Curr Oncol, Vol. 21, pp. 329-336; doi: http://dx.doi.org/10.3747/co.21.2241

PRACTICE

GUIDELINE

Management of diarrhea induced by epidermal growth factor receptor tyrosine kinase inhibitors V Hirsh md,* N . Blais md msc/ R. Burkes md/ S. Verma md/ and K. Croitoru mdcm11 ABSTRACT T reatm en t for n o n -sm all-c ell lu n g ca n c e r ( n s c l c ) is m o v in g aw ay fro m trad itio n al c h em o th erap y tow ard p e r s o n a liz e d m e d ic in e . T h e re v e rs ib le ty ro s in e k in a se in h ib ito rs ( t k i s ) erlo tin ib and gefitinib w ere d e v e lo p e d to ta rg e t th e e p id e rm a l g ro w th fa c to r re cep to r ( e g f r ) . A fatin ib , an irreversible ErbB fam ­ ily blocker, w as d eveloped to blo ck e g f r (E rb B l), h u m an ep id erm al g ro w th fa cto r re c e p to r 2 (ErbB 2), an d E rbB 4 sig n allin g, and tran sp h o sp h o ry latio n o f E rbB 3. A ll o f th e fo regoing agents are efficacious in tre a tin g n s c l c , and th e ir adverse event profile is d if­ feren t fro m th at o f chem otherapy. Two o f the m ost co m m o n ad v erse events w ith e g f r t k i s are ra sh and d iarrh ea. H ere, w e focus on d iarrh ea. T he key to su ccessfu l m an ag em en t o f d iarrh ea is to trea t early an d agg ressiv ely u sin g p atien t education, diet, and a n tid iarrh eal m ed icatio n s such as loperam ide. We also p re sen t strateg ies for the effective assessm ent an d m an ag em en t o f e g f r TK i-induced diarrhea.

KEYWORDS N o n -sm all-cell lung cancer, epiderm al g row th factor recep to r, ty ro sin e k in ase in h ib ito rs, adverse events, d iarrh ea m an ag em en t

1. INTRODUCTION N o n -sm a ll-c ell lung ca n cer ( n s c l c ) , w ith its th ree m a in h isto lo g ic su b ty p e s, a d e n o carcin o m a, sq u a ­ m o u s cell carcin o m a, and large cell an ap lastic car­ cin o m a, acco u n ts for ap p ro x im ately 85% o f all lung c a n c e rs1’2. T h e h etero g en eo u s h istologies o f n s c l c have trad itio n ally b een gro u p ed b ecau se o f sim ila ri­ ties in tre a tm e n t and prognosis; how ever, evidence show s th at they can respond differently to treatm en t3. M ost p atien ts w ith n s c l c receive ch em otherapy as first-lin e treatm en t. H ow ever, in n s c l c patients w ith eith er an EGFR m u tatio n (10% —15% o f w h ite4 and 2 0 % -4 0 % o f A sian 5 n s c l c patients) or an A L K

m u tatio n (3% —5% o f n s c l c p atien ts)6,7, the appro ach to trea tm e n t is m o v in g to w ard targ e ted agents. A l­ th o u g h m an y such patien ts w ill u ltim ate ly receive chem otherapy, targ e ted agents allow for a p erso n a l­ ized ap p ro ach to tre a tm e n t th ro u g h identificatio n o f the presence o f gene profiles o r disease-specific genes th at control ca n cer grow th. W ith re sp e c t to the ep id erm al g ro w th fa cto r re ­ c e p to r ( e g f r ) , ty ro sin e k in a se in h ib ito rs ( t k i s ) have b een developed th at im p ed e p h o sp h o ry latio n o f its in tra c e llu la r ty ro sin e k in a se co m ponent, b lock in g d o w n stre a m sig n a llin g p ath w a y s a sso c ia te d w ith the p ro liferatio n an d su rv iv al o f ca n cer ce lls8,9. For patien ts w ith EG FR m u tatio n —po sitiv e n s c l c , e g f r t k i s are an effective treatm en t, esp ecially in the firstline se ttin g 10-12. H ow ever, b ec au se o f fu rth e r m u ta­ tions such as the T 790M m utation in exon 20 o f the ty ro sin e k in ase do m ain o f e g f r , am plification o f the M ET pro to -o n co g en e, or o th er m ech an ism s, patien ts alm ost invariably develop resistance to e g f r t k i s 1 3-15. T he reversible e g f r t k i s erlo tin ib and gefitinib com pete reversibly w ith a t p for the a t p b in d in g site o f the in trac ellu la r k in ase dom ain o f the e g f r re c e p ­ to r16. T he irreversible e g f r t k i s , such as afatin ib and d acom itinib, w ere developed to o vercom e resistan ce to the reversible e g f r t k i s by b in d in g irre v ersib ly to the active site o f the k in ase d om ain o f e g f r 16. T h ey also sim u ltan eo u sly in h ib it m ultiple E rbB recep to rs and oncogenic pathw ays. F or exam ple, a fa tin ib is an E rbB fam ily blocker th at blocks e g f r (E rb B l), hu m an epiderm al g ro w th facto r re cep to r 2 (ErbB 2), and E rbB 4 signalling, and tran sp h o sp h o ry la tio n o f E rbB 317,18. A dverse events ( a e s ) w ith the e g f r t k i s are d ifferent from those w ith chem otherapy, the m ost freq u en t and m anageable b eing rash and d ia rrh e a 8.

2.

EGFR TKI-INDUCED DIARRHEA

D iarrh ea induced by e g f r t k i s is m o st likely to o cc u r in the first 4 w eeks after treatm ent initiation19,20; diar­ rhea induced by afatinib is m ost likely to o ccu r w ith in the first 7 d ay s21. T h is ty p e o f d ia rrh e a is th o u g h t

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to be p rim a rily secretory, although the m ech an ism re m a in s u n clea r22,23. S e v e r a l p o s s ib le m e c h a n is m s fo r e g f r t k i — in d u ced d ia rrh e a have b een p o stu lated . O ne th eo ry p ro p o se s th at, in n o rm al g astro in te stin a l m u co sa, e g f r , a n egative re g u la to r o f chloride secretion, is o ften o v erex p re sse d 23. T h e e g f r t k is m ig h t block th at re g u latio n pathw ay, in creasin g chloride sec re­ tio n , w h ich w o u ld in d u ce s e c re to ry d ia rrh e a 23,24. A n altern ativ e th e o ry is th a t the e g f r t k is in h ib it e g fr sig n allin g , lead in g to a red u ctio n in g ro w th and im p aired h ea lin g o f the in testin a l ep ith eliu m w here e g f r is ex p ressed , sub seq u en tly cau sin g m ucosal at­ rophy25. It has also been suggested that a com bination o f factors cause e g fr TK i-induced d iarrhea, including altered g u t m otility, colonic c ry p t dam ag e, changes in the in testin al m icroflora, and altered colonic tra n s­ p o rt21. Finally, data from the S kin Toxicity Evaluation P ro to co l w ith P an itu m u m ab ( stepp ) trial show ed th at p atien ts u sin g a p rophylactic skin trea tm e n t reg im en th at in clu d ed oral doxycycline 100 m g tw ice daily w ere less likely th a n patien ts on a reactiv e skin tre a t­ m en t re g im e n to ex p erien ce any g ra d e o f d iarrh ea (56% an d 85% resp ectiv ely )26. D o x y cy clin e co u ld be ac tin g as an a n ti-in flam m ato ry or an a n tim ic ro ­ bial agent, su p p ressin g d iarrh ea cau sed by the e g fr in h ib ito r p a n itu m u m a b , su g g estin g th at an in flam ­ m a to ry o r in fectio u s co m p o n en t m ig h t be involved.

and g ra d e 3 is an in cre ase o f 7 or m ore stools. In addition, g rade 3 includes incontinence lim itin g selfcare activ ities o f daily living, w ith h o sp italizatio n indicated. G rade 4 is considered life-threaten in g w ith u rg en t in terv en tio n in d icated , an d g ra d e 5 is death. H ow ever, u sin g the C om m on T erm in o lo g y C ri­ teria f o r A d ve rse E ve n ts alone is no t sufficien t to provide a com plete assessm ent. D u rin g ev alu atio n o f the p atien t, additional inform ation should be g a th ­ ered, in clu d in g stool c h a rac te ristic s and co ex istin g sy m ptom s and th e ir d u ra tio n 28. In ad d itio n , cau ses o f d ia rrh e a o th er th a n the e g f r t k i should b e ru le d out. O th e r p o ten tial cau ses o f d ia rrh e a in clu d e m e d ic a tio n s (stool so fte n e rs, a n ta c id s, la x a tiv e s, an tib io tic s), d ie t in to le ra n c e s (lacto se, for in stan ce), ra d ia tio n toxicity, su rg eries (short bow el sy ndrom e or gastrectom y), fecal im p a c ­ tion, intestinal ob stru ctio n , and com orbid infections. L a b o ra to ry tests can ru le out som e cau ses o f d ia r­ rhea: n e u tro p e n ia can b e d etec ted fro m a com p lete b lo o d c o u n t a n d d iffe re n tia l, re n a l fu n c tio n a n d e le c tro ly te a b n o rm a litie s c a n b e a s s e ss e d u sin g blo o d tests, an d b a c te ria l p ath o g en s can be checked th ro u g h a stool c u ltu re or C lo strid iu m d ifficile to x in sc re e n . To ru le ou t c o e x is tin g d iso rd e rs su ch as bow el isch em ia, p erfo ratio n , o r o b stru c tio n , e v a lu ­ ation w ith ab d o m in al rad io g rap h y or en d o sco p y and b io p sy can be p e rfo rm e d 8,28,29.

3. ASSESSMENT AND GRADING

4. INCIDENCE OF DIARRHEA

T h e g u id elin e m o st co m m o n ly u sed to d eterm in e th e sev e rity o f d ia rrh e a is the C om m on T erm inology C riteria f o r A d ve rse E ve n ts fro m the U .S. N atio n al C an ce r In stitu te (Table i)27. T h e a e g ra d es are deter­ m in ed in p a rt by the in crease in the n u m b er o f stools p e r day o v er baseline: g ra d e 1 is an in cre ase o f less th a n 4 stools, g rad e 2 is an in crease o f 4 —6 stools,

In p h ase in clin ical tria ls involving e g fr t k is , the in ­ cidence o f d ia rrh e a v arie d su b stan tially by d ru g and d osage given (Table ii). In the trials, the in cid en ce o f d iarrh ea ran g ed fro m 18% to 95% , w ith up to 25% o f patien ts ex p e rien cin g g rad e 3 or h ig h er d iarrh ea. Interestingly, the incidence o f g rad e 3 d iarrh ea in th e Lux-Lung 3 trial, w h ich co m p ared afatin ib w ith chem otherapy, w as 14.4% for patien ts w ho re ­ ceived a fa tin ib 60. H ow ever, in the Lux-Lung 6 trial, w hich w as com pleted a fte r the Lux-Lung 3 trial, the incidence o f g ra d e 3 d iarrh ea w as 5.4% for patien ts w ho receiv ed a fa tin ib — a su b stan tial d iffe re n c e 67. T he m ain d iffe ren c es in th ese tria ls w ere th e ty p e o f ch e m o th erap y given (w hich w ould no t affec t th e a e profile o f p atien ts in the afatin ib arm ) an d th e eth n ic o rig in o f th e p a tie n t p o p u latio n . T h e Lux-L ung 6 tria l h ad an all-A sian po p u latio n ; the e th n ic ity o f the p atien t p o p u latio n in Lux-Lung 3 w as 72% ea ste rn A sian, 26% w hite, and 2% other. T he d ifference in se­ vere d iarrh ea had b een speculated to be a resu lt o f the differen ce in the eth n icities o f the stu d y pop u latio n s. H ow ever, a re cen t analysis co m p arin g the in cid en ce o f diarrhea in the tw o trials by eth n icity show ed co m ­ parab le re su lts b etw e en the gro u p s (g rad e 3 d iarrh ea o c c u rre d in 9.7% o f the A sian patien ts an d in 10.9% o f the n on-A sian p atients)68. T he trea tm e n t p ro to co ls for d ia rrh e a w ere co n sisten t across the tw o trials, but the h eig h ten ed aw aren ess o f the im p o rtan ce o f

table

i

Severity of diarrhea by grade Grade

ctcae description

1

Mild

Increase of fewer than 4 stools per day over baseline

2

Moderate

Increase of 4-6 stools per day over baseline

3

Severe

Increase of 7 or more stools per day over baseline; incontinence; hospitalization indicated; limits self-care activities of daily living

4

Life-threatening

Life-threatening consequences; urgent intervention indicated

5

Death

Death

= Common Terminology Criteria for Adverse Events (ver­ sion 4.03)27.

ctcae

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MANAGEMENT OF EGFR TKI-INDUCED DIARRHEA

ii Incidence of diarrhea with epidermal growth factor receptor tyrosine kinase inhibitors from selected clinical trials in non-small-cell lung cancer3

table

Tyrosine kinase inhibitor

Erlotinib 150 mg All studies Phase in studies Gefitinib 250 mg and 500 mg All studies 250 mg 500 mg Phase m studies 250 mg 500 mg Afatinib 40 mg and 50 mg All studies 40 mg 50 mg Phase in studies 40 mg 50 mg Dacomitinib 15 mg, 30 mg, and 45 mg All studies (phase ii) 30 mg 45 mg

Grade (%) of diarrhea All

>3

10-69 18-68

0-17 1-12

27-75 27-58 51-75 27-69 27-58 51-69

0-25 0-10 5-25 1-25 1-10 12-25

67-100 67-97 87-100 87-95 88-95 87

0-37 0-14 17-37 5-17 5-14 17

77-97 77 81-97

0-15 0 13-15

Adapted and updated from Hirsh 20118-12,30-66.

tr e a t i n g d ia r r h e a e a r ly m ig h t h a v e b e e n th e r e a s o n th a t th e in c id e n c e o f h ig h - g r a d e e v e n ts d r o p p e d in th e L u x -L u n g 6 tr ia l. In a d d i tio n , th e o n c o lo g is ts in th e L u x -L u n g 3 tr ia l w e r e le s s e x p e r ie n c e d a t t r e a t ­ in g e g f r t k i —in d u c e d d ia r r h e a b e c a u s e o f th e s m a ll n u m b e r o f p a t ie n t s ( 1 - 3 p a tie n ts ) in s o m e c e n tr e s .

5.

IMPACT OF DIARRHEA

D ia r r h e a c a n c a u s e d is c o m f o r t, f a tig u e , a n d s le e p d is ­ t u r b a n c e , a n d c a n a f f e c t s o c ia l f u n c ti o n in g b e c a u s e p a t ie n t s a r e r e lu c ta n t to le a v e th e h o u s e . A lte r a tio n s in g a s tr o i n te s tin a l tr a n s i t a n d d ig e s tio n c a n le a d to n u t r i t i o n a l d e f ic ie n c ie s t h a t c a n n e g a tiv e ly a f f e c t q u a l i t y o f life . S e v e r e d i a r r h e a c a n r e s u l t in f lu id a n d e l e c tr o l y te lo s s , w h ic h c a n le a d to d e h y d r a tio n , e l e c t r o l y t e im b a la n c e s , a n d r e n a l i n s u f f i c i e n c y 28. N o ta b ly , a l th o u g h m o s t c lin ic a l t r i a l r e s u lt s d o n o t r e p o r t m o d e ra te d ia rr h e a (g ra d e 2) a s a s e p a ra te c a te g o r y ( th e y u s u a lly r e p o r t a ll g r a d e s a n d g r a d e s 3 a n d 4 ), in o u r e x p e r t o p in io n , g r a d e 2 d i a r r h e a is n o t in c o n s e q u e n tia l a n d c a n h a v e a s ig n if ic a n t e f f e c t o n q u a l ity o f life . A lth o u g h d i a r r h e a c a n h a v e a p r o f o u n d e f f e c t o n p a tie n ts , a v a ila b le e v id e n c e s u g g e s ts th a t d i a r r h e a is

a n in d ic a t o r th a t e g f r t k i s a r e w o r k in g e f f e c tiv e ly . In a r e tr o s p e c tiv e s tu d y o f p a t ie n t s w ith n s c l c tr e a te d w i t h g e f it in ib o n th e E x p a n d e d A c c e s s P r o g r a m a t th e M D A n d e r s o n C a n c e r C e n te r, u n iv a r ia te a n d m u lt iv a r ia te a n a ly s e s w e r e u s e d to d e t e r m in e r e la tio n s h ip s b e tw e e n p a tie n t c h a r a c te r is tic s an d tr e a t m e n t o u tc o m e s . A m o n g p a t ie n t s w h o r e c e iv e d g e f itin ib 2 5 0 m g , th e p r e s e n c e o f d ia r r h e a w a s id e n ti­ fie d a s o n e o f th e in d e p e n d e n t p r e d ic to r s o f a p a r ti a l r e s p o n s e , a n d th e a b s e n c e o f d i a r r h e a w a s o n e o f th e p r e d ic to r s o f p r o g r e s s iv e d i s e a s e 69. A s tu d y o f e g f r t k i s th a t in c lu d e d d a t a f r o m p h a s e ii c lin ic a l tr ia ls o f g e f itin ib a n d e r lo t in ib in p a tie n ts w ith r e c u r r e n t a n d m e ta s ta ti c s q u a m o u s c e ll c a r c in o m a o f th e h e a d a n d n e c k s h o w e d a s im ila r a s s o c ia tio n b e t w e e n e g f r t k i —in d u c e d d i a r r h e a a n d c lin ic a l b e n e f it a n d a ls o a n a s s o c ia tio n w ith m o r e f a v o u r a b le o v e r a ll s u r v i v a l 70. F in a lly , c o m b in e d a e d a t a f r o m th e L u x -L u n g 3 a n d L u x -L u n g 6 t r ia ls c o m p a r in g a f a tin ib w ith c h e m o ­ t h e r a p y in p a t ie n t s w ith EG FR m u t a t i o n —p o s it iv e n s c l c s h o w e d a t r e n d to w a r d a h ig h e r r a te o f p r o ­ g r e s s io n - f r e e s u r v iv a l in p a tie n ts w h o h a d g r a d e 2 o r g r e a t e r d i a r r h e a in th e f ir s t 2 8 d a y s o f tr e a t m e n t w ith a f a tin ib ( c o m p a r e d w ith p a tie n ts w h o e x p e r ie n c e d n o a e s ) ; h o w e v e r, n o s ta tis t ic a lly s ig n if ic a n t d if f e r e n c e s w e r e o b s e r v e d 65.

6.

MANAGEMENT

D ia r r h e a a s s o c ia te d w ith ta k in g a n e g f r t k i u s u a lly r a n g e s f r o m m ild ( g r a d e 1) to m o d e r a te ( g r a d e 2). D ie t a r y c h a n g e s a n d a n t id ia r r h e a l m e d ic a tio n s a r e u s u a lly s u f fic ie n t to c o n tro l d ia r r h e a 8’28,29’71. H o w ­ e v e r, to a v o id e s c a la tio n o f s y m p to m s a n d to p r e v e n t d o s e r e d u c tio n o r d is c o n tin u a tio n o f th e e g f r t k i , it is c r itic a l to m a n a g e s y m p to m s a n d flu id in ta k e ea rly . M a n a g e m e n t o f e g f r t k i —in d u c e d d ia r r h e a is id e n tic a l to m a n a g e m e n t o f c h e m o th e ra p y - in d u c e d d ia r r h e a a n d in c lu d e s p a tie n t e d u c a tio n a n d b o th n o n p h a r m a c o lo g ic a n d p h a r m a c o lo g ic m a n a g e m e n t s tr a te g ie s .

6.1 Education and Nonpharmacologic Management Strategies P a tie n t e d u c a tio n s h o u ld id e a lly b e g in b e f o r e t r e a t ­ m e n t a n d c o n t in u e t h r o u g h o u t t r e a tm e n t. P a tie n ts s h o u ld b e a d v is e d to d is c u s s w ith th e h e a lth c a r e te a m a n y s y m p t o m s o f d i a r r h e a a s s o o n a s t h e y o c c u r . It is c r itic a l th a t p a t ie n t s u n d e r s ta n d th e im p o r ta n c e o f m a n a g i n g s y m p t o m s e a r ly a n d a g g r e s s iv e ly to a v o id e g f r t k i d is c o n tin u a tio n , w h ic h h a s n e g a tiv e c o n s e q u e n c e s . F o r th e f ir s t 4 w e e k s o f t r e a tm e n t, a n u r s e f a m i lia r w ith e g f r T K i-in d u c e d d ia r r h e a s h o u ld b e a s s ig n e d to s p e a k w ith th e p a t ie n t e v e r y w e e k , in p e r s o n o r o n th e te le p h o n e , to m o n it o r a e s th a t m ig h t o c c u r . P a tie n ts s h o u ld a ls o b e a d v i s e d o f n o n p h a r m a ­ c o lo g ic m a n a g e m e n t s tr a t e g ie s , w h ic h in c lu d e d i ­ e t a r y c h a n g e , f lu id in ta k e , a n d p r o b io tic s . A p a t ie n t

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w ho experiences diarrhea should adopt the b r a t diet (bananas, rice, applesauce, toast) and should elim inate greasy, spicy, and fried foods that can m ake sym ptom s w orse and also cruciferous veg­ etables that can increase bloating and abdom inal cram ping. For approxim ately 1 week after the patient experiences diarrhea, m ilk products should also be avoided because of the tem porary lactose intolerance caused by the decrease in lactase activity that can occur w ith epithelial dam age. D ietary changes are not recom m ended in anticipation o f diarrhea— that is, prophylactically. O nce sym ptom s improve, the patient can introduce foods such as eggs, pasta, and skinless chicken if tolerated8,28,29’71. In addition to dietary changes, patients should drin k 3 - 4 L o f fluid daily to prevent dehydration. To avoid hyponatrem ia or hypokalem ia from loss o f electrolytes, some o f the fluid intake should include sugar or salt21. T here is som e evidence that supplem entation w ith probiotics m ight reduce the severity o f chem o­ therapy-induced diarrhea and abdom inal discom ­ fort, w ith few or no a e s 7 2 . In a study by O sterlund et al., Lactobacillus supplem entation reduced the frequency o f grades 3 and 4 diarrhea73. Com pared w ith patients in the control arm o f the study, patients w ho received supplem entation w ith Lactobacillus during chem otherapy also reported less abdom inal discom fort and had fewer chem otherapy dose reduc­ tions73, findings that m ight potentially apply to e g f r t k i —induced diarrhea. However, no clinical trials have specifically evaluated the role o f probiotics in diarrhea caused by e g f r t k i s .

6.2 Pharmacologic Management Strategies Pharm acologic m anagem ent o f e g f r t k i —induced di­ arrhea is based on the grade o f diarrhea experienced (Table in) and is usually lim ited to loperam ide. No antidiarrheal m edication is taken prophylactically because constipation is a risk, especially if the patient is already taking narcotics for pain m anagem ent, and because not all patients will develop diarrhea. Should diarrhea arise, the patient’s current medication should be reviewed, w ith an emphasis on the removal o f stool softeners and laxatives. B efore patients initiate e g f r t k i therapy, they should be prescribed an antidiarrheal agent such as loperam ide and be advised to start tak in g it im ­ m ediately upon onset o f diarrhea. For mild (grade 1) diarrhea, the patient should take 4 mg (2 tablets) o f loperam ide im m ediately after sym ptom s begin and then 2 mg (1 tablet) after each loose stool to a m axim um o f 20 m g daily until 12 hours have passed w ith no episodes o f diarrhea. If diarrhea persists or becom es m oderate (grade 2), the patient should continue w ith loperam ide (to a m axim um o f 20 mg daily, as for grade 1) and be assessed for dehydration and electrolyte im balances. I f the diarrhea reaches grade 3 or 4, the patient should be hospitalized. At

th at point, loperam ide should be continued, and aggressive intravenous fluid replacem ent should be initiated. In addition, infection should be ruled out by stool culture, and if the patient is neutropenic, antibiotics should be given prophylactically8,21. A l­ though it m ight not be necessary for the oncologist to consult w ith a gastroenterologist on an outpatient basis to m anage a p atien t’s diarrhea, a gastroenter­ ologist m ight be consulted once a patient is adm itted to hospital, especially if an endoscopic evaluation is required. Alternatives to loperamide are diphenoxylate—at­ ropine and codeine, either o f w hich can be used w ith loperam ide. Patients should take 5 m g (2 tablets) o f diphenoxylate—atropine 4 tim es daily (m axim um o f 20 m g daily) or 30 m g codeine every 4 hours29. The dose o f the e g f r t k i should be m aintained in the presence o f grade 1 diarrhea. At grade 2, if the patient does not respond to loperamide after 48 hours, the e g f r t k i should be tem porarily discontinued until the diarrhea returns to grade 1, at which tim e the e g f r t k i should be resum ed using these guidelines: • • •

Low er the afatinib dose by 10 mg at a tim e to a m inim um dose o f 20 mg. Low er the erlotinib dose by 50 mg at a tim e to a m inim um dose o f 50 mg (no sufficient data on efficacy are available in the literature). Resume gefitinib only at the original dose (the dose of gefitinib cannot be lowered and no data on its efficacy with a modified schedule are available)8,21.

For grade 3 or 4 diarrhea, the e g f r t k i should be w ithheld until diarrhea reaches grade 1, after which the e g f r t k i should be resum ed using the guidelines already stated. The e g f r t k i should be perm anently discontinued if diarrhea does not reach grade 1 w ithin 14 days despite best supportive care and w ithholding o f the t k i 7,20. E arlier algorithm s have suggested the use of octreotide if dose reduction or discontinuation o f the e g f r t k i w as ineffective8, but in practice, the need for octreotide is extrem ely rare, and no direct clini­ cal study supports the efficacy o f octreotide in e g f r t k i —induced diarrhea. 7.

SUMMARY

In n s c l c , targeting the e g f r signalling pathw ay has been shown to be an effective strategy for treatm ent, resulting in im proved clinical outcom es. The clini­ cal success o f these treatm ents is associated w ith a num ber o f a e s , including diarrhea. The efficacy o f e g f r t k i s is frequently correlated w ith the presence o f diarrhea. The key to m anaging diarrhea is to educate pa­ tients about this a e before treatm ent starts. Patients should be m onitored weekly for the first 4 weeks of treatm ent, which is the period during which diarrhea

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MANAGEMENT OF EGFR TKI-INDUCED DIARRHEA

in Pharmacologic intervention for diarrhea induced by epidermal growth factor receptor (egfr) tyrosine kinase inhibitors (tkis)21, based on ctcae grade table

Grade 1 Mild

Intervention Stop laxatives. Drink 8-10 glasses of clear fluids daily. Immediately start loperamide: 4 mg (2 tablets) followed by 2 mg (1 tablet) after each loose stool (up to 20 mg daily) until bowel movements cease for 12 hours. Maintain dose level of egfr tki.

2 Moderate

See grade 1. Continue loperamide. Assess for dehydra­ tion and electrolyte imbalance. Consider in­ travenous fluids and electrolyte replacement. If diarrhea does not improve after 48 hours, temporarily discontinue egfr tki. Upon im­ provement to grade 1, restart egfr tki at a reduced dose (except gefitinib, which should be restarted at the original dose).

3 Severe

See grade 2 Plus: Use stool cultures to rule out an infec­ tious process. Apply aggressive intravenous fluid replacement for 24 hours or more. Use hospitalization to monitor the patient’s progress. Consider prophylactic antibiotics if the patient is also neutropenic. Temporarily discontinue egfr tki. Upon improvement to grade 1, restart egfr tki at a reduced dose (except gefitinib, which should be restarted at the original dose). Permanently discontinue egfr tki if diarrhea does not return to grade 1 within 14 days despite treatment discontinuation and best supportive care.

4 Life-threatening

See grade 3

5 Death = Common Terminology Criteria for Adverse Events (ver­ sion 4.03)27.

ctcae

w ill m o s t lik e ly o ccu r. N o n p h a rm a c o lo g ic m a n a g e ­ m e n t stra te g ie s in clu d e d ie ta ry ch a n g e s, su p p lem en tal h y d ra tio n , a n d e le c tro ly te re p le n ish m e n t. P h a rm a c o ­ lo g ic stra te g ie s in c lu d e th e a v o id a n c e o f la x a tiv e s a n d th e in tr o d u c tio n o f lo p e r a m id e o r d ip h e n o x y la te —

atropine. E arly m anagem ent o f e g f r TKi-induced diar­ rhea can low er the incidence o f high-grade events that could lead to hospitalization and d ru g discontinuation and, m ost im portantly, can im prove quality o f life for this group o f patients.

8. ACKNOWLEDGMENTS T h e authors ackn o w ledg e m ed ical w ritin g su p p o rt from C ath ie B e llin g h a m , PhD , o f N e w E v id en ce; th a t su p p o rt w as fu n d e d b y B o e h rin g e r In g elh eim (C anada).

9. CONFLICT OF INTEREST DISCLOSURES V H has p a rtic ip a te d on the ad v iso ry b o ard s o f B oehringer Ingelheim , Roche, A straZ eneca, Pfizer, A m gen, and M erck. NB has participated on the advi­ sory panel o f Boehringer Ingelheim . SV has received honoraria from or participated on the advisory boards o f B oehringer Ingelheim , Roche, A straZ eneca, and Pfizer, and has received research funding from Roche and Sanofi. KC has participated on advisory boards for Takea National and Boehringer Ingelheim and has received educational grants from Ferring, AbbVie, and Janssen. RB has no financial conflict o f interest relating to this paper.

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C orrespon den ce to: V era H irsh, Royal V ictoria Hospital, 687 Pine Avenue W est, M ontreal, Q uebec H3A 1A1. E -m ail: vera.hirsh@ m uhc.m cgill.ca * t t

§ 11

H em atology-O ncology Services, Santa C abrini Hospital, and D epartm ent o f Oncology, Faculty o f M edicine, M cG ill University, M ontreal, QC. D epartm ent of M edicine, University of M ontreal, M ontreal, QC. D iv isio n o f H e m ato lo g y /M ed ical O ncology, U niversity o f Toronto, M ount Sinai Hospital, and The Princess M argaret Hospital C ancer Centre, Toronto, ON. U niversity o f Toronto and M edical Oncology/ Hem atology, Sunnybrook Health Sciences C en­ tre, Toronto, ON. U niversity o f Toronto, and D ivision o f G astro­ enterology, Zane C ohen C entre for D igestive D iseases, M ount Sinai Hospital, Toronto, ON.

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