MEDICAL ONCOLOGY Mnging tretment-relted dverse events ssocited with egfr tyrosine kinse inhibitors in dvnced non-smll-cell lung cncer V. Hirsh md* ABSTRACT Non-smll-cell lung cncer (nsclc) hs the highest prevlence of ll types of lung cncer, which is the second most common cncer nd the leding cuse of cncer-relted mortlity in Cnd. The need for more effective nd less toxic tretment options for nsclc hs led to the development of gents trgeting the epiderml growth fctor receptor (egfr) medited signlling pthwy, such s egfr tyrosine kinse inhibitors (egfr-tkis). Although egfr-tkis re less toxic thn trditionl nti-neoplstic gents, they re commonly ssocited with cneiform-like rsh nd dirrhe. This review summrizes the clinicl presenttion nd cuses of egfr-tki induced rsh nd dirrhe, nd presents strtegies for effective ssessment, monitoring, nd tretment of these dverse effects. Strtegies to improve the mngement of egfr-tki relted dverse events should improve clinicl outcomes, complince, nd qulity of life in ptients with dvnced nsclc. KEY WORDS Epiderml growth fctor receptor, dverse drug rection, dverse drug event, skin rsh, dirrhe 1. INTRODUCTION Lung cncer remins the second most common cncer nd the leding cuse of cncer-relted mortlity in Cnd. In 2010, 24,400 new lung cncer cses nd 20,600 relted deths were predicted, representing significnt helth cre burden 1. The most common form of lung cncer, non-smll-cell lung cncer (nsclc), consists of heterogeneous group of histologies, of which denocrcinom, squmous cell crcinom, nd lrge-cell nplstic crcinom re the most frequent 2. Despite recent dvnces in tretment, prognosis is generlly poor in ptients with dvnced nsclc, nd the medin survivl rte is only 10 12 months with tretment 3. First-line tretment for nsclc is usully pltinum-bsed two-drug combintion chemotherpy, with or without bevcizumb for non-squmous pthology. For ptients with poor performnce sttus, single-gent chemotherpy is often recommended, but little evidence exists to guide recommendtions in this ptient group 4 6. Despite the success of pltinum doublets in first-line tretment, the introduction of third chemotherpeutic gent increses toxicity without improving efficcy 7. The stndrd pproch is to give chemotherpy gent s second-line tretment or n epiderml growth fctor receptor (egfr) tyrosine kinse inhibitor (tki). The egfr-tkis re better tolerted, hve more convenient method of dministrtion, nd cn be given for longer periods of time 7. In ddition, ptients with lte-stge nsclc re often symptomtic nd experience comorbidities tht ffect qulity of life 8. Effective tretment options of lower toxicity re therefore needed for ptients with dvnced nsclc. The need for more effective nd less toxic tretment options for nsclc hs led to the development of trgeted gents such s egfr inhibitors. A number of solid tumours, including 40% 80% of nsclc tumours, express or overexpress egfr. Severl studies showed tht high egfr expression is ssocited with poor prognosis in lung cncer ptients. Consequently, egfr is n ttrctive trget for the tretment of nsclc 8,9. Vrious clinicl trils hve demonstrted tht egfr inhibitors re cliniclly efficcious in the mngement of severl solid tumour types, such s those of brest, colon, pncres, hed nd neck, kidney, gstrointestinl strom, nd lung 10. The egfr-tkis impede phosphoryltion of the intrcellulr tyrosine kinse component of egfr nd thus block signl trnsduction pthwys ssocited with the prolifertion nd survivl of cncer cells 8. Given s second- or third-line therpy in dvnced nsclc, the egfr-tkis re cliniclly efficcious compred with supportive cre or chemotherpy 8,11 14. Erlotinib is n egfr-tki tht hs been pproved in the United Sttes, Cnd, nd mny other countries 126
EGFR-TKIs IN ADVANCED NSCLC round the world for use in nsclc, bsed on clinicl tril results showing it to be sfe nd efficcious. Another egfr-tki, gefitinib, ws recently grnted mrketing uthoriztion by the Europen Medicines Agency, the United Sttes, nd Cnd for the tretment of EGFR muttion positive nsclc 7. Newer egfrtkis such s ftinib (BIBW 2992) nd PF-00299804 re currently in development 15 21,. Although trgeted gents re generlly less toxic thn trditionl nti-neoplstic gents, egfr-tkis re ssocited with number of bothersome dverse effects tht need to be mnged in most ptients. Becuse egfr is expressed minly on cells of epithelil origin, such s those of the skin nd gstrointestinl trct, the most common dverse events of the egfr inhibitors re rsh nd dirrhe, which re the focus of the present pper. Strtegies to improve the ssessment nd mngement of egfr-tki relted dverse events such s rsh nd dirrhe should result in superior clinicl outcomes, better complince, nd improved qulity of life for ptients with dvnced nsclc 10. 2. RASH INDUCED BY EGFR-TKIs 2.1 Ptient Monitoring Before inititing tretment with n egfr-tki, physicins should educte their ptients bout the ssocited potentil side effects so tht such rections cn be mnged erly nd effectively. Becuse symptoms of rsh generlly pper s erly s 2 weeks into tretment, erly monitoring is essentil 10. Ptients should be dvised tht rsh is common compliction of egfr inhibitors nd n indiction of tretment efficcy 22. To prevent dose reduction or discontinution of therpy, it is lso importnt to inform ptients tht erly tretment of rsh cn prevent symptoms from worsening. Although not recommended in current guidelines, prophylctic tretments to prevent egfr-tki induced rsh hve been studied in number of trils. One rndomized double-blind tril compred prophylctic orl minocycline with plcebo in ptients treted with cetuximb for metsttic colorectl cncer (n = 48) 23. Ptients were lso rndomized to receive topicl tzrotene pplied either to the left or the right side of the fce. After 4 weeks of tretment with cetuximb, the minocycline group hd significntly lower totl fcil lesion count (p = 0.005). A trend ws lso observed suggesting tht lower proportion of treted ptients were experiencing moderte-to-severe itching (20% vs. 50% receiving plcebo, p = 0.05). The use of topicl tzrotene provided no clinicl benefit nd ws ssocited with significnt skin irrittion. A second rndomized double-blind tril in ptients (n = 61) receiving egfr-tkis compred prophylctic See lso NCT01085136, NCT01121393, NCT01000025, nd NCT00769067 t clinicltrils.gov/ct2/serch. tetrcycline tretment (500 mg twice dily) with plcebo over 4 weeks 24. Although tetrcycline did not prevent rsh, reduction in the severity of rsh ws observed. At week 4, grde 2 rsh ws reported in 17% of the tetrcycline group nd in 55% of the plcebo group (p = 0.04). Tretment lso improved certin qulity-of-life mesures, including skin burning or stinging nd skin irrittion. The stepp (Skin Toxicity Evlution Protocol with Pnitumumb) study compred primry pre-emptive skin tretment with rective skin tretment in ptients receiving pnitumumb in rndomized prospective study 25. Ptients on the pre-emptive rm received dily skin tretment for totl of 6 weeks, strting 24 hours before the first dose of pnitumumb. Pre-emptive tretment included skin moisturizer, sunscreen, 1% hydrocortisone crem, nd doxycycline 100 mg twice dily. Ptients on the rective rm received tretment fter the development of rsh. Compred with rective tretment, pre-emptive tretment reduced the incidence of grde 2 or greter rsh by more thn 50%, without dditionl side effects. Time to first occurrence of grde 2 or greter rsh ws lso significntly delyed in the pre-emptive rm. Additionl reserch is needed to determine the benefit of prophylctic tretment for the prevention of egfr-tki induced rsh. During the first 6 weeks of tretment, ptients should be ssessed weekly for ny signs of rsh. When symptoms of rsh re pprent, erly intervention is of key importnce to prevent more serious complictions. After 6 weeks of tretment, ssessment of skin toxicities cn be performed less frequently for exmple, every 6 8 weeks. Rsh ssessment cn be performed by ny member of the helth cre tem who is ble to relibly evlute it. 2.2 Cuses nd Incidence Epiderml growth fctor plys n integrl role in the growth nd kertiniztion of skin epithelium, nd egfrs re expressed within the folliculr epithelium, sebceous glnds, nd derml cpillries. It is therefore not surprising tht egfr inhibition leds to number of skin rections 10,26. Adverse skin rections occur in more thn 50% of ptients given egfr inhibitors; they re the most common tretment-relted dverse events. Skin rections ssocited with egfr inhibitors include xerosis (dry skin), pruritus, hir chnges nd lopeci, nil ltertions, nd hnd nd foot rections 10,26,27. The most common skin rection reported in ptients treted with egfr-tkis is folliculr cneiform eruption lso known s cne-like rsh or folliculitis. Inhibition of egfr is thought to lter kertinocyte prolifertion, differentition, migrtion, nd ttchment, which my explin the ppulopustulr rection nd xerosis seen with egfr-tkis 30. Incidence of rsh with egfr-tkis vries from 37% 78% in phse iii clinicl trils nd ppers to be 127
dose-dependent (Tble i). Tble ii presents detiled description of the clinicl trils tht hve exmined the incidence of rsh with egfr-tkis in nsclc. When rsh is not dequtely mnged, tretment complince my be negtively ffected, leding to dose modifictions or tretment discontinution, nd ultimtely reducing the overll clinicl benefits of tretment. Approprite strtegies re therefore needed to ssess nd mnge egfr-tki induced rsh 10,45. 2.3 Assessment nd Grding Acneiform rsh is defined s n eruption of ppules nd pustules, typiclly ppering on the fce, sclp, upper chest, nd bck 46. Although egfr-tki induced rsh most closely resembles cneiform rsh in presenttion, no comedones or blckheds re visible 10 (Figure 1). Rsh induced by egfr-tki usully ppers within 2 weeks of tretment strt nd generlly presents on the fce, shoulders, nd upper prt of the bck nd chest. The rsh tends to improve over time with continued use of the mediction nd resolves fully fter discontinution of tretment 10,26. However, in bout 35% of ptients, dry itchy skin of the rms nd legs my occur, which cn potentilly become secondrily infected with Stphylococcus ureus or Herpes simplex infection 10. The U.S. Ntionl Cncer Institute (nci) Common Terminology Criteri for Adverse Events (ctce) re tble i Incidence of cneiform rsh with epiderml growth fctor receptor (egfr) tyrosine kinse inhibitors (tkis) in non-smll-cell lung cncer trils egfr-tki Description Grdes (%) Erlotinib 150 mg All studies 33 79 3 10 Gefitinib 250 mg nd 500 mg Aftinib 40 mg nd 50 mg PF-00299804 30 mg nd 45 mg All 3 Phse iii studies 62 76 3 10 All studies 250 mg 500 mg Phse iii studies 250 mg 500 mg All studies 40 mg 50 mg Phse iii studies 50 mg All studies (phse ii) 30 mg 45 mg 34 75 34 66 57 75 37 67 37 66 57 67 67 100 90 100 67 92 78 68 100 69 68 85 0 13 0 4 4 13 2 13 2 4 12 13 0 25 0 7 0 25 14 0 15 0 15 No phse iii study results using PF-00299804 re vilble to dte. typiclly used to grde symptoms for clinicl trils, but those criteri hve some limittions for describing egfr-tki induced rsh 46 (Tble iii). The ctce grding uses the ffected percentge of body surfce re to ssess rsh severity, but egfr-tki induced rsh is typiclly restricted to the fce, sclp, nd upper torso. The ctce grding lso does not tke into ccount the severity of rsh complictions, which my include oozing, burning, crusting, or disfigurement 47. Given tht no other stndrd exists for grding egfr-tki induced rsh, the ctce grding remins the stndrd for ssessment. 2.4 Mngement Before inititing egfr-tki therpy, physicins should counsel their ptients bout preventive mesures to reduce the risk of skin rsh. The eductionl messges tht need to be communicted to ptients being prescribed egfr-tkis re these 10,22,27,45 : Any res of dry skin should be moisturized twice dily using thick, lcohol-free emollient. Sun exposure should be minimized. Where sun exposure is unvoidble, brod-spectrum sunscreen with sun protection fctor of 15 or higher should be pplied 1 2 hours before exposure, especilly on the fce nd upper body. Physicl sunscreens tht contin zinc oxide or titnium dioxide re preferble to chemicl sunscreens. Products tht dry the skin such s sops, lcohol-bsed or perfumed products, nd overthe-counter cne products should be voided. Becuse long hot showers cn lso dry the skin, shower time should be limited, nd lukewrm wter should be used. A number of tretment lgorithms hve been proposed for the mngement of skin rsh induced by egfr inhibitors; the lgorithm presented in Figure 2 represents n mlgm of existing frmeworks 10,27,48 50. The egfr-tki dosge should remin unchnged for ll ptients, except those with severe rsh (grde 3 or higher). Ptients with mild toxicities (grde 1) my need no intervention; however, tretment with topicl hydrocortisone (1% or 2.5% crem) or clindmycin (1% gel) is resonble. For ptients with moderte toxicities (grde 2), tretment with hydrocortisone (2.5% crem), clindmycin (1% gel), or pimecrolimus (1% crem) is recommended, with the ddition of either orl doxycycline (100 mg twice dily) or minocycline (100 mg twice dily). For ptients with severe toxicities (grde 3 or higher), concomitnt intervention is the sme s for moderte toxicities, with the ddition of methylprednisolone dose pck ( pckge contining specific number of pills to be tken t designted times over period of few dys). If the rsh does not dissipte sufficiently within 2 4 weeks, interruption of egfr inhibitor therpy is 128
EGFR-TKIs IN ADVANCED NSCLC tble ii Incidence of rsh nd dirrhe with epiderml growth fctor receptor (egfr) tyrosine kinse inhibitors (tkis) in non-smll-cell lung cncer (nsclc) clinicl trils egfr-tki Reference (study nme) Description Ptients (n) Grdes of rsh (%) Grdes of dirrhe (%) All 3 All 3 Erlotinib All studies Dose: 150 mg 33 79 3 10 10 69 0 17 Herbst et l., 2005 28 Phse iii; erlotinib 150 mg vs. plcebo; first-line (tribute) combintion therpy with pclitxel nd crbopltin; chemotherpy-nïve Totl: 1079 Erlotinib: 539 Plcebo: 540 61.7 7.2 67.9 12.4 Shepherd et l., 2005 11 Phse iii; erlotinib 150 mg vs. plcebo; second- or (br.21) third-line monotherpy fter filure with stndrd first- or second-line chemotherpy Totl: 731 Erlotinib: 488 Plcebo: 243 76 9 55 6 Cho et l., 2007 29 Phse ii; second-line erlotinib 150 mg fter filure with gefitinib Totl: 21 33.3 4.8 9.5 0 Gtzemeier et l., 2007 30 Phse iii; erlotinib 150 mg vs. plcebo; first-line combintion therpy with gemcitbine nd cispltin; (tlent) chemotherpy-nïve Totl: 1172 Erlotinib: 586 Plcebo: 586 nr 10 40 6 Jckmn et l., 2007 31 Phse ii; first-line erlotinib 150 mg; chemotherpy-nïve Totl: 80 78.8 6 68.8 5 Felip et l., 2008 12 Phse ii; second-line erlotinib 150 mg fter filure with pltinum-bsed chemotherpy Totl: 83 61 7 23 2 Lilenbum et l., 2008 32 Phse ii; first-line erlotinib 150 mg vs. chemotherpy (crbopltin nd pclitxel); chemotherpy-nïve Totl: 103 Erlotinib: 52 Chemotherpy: 51 65 8 44 6 Mok et l., 2009 33 Phse ii; first-line sequentil erlotinib 150 mg nd pltinum-bsed doublet chemotherpy [gemcitbine nd (fst-ct) cispltin (gc) or crbopltin] vs. chemotherpy lone Totl: 154 gc+erlotinib: 76 gc+plcebo: 78 65 3 22 0 Bennoun et l., 2010 34 Phse ii; everolimus plus erlotinib 150 mg (ee) vs. erlotinib 150 mg monotherpy (em); previously-treted ptients Totl: 133 ee: 66 em: 67 nr nr nr ee: 8 em: 5 Groen et l., 2010 35 Phse ii; sunitinib plus erlotinib 150 mg (se) vs. plcebo plus erlotinib 150 mg (pe); 2 or fewer previous chemotherpy regimens, including 1 or more pltinum-bsed regimens Totl: 132 nr nr nr se: 17.2 pe: 1.6 Kelly et l., 2010 36 Phse iib; prltrexte vs. erlotinib 150 mg; previously treted with pltinum-bsed chemotherpy Totl: 201 nr Erlotinib: nr nr 10 129
tble ii Continued egfr-tki Reference (study nme) Description Ptients (n) Grdes of rsh (%) Grdes of dirrhe (%) All 3 All 3 Scgliotti et l., 2010 37 Phse iii; sunitinib plus erlotinib 150 mg (se) vs. plcebo plus erlotinib 150 mg (pe); 2 or fewer previous chemotherpy regimens Totl: 960 nr se: 8.2 nr se: 10.4 pe: 2.5 pe: 1.7 Zho et l., 2010 38 Phse ii; erlotinib 150 mg plus cpecitbine; first-line in (ML 22206) elderly ptients with dvnced disese Totl: 62 nr nr nr nr Gefitinib All studies Doses: 250 mg nd 500 mg 34 75 0 13 27 75 0 25 250 mg: 250 mg: 250 mg: 250 mg: (idel 1) 46.6; 1; 39.8; 0; Fukuok et l., 2003 8 Phse ii; second-line gefitinib 250 mg or 500 mg fter filure with 1 or 2 chemotherpy regimens, t lest 1 pltinum-bsed Totl: 210 250-mg Arm: 104 500-mg Arm: 106 500 mg: 500 mg: 500 mg: 500 mg: 68.9 6.6 57.5 6.6 250 mg: 250 mg: 250 mg: 250 mg: (idel 2) 62; 0; 57; 1; Kris et l., 2003 39 Phse ii; gefitinib 250 mg vs. gefitinib 500 mg fter filure with 2 or more chemotherpy regimens contining cispltin or crbopltin nd docetxel Totl: 221 Gefitinib 250 mg: 106 Gefitinib 500 mg: 115 500 mg: 500 mg: 500 mg: 500 mg: 75 4 75 5 250 mg: 250 mg: 250 mg: 250 mg: (intct 1) 44.5; 3.6; 28.7; 3.6; Giccone et l., 2004 40 Phse iii; gefitinib 250 mg or 500 mg vs. plcebo; first-line combintion therpy with gemcitbine nd cispltin; chemotherpy-nïve Totl: 1093 Gefitinib 250 mg: 365 Gefitinib 500 mg: 365 Plcebo: 363 500 mg: 500 mg: 500 mg: 500 mg: 56.7 12.6 50.8 12.0 250 mg: 250 mg: 250 mg: 250 mg: (intct 2) 54.4; 3.2; 58.2; 9.9; Herbst et l., 2004 41 Phse iii; gefitinib 250 mg or 500 mg vs. plcebo; first-line combintion therpy with pclitxel nd crbopltin; chemotherpy-nïve Totl: 1037 Gefitinib 250 mg: 345 Gefitinib 500 mg: 347 Plcebo: 345 500 mg: 500 mg: 500 mg: 500 mg: 67.3 11.7 69.3 25.4 Thtcher et l., 2005 13 Phse iii; second- or third-line gefitinib 250 mg vs. plcebo fter filure of 1 or 2 previous chemotherpy (isel) regimens Totl: 1692 Gefitinib: 1129 Plcebo: 563 37 2 27 3 Kim et l., 2008 14 Phse iii; second-line gefitinib 250 mg vs. docetxel fter filure with up to 2 chemotherpy regimens, t lest (interest) 1 pltinum-bsed Totl: 1466 Gefitinib: 733 Docetxel: 733 49.4 2.1 35.0 2.5 Goss et l., 2009 42 Phse ii; first-line gefitinib 250 mg vs. plcebo; chemotherpy-nïve (instep) Totl: 201 Gefitinib: 100 Plcebo: 101 34 0 51 3 130
EGFR-TKIs IN ADVANCED NSCLC tble ii Continued egfr-tki Reference (study nme) Description Ptients (n) Grdes of rsh (%) Grdes of dirrhe (%) All 3 All 3 Mok et l., 2009 43 (ipss) Phse iii; first-line gefitinib 250 mg vs. crbopltin plus pclitxel (cp); chemotherpy-nïve Totl: 1217 Gefitinib: 609 cp: 608 66.2 3.1 46.6 3.8 Surmont et l., 2010 44 (eortc 08021 ilcp) Phse iii; mintennce gefitinib 250 mg vs. plcebo; ptients non-progressing on 4 cycles of pltinum-bsed chemotherpy Totl: 173 Gefitinib: 86 Plcebo: 87 40 nr 29 nr - Aftinib All studies Doses: 20 mg, 40 mg, 50 mg 33 100 0 25 0 100 0 33 (BIBW 2992) Miller et l., 2010 15 (lux-lung 1) Phse iib/iii; ftinib 50 mg vs. plcebo fter filure with chemotherpy (including pltinum) nd erlotinib or gefitinib Totl: 585 Aftinib: 390 Plcebo: 195 78 14 87 17 Ymmoto et l., 2010 17 (lux-lung 4) Phse i; ftinib 20 mg, 40 mg, or 50 mg fter filure with ny combintion of chemotherpy, erlotinib, nd gefitinib Totl: 12 20 mg: 33.3 20 mg: 0 20 mg: 0 20 mg: 0 40 mg: 100 40 mg: 0 40 mg: 66.7 40 mg: 0 50 mg: 66.7 50 mg: 0 50 mg: 100 50 mg: 33.3 Yng et l., 2010 16 (lux-lung 2) Phse ii; ftinib 40 mg or 50 mg in ptients with ctivting egfr muttions fter filure with 1 chemotherpy regimen nd no previous egfr-tki Totl: 129 40 mg: 90.0 40 mg: 6.7 40 mg: 96.7 40 mg: 6.7 50 mg: 91.9 50 mg: 25.3 50 mg: 93.9 50 mg: 21.2 Ongoing study 18 (lux-lung 5) Phse iii; ftinib 40 mg plus pclitxel vs. investigtor s choice of single-gent chemotherpy fter progression with ftinib monotherpy Totl: 900 nr nr nr nr Ongoing study 19 (lux-lung 6) Phse iii; ftinib vs. cispltin plus gemcitbine; first-line in ptients with egfr ctivting muttion Totl: 330 nr nr nr nr PF-00299804 All studies Doses: 15 mg, 30 mg, nd 45 mg 68 100 0 15 77 97 0 15 Jnne et l., 2009 20 (A7471002) Phse ii; PF-00299804 45 mg in denocrcinom nd non-denocrcinom ptients fter filure with t lest 1 chemotherpy regimen nd erlotinib Totl: 34 Adenocrcinom: 30 Non-denocrcinom: 4 84.9 15.1 81.1 13.2 Mok et l., 2010 20 Phse ii; first-line PF-00299804 30 mg or 45 mg in dvnced nsclc with egfr muttion Totl: 74 30 mg: 69 30 mg: 0 30 mg: 77 30 mg: 0 45 mg: 68 45 mg: 15 45 mg: 97 45 mg: 15 131
tble ii Continued Grdes of rsh (%) Grdes of dirrhe (%) All 3 All 3 Description Ptients (n) egfr-tki Reference (study nme) Tolerble in both gents Tolerble in both gents Totl: 188 Erlotinib: 94 PF-00299804: 94 Rmlingm et l., 2010 19 Phse ii; PF-00299804 45 mg vs. erlotinib 150 mg in dvnced nsclc ptients who were erlotinib-nïve nd hd filed t lest 1 chemotherpy regimen Totl: 13 100 45 mg: 15.4 92 nr Tkhshi et l., 2010 21 Phse i; PF-00299804 15 mg, 30 mg, or 45 mg in dvnced solid-tumour ptients who hd filed ll stndrds of cre Totl: 720 nr nr nr nr Ongoing study 24 Phse iii; PF-00299804 45 mg vs. plcebo in dvnced (br.26) nsclc ptients fter filure with t lest 1 chemotherpy regimen nd erlotinib or gefitinib (or both) Totl: 160 nr nr nr nr Ongoing study 25 Phse ii; PF-00299804 45 mg vs. erlotinib 150 mg in (A7471028) dvnced nsclc ptients fter filure with t lest 1 chemotherpy regimen Adverse events by dose subgroup not given. nr = not reported; eortc = Europen Orgnistion for Reserch nd Tretment of Cncer. figure 1 Rsh induced by epiderml growth fctor receptor. tble iii U.S. Ntionl Cncer Institute grding for cneiform rsh Grde 1 Grde 2 Ppules or pustules, or both, covering less thn 10% of body surfce re, which my or my not be ssocited with symptoms of pruritus or tenderness Ppules or pustules, or both, covering 10% 30% body surfce re, which my or my not be ssocited with symptoms of pruritus or tenderness Associted with psychosocil impct Limits instrumentl ctivities of dily living Grde 3 Ppules or pustules, or both, covering more thn 30% body surfce re, which my or my not be ssocited with symptoms of pruritus or tenderness Grde 4 Grde 5 Limits self-cre ctivities of dily living Associted with locl superinfection, with orl ntibiotics indicted Ppules or pustules, or both, covering ny percentge of body surfce re, which my or my not be ssocited with symptoms of pruritus or tenderness nd which re ssocited with extensive superinfection, with intrvenous ntibiotics indicted Life-thretening consequences Deth Adpted from the Common Terminology Criteri for Adverse Events, 2010 46. recommended in ccordnce with the prescribing informtion 10,27. Novel tretments for egfr-tki induced rsh, such s mendione lotion, retinoids, nd lph-hydroxy cids, re under investigtion in preliminry studies. However, until controlled studies re performed, their efficcy remins unknown, becuse rsh often resolves spontneously in ptients tking egfr-tkis 47. Becuse the hlf-life of egfr-tkis is long, mngement of dverse skin rections should continue 132
EGFR-TKIs IN ADVANCED NSCLC figure 2 Mngement of rsh induced by epiderml growth fctor receptor (egfr) tyrosine kinse inhibitor (tki). ctce = Common Terminology Criteri for Adverse Events; dl = ctivities of dily living. Adpted from Eby et l., 2008 48 ; Hrndi et l., 2009 27 ; Lynch et l., 2007 10. Guidelines presented here recommend tretment with minocycline for moderte-to-severe rsh only. However, erly tretment of mild rsh cn prevent the development of more severe forms nd the need for higher, more toxic doses of minocycline. Erly tretment of mild rsh with 50 mg minocycline plus 1% hydrocortisone is therefore resonble option. b Topicl steroids should be pulsed ccording to institution guidelines. until those rections hve sufficiently diminished or resolved, even if tretment is discontinued or reduced. Once dverse rections hve sufficiently resolved, egfr-tki therpy my be restrted or esclted to the originl dosing scheme, with resonble confidence tht toxicities will be well mnged 27. 2.5 Rsh As n Indictor of Tretment Response Numerous studies hve shown significnt correltion between skin rsh severity nd response to egfr inhibitor tretment 10,26,47. In nsclc, severl gefitinib nd erlotinib trils hve supported tht finding 22,39,51. A phse ii study by Kris et l. 39 (idel) exmined the efficcy nd sfety of gefitinib (250 mg vs. 500 mg dily) in ptients with pre-treted dvnced nsclc. Although efficcy outcomes were similr cross dose groups, skin toxicity ws reported in 86% of ptients (72 of 84) with symptom improvement [ 2-point increse in score on the Functionl Assessment of Cncer Therpy Lung (fct-l) scle], but in only 58% of ptients (76 of 132) with 133
no symptom improvement (observed difference: 28%; 95% confidence intervl: 17% to 39%). A retrospective study by Mohmed et l. 51 nlyzed the clinicl chrcteristics of ptients who were ssocited with survivl fter tretment with gefitinib s prt of the Expnded Access Progrm. Medin survivl ws longer in ptients who developed skin rsh thn in those who did not (10.8 months vs. 4.0 months, p < 0.0001) 26,51. A phse iii study by Shepherd et l. 11 (br.21) exmined the efficcy nd sfety of erlotinib in ptients with pre-treted dvnced nsclc. Rsh occurred in 76% of ptients given erlotinib (368 of 485), with 9% experiencing severe (grde 3 or higher) rsh. A retrospective study by Wcker et l. 22 nlyzed the ssocition between rsh nd clinicl outcome using dt from the study by Shepherd nd collegues nd lso dt from phse iii study compring single-gent gemcitbine with gemcitbine plus erlotinib s first-line therpy for dvnced pncretic cncer (p.3) 52. The response rte ws 1% mong ptients who did not develop rsh compred with 10% mong those who developed grde 1 rsh nd 13% mong those who developed grde 2 or higher rsh (grde 1 vs. grde 0, p = 0.048; grde 2 vs. grde 0, p = 0.017). After controlling for bseline fctors in multivrite nlyses, the presence of rsh correlted strongly with overll nd progressionfree survivl; the correltions incresed with rsh severity (p < 0.05) 22,26. The positive reltionship between skin rsh nd response or survivl (or both) suggests tht rsh could be potentil surrogte mrker for egfr-tki efficcy. Whether rsh reflects the locl effects of egfr inhibition in skin or indictes systemic inflmmtory rection, it my serve s useful phrmcodynmic mrker of trget inhibition 22. The reltionship between rsh nd survivl is currently being evluted in ongoing studies, nd results should help guide the use of egfr-tkis. 3. DIARRHEA INDUCED BY EGFR-TKIs 3.1 Ptient Monitoring nd Dirrhe Cuses nd Incidence Ptients should be dvised to immeditely discuss ny symptoms of dirrhe with their helth cre tem. The dirrhe cn then be mnged erly nd effectively, preventing dose reductions or tretment discontinution. Becuse dirrhe is common side effect of mny cncer tretment regimens, mngement of dirrhe in the oncology setting is well estblished 53 55. Dirrhe induced by egfr-tkis is thought to be result of excess chloride secretion, cusing secretory form of dirrhe 10. Severe dirrhe cn result in fluid nd electrolyte losses, which my led to dehydrtion, electrolyte imblnces, nd renl insufficiency. Nutritionl deficiencies cn lso develop from ltertions in gstrointestinl trnsit nd digestion, negtively ffecting ptient s qulity of life 55. The incidence of dirrhe with egfr-tkis vries from 27% to 87% in phse iii clinicl trils, with up to 25% of ptients experiencing severe rections (grde 3 or higher; Tble iv). Tble ii gives detiled description of the clinicl trils tht hve exmined the incidence of dirrhe with egfr-tkis in nsclc. 3.2 Assessment nd Grding The first step in the ssessment of egfr-tki induced dirrhe is to rule out other potentil cuses. Possible cuses of dirrhe include medictions such s lxtives, stool softeners, ntcids, or ntibiotics; dietry fctors, such s excess consumption of fibre or lctose; comorbid infections; intestinl obstruction; fecl impction; surgeries such s short-bowel or gstrectomy; nd rdition toxicity. Lbortory investigtions re lso useful to rule out other cuses of dirrhe. Recommended tble iv Incidence of dirrhe with epiderml growth fctor receptor (egfr) tyrosine kinse inhibitors (tkis) in non-smll-cell lung cncer trils egfr-tki Description Grde (%) Erlotinib All studies 10 69 0 17 150 mg Phse iii studies 40 68 2 12 Gefitinib All studies 27 75 0 25 250 mg nd 500 mg 250 mg 27 58 0 10 All 3 500 mg 51 75 5 25 Phse iii studies 27 69 3 25 250 mg 27 58 3 10 500 mg 51 69 12 25 Aftinib All studies 67 100 0 33 40 mg nd 50 mg 40 mg 67 97 0 7 50 mg 87 100 17 33 Phse iii studies 50 mg 87 17 PF-00299804 All studies (phse ii) 77 97 0 15 15 mg, 30 mg, nd 45 mg 30 mg 77 0 45 mg 81 97 13 15 No phse iii study results using PF-00299804 re vilble to dte. 134
EGFR-TKIs IN ADVANCED NSCLC lbortory investigtions include complete blood count nd differentil to rule out neutropeni, blood tests to ssess renl function nd to determine the presence of electrolyte bnormlities, nd stool culture or Clostridium difficile toxin screen to identify whether bcteril pthogens re present. Other investigtions my include bdominl rdiogrphy, endoscopy, or biopsy to rule out co-existing disorders such s bowel obstruction or perfortion. Additionl informtion such s the durtion of the episode, stool chrcteristics, nd co-existing symptoms should lso be obtined during the ptient evlution 54,55. The nci ctce re generlly used to grde dirrhe severity (Tble v). However, becuse the nci criteri do not provide complete ssessment, the dditionl informtion lredy described should be obtined during the ptient evlution 54,55. 3.3 Mngement Although egfr-tki induced dirrhe is usully mild to moderte, erly mngement is essentil to prevent dose reduction or discontinution of nticncer therpies. The mngement of egfr-tki induced dirrhe is identicl to tht of chemotherpy-induced dirrhe nd cn generlly be hndled using dietry chnges nd ntidirrhel medictions 53 55. Dietry modifictions re not recommended in nticiption of dirrhe, nd ptients without symptoms my et n unrestricted diet. Ptients experiencing dirrhe should void foods tht excerbte symptoms, such s gresy, spicy, nd fried items. An initil brt diet of bnns, rice, pple suce, nd tost is often helpful until symptoms begin to resolve. Foods tht re difficult to digest such s cbbge, Brussels sprouts, nd broccoli should be voided, becuse those foods my increse bdominl crmping nd bloting. Once dirrhe begins to improve, tble v Grde 1 Grde 2 Grde 3 Grde 4 Grde 5 U.S. Ntionl Cncer Institute grding for dirrhe Increse of fewer thn 4 stools per dy over bseline Increse of 4 6 stools per dy over bseline Increse of 7 or more stools per dy over bseline Incontinence Hospitliztion indicted Limits self-cre ctivities of dily living Life-thretening consequences Urgent intervention indicted Deth Adpted from the Common Terminology Criteri for Adverse Events, v4.03, 2010 46. other foods such s pst, chicken without skin, nd eggs my be dded s tolerted 53 55. Dily fluid intke of pproximtely 3 4 L is recommended to void dehydrtion from volume loss ttributble to dirrhe. At lest some of the fluids should contin sugr or slt to void hypontremi nd hypoklemi cused by electrolyte loss. Good options include non-cffeinted beverges, geltine products, nd cler broths. Milk products should be voided for bout week fter dirrhe episode becuse lctse ctivity my be diminished during prolonged dirrhe, resulting in temporry lctose intolernce 53 55. The phrmcologic mngement of dirrhe is usully limited to tretment with over-the-counter lopermide (Figure 3). Ptients should begin tking lopermide t the first sign of dirrhe, strting with 4 mg (2 tblets), followed by 2 mg (1 tblet) every 4 hours or fter ech loose stool to mximum dose of 20 mg (10 tblets) dily. If dirrhe persists for more thn 24 hours, the dose of lopermide my be incresed to 4 mg, followed by 2 mg every 2 hours. After 12 hours hve pssed with no episodes of dirrhe, phrmcologic tretment cn be stopped, nd the ptient s diet cn be expnded s tolerted 53 56. If ptients present with grde 3 or 4 dirrhe, dose reduction or discontinution of egfr-tkis my be necessry. If dirrhe fils to resolve fter dose reduction or discontinution, use of octreotide my be considered. It is very unlikely tht octreotide would be needed to combt egfr-tki induced dirrhe s it is for chemotherpy-induced dirrhe; no evidence supports its use in the egfr-tki setting. In generl, most physicins would therefore discontinue egfr-tki therpy rther thn strt tretment with octreotide. Once severe dirrhe hs subsided, egfr-tkis my be restrted t lower dose. 4. SUMMARY Despite the success of pltinum doublets, the need for more effective gents in the tretment of dvnced nsclc remins. Becuse nsclc ptients re often symptomtic nd my hve number of comorbidities, effective, low-toxicity tretment options re lso required. The dvent of trgeted therpies hs led to the development of number of less toxic nticncer gents 8,10. Trgeting the egfr pthwy hs proved to be n effective strtegy in number of cncers, including nsclc. Clinicl trils using egfr-tkis in nsclc hve demonstrted promising nticncer ctivity, resulting in improved tumour control nd ptient survivl 8,10. Although egfr-tkis hve been successful in improving clinicl outcomes, they often result in number of bothersome side effects, such s rsh nd dirrhe. Strtegies to mnge those dverse effects re essentil to increse ptient complince, 135
figure 3 Mngement of dirrhe induced by epiderml growth fctor receptor (egfr) tyrosine kinse inhibitor (tki). Adpted from BC Cncer Agency, 2004 54 ; Moore et l., 2007 52 ; nd Sltz, 2003 53. Strting dose is 4 mg, followed by 2 mg for mximum of 20 mg dily. qulity of life, nd overll tretment outcome. With proper nd erly mngement, egfr-tkis my provide less toxic tretment option for ptients with dvnced nsclc 8,10. 5. CONFLICT OF INTEREST DISCLOSURES The uthor cknowledges medicl writing support from Ann Christofides msc rd of SAGE Medic; her support ws funded by Boehringer Ingelheim Cnd. 6. REFERENCES 1. Cndin Cncer Society s Steering Committee. Cndin Cncer Sttistics 2010. Toronto, ON: Cndin Cncer Society; 2010. [Avilble online t: www.cncer.c/cnd-wide/ bout cncer/cncer sttistics/~/medi/ccs/cnd wide/ Files List/English files heding/pdf not in publictions section/ Cndin Cncer Sttistics2020102020English.shx; cited September 14, 2010] 2. United Sttes, Ntionl Institutes of Helth, Ntionl Cncer Institute (nci). Non-smll cell lung cncer tretment (PDQ) [Web pge]. Helth professionl version. Bethesd, MD: nih. [Avilble t: www.cncer.gov/cncertopics/pdq/ tretment/non-smll-cell-lung/helthprofessionl; cited September 12, 2010] 3. Sndler A, Yi J, Dhlberg S, et l. Tretment outcomes by tumour histology in Estern Coopertive Group study E4599 of bevcizumb with pclitxel/crbopltin for dvnced non-smll cell lung cncer. J Thorc Oncol 2010;5:1416 23. 4. Ntionl Comprehensive Cncer Network (nccn). NCCN Clinicl Prctice Guidelines in Oncology: Non-Smll Cell Lung Cncer. Ver. 2.2010. Fort Wshington, PA: nccn; 2010. 136
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