONCOLOGY LETTERS 2: 3-11, 2011 Metsttic colorectl cncer in the elderly: An overview of the systemic tretment modlities (Review) Rfł Stec 1, Lubomir Bodnr 1, Mrt Smoter 1, Michł Mączewski 2 nd Cezry Szczylik
Categories
Published
of 9
All materials on our website are shared by users. If you have any questions about copyright issues, please report us to resolve them. We are always happy to assist you.
Related Documents
Share
Transcript
ONCOLOGY LETTERS 2: 3-11, 2011 Metsttic colorectl cncer in the elderly: An overview of the systemic tretment modlities (Review) Rfł Stec 1, Lubomir Bodnr 1, Mrt Smoter 1, Michł Mączewski 2 nd Cezry Szczylik 1 1 Deprtment of Oncology, Militry Institute of Medicine; 2 Deprtment of Clinicl Physiology, Medicl Center of Postgrdute Eduction, Wrsw, Polnd Received July 22, 2010; Accepted October 26, 2010 DOI: /ol Abstrct. Colorectl cncer (CRC) is one of the most frequently occurring types of cncer. Worldwide, more thn 800,000 new cses of CRC re dignosed ech yer. The medin ges t CRC dignosis nd deth re 71 nd 75 yers, respectively. The mjority ot ptients (50-60%) with colorectl cncer re dignosed t stge IV disese. Ptients ged 65 or older re chrcterized by higher incidence of significnt co-morbidities, decresed regenertive cpcity of bone mrrow nd worse generl performnce. Anti-neoplstic therpies used for the tretment of colorectl cncer include irinotecn, oxlipltin, 5-fluorourcil, leucovorin, cpecitbine nd monoclonl ntibodies. Anlysis of the efficcy of the presented chemotherpeutic nd chemoimmunotherpeutic regimens in the tretment of metsttic CRC in ptients older thn 65 nd 70 yers compred to younger ptients, generlly demonstrted comprble efficcy, time to disese progression nd overll survivl. Age criterion should not be considered when ssessing the eligibility of ptients with metsttic CRC for tretment of the bove-mentioned chemotherpeutic nd chemoimmunotherpeutic regimens. Tretment should be individulized bsed on the potentil risks nd benefits nticipted for ech ptient. Contents 1. Introduction 2. Toxicity nd efficcy of chemotherpy in ptients older thn 65 yers 3. Chemotherpy 4. Trgeted therpies 5. Conclusions Correspondence to: Dr Rfł Stec, Deprtment of Oncology, Militry Institute of Medicine in Wrsw, 128 Szserów Street, Wrsw, Polnd E-mil: Key words: colorectl cncer, chemotherpy, trgeted therpies, efficcy, toxicity, elderly ptients 1. Introduction Colorectl cncer (CRC) is one of the most common types of cncer. Worldwide, over 800,000 new cses of CRC re dignosed ech yer (1). The incidence of CRC increses with ge in subjects more thn 40 yers of ge, while rpid increse in incidence is found in individuls older thn 50 yers of ge. The medin ges t CRC dignosis nd deth re 71 nd 75 yers, respectively (2). The mjority of ptients (50-60%) with colorectl cncer re dignosed t stge IV of the disese (3). Pllitive chemotherpy is the only therpeutic option currently vilble. It provides ptients with the opportunity of prolonged survivl nd n improvement in the qulity of life. Anti-neoplstic therpies used for the tretment of CRC include irinotecn, oxlipltin, 5-fluorourcil, leucovorin nd cpecitbine s well s monoclonl ntibodies, bevcizumb, pnitumumb nd cetuximb. Therpeutic decisions involving ptients bove 65 yers of ge (currently the lrgest group mong colorectl cncer ptients) re serious issue in oncology. This group is chrcterized by higher incidence of significnt co-morbidities (crdiovsculr disorders, metbolic disorders, decresed glomerulr filtrtion rte nd liver disorders), decresed regenertive cpcity of bone mrrow (higher incidence nd intensity of hemtologicl complictions of chemotherpy) s well s worse generl performnce. 2. Toxicity nd efficcy of chemotherpy in ptients older thn 65 yers In their study regrding the phrmcology of cytotoxic gents used in oncology, Lichtmn nd Villni (4) presented differences in the toxicity profile nd grde between younger nd older ptients. Antimetbolite 5-fluorourcil ws found to cuse stomtitis in ptients 70 yers of ge compred to younger subjects (19 nd 11%, respectively). The fluoropyrimidine derivtive cpecitbine, dministered orlly, is chrcterized by specific toxicity profile, mnifesting s hnd-foot syndrome for which the intensity nd incidence is ge-ssocited. The topoisomerse I inhibitor, irinotecn, used in elderly ptients is ssocited with higher incidence nd toxicity grde of dirrhe. 4 Stec et l: Colorectl cncer in the elderly Tble I. Toxicity of ILF nd LF regimens in ptients younger nd older thn 70 yers of ge. Ptients 70 yers of ge Ptients 70 yers of ge Toxicities of grde 3 (%) ilf lf ilf lf P-vlue Leucopeni Neutropeni Thrombocytopeni Nuse Dirrhe Vomiting Stomtitis Hnd-foot syndrome Heptotoxicity Infection without neutropeni Thrombosis Bsed on the results of Folprecht et l (5). ILF, irinotecn in combintion with leucovorin nd 5 flourourcil; LF, leucovorin nd 5-fluorourcil. Tble II. Efficcy of ILF nd LF regimens in ptients younger nd older thn 70 yers of ge. Ptients 70 yers of ge Ptients 70 yers of ge ILF LF ILF LF Medin time to disese progression (months) (n=776) (n=1308) (n=220) (n=376) P-vlue Medin overll survivl (months) (n=765) (n=1308) (n=219) (n=375) P-vlue Complete response rte (%) (n=745) (n=1218) (n=208) (n=346) P-vlue Bsed on the results of Folprecht et l (5). ILF, irinotecn in combintion with leucovorin nd 5 flourourcil; LF, leucovorin nd 5-fluorourcil. 3. Chemotherpy Irinotecn. Folprecht et l (5) evlutted 2691 ptients treted with irinotecn in combintion with leucovorin nd 5-fluorourcil (ILF regimen) compred to leucovorin nd 5-fluorourcil (LF regimen) s first-line therpy for metsttic colorectl cncer. Toxicity nd effectiveness were compred in the two groups of ptients: below nd bove 70 yers of ge. A totl of 599 (22.3%) ptients were 70 yers of ge, including 185 (6.9%) ptients 75 yers of ge nd 1% 80 yers. No differences in effectiveness were found for the ILF regimen between the ge groups 70 nd 70. The objective response rte ws 46.6 nd 50.5%, respectively; medin time to disese progression ws 8.2 nd 9.2 months, respectively, nd medin overll survivl ws 17.1 nd 17.6 months, respectively. Effectiveness of the LF regimen ws reduced, but no differences were found between the ge groups 70 nd 70 yers. The objective response rte ws 29 nd 30.3%, respectively; medin time to disese progression ws 6.3 nd 7.0 months, respectively, nd medin overll survivl ws 14.7 nd 14.2 months, respectively. The results re shown in Tble II. Addition of irinotecn to the chemotherpy resulted in significnt increse in the incidence of grde 4 toxicity (leucopeni, neutropeni, dirrhe, nuse nd vomiting) in the two ptient groups. However, no differences in toxicity were found between the ge groups 70 nd 70 yers prt from heptotoxicity which ws more common in the elderly ptients. Anlysis of the 70 yers of ge subgroup reveled higher incidence of grde 4 neutropeni vs. the 70 yers of ge subgroup (24.3 nd 16.1%, respectively) mong the ptients treted with the LF regimen. These results re shown in Tble I. ONCOLOGY LETTERS 2: 3-11, Tble III. Assessment of response to cpecitbine chemotherpy nd FOLFIRI regimen in ptients bove 65 yers of ge (n=123). Cpecitbine FOLFIRI (n=56) (n=67) n % n % χ 2 p-vlue Overll response b Complete response c c Prtil response Stble disese Progressive disese Not evluble Bsed on the results by Stec et l (10). b Complete plus prtil response. c Vlues clculted by the Chi-squre (χ 2 ) test with Ytes correction. FOLFIRI, 5-fluorourcil, leucovorin nd irinotecn. Bsed on this nlysis the uthors concluded tht both the toxicity profile nd benefits of ILF chemotherpy were similr irrespective of ptient ge, i.e., below or bove 70 yers. Cpecitbine monotherpy. Feliu et l (6) ssessed the efficcy nd tolerbility of cpecitbine in 51 ptients 70 yers of ge s first-line therpy for metsttic CRC. The tretment ws well-tolerted. The initil dose of cpecitbine depended on clernce of cretinine. The toxicity profile (grde 3 toxicity) included nuse nd vomiting in 1 ptient (2%), dirrhe in 3 ptients (6%), hnd-foot syndrome in 3 ptients (6%), neutropeni in 1 (2%) ptient nd thrombocytopeni in 2 (4%) ptients. This toxicity ws significntly less dverse thn in the cse of the ILF nd LF regimens. Cpecitbine monotherpy resulted in 24% objective response rte. The medin time to disese progression ws 7 months nd the medin overll survivl ws 11 months. The results re comprble to those of the LF regimen-bsed chemotherpy nd worse thn the results of the ILF regimen. Cssidy et l (7) evluted findings of two extensive phse III studies tht nlyzed the efficcy nd sfety of orl cpecitbine therpy compred with intrvenous 5-fluorourcil/ leucovorin. Both ge (80 yers or older) nd cretinine clernce exhibited n impct on the sfety profile (incresed incidence of grde 3 or 4 gstrointestinl toxicities such s stomtitis nd dirrhe, nd grde 3 or 4 tretment-relted dverse events) of cpecitbine therpy (p=0.04 nd p=0.05, respectively). A dose reduction in cpecitbine ws effective in lleviting the toxicities chrcteristic of infused fluoropyrimidines (stomtitis, dirrhe nd hnd-foot syndrome). The dose modifiction of cpecitbine ws ssocited wih minor increse in the risk of disese progression or deth nd only in ptients requiring dose reduction up to 50% of the bseline dose [hzrd rtio (HR), 1.06; 95% CI ; p=0.67]. In ptients treted with the 5-fluorourcil/leucovorin regimen, dose reduction ws ssocited with 30% increse in the risk of disese progression or deth, but ws not sttisticlly significnt (HR, 1.30; 95% CI ; p=0.19) Ho et l (8) ssessed the efficcy nd toxicity of systemic gents in the elderly (ged 70). The most common first-line chemotherpy regimens were single-gent 5-fluorourcil or cpecitbine. Other chemotherpy regimens included oxlipltin- nd irinotecn-bsed regimens. The overll survivl between ptients treted with 5-fluorourcil vs. cpecitbine ws not sttisticlly significnt (p=0.65). An incresed incidence of toxicity ws observed in ptients treted with 5-fluorourcil vs. cpecitbine (43 nd 33%, respectively). The Dnish single centre [Jensen et l (9)] compred the benefits nd toxicities of pllitive chemotherpy of metsttic CRC bsed on cpecitbine (monotherpy or in combintion with oxlipltin) in 203 non-elderly nd 57 elderly ptients. No differences were observed between the non-elderly nd elderly ptients ( 70 nd 70 yers) with regrd to the objective response rte (33 vs. 37%, respectively) (p=0.61) nd time to disese progression (6.0 vs. 5.5 months, respectively) (HR, 1.09; 95% CI ; p=0.84). A difference (trend) ws found in overll survivl between ptients younger nd older thn 70 yers (12.5 vs. 8.4 months, respectively) (HR, 1.48; 95% CI ; p=0.07). More infections (p=0.03) nd neuropthies (p=0.02) were noted mong the younger ptients with similr grde 3 or 4 dverse events (p 0.05) in the two groups. Irinotecn compred to cpecitbine. Stec et l (10) retrospectively nlyzed the efficcy nd tolerbility of cpecitbine chemotherpy nd FOLFIRI regimen in ptients with metsttic CRC over the ge of 65 yers. No differences in the objective response rte were found between the two nlyzed groups. A trend towrds slightly higher overll response rte (28.1%) [complete response (CR), 9.4% nd prtil response (PR), 18.7%] ws found in the group treted with the FOLFIRI regimen compred to ptients treted with the cpecitbine monotherpy (16.4%; CR, 4.1% nd PR, 12.3%); however, this difference did not rech sttisticl significnce (χ 2 =2.18; p=0.1398). The results re shown in Tble III. Multivrite nlysis (Tble IV) reveled three independent predictive fctors ffecting time to disese progression: gender (HR, 0.57; p=0.007), pretretment CEA level (HR, 1.81; p=0.012) nd loction of metstses (HR, 1.66; p=0.03). Fctors such s type of chemotherpy nd Krnofsky performnce sttus hd no sttisticlly significnt effect. 6 Stec et l: Colorectl cncer in the elderly Tble IV. Multivrite nlysis of time to disese progression. Covrite hr (95% CI) P-vlue Gender Mle vs. femle 0.57 ( ) Loction of metstses Liver vs. other 1.66 ( ) Pretretment CEA level (µg/l) 5 vs. ( ) Krnofsky performnce sttus 80% vs. 80% - 0.050 Chemotherpy FOLFIRI vs. cpecitbine - 0.050 Bsed on the results by Stec et l (10). CEA, crcinoembryonic ntigen; FOLFIRI, 5-fluorourcil, leucovorin nd irinotecn; CI, confidence intervl; HR, hzrd rtio. Bold, sttisticlly significnt. Multivrite nlysis (Tble V) reveled prognostic significnce of 3 out of 4 fctors tht were significnt predictors in univrite nlysis: gender (p= ), WHO performnce sttus (HR, 0.51; p=0.013), nd pretretment CEA level (HR, 3.21; p=0.0001). The number of involved orgns ws not significnt predictor in the multivrite nlysis. Grde 3 nd 4 neutropeni ws observed more commonly in the group of ptients receiving combined chemotherpy vs. monotherpy (grde 3, 11.9 vs. 3.6%; grde 4, 7.5 vs. 0%; grde 3 + 4, 19.4 vs. 7.5%). Other grde 3 nd 4 hemtologicl toxicities did not differ between the study groups, i.e., nemi in the FOLFIRI group: grde 3, 1.5%; grde 4, 0%; nd cpecitbine group: grde 3, 1.8%; grde 4, 0%. Similrly, no difference ws noted for thrombocytopeni in the FOLFIRI group: grde 3 + 4, 0%; nd the cpecitbine group: grde 3, 1.8%; grde 4, 0%. Tble V. Multivrite nlysis of overll survivl. Covrite hr (95% CI) P-vlue Primry loction Sigmoid colon vs. colon/rectum - 0.05 Pretretment CEA level (µg/l) 5 vs. ( ) Chemotherpy FOLFIRI vs. cpecitbine - 0.05 Age 70 vs. 70 yers - 0.05 Gender Mle vs. femle 0.57 ( ) WHO performnce sttus 0 vs ( ) Number of orgns involved 1 vs. 2 - 0.05 Bsed on the results by Stec et l (10). CEA, crcinoembryonic ntigen; FOLFIRI, 5-fluorourcil, leucovorin nd irinotecn; CI, confidence intervl; HR, hzrd rtio. Bold, sttisticlly significnt. Assessment of grde 3 nd 4 non-hemtologicl toxicities showed tht hnd-foot syndrome ws significntly different only in the cpecitbine-treted ptients (19.6%). Adverse effects re shown in Tble VI. The nlysis ws performed retrospectively, nd the findings should be viewed in considertion of this limittion. Although the nlysis involved more thn 120 ptients, the smple size my not hve been sufficiently lrge enough to detect differences in efficcy between the two ptient cohorts. Tble VI. Toxicities relted to cpecitbine chemotherpy nd FOLFIRI regimen in ptients bove 65 yers of ge (n=123). CTC NCI toxicity grde I II III IV F C F C F C F C P-vlue Neutropeni 10 (14.9%) 3 (5.4%) 10 (14.9%) 2 (3.6%) 8 (11.9%) 2 (3.6%) 5 (7.5%) Anemi 11 (16.4%) 6 (10.7%) 14 (20.9%) 2 (3.6%) 1 (1.5%) 1 (1.8%) Thrombocytopeni 6 (8.9%) 11 (19.6%) 1 (1.5%) 4 (7.1%) - 1 (1.8%) Vomiting 2 (3.0%) - 6 (8.9%) 2 (3.6%) 5 (7.5%) 3 (5.4%) Nuse 1 (1.5%) - 12 (17.9%) 2 (3.6%) 7 (10.4%) 3 (5.4%) Dirrhe 2 (3.0%) 1 (1.8%) 9 (13.4%) 3 (5.4%) 4 (6.0%) 2 (3.6%) 2 (3.0%) 1 (1.8%) Mucositis 1 (1.5%) (1.8%) - 2 (3.6%) Astheni - 1 (1.8%) 7 (10.4%) 5 (8.9%) 9 (13.4%) 5 (8.9%) - 1 (1.8%) Hnd-foot syndrome - 1 (1.8%) - 8 (14.3%) - 11 (19.6%) Bsed on the results by Stec et l (10). C, cpecitbine; F, FOLFIRI: 5-fluorourcil, leucovorin nd irinotecn. Bold, sttisticlly significnt. ONCOLOGY LETTERS 2: 3-11, Tble VII. Efficcy of CAPOX in comprison to FUFOX in first-line chemotherpy in ptients ged 70 nd 70 yers of ge. Age 70 yers Age 70 yers FUFOX 70 yers CAPOX 70 yers (n=330) (n=138) (n=63) (n=75) Medin time to disese progression (months) Medin overll survivl (months) Response (%) CR + PR CR PR SD Bsed on the findings of Arkenu et l (11). CR, complete response; PR, prtil response; CR + PR, objective response; SD, stble disese. Tble VIII. Toxicity of FUFOX nd CAPOX s first-line chemotherpy in ptients ged 70 nd 70 yers of ge. Toxicities of grde 3 nd 4 (%) Age 70 yers Age 70 yers FUFOX 70 yers CAPOX 70 yers Neutropeni Thrombocytopeni Anemi Totl Nuse Dirrhe Vomiting Mucositis Hnd-foot syndrome (grde 2/3) Totl Bsed on the findings of Arkenu et l (11). Oxlipltin. Arkenu et l (11) compred the bovementioned chemotherpeutic regimens in ptients with metsttic CRC in rndomized phse III clinicl tril. The uthors pid prticulr ttention to efficcy nd sfety of the tretment in ptients bove 70 yers of ge who ccounted for pproximtely 30% of the study popultion. The nlysis consisted of 468 ptients, including 138 ptients bove 70 yers of ge. The nlysis imed to compre CAPOX regimen (oxlipltin 70 mg/m, dys 1 nd 8; cpecitbine 2 x 1000 mg/m; dys 1-14 every 3 weeks; fter 7 cycles oxlipltin only on Dy 1 to reduce the risk of peripherl neuropthy) nd FUFOX regimen (oxlipltin 50 mg/m, 2-h infusion, leucovorin 500 mg/m, 2-h infusion, 5-fluorourcil 2000 mg/m, 22-h infusion; dys 1, 8, 15, 22 every 5 weeks; fter 5 cycles oxlipltin only on Dys 1 nd 15 to reduce the risk of peripherl neuropthy) in ptients older thn 70 yers of ge s well s to compre the two ge groups (below nd bove 70 yers of ge) which were treted with these chemotherpeutic regimens. No differences were observed between ptients treted with the CAPOX nd FUFOX regimens, irrespective of ge with regrd to the objective response rte (52 vs. 49%) nd time to disese progression (7.5 vs. 7.6 months) (HR, 1.07; 95% CI ; p=0.54). No difference ws found in ptients older thn 70 yers with regrd to time to disese progression (7.6 months for CAPOX vs. 7.9 months for FUFOX) nd medin overll survivl (14.2 months for CAPOX vs months for FUFOX). A difference ws found in overll survivl between ptients younger nd older thn 70 yers, with overll suvivl being shorter in the ltter group (14.4 vs months) (HR, 1.37; 95% CI ; p=0.03, Tble VII). The comprison of grde 3 nd 4 non-hemtologicl toxicities in ptients bove thn 70 yers of ge compred to those below 70 yers, showed higher incidence in the former group with regrd to dirrhe (21 vs. 12%), nuse (11 vs. 8%) nd vomiting (9 vs. 4%), respectively, nd lower incidence of peripherl neuropthy (12 vs. 21%), respectively. The comprison of grde 3 nd 4 hemtologicl toxicities in the sme two groups of ptients, showed higher incidence of neutropeni, nemi nd thrombocytopeni in the group of ptients bove 70 yers of ge (Tble VIII). Twelves et l (12) compred the efficcy nd toxicity of XELOX regimen between ptients older (n=44) nd younger (n=52) thn 65 yers of ge. No significnt differences were 8 Stec et l: Colorectl cncer in the elderly Tble IX. Dose reduction nd tretment discontinution due to toxicity in ptients older nd younger thn 65 yers of ge. Ptient ge 65 yers 65 yers (n=52) (n=44) Cpecitbine Dose reduction 18 (35%) 18 (41%) Medin time to dose reduction 76 dys 90 dys Oxlipltin Dose reduction 17 (33%) 17 (39%) Medin time to dose reduction 106 dys 90 dys Tretment discontinution due to 10 (19%) 6 (14%) toxicity Deth 0 3 (7%) b Bsed on the findings of Twelves et l (12). b Only one cse ws tretment-relted. found between the two groups with regrd to time to disese progression (p=0.85) nd overll survivl (p=0.65). A higher objective response rte of 58% (95% CI 43-71) vs. 52% (95% CI 37-69) nd stble disese rte of 35% (95% CI 22-49) compred to 27% (95% CI 15-43) were found for younger ptients compred to ones older thn 65 yers of ge. No significnt differences were found for grde 3 nd 4 toxicities between ptients younger nd older thn 65 yers of ge, prt from hnd-foot syndrome which ws observed only in ptients younger thn 65 yers of ge. The percentge of ptients in whom drug doses were reduced or the tretment ws discontinued due to toxicity ws lso comprble in the two ptient groups (Tble IX). Feliu et l (13) ssessed the efficcy nd tolernce of the chemotherpeutic regimen XELOX in 50 ptients who were 70 yers or older s first-line therpy for metsttic CRC. The medin time to disese progression ws 5.8 months (95% CI ) nd the medin overll survivl ws 13.2 months (95% CI ). In this group of ptients, the objective response rte ws 36% (95% CI 28-49), the stble disese rte ws 36% (18 ptients) nd disese progression ws noted in 14 (28%) ptients. The tretment ws well-tolerted. Grde 3 toxicities were found in 14 (28%) ptients: in 11 (22%) dirrhe, in 8 (16%) wekness, in 7 (14%) nuse/vomiting, in 3 (6%) neutropeni, in 3 (6%) thrombocytopeni nd in 2 (4%) hnd-foot syndrome. Findings of n nlysis of 1408 ptients (213 ptients bove 70 yers of ge) regrding the efficcy/sfety of FOLFOX regimen were reported by Tbh-Fisch et l (14). Prticulr ttention ws pid to the efficcy nd sfety of the tretment in ptients bove 70 yers of ge. The nlysis involved comprison of FOLFOX regimen (djuvnt, first-line nd second-line chemotherpy) in younger nd older ptients. Neutropeni, thrombocytopeni, st
Search
Related Search
We Need Your Support
Thank you for visiting our website and your interest in our free products and services. We are nonprofit website to share and download documents. To the running of this website, we need your help to support us.

Thanks to everyone for your continued support.

No, Thanks