Curr Oncol, Vol. 21, pp, 181-186 doi: http://dx.doi.org/10.3747/co.21.1963
O R I G I N A L
A R T I C L E
Factors associated with delayed time to adjuvant chemotherapy in stage in colon cancer A. C han m d ,* R. W oods m s A H. K en n ecke m d , * a n d S. G ill ABSTRACT
md m ph *
p a tie n t’s tr a n s itio n fro m s u rg e ry to f i r s t c y c le o f a d ju v a n t c h e m o th e ra p y .
Background Conclusions A d ju v an t c h e m o th e ra p y sta rte d m o re th a n 56 days a fte r co lo n c a n c e r re se c tio n has b een a sso c ia te d w ith le sse r o v erall s u rv iv a l a m o n g p a tie n ts w ith stag e hi co lo n can cer. T h e o b jectiv e o f th e p re se n t p o p u la tio n -b a s e d stu d y w as to d e te rm in e , in re fe rre d p a tie n ts w ith re se c te d stag e in colon can cer, fa c to rs a sso c ia te d w ith d elay e d tim e to a d ju v a n t c h e m o th e ra p y ( t t a c ) , d efin ed as m ore th a n 56 days fro m th e d ate o f su rg ery.
M ore th an h a lf the p atien ts failed to receive adjuv an t ch e m o th erap y w ith in the reco m m en d ed t t a c o f 56 days. D elayed t t a c w as asso c ia te d w ith p ro c essrelated delays ra th e r th an w ith patient- or d iseaserelated factors. E ffo rts to im prove tim ely referral, tria g e o f co n su ltatio n s, an d ch e m o th e rap y w a it lists are req u ired .
KEYWORDS Methods C olon cancer, stage in, delay, ad ju v an t th erap y E lig ib le p a tie n ts h a d b ee n d ia g n o se d w ith stag e hi co lo n c a n c e r an d h a d re ceiv ed at le a st 1 cycle o f a d ju v an t c h e m o th e ra p y at o n e o f th e fo u r re g io n a l c a n c e r tre a tm e n t sites d u rin g 2 0 0 8 —2009. P ro g n o s tic an d tre a tm e n t in fo rm atio n w as p ro sp ectiv ely co l lecte d th ro u g h th e B C C an ce r A g e n c y ’s GI C an cers O u tc o m e s U n it, a n d C h a rlso n c o m o rb id ity sco re w as re tro s p e c tiv e ly d e te rm in e d b y c h a rt review . C h i-s q u a re a n d W ilc o x o n ra n k -s u m te s ts w e re u se d to m e a su re a sso c ia tio n s b e tw e e n th e tim in g o f a d ju v a n t c h e m o th e ra p y an d selec t p ro g n o stic an d tre a tm e n t v aria b les.
Results M e d ia n t t a c fro m s u rg e ry fo r th e 395 in c lu d e d p a tie n ts w a s 58 d a y s, w ith 54% o f th e p a tie n ts r e c e i v i n g a d ju v a n t c h e m o th e r a p y b e y o n d th e re c o m m e n d e d 56 d a y s. O n m u ltiv a r ia te a n a ly s is , o n ly tr e a tm e n t at th e h ig h e s t-v o lu m e s ite w a s in d e p e n d e n t ly a s s o c ia te d w ith d e la y e d t t a c . C o m o r b id ity in d e x , a g e , p e r f o r m a n c e s t a t u s , T s ta g e , tu m o u r lo c a tio n , a n d o ra l c h e m o th e ra p y (c o m p a re d w ith in tra v e n o u s) w e re n o t in d e p e n d e n tly a s s o c ia te d w ith d e la y e d t t a c . D e la y s w e re o b s e rv e d d u rin g e a c h in te rv a l a s s o c ia te d w ith th e
1.
INTRODUCTION
C olon cancer is responsible for 8900 deaths annually in C anada and represents the 2nd m ost com m on cause o f cancer-related m orbidity and m o rtality 1. T he use o f adjuvant chem otherapy for resected stage h i colon can cer has b een show n to significantly low er recu rren ce rates and to im prove overall su rv iv al2. T he curren t standard o f treatm en t includes 5-fluorouracil (5fu)— b ase d ch em o th erap y w ith an y o f 5 fu—leu co v o rin 3,4, 5 fu—o x alip latin 5,6, an d ca p ecitab in e7. In clin ical trials, ad ju v an t chem o th erap y is ty p i cally in itia te d w ith in 6 —8 w eeks a fte r surgery, but it h as b een show n that, outside o f the clinical trial setting, up to 19% o f patients do not receive adjuv an t th e ra p y w ith in th a t p e rio d 8. S everal re cen t m e ta analyses have co nfirm ed that delayed ad m in istratio n o f adjuvant chem otherapy after curative surgery is as sociated w ith significantly lesser overall su rv iv al9’10. In the p re sen t study, w e u sed a c o n tem p o rary p o p u latio n -b ase d p atien t co h o rt in the p ro v in ce o f B ritish C olum bia to asc e rta in the tem poral facto rs an d p atien t c h a rac te ristic s asso c ia te d w ith delayed d eliv ery o f ad ju v an t ch e m o th erap y in re ferred p a tien ts w ith re se c te d stage in colon cancer.
_____________________________________________________ C urrent O ncology— V olume 21 , N umber 4 , A ugust 2014 Copyright © 2014 Multimed Inc. Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
181
CHAN et al.
2.
METHODS
2.1 Data Source P atien ts w ith re se c te d stag e in co lo n c a n c e r w ho w ere re ferred to the B C C an c e r A g en cy ( b c c a ) w ere identified in th e GI C ancers O utcom es U nit database. T he b c c a is a provincial cancer agency responsible for tre a tm e n t p olicy and fu n d in g o f all system ic therapy in a p ro v in ce o f 4.4 m illion. O f all p atien ts w ith a d iag n o sis o f colon cancer, 65% are referred to one o f five treatm ent centres. Data relatin g to receip t o f chem o th erap y is ca p tu red in the p ro v in cial p h a rm a c y database. F or the p u rp o se s o f th e p re sen t an alysis, tw o o f the ca n c e r cen tres w ere co n sid ered to g eth er (“ce n tre C ”) b ec au se o f low p a tient volum es at the m ost new ly opened cancer centre. P ro v in cial trea tm e n t g u id elin es d u rin g the study p erio d re co m m en d ed th at adjuvant chem otherapy be in itiated w ith in 8 w eeks o f definitive surgery. For eligible p atien ts w ith stage in colon cancer, the re c o m m en d ed reg im en is 6 m onths o f m odified f o l f o x 6 (le u c o v o rin , 5 -flu o ro u rac il, o x alip latin ); a d ju v an t ca p ecitab in e is reco m m en d ed fo r p atien ts d eem ed to be inelig ib le for f o l f o x 6 .
2.2 Patient Selection P atien ts w ith re sected stage in colon ca n c e r referred to th e b c c a b etw een Jan u a ry 1, 2008, and D ecem b e r 31, 2009, an d tre a te d w ith at le a st 1 cycle o f ad ju v an t ch em o therapy w ere included. P atients w ere exclu d ed i f th ey h ad p rev io u sly b een d iag n o sed w ith a colon cancer, i f any p o rtio n o f th e ir colon ca n cer tre a tm e n t (in cluding su rg e ry o r chem otherapy) w as p e rfo rm e d o u tsid e o f B ritish C o lu m b ia, o r i f the re ferral w as for a second opinion. T h e stu d y w as a p p ro v e d by th e U n iv e rsity o f B ritish C o lu m b ia R esearch E thics B oard.
2.3 Data Collection P a tie n t d a ta c o lle c te d in c lu d e d age, sex, E a ste rn C o o p era tiv e O n co lo g y G ro u p ( e c o g ) p e rfo rm a n c e s ta tu s (as r e p o r te d b y th e tr e a tin g p h y s ic ia n at co n su ltatio n ), ty p e o f chem otherapy, an d reg io n al tre a tm e n t ce n tre. D ise a se fa c to r d a ta — in c lu d in g tu m o u r lo catio n , T stag e, N stage, histology, and g ra d e — w ere ab stra cted fro m the GI C an cers O ut co m es U nit database. C om o rb id ities, scored using th e C h arlso n co m o rb id ity index, w ere d eterm in e d fro m a re tro sp ectiv e ch a rt review . T h e tim e fro m cu rativ e su rg e ry to in itiatio n o f ad ju v an t ch em o th erap y ( t t a c ) w as reco rd ed , as w ere th e in terv a ls b etw e en the tim e s o f surgery, h ospital d isch arg e, re ferral to b c c a , first m edical oncology c o n s u lta tio n , an d first cy cle o f a d ju v a n t c h e m o therapy. D elayed t t a c w as defined as in itiatio n o f ch e m o th erap y m ore than 56 days a fte r surgery.
2.4 Statistical Analysis C h i-sq u are an d W ilcoxon ra n k -su m tests w ere u sed to assess d ifferen ces in c h a rac te ristic s and tim e in terv a ls for p atien ts w ho re ceiv ed delayed a n d tim ely ad ju v an t chem otherapy. M u ltiv a riate analy sis w ith logistic reg ressio n w as u sed to investigate in d e p e n dent p atien t an d tu m o u r c h a rac te ristic s p re d ic tiv e o f delayed chem otherapy.
3.
RESULTS
O f 395 re ferred p atien ts w ith re se c te d stage h i colon ca n cer w ho m et the inclusion c rite ria over the 2 -y ear study p erio d , 54% also m et the definition for delayed t t a c . M ed ian tim e fro m su rg e ry to ad ju v an t ch e m o th erap y w as 58 days. Table i p re sen ts the c h a ra c te ristic s o f th e full co h o rt and o f the tim ely an d delayed th erap y groups. M ed ian age at diag n o sis w as 65 y ears, a n d 52% o f p atien ts w ere m en. B y e n try c rite ria , all p atien ts h a d n o d e -p o sitiv e d ise a se (63% , N1 d ise a se ; th e re m a in d er, N 2 disease). M o st p a tie n ts h a d T3 tu m o u rs lo cated in the p ro x im al colon. N o sig n ifican t d ifferen ces in age o r sex w ere o b serv ed b etw e en the tim e ly and delayed ch em o th erap y groups. A lso, no significant differences w ere observed in nodal status, tu m o u r stag e, o r location o f th e p rim a ry tu m o u r. O ral ad juvant capecitab in e w as given to 40 % o f the patients, but the p ro p o rtio n o f patients receiv in g oral capecitabine com pared w ith intravenous f o l f o x 6 w as not d iffe ren t b etw een the delayed and tim ely groups. M ost p atien ts h ad a C h arlso n co m o rb id ity in d ex o f 0 —1 an d an e c o g p e rfo rm a n c e o f 0 —1. O n u n iv a ria te an aly sis (Table i), an e c o g p er fo rm an ce statu s o f 2 o r m ore w as asso c ia te d w ith a significant delay in adjuvant ch em otherapy ; a h ig h er score on the C h arlso n co m o rb id ity index w as not. Flowever, in m u ltiv ariate an aly sis (Table n), p erfo r m ance statu s did no t re ta in a significant asso ciatio n w ith delayed ch e m o th erap y {p = 0.079). Patients w ere w ell distrib u ted across h ealth re gions, w ith the m ost u rb a n centre (centre A) receiv in g the highest percentage o f referrals overall. C om pared w ith the o ther centres, centre A h ad a significantly h ig h er proportion o f patients w ho received delayed chem otherapy, and centre w as the only factor to retain significance in the m ultivariate analysis (p = 0.0004). T he m o st co m m on seq u en ce o f events w as sur gery, h ospital d isch arg e, re ferral to b c c a , m edical oncology consultation, and initiation o f adjuvant ch e m otherapy. T h at seq u en ce o c c u rre d in 69% o f cases. A s seen in Table in, significant tem p o ral d ifferen ces betw een the tim ely and delayed chem otherapy groups w ere identified in all in terv als. O v erall, th e av erag e tim e from su rg ery to referral w as 15 days; fro m refer ral to m edical oncology co n su ltatio n , 21 days; and from m edical oncology co n su ltatio n to in itiatio n o f chem otherapy, 20 days. A ll o f those in terv a ls w ere
I C urrent O ncology— V olume 21, N umber 4, A ugust 2014 | Copyright © 2014 Multimed Inc. Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
DELAYED TIME TO ADJUVANT CHEMOTHERAPY
table
i
Patient and tumour characteristics by time to adjuvant chemotherapy Variable
Patients (n)
Time to adjuvant chemotherapy
p Valuea
Overall
56 Days
395
182
213
Age at diagnosis (years) Median
65
66
65
57-72
57-72
58-72
Women
188 (48)
92 (50)
96 (45)
Men
207 (52)
90 (50)
117(55)
N1
249 (63)
119(65)
130(61)
N2
146 (37)
63 (35)
83 (39)
Tl/2
49 (12)
24 (13)
25 (12)
T3
276 (70) 68(17)
132 (73) 25 (14)
144 (68)
T4 TX
2(1)
1(1)
1(1)
Proximal
226 (57)
103 (57)
Distal
168 (43)
79 (43)
123 (58) 89 (42)
1(0)
0(0)
1 (1)
0
287 (73)
128 (70)
159 (75)
1
72 (18)
35 (19)
37(17)
2
29 (7)
16(9)
13(6)
3
5(1)
2(1)
3(1)
4
2(1)
Unknown
0(0)
1(1) 0(0)
1(1) 0(0)
0
101 (26)
44 (24)
57 (27)
1
93 (24)
49 (27)
44 (21)
2
22(6)
5(3)
17 (8)
1(0) 178 (45)
0(0) 84 (46)
1(1) 94 (44)
A
124 (31)
42 (23)
82 (39)
B
79 (20)
31(17)
48 (23)
C
110(28)
58 (32)
52 (24)
D
82 (21)
51 (28)
31 (15)
Intravenous 5 fu ± oxaliplatin
235 (60)
104 (57)
131 (62)
Oral capecitabine monotherapy
160 (40)
78 (43)
82 (39)
Interquartile range
0.8119
Sex [n (%)] 0.2771
N Stage [« (%)] 0.3718
Pathologic T stage [n (%)] 0.2370
43 (20)
Tumour location [n (%)]
Colon nos cci
0.7755
score \n (%)] 0.5802
ECOG PS [n ( % )]
3 Unknown
0.0257
Centre [n (%)] 0.0002
Chemotherapy type [n (%)] 0.3790
a Unknown, TX, and colon nos were removed before statistical testing was performed. Scores of 2 or 3 on the ecog ps and scores 2, 3, or 4 on the cci were pooled for statistical testing. nos = not otherwise specified; cci = Charlson comorbidity index; ecog ps = Eastern Cooperative Oncology Group performance status; 5 fu = 5-fluorouracil. __________________________________________________ C urrent O ncology— V olume 21, N umber 4, A ugust 2014 Copyright © 2014 Multimed Inc. Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
183
CHAN etal.
table
ii Multivariate model for predictors of delayed adjuvant chemotherapy Type h i p valuea
Comparison
OR
95% cl
p Valuea
Age at diagnosis Sex N Stage Pathologic T stage
0.7320 0.2664 0.5219 0.1888
cci
Tumour location score
0.6174 0.8270
ECOG PS
0.0789
Centre
0.0004
Chemotherapy type
0.7238
Per year Men vs. women N2 vs. N1 T3 vs. T1/T2 T4 vs. T1/T2 Distal vs. proximal 1 vs. 0 2+ vs. 0 1 vs. 0 2 and 3 vs. 0 Unknown vs. 0 B vs. A C vs. A D vs. A Capecitabine vs. folfox
l 1.27 1.16 1.04 1.76 0.9 0.9 0.81 0.8 3.47 1.04 0.68 0.42 0.28 1.1
0.97, 1.02 0.83, 1.95 0.74, 1.82 0.54, 2.02 0.79, 3.93 0.58,1.38 0.52, 1.57 0.39, 1.71 0.44, 1.46 1.14, 10.51 0.6, 1.8 0.36, 1.28 0.24, 0.74 0.15, 0.54 0.65, 1.85
0.7320 0.2664 0.5219 0.9006 0.1690 0.6174 0.7107 0.5850 0.4632 0.0279 0.8990 0.2269 0.0027 0.0001 0.7238
Variable
a The type h i p value column represents the variable’s overall contribution to the model; thep value column represents the specific comparison (“Comparison” column) involving the variable. or = odds ratio; cl = confidence limits; cci = Charlson comorbidity index; ecog ps = Eastern Cooperative Oncology Group performance status; folfox = leucovorin-5-fluorouracil-oxaliplatin.
ta b le hi
Differences in process time intervals between timely and delayed adjuvant chemotherapy Variable
Surgery to referral (days) Median Interquartile range Range Referral to medical oncology consultation (days) Median Interquartile range Range Medical oncology consultation to chemotherapy (days) Median Interquartile range Range
sig n ifican tly in cre ased in the delayed ttac cohort. O n average, the delayed co h o rt co m m en c ed adju v a n t ch em o th erap y 67 days a fte r su rg ery ; the tim ely co h o rt s ta rte d adjuvant chem o th erap y an average o f 43 days a fte r surgery. 4.
D IS C U S S IO N
In this population-based analysis exam ining the fac tors associated w ith ttac, m ore than h a lf the patients referred w ith resected stage in colon cancer (54%) re ceived delayed adjuvant chemotherapy. This real-world
184
Time to adjuvant chemotherapy Overall
56 Days
(n=370) 15 10-22 1-106 («=349) 21 14-27 0-55 (w=395) 20 12-28 0-121
(n=164) 12 9-17 2-41 («=156) 17 12-22 0-40 («=182) 14 7-21 0-48
(n=206) 18 12-27 1-106 («=193) 23 17-31 0-55 («=213) 26 15-36 0-121
p Value
O R I G I N A L
A R T I C L E
Factors associated with delayed time to adjuvant chemotherapy in stage in colon cancer A. C han m d ,* R. W oods m s A H. K en n ecke m d , * a n d S. G ill ABSTRACT
md m ph *
p a tie n t’s tr a n s itio n fro m s u rg e ry to f i r s t c y c le o f a d ju v a n t c h e m o th e ra p y .
Background Conclusions A d ju v an t c h e m o th e ra p y sta rte d m o re th a n 56 days a fte r co lo n c a n c e r re se c tio n has b een a sso c ia te d w ith le sse r o v erall s u rv iv a l a m o n g p a tie n ts w ith stag e hi co lo n can cer. T h e o b jectiv e o f th e p re se n t p o p u la tio n -b a s e d stu d y w as to d e te rm in e , in re fe rre d p a tie n ts w ith re se c te d stag e in colon can cer, fa c to rs a sso c ia te d w ith d elay e d tim e to a d ju v a n t c h e m o th e ra p y ( t t a c ) , d efin ed as m ore th a n 56 days fro m th e d ate o f su rg ery.
M ore th an h a lf the p atien ts failed to receive adjuv an t ch e m o th erap y w ith in the reco m m en d ed t t a c o f 56 days. D elayed t t a c w as asso c ia te d w ith p ro c essrelated delays ra th e r th an w ith patient- or d iseaserelated factors. E ffo rts to im prove tim ely referral, tria g e o f co n su ltatio n s, an d ch e m o th e rap y w a it lists are req u ired .
KEYWORDS Methods C olon cancer, stage in, delay, ad ju v an t th erap y E lig ib le p a tie n ts h a d b ee n d ia g n o se d w ith stag e hi co lo n c a n c e r an d h a d re ceiv ed at le a st 1 cycle o f a d ju v an t c h e m o th e ra p y at o n e o f th e fo u r re g io n a l c a n c e r tre a tm e n t sites d u rin g 2 0 0 8 —2009. P ro g n o s tic an d tre a tm e n t in fo rm atio n w as p ro sp ectiv ely co l lecte d th ro u g h th e B C C an ce r A g e n c y ’s GI C an cers O u tc o m e s U n it, a n d C h a rlso n c o m o rb id ity sco re w as re tro s p e c tiv e ly d e te rm in e d b y c h a rt review . C h i-s q u a re a n d W ilc o x o n ra n k -s u m te s ts w e re u se d to m e a su re a sso c ia tio n s b e tw e e n th e tim in g o f a d ju v a n t c h e m o th e ra p y an d selec t p ro g n o stic an d tre a tm e n t v aria b les.
Results M e d ia n t t a c fro m s u rg e ry fo r th e 395 in c lu d e d p a tie n ts w a s 58 d a y s, w ith 54% o f th e p a tie n ts r e c e i v i n g a d ju v a n t c h e m o th e r a p y b e y o n d th e re c o m m e n d e d 56 d a y s. O n m u ltiv a r ia te a n a ly s is , o n ly tr e a tm e n t at th e h ig h e s t-v o lu m e s ite w a s in d e p e n d e n t ly a s s o c ia te d w ith d e la y e d t t a c . C o m o r b id ity in d e x , a g e , p e r f o r m a n c e s t a t u s , T s ta g e , tu m o u r lo c a tio n , a n d o ra l c h e m o th e ra p y (c o m p a re d w ith in tra v e n o u s) w e re n o t in d e p e n d e n tly a s s o c ia te d w ith d e la y e d t t a c . D e la y s w e re o b s e rv e d d u rin g e a c h in te rv a l a s s o c ia te d w ith th e
1.
INTRODUCTION
C olon cancer is responsible for 8900 deaths annually in C anada and represents the 2nd m ost com m on cause o f cancer-related m orbidity and m o rtality 1. T he use o f adjuvant chem otherapy for resected stage h i colon can cer has b een show n to significantly low er recu rren ce rates and to im prove overall su rv iv al2. T he curren t standard o f treatm en t includes 5-fluorouracil (5fu)— b ase d ch em o th erap y w ith an y o f 5 fu—leu co v o rin 3,4, 5 fu—o x alip latin 5,6, an d ca p ecitab in e7. In clin ical trials, ad ju v an t chem o th erap y is ty p i cally in itia te d w ith in 6 —8 w eeks a fte r surgery, but it h as b een show n that, outside o f the clinical trial setting, up to 19% o f patients do not receive adjuv an t th e ra p y w ith in th a t p e rio d 8. S everal re cen t m e ta analyses have co nfirm ed that delayed ad m in istratio n o f adjuvant chem otherapy after curative surgery is as sociated w ith significantly lesser overall su rv iv al9’10. In the p re sen t study, w e u sed a c o n tem p o rary p o p u latio n -b ase d p atien t co h o rt in the p ro v in ce o f B ritish C olum bia to asc e rta in the tem poral facto rs an d p atien t c h a rac te ristic s asso c ia te d w ith delayed d eliv ery o f ad ju v an t ch e m o th erap y in re ferred p a tien ts w ith re se c te d stage in colon cancer.
_____________________________________________________ C urrent O ncology— V olume 21 , N umber 4 , A ugust 2014 Copyright © 2014 Multimed Inc. Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
181
CHAN et al.
2.
METHODS
2.1 Data Source P atien ts w ith re se c te d stag e in co lo n c a n c e r w ho w ere re ferred to the B C C an c e r A g en cy ( b c c a ) w ere identified in th e GI C ancers O utcom es U nit database. T he b c c a is a provincial cancer agency responsible for tre a tm e n t p olicy and fu n d in g o f all system ic therapy in a p ro v in ce o f 4.4 m illion. O f all p atien ts w ith a d iag n o sis o f colon cancer, 65% are referred to one o f five treatm ent centres. Data relatin g to receip t o f chem o th erap y is ca p tu red in the p ro v in cial p h a rm a c y database. F or the p u rp o se s o f th e p re sen t an alysis, tw o o f the ca n c e r cen tres w ere co n sid ered to g eth er (“ce n tre C ”) b ec au se o f low p a tient volum es at the m ost new ly opened cancer centre. P ro v in cial trea tm e n t g u id elin es d u rin g the study p erio d re co m m en d ed th at adjuvant chem otherapy be in itiated w ith in 8 w eeks o f definitive surgery. For eligible p atien ts w ith stage in colon cancer, the re c o m m en d ed reg im en is 6 m onths o f m odified f o l f o x 6 (le u c o v o rin , 5 -flu o ro u rac il, o x alip latin ); a d ju v an t ca p ecitab in e is reco m m en d ed fo r p atien ts d eem ed to be inelig ib le for f o l f o x 6 .
2.2 Patient Selection P atien ts w ith re sected stage in colon ca n c e r referred to th e b c c a b etw een Jan u a ry 1, 2008, and D ecem b e r 31, 2009, an d tre a te d w ith at le a st 1 cycle o f ad ju v an t ch em o therapy w ere included. P atients w ere exclu d ed i f th ey h ad p rev io u sly b een d iag n o sed w ith a colon cancer, i f any p o rtio n o f th e ir colon ca n cer tre a tm e n t (in cluding su rg e ry o r chem otherapy) w as p e rfo rm e d o u tsid e o f B ritish C o lu m b ia, o r i f the re ferral w as for a second opinion. T h e stu d y w as a p p ro v e d by th e U n iv e rsity o f B ritish C o lu m b ia R esearch E thics B oard.
2.3 Data Collection P a tie n t d a ta c o lle c te d in c lu d e d age, sex, E a ste rn C o o p era tiv e O n co lo g y G ro u p ( e c o g ) p e rfo rm a n c e s ta tu s (as r e p o r te d b y th e tr e a tin g p h y s ic ia n at co n su ltatio n ), ty p e o f chem otherapy, an d reg io n al tre a tm e n t ce n tre. D ise a se fa c to r d a ta — in c lu d in g tu m o u r lo catio n , T stag e, N stage, histology, and g ra d e — w ere ab stra cted fro m the GI C an cers O ut co m es U nit database. C om o rb id ities, scored using th e C h arlso n co m o rb id ity index, w ere d eterm in e d fro m a re tro sp ectiv e ch a rt review . T h e tim e fro m cu rativ e su rg e ry to in itiatio n o f ad ju v an t ch em o th erap y ( t t a c ) w as reco rd ed , as w ere th e in terv a ls b etw e en the tim e s o f surgery, h ospital d isch arg e, re ferral to b c c a , first m edical oncology c o n s u lta tio n , an d first cy cle o f a d ju v a n t c h e m o therapy. D elayed t t a c w as defined as in itiatio n o f ch e m o th erap y m ore than 56 days a fte r surgery.
2.4 Statistical Analysis C h i-sq u are an d W ilcoxon ra n k -su m tests w ere u sed to assess d ifferen ces in c h a rac te ristic s and tim e in terv a ls for p atien ts w ho re ceiv ed delayed a n d tim ely ad ju v an t chem otherapy. M u ltiv a riate analy sis w ith logistic reg ressio n w as u sed to investigate in d e p e n dent p atien t an d tu m o u r c h a rac te ristic s p re d ic tiv e o f delayed chem otherapy.
3.
RESULTS
O f 395 re ferred p atien ts w ith re se c te d stage h i colon ca n cer w ho m et the inclusion c rite ria over the 2 -y ear study p erio d , 54% also m et the definition for delayed t t a c . M ed ian tim e fro m su rg e ry to ad ju v an t ch e m o th erap y w as 58 days. Table i p re sen ts the c h a ra c te ristic s o f th e full co h o rt and o f the tim ely an d delayed th erap y groups. M ed ian age at diag n o sis w as 65 y ears, a n d 52% o f p atien ts w ere m en. B y e n try c rite ria , all p atien ts h a d n o d e -p o sitiv e d ise a se (63% , N1 d ise a se ; th e re m a in d er, N 2 disease). M o st p a tie n ts h a d T3 tu m o u rs lo cated in the p ro x im al colon. N o sig n ifican t d ifferen ces in age o r sex w ere o b serv ed b etw e en the tim e ly and delayed ch em o th erap y groups. A lso, no significant differences w ere observed in nodal status, tu m o u r stag e, o r location o f th e p rim a ry tu m o u r. O ral ad juvant capecitab in e w as given to 40 % o f the patients, but the p ro p o rtio n o f patients receiv in g oral capecitabine com pared w ith intravenous f o l f o x 6 w as not d iffe ren t b etw een the delayed and tim ely groups. M ost p atien ts h ad a C h arlso n co m o rb id ity in d ex o f 0 —1 an d an e c o g p e rfo rm a n c e o f 0 —1. O n u n iv a ria te an aly sis (Table i), an e c o g p er fo rm an ce statu s o f 2 o r m ore w as asso c ia te d w ith a significant delay in adjuvant ch em otherapy ; a h ig h er score on the C h arlso n co m o rb id ity index w as not. Flowever, in m u ltiv ariate an aly sis (Table n), p erfo r m ance statu s did no t re ta in a significant asso ciatio n w ith delayed ch e m o th erap y {p = 0.079). Patients w ere w ell distrib u ted across h ealth re gions, w ith the m ost u rb a n centre (centre A) receiv in g the highest percentage o f referrals overall. C om pared w ith the o ther centres, centre A h ad a significantly h ig h er proportion o f patients w ho received delayed chem otherapy, and centre w as the only factor to retain significance in the m ultivariate analysis (p = 0.0004). T he m o st co m m on seq u en ce o f events w as sur gery, h ospital d isch arg e, re ferral to b c c a , m edical oncology consultation, and initiation o f adjuvant ch e m otherapy. T h at seq u en ce o c c u rre d in 69% o f cases. A s seen in Table in, significant tem p o ral d ifferen ces betw een the tim ely and delayed chem otherapy groups w ere identified in all in terv als. O v erall, th e av erag e tim e from su rg ery to referral w as 15 days; fro m refer ral to m edical oncology co n su ltatio n , 21 days; and from m edical oncology co n su ltatio n to in itiatio n o f chem otherapy, 20 days. A ll o f those in terv a ls w ere
I C urrent O ncology— V olume 21, N umber 4, A ugust 2014 | Copyright © 2014 Multimed Inc. Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
DELAYED TIME TO ADJUVANT CHEMOTHERAPY
table
i
Patient and tumour characteristics by time to adjuvant chemotherapy Variable
Patients (n)
Time to adjuvant chemotherapy
p Valuea
Overall
56 Days
395
182
213
Age at diagnosis (years) Median
65
66
65
57-72
57-72
58-72
Women
188 (48)
92 (50)
96 (45)
Men
207 (52)
90 (50)
117(55)
N1
249 (63)
119(65)
130(61)
N2
146 (37)
63 (35)
83 (39)
Tl/2
49 (12)
24 (13)
25 (12)
T3
276 (70) 68(17)
132 (73) 25 (14)
144 (68)
T4 TX
2(1)
1(1)
1(1)
Proximal
226 (57)
103 (57)
Distal
168 (43)
79 (43)
123 (58) 89 (42)
1(0)
0(0)
1 (1)
0
287 (73)
128 (70)
159 (75)
1
72 (18)
35 (19)
37(17)
2
29 (7)
16(9)
13(6)
3
5(1)
2(1)
3(1)
4
2(1)
Unknown
0(0)
1(1) 0(0)
1(1) 0(0)
0
101 (26)
44 (24)
57 (27)
1
93 (24)
49 (27)
44 (21)
2
22(6)
5(3)
17 (8)
1(0) 178 (45)
0(0) 84 (46)
1(1) 94 (44)
A
124 (31)
42 (23)
82 (39)
B
79 (20)
31(17)
48 (23)
C
110(28)
58 (32)
52 (24)
D
82 (21)
51 (28)
31 (15)
Intravenous 5 fu ± oxaliplatin
235 (60)
104 (57)
131 (62)
Oral capecitabine monotherapy
160 (40)
78 (43)
82 (39)
Interquartile range
0.8119
Sex [n (%)] 0.2771
N Stage [« (%)] 0.3718
Pathologic T stage [n (%)] 0.2370
43 (20)
Tumour location [n (%)]
Colon nos cci
0.7755
score \n (%)] 0.5802
ECOG PS [n ( % )]
3 Unknown
0.0257
Centre [n (%)] 0.0002
Chemotherapy type [n (%)] 0.3790
a Unknown, TX, and colon nos were removed before statistical testing was performed. Scores of 2 or 3 on the ecog ps and scores 2, 3, or 4 on the cci were pooled for statistical testing. nos = not otherwise specified; cci = Charlson comorbidity index; ecog ps = Eastern Cooperative Oncology Group performance status; 5 fu = 5-fluorouracil. __________________________________________________ C urrent O ncology— V olume 21, N umber 4, A ugust 2014 Copyright © 2014 Multimed Inc. Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).
183
CHAN etal.
table
ii Multivariate model for predictors of delayed adjuvant chemotherapy Type h i p valuea
Comparison
OR
95% cl
p Valuea
Age at diagnosis Sex N Stage Pathologic T stage
0.7320 0.2664 0.5219 0.1888
cci
Tumour location score
0.6174 0.8270
ECOG PS
0.0789
Centre
0.0004
Chemotherapy type
0.7238
Per year Men vs. women N2 vs. N1 T3 vs. T1/T2 T4 vs. T1/T2 Distal vs. proximal 1 vs. 0 2+ vs. 0 1 vs. 0 2 and 3 vs. 0 Unknown vs. 0 B vs. A C vs. A D vs. A Capecitabine vs. folfox
l 1.27 1.16 1.04 1.76 0.9 0.9 0.81 0.8 3.47 1.04 0.68 0.42 0.28 1.1
0.97, 1.02 0.83, 1.95 0.74, 1.82 0.54, 2.02 0.79, 3.93 0.58,1.38 0.52, 1.57 0.39, 1.71 0.44, 1.46 1.14, 10.51 0.6, 1.8 0.36, 1.28 0.24, 0.74 0.15, 0.54 0.65, 1.85
0.7320 0.2664 0.5219 0.9006 0.1690 0.6174 0.7107 0.5850 0.4632 0.0279 0.8990 0.2269 0.0027 0.0001 0.7238
Variable
a The type h i p value column represents the variable’s overall contribution to the model; thep value column represents the specific comparison (“Comparison” column) involving the variable. or = odds ratio; cl = confidence limits; cci = Charlson comorbidity index; ecog ps = Eastern Cooperative Oncology Group performance status; folfox = leucovorin-5-fluorouracil-oxaliplatin.
ta b le hi
Differences in process time intervals between timely and delayed adjuvant chemotherapy Variable
Surgery to referral (days) Median Interquartile range Range Referral to medical oncology consultation (days) Median Interquartile range Range Medical oncology consultation to chemotherapy (days) Median Interquartile range Range
sig n ifican tly in cre ased in the delayed ttac cohort. O n average, the delayed co h o rt co m m en c ed adju v a n t ch em o th erap y 67 days a fte r su rg ery ; the tim ely co h o rt s ta rte d adjuvant chem o th erap y an average o f 43 days a fte r surgery. 4.
D IS C U S S IO N
In this population-based analysis exam ining the fac tors associated w ith ttac, m ore than h a lf the patients referred w ith resected stage in colon cancer (54%) re ceived delayed adjuvant chemotherapy. This real-world
184
Time to adjuvant chemotherapy Overall
56 Days
(n=370) 15 10-22 1-106 («=349) 21 14-27 0-55 (w=395) 20 12-28 0-121
(n=164) 12 9-17 2-41 («=156) 17 12-22 0-40 («=182) 14 7-21 0-48
(n=206) 18 12-27 1-106 («=193) 23 17-31 0-55 («=213) 26 15-36 0-121
p Value
