A Cohort Study of Symptom Burden and Therapeutic Selection in Neuroendocrine Tumors (NETs)
Conditions: Neuroendocrine Tumors, Gastroenteropancreatic Neuroendocrine Tumor, Lung Neuroendocrine Neoplasm, Neuroendocrine Carcinoma
Sponsor: University of Iowa

St u d y:  Ne ur oe n d ocri ne T u m ors - P atie nt Re p orte d O utc o mes ( N E T- P R O) 
D oc u me nt Title: ' N E T P R O Pr ot oc ol. p df'
 D ate: A p pr o ve d b y I R B o n 2 0 2 2- 05- 0 6
U pl o a de d: 2 0 2 2- 0 5- 1 1
N C T N u m ber: N C T 0 5 0 6 4 1 5 0

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
1  
 
N E T -P R O  St u d y Pr ot oc ol  
 
D at e: A pril 2 0 2 2  
 
V ersi o n: 1. 3  
 
S p o ns or : P ati e nt-C e nt er e d O utc o m es R es e arc h I nstit ut e  
C o ntr act N u m b er : R D-2 0 2 0 C 2 -2 0 3 2 9  
Pr oj ect P eri o d : 7/ 1/ 2 0 2 1- 6/ 3 0/ 2 0 2 4 ( 3 6 m o nt hs)  
 
C o nt act Pri nci p al I n v esti g at or: Mic h a el O’ R or k e, S 4 5 1 , D e p art m e nt of E pi d e mi ol o gy, U ni v ersit y of I o w a, 
C oll e g e of P u blic H e alt h, 1 4 5 N Riv ersi d e Dr, I o w a Cit y, I A 5 2 2 4 2,  
+ 1 3 1 9 3 8 4 -1 5 6 0  
mic h a el -or or k e @ ui o w a. e d u      
 
Pr oj ect C o or di n at or : Bri a n Gr yzl a k, S 4 1 4 C P H B,  U niv ersit y of I o w a, I o w a City, I A 5 2 2 4 2 
+ 1 3 1 9 3 3 5 -8 2 1 8  
bri a n -gr yzl a k @ ui o w a. e d u   
 
P art n eri n g P ati e nt A d v oc ac y Or g a niz ati o ns:  
N ort h er n C alif or ni a C arci N E T C o m m u nity ( N or C al C arci N E T) htt ps:// n orc alc arci n et. or g/   
T h e N e ur o e n d ocri n e C a nc er A w ar e n ess N et w or k ( N C A N)  htt ps:// w w w. n etc a nc er a w ar e n ess. or g/   
T h e N e ur o e n d ocri n e T u m or R es e arc h F o u n d ati o n ( N E T R F)  htt ps:// n etrf. or g/   
T h e H e ali n g N E T F o u n d ati o n  htt ps:// w w w.t h e h e ali n g n et. or g/   
 
P artici p ati n g P C O RI N et w or ks  & Sit es  
G P C  ( 6): U niv ersity of I o w a, Alli n a H e alt h, U niv ersit y of K a ns as M e dic al C e nt er, M e dic al C oll e g e of 
Wisc o nsi n, U ni v ersity of T ex as  S o ut h w est er n M e dic al C e nt er, U ni v ersit y of Ut a h  
O n e Fl ori d a  ( 1): U ni v ers ity of Fl ori d a 
S T A R  ( 4): M e dic a l U niv ersity of S o ut h C ar oli n a, U ni v ersit y of  N ort h C ar oli n a at C h a p el Hill, V a n d er bilt 
U ni v ersity M e dic al C e nt er, M a y o Cli nic  
P A T H ( 3):  U niv ersit y of Pitts b ur g h M e dic al C e nt er, O hi o St at e U niv ersit y, U n i v ersit y of Mic hi g a n 
 
 
 
 
 

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
3  
A b br e vi ati o ns  
 
A b br e vi ati o n  M e a ni n g  
B R E  
B usi n ess R e ply E nv el o p e  
C D M  
C o m m o n D at a M o d el  
C E R  
C o m p ar ati v e Eff ectiv e n ess R es e arc h  
C g A  
C hr o m o gr a ni n A  
C R Ns  
Cli nic al R es e arc h N et w or ks  
E M R  
El ectr o nic M e dic al R ec or d  
E O R T C  
E ur o p e a n Or g a niz ati o n f or R es e arc h a n d Tr e at m e nt of C a nc er  
F D A  
F e d er al Dr u g A d mi nistr ati o n  
G 1/ G 2/ G 3  
Gr a d e 1, 2, 3 t u m ors  
G E P  
G astr o e nt er o p a ncr e atic  
G F R  
Gl o m er ul ar Filtr ati o n R at e  
H R Q oL  
H e alt h -r el at e d Q u ality of Lif e 
I R B 
I nstit uti o n al R evi e w B o ar d  
M CI D  
Mi ni m al Cli nic al I m p ort a nt Diff er e nc e  
m T O R  
M a m m ali a n t ar g et of r a p a m yci n  
N A A C C R  
N ort h A m eric a n Ass oci ati o n of C e ntr al C a nc er R e gistri es  
N E Cs  
N e ur o e n d ocri n e c arci n o m as  
N E T -P R O  
N e ur o e n d ocri n e T u m ors - P ati e nt R e p ort e d O utc o m es ( St u dy Titl e)  
N E Ts  
N e ur o e n d ocri n e t u m ors  
O S  
O v er all s ur viv al  
P A C  
P ati e nt A dv oc acy C o m mitt e e  
P C O RI  
P ati e nt C e nt er e d O utc o m es R es e arc h I nstit ut e  
P C O R n et  
P ati e nt C e nt er e d O utc o m es R es e arc h N et w or k  
P F S  
Pr o gr essi o n Fr e e S ur viv al  
P HI  
P ati e nt H e alt h I nf or m ati o n 
P H R  
P ers o n al H e alt h R ec or d r es e arc h p ort al ( i. e.: St u dy W e b P ort al)  
PI  
Pri nci p al I nv esti g at or  
P P V  
P ositi v e Pr e dictiv e V al u e  
P R Os  
P ati e nt R e p ort e d O utc o m es  
P R R T  
P e pti d e R ec e pt or R a di o n ucli d e T h er a py  
S E E R  
S ur v eill a nc e E pi d e mi ol o gy E n d R es ults  
S S As  
S o m at ost ati n a n al o g u es  
T D P S  
Ti m e D e p e n d e nt Pr o p e nsity Sc or e  
UI C C  
U ni v ersity of I o w a C o or di n ati n g C e nt er  
W H O  
W orl d H e alt h Or g a niz ati o n  
 
 
 
 
 
 
 

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
4  
T a bl e of C o nt e nts  
C o nt e nts  
Pr ot oc ol V ersi o n a n d A m e n d m e nt Tr ac ki n g  ................................................................................................. 2  
A b br e vi ati o ns  ................................................................................................................................................ 3  
T a bl e of C o nt e nts  .......................................................................................................................................... 4  
P R O T O C OL S Y N O P SI S  .................................................................................................................................... 8  
1.  
I N T R O D U C TI O N ........................................................................................................................... 1 0  
1. 1.  
B ac k gr o u n d  ...................................................................................................................................................... 1 0  
1. 1. 1.  
H e alt h r el at e d q u alit y of lif e i m p act of N E Ts  ........................................................................... 1 0  
1. 1. 2.  
N o m e ncl at ur e of N E Ts  ....................................................................................................................... 1 0  
1. 1. 3.  
G a ps i n O pti m al t h er a p y s el ecti o n a n d s e q u e nci n g  ............................................................... 1 1  
1. 1. 4.  
I m p ort a nt N E T s u b gr o u ps ............................................................................................................... 1 3  
1. 1. 5.  
Si g nific a nc e ............................................................................................................................................. 1 3  
1. 1. 6.  
P ot e nti al t o a d v a nc e r ar e dis e as e r es e arc h usi n g P C O R n et  ............................................... 1 4  
2.  
S P E CI FI C AI M S  ............................................................................................................................. 1 5  
2. 1.  
P ur p os e  .............................................................................................................................................................. 1 5  
3.  
S T U D Y O V E R VI E W  ....................................................................................................................... 1 7  
3. 1.  
O v er vi e w a n d a p pr o ac h  .............................................................................................................................. 1 7  
3. 2.  
S etti n g  ................................................................................................................................................................ 1 7  
4.  
S T U D Y D E SI G N ............................................................................................................................. 1 9  
4. 1.  
Ti m e a nc h ors f or st u d y c o h ort ................................................................................................................. 1 9  
4. 2.  
I ncl usi o n / E xcl usi o n Crit eri a ..................................................................................................................... 1 9  
4. 3.  
C o h ort I d e ntific ati o n a n d S el ecti o n  ....................................................................................................... 1 9  
4. 3. 1.  
P ot e nti al m o d es of s u bj ect i d e ntific ati o n  ....................................................................................... 1 9  
4. 4.  
D e v el o p m e nt of a N E T C o m p ut a bl e P h e n ot y p e  ................................................................................ 1 9  
5.  
R E C R UI T M E N T, E N R OLL M E N T A N D S T U D Y A C TI VI TI E S  .............................................................. 2 1  
5. 1.  
O v er vi e w  ........................................................................................................................................................... 2 1  
5. 2.  
R ol es a n d r es p o nsi biliti es of e nr olli n g sit es a n d UI C C  ................................................................... 2 1  
5. 2. 1.  
U ni v ersit y of I o w a C o or di n ati n g C e nt er ( UI C C) r ol es a n d r es p o nsi biliti es ...................... 2 1  
5. 2. 2.  
E nr olli n g sit e r ol es a n d r es p o nsi biliti es  ......................................................................................... 2 1  
5. 3.  
I d e ntif yi n g p ati e nts f or r ecr uit m e nt at p artici p ati n g sit es .......................................................... 2 2  
5. 3. 1.  
D at a el e m e nts us e d t o i d e ntif y p ot e nti al s u bj ects f or r ecr uit m e nt  ..................................... 2 2  
5. 4.  
Assi g ni n g a n d m ai nt ai ni n g u ni q u e I Ds a n d P H R cr e d e nti al li n k a g e t o p ati e nts  ................. 2 2  
5. 5.  
P ati e nt r ecr uit m e nt a n d r ecr uit m e nt m at eri als  - i niti al c o nt acts ............................................. 2 2  
5. 5. 1.  
E -m ail  ............................................................................................................................................................. 2 3  

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
5  
5. 5. 2.  
Dir ect -t o-p ati e nt c o m m u nic ati o n ( e. g., M y C h art, ot h er E M R m ess a gi n g, etc.)  ............... 2 3  
5. 5. 3.  
L ett er  ............................................................................................................................................................. 2 3  
5. 5. 4.  
St u d y p ac k ets  ............................................................................................................................................. 2 3  
5. 6.  
P ati e nt r ecr uit m e nt c o nt acts a n d r ecr uit m e nt m at eri als –  f oll o w-u p c o nt acts  .................. 2 3  
5. 7.  
E nr oll m e nt vi a N E T -P R O P H R r es e arc h p ort al  ................................................................................. 2 4  
5. 7. 1.  
P ati e nt -R e p ort e d Eli gi bilit y Crit eri a  ................................................................................................. 2 4  
5. 7. 2.  
Eli gi bilit y o utc o m es  ................................................................................................................................. 2 4  
5. 7. 3.  
R e vi e w a n d Si g ni n g I nf or m e d C o ns e nt D oc u m e nt  ..................................................................... 2 5  
5. 8.  
E nr oll m e nt vi a St u d y P ac k et  ..................................................................................................................... 2 5  
5. 9.  
E nr oll m e nt M o nit ori n g a n d R e p orti n g  ................................................................................................. 2 5  
5. 1 0.  
P ost -c o ns e nt st u d y pr oc e d ur es  .......................................................................................................... 2 5  
5. 1 0. 1.  
B as eli n e s ur v e y  .......................................................................................................................................... 2 6  
5. 1 0. 1. 1.  
P artici p ati o n vi a t h e N E T -P R O P H R  ............................................................................................. 2 6  
5. 1 0. 1. 2.  
P artici p ati o n vi a p a p er st u d y p ac k et  ........................................................................................... 2 6  
5. 1 0. 2.  
UI C C R e mi n d er C o nt acts ........................................................................................................................ 2 6  
5. 1 0. 3.  
F oll o w -u p s ur v e ys  .................................................................................................................................... 2 6  
5. 1 0. 4.  
S u bj ect C o m p e ns ati o n  ............................................................................................................................ 2 7  
5. 1 1.  
P ost -e nr oll m e nt m o nit ori n g  ................................................................................................................ 2 7  
5. 1 2.  
P o p ul ati o n of C D M P C O R n et_ T RI A L t a bl e  ...................................................................................... 2 7  
5. 1 3.  
D at a Cr oss w al ks  ........................................................................................................................................ 2 7  
6.  
D A T A S O U R C E S  ........................................................................................................................... 2 9  
6. 1.  
E M R d at a –  Cli nic al a n d billi n g d at a fr o m t h e P C O R n et C D M  ..................................................... 2 9  
6. 2.  
E M R d at a –  A bstr act e d m e dic al r ec or d d at a ( p er c h art r e vi e w)  ............................................... 3 0  
6. 2. 1.  
C h art r e vi e w f or m  .................................................................................................................................... 3 0  
6. 2. 2.  
C h art r e vi e w tr ai ni n g .............................................................................................................................. 3 0  
6. 3.  
P ati e nt s ur v e ys  ............................................................................................................................................... 3 0  
6. 4.  
P ati e nt st u d y w e bsit e n a vi g ati o n ............................................................................................................ 3 1  
7.  
S T U D Y O U T C O M E S  ...................................................................................................................... 3 2  
7. 1.  
Pri m ar y O utc o m es  ........................................................................................................................................ 3 2  
7. 2.  
S ec o n d ar y O utc o m es  .................................................................................................................................... 3 3  
8.  
C O M P A R A T O R S  ........................................................................................................................... 3 6  
8. 1.  
Ai m 1 ( Fr e q u e nc y of tr e at m e nt r e gi m e ns)  ......................................................................................... 3 6  
8. 2.  
Ai m 2 ( Tr e at m e nt s el ecti o n a n d o utc o m es)  ....................................................................................... 3 6  
8. 3.  
Ai m 3 ( C o m p ar ati v e eff ecti v e n ess of P R R T r e gi m e ns)  .................................................................. 3 6  
9.  
S T A TI S TI C AL A N AL Y SI S PL A N  ....................................................................................................... 3 7  

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
6  
9. 1.  
G e n er al St atistic al A p pr o ac h  .................................................................................................................... 3 7  
9. 1. 1.  
Ai m 1  .............................................................................................................................................................. 3 7  
9. 1. 2.  
Ai m 2  .............................................................................................................................................................. 3 7  
9. 1. 3.  
Ai m 3  .............................................................................................................................................................. 3 7  
9. 2.  
S a m pl e Si z e a n d P o w er  ............................................................................................................................... 3 7  
9. 2. 1.  
Ai m 1  .............................................................................................................................................................. 3 7  
9. 2. 2.  
Ai m 2  .............................................................................................................................................................. 3 8  
9. 2. 3.  
Ai m 3  .............................................................................................................................................................. 3 8  
9. 3.  
A d dr essi n g c o nf o u n di n g  ............................................................................................................................. 3 9  
9. 4.  
A d dr essi n g cl ust eri n g of sit e  .................................................................................................................... 3 9  
9. 5.  
H a n dli n g missi n g d at a  ................................................................................................................................. 3 9  
1 0.  
D A T A M O NI T O RI N G & Q U ALI T Y C O N T R OL  ................................................................................. 4 0  
1 0. 1.  
M et h o ds t o est a blis h v ali dit y of t h e N E T C o m p ut a bl e P h e n ot y p e  ....................................... 4 0  
1 0. 2.  
D et ails o n p o p ul ati o n of t u m or t a bl e d at a  ..................................................................................... 4 0  
1 0. 2. 1.  
T u m or t a bl e q u alit y scri pts  .................................................................................................................. 4 1  
1 0. 3.  
E v al u ati n g a n d A d a pti n g t h e N E T P ati e nt H e alt h R ec or d ( N E T P H R)  ................................ 4 1  
1 1.  
N E T -P R O TI M ELI N E ...................................................................................................................... 4 3  
1 2.  
E n g a g e m e nt a n d s h ari n g of r es ults c ust o miz e d t o l oc al s etti n gs of c ar e  ................................... 4 8  
1 3.  
S T U D Y G O V E R N A N C E A N D P OLI CI E S  .......................................................................................... 4 9  
1 3. 1.  
St u d y l e a d ers hi p a n d M a n a g e m e nt  ................................................................................................... 4 9  
1 3. 2.  
U ni v ersit y of I o w a C o or di n ati n g C e nt er ( UI C C) R ol es a n d R es p o nsi biliti es .................... 4 9  
1 3. 3.  
N E T -P R O St e eri n g C o m mitt e e  ............................................................................................................. 4 9  
1 3. 3. 1.  
Pri m ar y f u ncti o ns of t h e St e eri n g C o m mitt e e  .............................................................................. 4 9  
1 3. 4.  
R ol e a n d P ur p os e of t h e St a k e h ol d er C o m mitt e es  ..................................................................... 5 2  
1 3. 4. 1.  
N E T -P R O St a k e h ol d er C o m mitt e es –  M e m b ers hi p a n d Affili ati o ns  .................................... 5 3  
1 3. 5.  
V oti n g at c o m mitt e e m e eti n gs  ............................................................................................................ 5 5  
1 3. 6.  
Att e n d a nc e at c o m mitt e e m e eti n gs  .................................................................................................. 5 5  
1 3. 6. 1.  
C o -C h airs  ...................................................................................................................................................... 5 5  
1 3. 6. 2.  
M e m b ers  ....................................................................................................................................................... 5 5  
1 3. 7.  
R es ol u ti o n of dis p ut es ............................................................................................................................ 5 6  
1 4.  
S T U D Y R E S P O N SI BILI TI E S  ............................................................................................................ 5 7  
1 4. 1.  
I n v esti g at or R es p o nsi bilit y / P erf or m a nc e ..................................................................................... 5 7  
1 4. 2.  
Sit e c o m m u nic ati o ns  ............................................................................................................................... 5 7  
1 4 . 3. 
St u d y d oc u m e nt ati o n  .............................................................................................................................. 5 7  
1 4. 4.  
Pr ot oc ol D e vi ati o ns  ................................................................................................................................. 5 7  

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
7  
1 4. 5.  
P u blic ati o n p olici es  .................................................................................................................................. 5 7  
1 4 . 5. 1. 
G e n er al g ui d a nc e f or t h e assi g n m e nt of a ut h ors hi p:  ................................................................. 5 7  
1 5.  
P R O T E C TI O N O F H U M A N S U BJ E C T S  ........................................................................................... 5 8  
1 5. 1.  
Ris k t o H u m a n S u bj ects  ......................................................................................................................... 5 8  
1 5. 1. 1.  
St u d y Pr oc e d ur es, M at eri als a n d P ot e nti al Ris ks  ........................................................................ 5 8  
1 5. 1. 2.  
A d e q u at e Pr ot ecti o n a g ai nst Ris ks  .................................................................................................... 5 8  
1 5. 1. 3.  
P ot e nti al B e n efits t o P ati e nts  .............................................................................................................. 5 8  
1 5. 1. 4.  
R e pr es e nt ati v e n ess of t h e di v ersit y of t h e p ati e nt p o p ul ati o n  ............................................. 5 8  
R E F E R E N C E S  ................................................................................................................................................ 6 0  
A P P E N DI X A: N E T di a g n osis c o d es (I C D -9/ 1 0), I C D -O -3 c o d es, a n d hist ol o gy c o d es .................................. 6 3  
A P P E N DI X B: N E T C o m p ut a bl e P h e n oty p e –  t ec h nic al s p ecific ati o n ( S A S c o d e)........................................ 6 6  
A P P E N DI X C: Pr e - a n d P ost -C o ns e nt C o nt acts  ............................................................................................ 7 5  
 
 
 

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
8  
P R O T O C OL S Y N O P SI S  
N e ur o e n d ocri n e t u m ors ( N E Ts) ar e a gr o u p of r ar e a n d h et er o g e n e o us n e o pl as ms w hic h ar e ty pic all y 
sl o w-gr o wi n g i n n at ur e. T h us, p ati e nts wit h N E Ts ex p eri e nc e a pr ol o n g e d cli nic al c o urs e wit h  activ e 
dis e as e , wit h t h e hi g h est s y m pt o m b ur d e ns i n p ati e nts wit h g astr o e nt er o p a ncr e atic ( G E P ) a n d 
br o nc h o p ul m o n ary N E Ts . H o w e v er, a ss ess m e nt of h e alt h -r el at e d q u alit y of lif e ( H R Q oL) a n d p ati e nt 
r e p ort e d o utco m es ( P R Os)  o utsi d e of t h er a py tri als still r e m ai ns sc arc e a nd of p o or q u alit y . W h at's 
m or e, t h er e ar e n o cl e ar co ns e ns us g ui d eli n es as t o t h e o pti m u m s e q u e nci n g of t h er a p e utic o pti o ns  
f or N E T p ati e nts. As cli nici a ns att e m pt t o t ail or tr e at m e nt s el ecti o n o n t h e c h ar act eristics of t h e p ati e nt 
a n d t h eir t u m or, N E T p ati e nts m ust n a vi g at e a pr otr act e d s e q u e nc e of tr e at m e nt d ecisi o ns as b e n efits 
w a n e a n d t h e n ext m o d ality is tri e d . T h e p ur p os e of t his st u d y is t o p art n er wit h p ati e nts t o e x a mi n e 
t h e i m p act of tr e at m e nt ch oic es o n Q oL a n d P R Os t o ac hi e v e t h e g o al  of all e vi ati n g u n d u e t o xicit y a n d 
o pti mizi n g eff ecti v e n ess a n d s e q u e nci n g of t h er a p y f or N E T p ati e nts.  
 
T h e N e ur o e n d ocri n e T u m or  –  P ati e nt R e p ort e d O utc o m es ( N E T -P R O)  pr oj ect is a pr os p ectiv e c o h ort 
st u dy of all n e wl y occ urri n g G E P  a n d l u n g N E T c as es a g e d 1 8 y e ars a n d ol d er  di a g n os e d b et w e e n 
0 1/ 0 1/ 2 0 1 9 a n d  1 2/ 3 1/ 2 0 2 3 . P artici p a nts will b e r ecr uit e d acr oss 1 4 p artici p ati n g P ati e nt C e nt er e d 
O utc o m es R es e arc h N et w or k ( P C O R n et ) sit es (fr o m acr oss 4 P C O R n et cli nic al r es e arc h n et w or ks), 
e nr olli n g a n av er a g e of 2 1 5 p ati e nts p er sit e o v er t h e 3 -y e ar st u dy p er i o d ( ~3, 0 0 0 p ati e nts t ot al ), 
all o wi n g u p t o a m axi m u m of 6 0 m o nt hs of f oll o w -u p . P articip a nts will c o m pl et e f o ur o nli n e ( or p a p er ) 
s urv eys o v er 1 8 m o nt hs; t h es e s urv eys will f oc us o n p ati e nt-r e p ort e d o utc o m es, i ncl u di n g q u esti o ns o n 
q u alit y of lif e, tr e at m e nt d ecisi o ns, a n d ex p eri e nc es wit h c a nc er c ar e. T h es e s urv e y d at a will b e li nk e d t o 
i n di vi d u al p artici p a nt l ev el t u m or a n d cli nic al c h ar act eristics fr o m m e dic al r ec or d d at a.  
 
P r oj ect s p ecific ai ms : 
AI M 1: T o d escri b e t h e f r e q u e nc y of tr e at m e nt r e gi m e ns a n d e x a mi n e t h eir ass oci ati o n wit h  s y m pt o m 
b ur d e n a n d  P R Os a n d H R Q oL o utc o m es.  E nr oll a c o h ort of p ati e nts t o c oll ect H R Q oL a n d P R Os d at a 
e v ery 6 m o nt hs, f or 1 8 m o nt hs (i. e.: b as eli n e, 6, 1 2 a n d 1 8 m o nt h f oll o w -u p s ur v e ys).  W e will d et er mi n e 
w h at c o m bi n ati o ns of t h er a py ar e b ei n g us e d, a n d t h e c h a n g es i n s y m pt o ms , P R Os a n d H R Q oL 
ass oc i at e d wit h t h es e diff er e nt  t h er a p e utic c h oic es.  
 
AI M 2: T o e x a mi n e t h e ass oci ati o n of p ati e nt, cli nic al, a n d t u m or c h ar act eristics o n tr e at m e nt c h oic e. 
W e will us e  E M R  d at a  t o i nv esti g at e t h e i m p act of pr e -existi n g c o m or bi diti es (i. e.: c ar di o v asc ul ar, r e n al 
a n d li v er dis e as e a n d di a b et es), pr o g n ostic t u m or f act ors ( d eri v e d fr o m c a nc er r e gistr y  d at a) i. e.: st a g e, 
gr a d e a n d n o d al st at us, o n t h e s el ecti o n of t h er a pi es r ec eiv e d a n d o utc o m es of s ur vi v al a n d dis e as e 
pr o gr essi o n  (c oll ect e d vi a t ar g et e d c h art r evi e ws). 
 
AI M 3: T o c o m p ar e t h e eff ecti v e n ess of p e pti d e r ec e pt or r a di o n ucli d e t h er a p y ( P R R T) r e gi m e ns o n 
o utc o m es of r e n al t o x icit y, dis e as e pr o gr essi o n, a n d p ati e nt s y m pt o ms a n d H R Q oL. W e will utiliz e t h e 
c o m bi n e d P R Os g at h er e d i n ai m 1 a n d E M R d at a mi n e d i n ai m 2 (i. e.: pr e dict ors), t o c o m p ar e t h e 
eff ectiv e n ess of v ari o us P R R T tr e at m e nt c o m bi n ati o ns a n d s e q u e nc es, o n o utc o m es of r e d uc e d 
cr e ati ni n e cl e ar a nc e (r e n al t oxicit y), H R Q oL a n d s y m pt o m b ur d e n, a n d  s urvi v al a n d dis e as e pr o gr essi o n. 
W e will f urt h er st u dy t h e h et er o g e n eity of t h es e tr e at m e nt eff ects by gr a d e of diff er e nti ati o n ( G 1/ 2 vs 
G 3) a n d N E T s u bsit e ( G E P vs l u n g).  
 
AI M 4: T o d e v el o p a n d l e v er a g e P C O R n et i nfr astr uct ur e f or t h e st u d y of N E Ts a n d o t h er r ar e dis e as es, 
a n d t o diss e mi n at e l ess o ns l e ar n e d . Fi n ally, w e pl a n t o s h ar e t h e i nfr astr uct ur e  t his st u dy will g e n er at e 
(i. e.: el ectr o nic i d e ntific ati o n of N E T p ati e nts, e ntr y a n d c o m pl eti o n of t u m or t a bl e d at a  i n P C O R n et, a n d 
a u ni q u e N E T p ers o n al h e alt h r ec or d r es e arc h p ort al), t o f ost er f ut ur e st u di es i n N E Ts a n d ot h er r ar e 

 
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dis e as es util izi n g t h e P C O R n et d at a r es o urc e, a n d ex p a n d o ur pr os p ectiv e e nr oll m e nt t hr o u g h o ur f o ur 
n ati o n ally r e pr es e nt ativ e p art n eri n g  p ati e nt a d v oc at e or g a niz ati o ns .  
 
 
 

 
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1.  I N T R O D U C TI O N 
1. 1.  B ac k gr o u n d  
N E Ts ar e a gr o u p of r ar e a n d h et er o g e n e o us n e o pl as ms t h at ori gi n at e i n s p eci aliz e d n e ur o e n d ocri n e 
c ells, pr e d o mi n a ntl y i n t h e s m all b o w el, p a ncr e as a n d l u n g, c oll ecti v el y aff ecti n g f e w er t h a n  1 7 2 , 0 0 0 
i n di vi d u als i n t h e U nit e d St at es [ 1]. Alt h o u g h N E Ts m ay aris e i n m ost or g a ns, m or e t h a n h alf ori gi n at e 
fr o m e n d ocri n e c ells of t h e g astr oi nt esti n al tr act a n d t h e p a ncr e as [ 2], r ef err e d t o as 
g astr o e nt er o p a ncr e atic N E Ts ( G E P -N E Ts). B ot h G E P -N E Ts a n d l u n g N E Ts, i ncl u di n g t y pic al a n d at y pic al 
c arci n oi d t u m ors a n d br o nc hi al N E Ts, m e et t h e crit eri a f or or p h a n dis e as e st at us. D es pit e t his, t h e a g e -
a dj ust e d i nci d e nc e r at e of N E Ts i ncr e as e d 6. 4 -f ol d fr o m 1 9 7 3 ( 1. 0 9 p er 1 0 0  0 0 0) t o 2 0 1 2 ( 6. 9 8 p er 
1 0 0  0 0 0) [ 3, 4], a n d s er v es o nl y t o hi g hli g ht t h e gr o wi n g i m p act a n d b ur d e n t h es e c a nc ers will c o nti n u e 
t o h av e o n t h e h e alt h of o ur p o p ul ati o n. 
 
1. 1. 1.  H e alt h r el at e d q u alit y of lif e i m p act of  N E Ts  
N E Ts ar e t y pic ally sl o w -gr o wi n g i n n at ur e wit h pr ol o n g e d s urviv al a n d si g nific a nt s y m pt o m b ur d e ns,  
h o w ev er f e w st u di es h a v e ex a mi n e d q u alit y of lif e i m p acts. T h eir v a g u e a nt ec e d e nt si g ns a n d sy m pt o ms 
c a us e si g nific a nt d el a y a n d diffic ult y i n t h eir di a g n osis a n d d et ecti o n [ 3]. M et ast atic dis e as e is o bs erv e d 
i n u p t o 4 0 % of N E Ts at i n iti al di a g n osis [ 1], a n d m a ny p ati e nts wit h li v er or ot h er dist a nt m et ast as es 
ex p eri e nc e c arci n oi d sy n dr o m e, a dir ect r es ult of t h e t u m ors c a p acity t o s y nt h esiz e a n d s ecr et e a n 
exc ess of bi o acti v e a mi n es, p e pti d es, a n d p ol y p e pti d es . C arci n oi d sy n dr o m e m a nif ests wit h cli nic al 
s y m pt o ms r a n gi n g fr o m w at er y di arr h e a a n d fl us hi n g t o br o nc h os p as m,  t o hy p ot e nsi o n a n d ri g ht -si d e d 
c ar di ac d eficits (c arci n oi d h e art dis e as e) d u e t o s er ot o ni n h y p ers ecr eti o n [ 4]. I n f act, a S urv eill a nc e 
E pi d e mi ol o gy  a n d E n d R es ults ( S E E R) a n alysis h as s h o w n t h at 1 9 % of all N E T p ati e nts h a v e sy m pt o ms of 
c arci n oi d sy n dr o m e at di a g n osis, i ncr e asi n g t o o v er 5 0 % i n p ati e nts wit h m et ast atic w ell -diff er e nti at e d 
s m all b o w el N E Ts [ 5]. T h us, N E T  p ati e nts ty pic all y ex p eri e nc e pr ol o n g e d s urviv al wit h activ e dis e as e, a n d 
m a ny h av e si g nific a nt sy m pt o m b ur d e ns. Wit h a c o nsci o us s hift i n m e dic al pr actic e fr o m dis e as e -
c e nt er e d t o p ati e nt-ori e nt at e d c ar e, q u alit y of lif e r e pr es e nts a n i m p ort a nt m e as ur e f or g a u gi n g p ati e nt 
p ers p ectiv es o n tr e at m e nt eff ectiv e n ess a n d o utc o m es. H o w e v er, t h e ass ess m e nt of h e alt h -r el at e d 
q u alit y of lif e ( H R Q oL) i n N E T p ati e nts is r el ativ ely i nfr e q u e nt  a n d tr a nsf er of H R Q oL r es ults i nt o cli nic al 
pr actic e is hi n d er e d b y t h e oft e n li mit e d q u alit y of H R Q oL o utc o m es r e p orti n g [ 6]. U ns ur prisi n gl y, w h er e 
t h es e st u di es h av e b e e n u n d ert a k e n, s o m e h a v e i d e ntifi e d w ors e H R Q oL  sc or es i n N E T p ati e nts as 
c o m p ar e d wit h t h e g e n er al p o p ul ati o n [ 7-1 0] , s p ecific ally p o or er p ati e nt-r e p ort e d o utc o m es a n d u n m et 
n e e ds [ 1 1, 1 2]. I n f act, a hi g h pr e v al e nc e of m o d er at e t o s ev er e s y m pt o ms es p eci all y tir e d n ess ( 4 4-5 0 %), 
l ac k of w ell-b ei n g ( 3 7 -4 9 %) a n d a nxi ety ( 3 0 -4 0 %) , h av e b e e n o bs erv e d u p t o fi v e y e ars aft er  di a g n osis, 
wit h t h e hi g h est sy m pt o m b ur d e ns i n p ati e nts wit h br o nc h o p ul m o n ary a n d G E P -N E Ts [ 1 3].  
 
1. 1. 2.  N o m e ncl at ur e of N E Ts  
T h e c o m pl ex a n d c o nf usi n g n o m e ncl at ur e of N E Ts c o ntri b ut es t o a t hi n evi d e nc e b as e f or o pti m al 
m a n a g e m e nt. T his is v ery u nf ort u n at e as t u m or diff er e nti ati o n a n d t u m or pr olif er ati o n ar e i m p ort a nt 
i n dic ati o ns of u n d erl yi n g t u m or bi ol o gy, c arryi n g pr e dicti v e, pr o g n ostic, a n d t h er a p e utic si g nific a nc e. I n 
2 0 1 0 t h e W orl d H e alt h Or g a niz ati o n ( W H O) i ntr o d uc e d a c o m m o n fr a m e w or k f or t h e cl assific ati o n of 
N E Ts [ 1 4], m or p h ol o gic ally dic h ot o mizi n g t h e t u m ors i nt o w ell diff er e nti at e d N E Ts, a n d p o orl y 
diff er e nti at e d n e ur o e n d ocri n e c arci n o m as ( N E Cs) o n t h e b asis of t h e t u m or ’s mit otic r at e a n d Ki 6 7 i n d ex 
[ 1 5]. H o w ev er, t his dic h ot o m o us gr a di n g crit eri a is i m p erf ect, a n d a n e w s u bs et of w ell -diff er e nti at e d 
gr a d e 3 N E Ts ( pr e d o mi n a ntl y i n t h e p a ncr e as, st o m ac h a n d c ol o n) h as si nc e b e e n r ec o g niz e d, wit h a 

 
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w ors e pr o g n osis t h a n G 2 N E Ts, a n d n o n -st a n d ar diz e d tr e at m e nts str a d dli n g G 1/ 2 t u m ors an d p o or er 
pr o g n osis N E Cs [ 1 6] ( Fi g ur e 1).  
 
1. 1. 3.  G a ps i n O pti m al t h er a p y s el ecti o n a n d s e q u e nci n g  
Fi g ur e 2  pr es e nts a n al g orit h mic o v er vi e w of t h e i nv esti g ati o n a n d tr e at m e nt of G E P -N E Ts (t h e m ost 
c o m m o n N E T s u bt y p e) [ 1 7]. F or l o w t o i nt er m e di at e gr a d e N E Ts, s ur g er y r e m ai ns t h e m ai nst ay of 
tr e at m e nt a n d t h e r e q uir e m e nt f or a dj uv a nt t h er a py is q u esti o n a bl e [ 1 8-2 0] . H o w e v er, as o v er h alf of 
G E P -N E Ts pr es e nt wit h m et ast as es at t h e ti m e of di a g n osis, t h e y ar e n ot c o nsi d er e d c a n di d at es f or 
c ur ati v e s ur g ery, a n d s o m a ny ar e off er e d s o m e f or m of l o n g -t er m m e dic al tr e at m e nt f or s y m pt o m r eli ef 
a n d t u m or gr o wt h s u p pr essi o n. S o m at ost ati n a n al o g u es ( S S As) ar e est a blis h e d first -li n e a g e nts f or l o w-
gr a d e G E P -N E Ts, l ar g el y giv e n t h eir d e m o nstr at e d i m pr o v e m e nts i n ov er all s urviv al i n t w o pl ac e b o -
c o ntr oll e d r a n d o miz e d tri als ( P R O MI D  a n d CL A RI N E T ) [ 2 1, 2 2]. H o w ev er, t h er e ar e n o cl e ar c o ns e ns us 
g ui d eli n es as t o t h e o pti m u m s e q u e nci n g of ot h er t h er a p e utic o pti o ns [ 1 7, 2 1, 2 3 -2 7] . S yst e mic, n o n-
liv er dir ect e d t h er a pi es m ay i ncl u d e p e pti d e r ec e pt or r a di o n ucli d e t h er a py ( P R R T), i nt erf er o n al p h a, 
e v er oli m us ( a n m T O R i n hi bit or), s u niti ni b ( a tyr osi n e ki n as e i n hi bit or), b e v aciz u m a b a n d c yt ot oxic a g e nts 
[ 1 7]. Liv er-dir ect e d t h er a pi es i ncl u d e a bl ativ e t h er a py, tr a ns art eri al e m b oliz ati o n a n d 
c h e m o e m b oliz ati o n, a n d i nt er n al r a di ati o n t h er a py wit h yttri u m-9 0  c o at e d micr os p h er es [ 2 8]. 
I nt er esti n gl y, a n ass ess m e nt of t h e cli nic al b e n efit of syst e mic tr e at m e nts i n G E P-N E Ts f o u n d t h at 
c urr e ntl y us e d tr e at m e nts h a d l o w h e alt h b e n efit sc or es acc or di n g t o t h e A S C O -N H B, a n d n o n e c o ul d b e 
gr a d e d as m e a ni n gf ully cli nic all y b e n efici al acc or di n g t o t h e E S M O -M C B S [ 2 9]. T h er ef or e, o n e of t h e 
gr e at est c h all e n g es i n t h e c urr e nt N E T o nc ol o gy m a n a g e m e nt l a n dsc a p e is h o w b est t o s e q u e nc e t h es e 
m a ny t h er a p e utic o pti o ns (if w arr a nt e d at all), a n d h o w t o t ail or tr e at m e nt  s el ecti o n o n t h e b asis of t h e 
i n di vi d u al c h ar act eristics of t h e t u m or a n d p ati e nt. 
 
P R R T r e pr es e nts a tr u e br e a kt hr o u g h i n tr e at m e nt of N E Ts b ut m a ny q u esti o ns r e m ai n a b o ut 
s e q u e nci n g of P R R T wit h ot h er t h er a pi es. P R R T is a f or m of m ol ec ul arl y t ar g et e d t her a py, t h e m ai n g o al 
of w hic h is t o s el ecti v el y d eliv er a hi g h d os e of r a di ati o n t o t h e t u m or c ells, t h us li miti n g irr a di ati o n of 
n or m al tiss u es. U nf ort u n at el y, d u e t o t u b ul ar r e a bs or pti o n a n d i ntr ac ell ul ar tr a p pi n g of t h e 
r a di o n ucli d e, P R R T t h er a pi es c a n acc u m ul at e i n t h e r e n al c ort ex i n d uci n g t oxicit y [ 3 0]. Pr o p er ki d n ey 
pr ot ecti o n, wit h t h e c o -i nf usi o n of p ositi v ely c h ar g e d a mi n o aci ds, is m a n d at ory. W hilst  t h e r a di ati o n 
d os e t o t h e ki d n e ys c a n b e r e d uc e d wit h t his pr e -tr e at m e nt, t h e ki d n e y r e m ai ns a d os e li miti n g or g a n 
Fi g ur e 1 : W H O 2 0 1 7 G E P -N E T n o m e ncl at ur e a n d cl assific ati o n  

 
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[ 3 1] wit h a cr e ati ni n e cl e ar a nc e l oss of a b o ut 3. 8 % p er y e ar f or 1 7 7L u -octr e ot at e a n d 7. 3 % p er y e ar f or 
9 0 Y -D O T A T O C [ 3 2]. M or e ov er, st u di es h av e d e m o nstr at e d a hi g h er a n d m or e p ersist e nt d ecli n e i n 
cr e ati ni n e cl e ar a nc e if risk f act ors f or d el ay e d r e n al t oxicit y ar e pr es e nt, p artic ul arl y l o n g -st a ndi n g a n d 
p o orly c o ntr oll e d di a b et es a n d h y p ert e nsi o n [ 3 3, 3 4]. O n J a n u ar y 2 6, 2 0 1 8, t h e US F o o d a n d Dr u g 
A d mi nistr ati o n ( F D A) a p pr o v e d L ut a t h er a ( 1 7 7L u-D O T A T A T E), a r a di ol a b el e d s o m at ost ati n a n al o g, f or 
t h e tr e at m e nt of a d ults wit h s o m at ost ati n r ec e pt or– p ositiv e G E P -N E Ts [ 3 5]. L ut at h er a, is t h e first 
r a di o p h ar m ac e utic al t o b e a p pr o v e d b y t h e F D A f or t his p ati e nt p o p ul ati o n. W e ar e li k ely t o s e e a n 
i ncr e as e i n t h e us e of 1 7 7L u-D O T A T A T E o utsi d e s p eci alist N E T c e nt ers. T h er ef or e , r e al-w orl d d at a o n 
v ari a bl es t h at m ay i nfl u e nc e p ati e nt r e p ort e d o utc o m es (i. e.: t oxiciti es a n d a dv ers e eff ects) a n d ris k of 
pr o gr essi o n aft er  P R R T i n c o m bi n ati o n wit h ot h er bi ol o gic al t h er a pi es , is m uc h n e e d e d.  
 
O pti m al s e q u e nci n g of t h er a py is a k ey c o nc er n f or m ost p ati e nts. As N E Ts ar e r el ati v ely sl o w -gr o wi n g, 
e v e n p ati e nts wit h m et ast atic dis e as e c a n b e ex p ect e d t o b e t r e at e d f or pr otr act e d p eri o ds of ti m e, a n d 
m ust n avi g at e a pr ol o n g e d s e q u e nc e of tr e at m e nt d ecisi o ns as b e n efits w a n e a n d t h e n ext m o d alit y is 
tri e d [ 2 6]. N E T p ati e nts h a v e b e e n l eft w o n d eri n g n ot o nl y ‘ w h at t h er a py w o ul d b e b est t o try n ext ?’, 
b ut ‘if I w er e t o t a k e t his o pti o n n o w, w h at tr e at m e nt o pt i o ns will b e cl os e d off t o m e i n t h e f ut ur e ?’ 
(p ers o n al c o m m u nic ati o n,  J os h M ail m a n, l e a d p ati e nt a d v oc at e C o-I). As n u m er o us t oxiciti es m a y r es ult 
fr o m t h es e t h er a pi es i ncl u di n g h e m at ol o gic [ 3 6-3 8] , r e n al [ 2 7], a n d h e p at oxicit y [ 3 9], p ati e nts m ay r u n 
o ut of r esili e nc e t o wit hst a n d t oxic it y b ef or e t h e y r u n o ut of t h er a p e utic o pti o ns. T his r e al c o nc er n w as 
u n d ersc or e d i n a r ec e nt n et w ork m et a -a n al ysis of 3 0 r a n d o miz e d tri als fi n di n g s ev er e a n d lif e -
t hr e at e ni n g a dv ers e eff ects r a n g e d fr o m 3. 0 % t o 8 3. 9 % d e p e n di n g o n t h e tr e at m e nt c o m bi n ati o ns 
utiliz e d [ 4 0], u n d erli ni n g t h e i m p ort a nc e of miti g ati n g t oxicit y a n d o pti mizi n g s e q u e nci n g of t h er a py f or 
p ati e nts wit h pr ol o n g e d s ur vi v al.  
Fi g ur e 2 : Ov ervi e w of tr e at m e nt f or G E P-N E Ts  
S S A: S o m at ost ati n A n al o g u es, P R R T: P e pti d e r ec e pt or r a di o n ucli d e t h er a py, 5 F U: 5 -fl u or o ur acil, S T Z: Str e pt oz oci n-b as e d 
c h e m ot h er a py, C A P T E M: c a p ecit a bi n e wit h t e m oz ol o mi d e, S RI: s o m at ost ati n r ec e pt or i m a gi n g, T A E: Tr a ns -art eri al e m b oliz ati o n, 
T A C E: Tr a ns -art eri al c h e m o e m b oliz ati o n, C S: r efr act or y c arci n oi d s y n dr o m e, R F A: r a di ofr e q u e nc y a bl ati o n.  
 

 
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1. 1. 4.  I m p ort a nt N E T s u b gr o u ps 
M et ast atic w ell -diff er e nti at e d gr a d e 3 N E Ts ar e a c h all e n gi n g a n d h et er o g e n e o us s u b gr o u p. 
Pr e d o mi n a ntly l oc aliz e d t o t h e p a ncr e as, st o m ac h a n d c ol o n t h e pr o g n osis of t h es e t u m ors is p o or er 
t h a n gr a d e 2 N E Ts. C urr e nt E ur o p e a n a n d A m eric a n g ui d eli n es r ec o m m e n d s urgic al r es ecti o n f or 
l oc aliz e d dis e as e (irr es p ectiv e of gr a d e), b ut c h e m ot h er a py is i n dic at e d i n  gr a d e 3 N E Ts, p artic ul a rly if it 
w o ul d e n a bl e a s ur gic al pr oc e d ur e  [ 1 6]. R es e arc h ers fr o m t h e U ni v ersit y of I o w a [ 4 1] a n d V a n d er bilt ( Dr 
S at y a D as, C o -I), t w o l ar g e d e dic at e d m ulti disci pli n ar y N E T cli nics, ar e s h o wi n g t h at e arli er utiliz ati o n of 
P R R T ( n e o -a dj uv a ntly) i n t h es e p ati e nts m ay i m pr ov e p ati e nt o utc o m es ( pr o gr essi o n -fr e e s ur viv al), 
i n dic ati n g t h at t h er e m a y b e ot h er tr e at m e nt s e q u e nc es a n d c o m bi n ati o ns i n t his s u b gr o u p of e q u al or 
gr e at er eff ecti v e n ess, a n d wit h p ot e nti ally r e d uc e d l o n g -t er m t oxiciti es.   
 
T h er e ar e c urr e ntl y s ev er al o n g oi n g N E T p h as e III cli nic al tri als. N E T T E R 2  ex a mi n es L ut at h er a ( 1 7 7 -L u 
D O T A T A T E) i n c o m p aris o n t o hi g h d os e S S A i n hi g h er G 2 a n d l o w G 3 G E P -N E T p ati e nts. C O M P E T E   
c o m p ar es L u1 7 7 -D O T A T O C wit h ev er oli m us tr e at m e nt i n G 1/ G 2 G E P -N E T p ati e nts. T h e C A BI N E T  tri al is 
c o m p ari n g us e of a t yr osi n e ki n as e i n hi bit or vs pl ac e b o i n a v ari et y of N E T p ati e nts pr evi o usly tr e at e d 
wit h ev er oli m us.  F urt h er, a m or e r ec e nt p h as e III tri al C O M P O S E  ( n ot y et r ecr uiti n g), will ev al u at e t h e 
effic ac y, s af et y & p ati e nt -r e p ort e d o utc o m es of 1 7 7L u -E d otr e oti d e t o b est st a n d ar d of c ar e o pti o ns 
(i ncl u di n g c h e m ot h er a py a n d e v er oli m us) i n G 2/ G 3 G E P-N E Ts. I m p ort a ntly h o w ev er, t h es e tri als will 
t a k e s e v er al m or e y e ars t o r e p ort r es ults a n d will e nr oll f e w er t h a n 4 0 0 p ati e nts e ac h. M or e o v er, t h er e 
is a m ar k e d diss ervic e i n t h es e cli nic al tri als t o p ati e nts wit h l u n g N E Ts. I n f act, ty pic al a n d at y pic al 
c arci n oi ds (l o w-gr a d e  N E Ts of t h e l u n g a n d br o nc h us)  ar e n e gl ect e d dis e as es i n r es p ect t o b ot h hi g h -
gr a d e N E Ts of t h e l u n g (i. e.: s m all -c ell l u n g c a nc er a n d l ar g e -c ell n e ur o e n d ocri n e c arci n o m a) a n d G E P -
N E Ts, wit h  t h er a p e utic o pti o ns oft e n extr a p ol at e d fr o m st u di es u n d ert ak e n i n p ati e nts wit h G E P-N E Ts 
[ 4 2]. T h e c o n d uct of a c o m p ar ati v e eff ecti v e n ess r es e arc h ( C E R ) st u dy i n t h e s etti n g of ty pic al a n d 
at y pic al c arci n oi ds  is p artic ul arl y w arr a nt e d.  
 
1. 1. 5.  Si g nific a nc e  
T h e l ac k of c o ns e ns us g ui d eli n es as t o t h e o pt i m u m s e q u e nci n g of tr e at m e nts, m e a ns t h at N E T p ati e nts 
a n d cli nici a ns ar e c o nfr o nt e d wit h v ery r e al a n d diffic ult tr e at m e nt d ecisi o ns. D u e t o t h e r el ativ ely s m all 
n u m b er of p ati e nts i ncl u d e d i n cli nic al tri al s r el at e d t o t h e i m p ort a nt N E T s u b gr o u ps pr e vi o usl y 
hi g hli g ht e d , it is diffic ult t o e v al u at e b ot h t h e f act ors t h at m ay aff ect tr e at m e nt r ec ei pt a n d t h eir 
i nfl u e nc e o n p ati e nt-r e p ort e d o utc o m es a n d pr o g n osis. O ur l ar g e st u dy’s ri g or o us c oll ecti o n of 
s y m pt o m, t u m or a n d tr e at m e nt b ur d e ns a n d t h eir i m p acts o n H R Q oL i n dic at ors will i m pr o v e p ati e nt 
o utc o m es t hr o u g h t h e a p plic ati o n of m or e i nf or m e d tr e at m e nt s e q u e nci n g a n d m o nit ori n g of dis e as e 
b ur d e n. W hil e p ati e nts wit h a l oc aliz e d, r es ect a bl e t u m or m a y g o str ai g ht t o s ur g er y, t h os e wit h l oc ally 
a dv a nc e d or s y nc hr o n o us m et ast atic dis e as e m a y b e n efit fr o m t h e d eli v ery of a m or e c o m plic at e d s eri es 
of tr e at m e nts w hic h ar e s o m e w h at p ers o n aliz e d t o t h e pr ef er e nc e of t h e p ati e nt a n d t h e pr olif er ativ e 
pr ofil e of t h eir t u m or.  
 
T h e N E T -P R O  st u dy will a d dr ess at l e ast thr e e l ar g e c h all e n g es p ati e nts f ac e i n w h at t h ey ar e off er e d f or 
t h e c urr e nt m a n a g e m e nt of N E Ts.  
a.  U nk n o w n o pti m al s e q u e nci n g of syst e mic a n d n o n -syst e mic t h er a p e utic o pti o ns. B ec a us e 
cli nici a ns c urr e ntly d o n ot u n d erst a n d w h at o pti o ns ( wit h t h e l o w est t oxi citi es) s h o ul d b e tri e d 
first gi v e n a p ati e nt’s p artic ul ar pr olif er ativ e t u m or b ur d e n, t h ey ar e n ot a bl e t o pr o vi d e 
e vi d e nc e -b as e d r ec o m m e n d ati o ns. O ur c o m m u nic ati o ns wit h N E T p ati e nts a n d o ur p ati e nt 
a dv oc ac y p art n ers str o n gl y att est t h at t his is a r es e ar c h q u esti o n t h at is i m p ort a nt t o t h e m. T his 
is w h at is drivi n g o ur st u dy ai m 3 , w hic h will c o m p ar e t h e eff ecti v e n ess of v ari o us P P R T 
tr e at m e nt c o m bi n ati o ns a n d s e q u e nc es o n o utc o m es of r e n al t oxicity a n d r a di o gr a p hic e vi d e nc e 

 
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of dis e as e pr o gr essi o n. T his p r os p ecti v e C E R st u dy m ay ulti m at ely h el p i m pr o v e t h e 
st a n d ar diz ati o n a n d o pti miz ati o n of P R R T pr oc e d ur es [ 4 3], i ncr e asi n g t h er a py eff ecti v e n ess, 
dri vi n g a d o pti o n of pr ot ecti v e i nt er v e nti o ns, a n d i m pr o vi n g p ati e nt o utc o m es.  
b.  Tr e at m e nt of gr a d e 3 w ell diff er e nti at e d N E Ts is a n ar e a of c o ntr ov ers y. D at a fr o m t w o of o ur 
p artici p ati n g sit es (I o w a a n d V a n d er bilt) is s u p p orti v e of e arli er i niti ati o n of P R R T i n t h es e 
p ati e nts ( n e o -a dj uv a nt s etti n g), a n d a l ar g e C E R st u dy wit h t ar g et e d c h art r evi e w a n d el ectr o nic 
m e dic al r ec or d ( E M R ) d at a w o ul d b e a bl e t o ass ess es pr o gr essi o n -fr e e s ur viv al o utc o m es.  
c. L u n g N E Ts ar e a n u n d ers erv e d N E T c o h ort c urr e ntly pr escri b e d t h e s a m e 
tr e at m e nt/ m a n a g e m e nt pr actic es as G E P-N E Ts, ev e n t h o u g h t h e y ar e r ec o g niz e d as a s p ecific 
e ntit y; t h e l o w er fr e q u e ncy of t h es e t u m ors at si n gl e ac a d e mic m e dic al i nstit uti o ns pr ecl u d es 
r o b ust i nv esti g ati o n a n d i ncl usi o n i n r a n d o miz e d tri als. C E R st u di es i n l u n g N E Ts ar e t h er ef or e 
p artic ul arl y a p p e ali n g i n t his oft e n n e gl ect e d p o p ul ati o n.  
 
1. 1. 6.  P ot e nti al t o a d v a nc e r ar e dis e as e r es e arc h usi n g P C O R n et  
T h er e is c urr e ntly n o l ar g e n ati o n ally r ecr uiti n g pr os p ecti v e st u dy of N E T p ati e nts . T h e P C O R n et r es o urc e 
is t h e i d e al pl atf or m t o ev al u at e i n l ar g e p ati e nt n u m b ers, r e al-w orl d C E R q u esti o ns o n t h e dis e as e 
b ur d e n a n d tr e at m e nt eff ects a n d t oxiciti es t h at m att er m ost t o N E T p ati e nts, t h eir c ar e giv ers, a n d 
cli nici a ns i n v ol v e d i n t h eir c ar e. W e ex p ect t h at t h e l ess o ns l e ar n e d b y p art n eri n g wit h p ati e nts t o d esi g n 
t h e i nt er acti v e N E T p ati e nt h e alt h r ec or d ( P H R ) p ort al will yi el d g e n er aliz a bl e k n o wl e d g e a b o ut t h e 
i nf or m ati o n n e e ds f or ot h er r ar e dis e as e p o p ul ati o ns. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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2.  S P E CI FI C AI M S  
 
T h e ai ms of t his pr oj ect will b e a d dr ess e d t hr o u g h t h e c o n d uct of a pr os p ectiv e c o h ort st u dy. T h e 
g e n er al a p pr o ac h t o t h e cr e ati o n a n d w or kfl o w of t his c o h ort (i n r ef er e nc e t o t h e st u dy s p ecific a i ms) 
ar e bri efly o utli n e d b el o w.  
 
2. 1.  P ur p os e  
T h e p ur p os e of t his pr oj ect is t o p art n er wit h p ati e nts o n C E R t o ac hi ev e t h e g o al of miti g ati n g t oxicit y 
a n d o pti mizi n g eff ecti v e n ess a n d s e q u e nci n g of t h er a py f or p at e nts wit h N E Ts . 
I n or d er t o ac hi ev e t his o v er all g o al, w e h av e f o ur s p ecific ai ms. Ai m 1 a d dr ess es t h e p ati e nt q u esti o n of 
‘ w h at t h er a py w o ul d b e b est t o try n ext ?’ i n t h e c o nt ext of s y mpt o m b ur d e n a n d q u alit y of lif e. Ai m 2 
a d dr ess es p ati e nt c o nc er ns s urr o u n di n g t h e q u esti o n of ‘If I w er e t o t a k e t his o pti o n n o w, w h at 
tr e at m e nt o pti o ns will b e cl os e d off t o m e i n t h e f ut ur e’, by ex a mi ni n g p ati e nt a n d t u m or f act ors 
ass oci at e d wit h o v er all s urvi v al a n d dis e as e pr o gr essi o n.  Ai m 3 l e v er a g es t h e d at a o bt ai n e d i n ai ms 1 
a n d 2 t o i nf or m a c o m p ar ati v e eff ecti v e n ess st u dy of c o nt e m p or ar y c o nc er n , wit h a f oc us o n p ati e nt -
c e nt er e d q u alit y of lif e a n d t oxicit y o utc om es. Ai m 4 will ai d diss e mi n ati o n of o ur st u dy r es ults a n d 
c o ntri b ut e t o P C O R n et r ar e dis e as e i nfr astr uct ur e.  
 
AI M 1: T o d escri b e t h e fr e q u e nc y of tr e at m e nt r e gi m e ns r ec ei v e d b y li n e of t h er a p y, a n d  e x a mi n e t h eir 
ass oci ati o n wit h s y m pt o m b ur d e n a n d c h a n g es i n 6, 1 2 a n d 1 8 m o nt h H R Q oL  o utc o m es. T h e i nfl u e nc e 
of p ati e nt pr ef er e nc es, b eli efs, attit u d es, a n d e x p eri e nc e of c ar e o n c h oic e of t h es e tr e at m e nt 
r e gi m e ns will als o b e e x a mi n e d. 
Ex p ect e d o utc o m es  of ai m 1:  T his ai m will e n a bl e t h e asc ert ai n m e nt of p ati e nt -r e p ort e d o utc o m es 
( P R Os) r el at e d t o t h e ex p eri e nc e of sy m pt o m b ur d e n a n d t oxiciti es f or v ari o us t h er a pies ( a n d 
c o m bi n ati o n tr e at m e nts) a n d ex pl or e t h e p ati e nt’s attit u d es a n d b eli efs t h at i m p act t h e c h oic e of 
tr e at m e nt s e q u e nci n g b ey o n d t h e b asis of cli nic al a n d t u m or c h ar act eristics. D escri pti v e a n alys es of 
t h es e i m p ort a nt P R Os (t h at d o n ot exist i n t h e p ati e nt’s E M R  will d et er mi n e w h at c o m bi n ati o ns of 
t h er a py ar e b ei n g us e d, a n d t h e c h a n g es i n sy m pt o ms a n d H R Q oL ass oci at e d wit h t h es e t h er a p e utic 
c h oic es.  
 
AI M 2: T o e x a mi n e t h e ass oci ati o n of p ati e nt, cli nic al, a n d t u m or c h ar act eristics o n t h e s el ecti o n of 
first-li n e a n d b e y o n d tr e at m e nt r e gi m e ns a n d c o m p ar e t h e eff ects of c o m m o n tr e at m e nt s e q u e nc es 
o n fr e q u e nc y of s u bs e q u e nt tr e at m e nts r ec ei v e d a n d o utc o m es of o v er all s ur vi v al a n d dis e as e 
pr o gr essi o n.  
Ex p ect e d o utc o m es of ai m 2:  T his ai m will c oll ect  existi n g E M R d at a a m o n g t h e p ati e nts i d e ntifi e d i n ai m 
1. W e will i nv esti g at e t h e p ati e nts ’ pr e -e xisti n g c o m or bi diti es (i. e.: c ar di ov asc ul ar, r e n al a n d liv er dis e as e 
a n d di a b et es), pr o g n ostic t u m or f act ors ( d eri v e d fr o m t h e p o p ul ati o n of P C O R n et c a nc er r e gistry t u m or 
d at a t a bl es i. e.: st a g e, gr a d e n o d al st at us, mit otic c o u nt a n d Ki -6 7 i n d ex) a n d t h e e ff ect of t h es e o n t h e 
s el ecti o n of m ulti pl e li n e t h er a pi es r ec eiv e d. W e will a d diti o n ally ex a mi n e  t h e eff ect of t h es e p ati e nt, 
cli nic al a n d t u m or f act ors o n o utc o m es p ull e d vi a t ar g et e d c h art r evi e ws i. e.:  dis e as e pr o gr essi o n a n d 
o v er all s urvi v al.  
 
AI M 3:  T o c o m p ar e t h e eff ecti v e n ess of P R R T  r e gi m e ns o n o utc o m es of r e n al t oxicit y, dis e as e 
pr o gr essi o n, a n d p ati e nt -r e p ort e d s y m pt o ms a n d H R Q oL.  
Ex p ect e d o utc o m es of ai m 3:  W e will c o m pl et e a c o m p ar ati v e eff ecti v e n ess st u dy of P P R T wit h or 
wit h o ut a d mi nistr ati o n of ot h er s yst e mic t h er a pi es ( e. g .: e v er oli m us). W e will utiliz e t h e c o m bi n e d 
P R O’s g at h er e d i n ai m 1 a n d E M R d at a mi n e d i n ai m 2 (i. e.: pr e dict ors), t o c o m p ar e t h e eff ecti v e n ess of 
v ari o us P R R T tr e at m e nt c o m bi n ati o ns a n d s e q u e nc es, o n o utc o m es of r e d uc e d cr e ati ni n e cl e ar a nc e 
(r e n al t oxicity) a n d H R Q oL a n d s y m pt o m b ur d e n. W e will a d diti o n ally ex a mi n e t h e eff ect o n dis e as e 

 
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pr o gr essi o n of e m b oliz ati o n t h er a py a n d c h e m ot h er a py pri or  t o/f oll o wi n g P R R T. Ex pl ori n g t h e 
eff ectiv e n ess of t h es e o utc o m es i n gr a d e 3 w ell diff er e nti at e d N E Ts a n d l u n g N E Ts (c urr e nt ar e as of 
c o ntr o v ers y a n d u n d er st u dy r es p ecti v el y) will b e gr e atl y b e n efici al.  
 
AI M 4: T o diss e mi n at e l ess o ns l e ar n e d a n d e x p a n d e nr oll m e nt of t h e pr os p ecti v e c o h ort t o ot h er 
i nt er est e d P C O R n et sit es, p ati e nt a d v oc at e or g a niz ati o ns, a n d t o us e t h e i nfr astr uct ur e d e v el o p e d t o 
ai d i n t h e st u d y of ot h er r ar e dis e as es.  
Ex p ect e d o utc o m es of ai m 4:  By c oll a b or ati n g wit h s ev er al k ey n ati o n al N E T p ati e nt a dv oc acy 
or g a niz ati o ns, a n d b y f ulfilli n g o ur st ak e h ol d er e n g a g e m e nt pl a n, w e will f as hi o n a r o b ust a n d e arly 
diss e mi n ati o n pl a n distri b uti n g fi n di n gs t o N E T p ati e nts b ef or e t h e cl os e of t h e st u dy. P art n eri n g wit h 1 4 
p artici p ati n g sit es fr o m 4 P C O R n et cli nic al r es e arc h n et w orks ( C R Ns) a n d t h eir i nstit uti o n al m e di a 
o ut l ets, w e will s h ar e r es ults t h at ar e c ust o miz e d t o l oc al s etti n gs of c ar e. T h e N E T p ati e nt p h e n oty p e, 
t u m or t a bl e d at a q u ality c ur ati o n scri pts, a n d N E T p ati e nt h e alt h r ec or d ( N E T P H R) p ort al i nfr astr uct ur e 
t his st u dy will g e n er at e, will b e l o a d e d t o o p e n-s o urc e t o ol-s h ari n g sit es a n d t o t h e P C O R n et C o m m o ns.  
T h es e t o ols will b e us ef ul f or f ost eri n g ot h er C E R st u di es i n N E Ts a n d c o ul d e asily b e r e -p ur p os e d f or 
a p plic ati o ns i n ot h er r ar e dis e as es. Fi n ally, w e ex p ect t o s u b mit gr a nts t o c o n d uct n e w st u di es wi t h t his 
i nfr astr uct ur e, i ncl u di n g f oll o wi n g m or e p ati e nts f or l o n g er-t er m o utc o m es of t his i n d ol e nt dis e as e. If 
o ur N E T P H R p ort al is f o u n d t o off er v al u e t o p ati e nts, w e ex p ect t o m ai nt ai n it as p art of t his o n g oi n g 
r es e arc h. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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3.  S T U D Y O V E R VI E W  
3. 1.  O v er vi e w a n d a p pr o ac h  
W e will c o n d uct a pr os p ecti v e c o h ort st u dy of a p pr oxi m at el y 3, 0 0 0 p ati e nts wit h G E P -N E Ts a n d l u n g 
N E Ts l ev er a gi n g d at a m arts fr o m 1 4 p art n eri n g P C O R n et sit es t o d escri b e t h e ex p eri e nc e of s y m pt o m 
b ur d e n, s e q u e nci n g of t h er a pi es a n d t h eir ass oci at e d t oxiciti es o n o utc o m es r el ev a nt t o p ati e nts , 
i ncl u di n g H R Q oL a n d ov er all s ur vi v al.  
O ur first st e p will b e t o e nr oll a c o h ort of p ati e nts t o c oll ect p ati e nt r e p ort e d o utc o m es d at a ev ery 6 
m o nt hs. St e p t w o will i n v olv e t h e extr acti o n a n d assi mil ati o n of cli nic al d a t a fr o m E M R  a n d t ar g et e d 
c h art r evi e ws of t h es e s a m e p ati e nts. T h e t hir d st e p will l e v er a g e t h e f ull d at as et t o c h ar act eriz e 
tr e at m e nt r e gi m e ns a n d c o m p ar e t h eir eff ecti v e n ess. W e will f urt h er st u dy t h e h et er o g e n eity of t h es e 
tr e at m e nt eff ects by gr a d e of diff er e nti ati o n ( G 1/ 2 vs G 3) a n d N E T s u bsit e ( G E P vs l u n g). Fi n ally, w e pl a n 
t o s h ar e t h e i nfr astr uct ur e d e v el o p e d t hr o u g h o ur ai ms (i. e.: t h e N E T P H R p ort al, N E T p h e n ot y p e, 
C o m m o n D at a M o d el ( C D M)  t u m or t a bl e q u alit y c ur ati o n p ack a g e), diss e mi n at e o ur st udy fi n di n gs a n d 
ex p a n d o ur pr os p ec ti v e e nr oll m e nt t hr o u g h o ur f o ur n ati o n ally r e pr es e nt ativ e p art n eri n g p ati e nt 
a dv oc at e or g a niz ati o ns .  
T h e  st u dy s etti n g, r el e v a nt ti m e a nc h ors f or c o h ort d eri v ati o n, th e  s p ecific crit eri a f or i ncl usi o n, a n d 
m et h o ds f or c oh ort i d e ntific ati o n a n d s el ecti o n  ar e d et ail e d b el o w.  
 
3. 2.  S etti n g  
W e h av e i d e ntifi e d 1 4 P C O R n et p art n ers ( T a bl e 1), c h os e n as s u bc o ntr act e d sit es f or t h e N E T -P R O st u dy 
b as e d o n t h eir p ot e nti al t o pr os p ectiv ely r ecr uit o n av er a g e 2 1 5 p ati e nts o v er t h e 6 0 m o nt h s st u dy 
p eri o d. I m p ort a ntl y, all 4 p art n eri n g C R Ns h av e pr e vi o usl y c oll a b or at e d i n t h e P C O R n et C a nc er 
C oll a b or ati v e R es e arc h Gr o u p , a n d 3 of t h e n et w orks p artici p at e d i n a P C O R n et R a pi d C ycl e Pr oj ect of 
m ol ec ul ar t ar g et e d t h er a pi es t o effici e ntly s h ar e i n d ivi d u al-l e v el d at a [ 4 4, 4 5]. All 4 C R N p art n ers ar e 
a bl e t o  li n k N ort h A m eric a n Ass oci ati o n of C e ntr al C a nc er R e gistri es ( N A A C C R) r e q uir e d v ari a bl es t o 
t h eir C D Ms . 
As s h o w n i n T a bl e 1, 1 2 of o ur  1 4 P C O R n et p art n ers ar e affili at e d wit h a n N CI -d esi g n at e d 
C o m pr e h e nsiv e C a nc er C e nt er. T h es e ar e i nstit uti o ns d e dic at e d t o r es e arc h i n t h e d e v el o p m e nt of m or e 
eff ectiv e a p pr o ac h es t o pr e v e nti o n, di a g n osis a n d tr e at m e nt of c a nc er i nv olvi n g a m ulti disci pli n ary t e a m 
a p pr o ac h wit h s kill e d cli nici a ns a n d s p eci aliz e d t u m or b o ar ds. I m p ort a ntly, t h es e 1 4 p art n ers als o r efl ect 
t h e di v ers e cli nic al e nvir o n m e nts acc essi bl e t o N E T p ati e nts, i ncl u di n g a mixt ur e of hi g h v ol u m e 
m ulti disci pli n ar y s p eci alist N E T  c e nt ers vs. s o m e l ess s p eci aliz e d u nits, e n a bli n g t h e ex a mi n ati o n of t h e 
r e al-w orl d ex p eri e nc es a n d o utc o m es  of c ar e acr oss a v ari ety of pr actic e s etti n gs.  
 
T a bl e 1: List of 1 4 P C O R n et p art n ers  
 
Cli nic al Sit e ( Cli nic al R es e arc h N et w or k ( C R N )) 
N CI C a nc er C e nt er D esi g n ati o n  
U ni v ersit y of I o w a ( G P C) *  
Y es  
Alli n a H e alt h ( G P C)  
N o  
U ni v ersit y of K a ns as M e dic al C e nt er ( G P C)  
Y es  
M e dic al C oll e g e of Wisc o nsi n ( G P C)  
Y es  
U ni v ersit y of T ex as  S o ut h w est er n M e dic al C e nt er ( G P C)  Y es  
U ni v ersit y of Ut a h ( G P C)  
Y es  
U ni v ersit y of Fl ori d a ( O n e Fl ori d a)  
N o  
M a y o Cli nic ( S T A R)  
Y es  
M e dic al U ni v ersit y of S o ut h C ar oli n a ( S T A R)  
Y es  
U ni v ersit y of N ort h C ar oli n a at C h a p el Hill ( S T A R)  
Y es  

 
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Cli nic al Sit e ( Cli nic al R es e arc h N et w or k ( C R N )) 
N CI C a nc er C e nt er D esi g n ati o n  
V a n d er bilt U ni v ersit y M e dic al C e nt er ( S T A R)  
Y es  
O hi o St at e U ni v ersit y ( P a T H)  
Y es  
U ni v ersit y of Mic hi g a n ( P a T H)  
Y es  
U ni v ersit y of Pitts b ur g h M e dic al C e nt er ( P a T H)  
Y es  
*I ncl u d es t h e U ni v ers it y of I o w a C o or di n ati n g C e nt er ( UI C C) 
 
 
 

 
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4.  S T U D Y D E SI G N  
4. 1.  Ti m e a nc h ors f or st u d y c o h ort  
 
St u d y P eri o d:  0 1/ 0 1/ 2 0 1 9 t o 1 2/ 3 1/ 2 0 2 3 ( 5 y e ars, m ax 6 0 m o nt hs f oll o w -u p)  
I n d e x D at e:  D at e  of di a g n osis of eli gi bl e N E T t u m or i n t h e st u dy p eri o d  
S o urc e D at a  R a n g e:  0 1/ 0 1/ 2 0 1 7 -1 2/ 3 1/ 2 0 2 3 ( 7 y e ars, i ncl u d es 2 -y e ar l o o k-b ac k p eri o d ) 
 
4. 2.  I ncl usi o n/ E xcl usi o n Crit eri a  
T o b e eli gi bl e f or t his pr os p ecti v e c o h ort st u dy s u bj ects m ust m e et all  of t h e f oll o wi n g crit eri a :  
i. 
I nci d e nt G E P-N E T/L u n g N E T  di a g n osis * (s e e A p p e n di x A ) 
ii. 
Di a g n os e d 0 1/ 0 1/ 2 0 1 9 -1 2/ 3 1/ 2 0 2 3  
iii. 
N o k n o w n p ri or G E P-N E T/L u n g N E T di a g n osi s  
i v. 
A g e d ≥1 8 y e ars at di a g n osis  
v.  
At l e ast o n e sit e e nc o u nt er wit hi n t h e st u dy peri o d of J a n u ar y 1, 2 0 1 9 t o D ec e m b er 3 1, 2 0 2 3  
 
* S e e A p p e n di x A  f or a f ull list of I nt er n ati o n al Cl assific ati o n of Dis e as es, Ni nt h R evisi o n, Cli nic al 
M o dific ati o n (I C D -9 -C M), T h e I nt er n ati o n al Cl assific ati o n of Dis e as es, T e nt h R e visi o n, Cli nic al 
M o dific ati o n (I C D -1 0 -C M) c o d e s us e d t o d efi n e a N E T di a g n osis. T his a p p e n dix als o lists t h e I C D-0 -3 sit e 
c o d es a n d eli gi bl e hist ol o gy c o d es  f or i m pl e m e nt ati o n i n t u m or r e gistr y d at a s o urc es.  
 
4. 3.  C o h ort I d e ntific ati o n a n d S el ecti o n  
S o m e st u dy sit es m a y fi n d it m ost eff ectiv e t o us e a hi g hl y s e nsitiv e p h e n oty p e t o  i d e ntify p artici p a nts 
fr o m t h eir cli nics; cli nic st aff c o ul d t h e n e asily scr e e n o ut t h e c o nc o mit a nt f als e p ositiv es t h at w o ul d als o 
b e fl a g g e d wit h s uc h a  s e nsiti v e p h e n oty p e. F or ot h er sit es, h o w e v er, r ecr uiti n g t hr o u g h e -m ail m a y b e  
m ost a p pr o pri at e. I n w hic h  c as e, hi g h p ositiv e pr e dictiv e v al u e w o ul d b e ess e nti al  t o e ns ur e t h e p ati e nts 
c o nt act e d act u all y h av e a N E T di a g n osis . I n or d er t o acc o m m o d at e t h es e v ari e d a p pr o ac h es, w e ar e 
d e v el o pi n g a st a g e d al g orit h m t h at b al a nc es s e nsitivity a n d p ositi v e pr e dicti v e v al u e ( P P V ) wit h e ac h 
st e p.  
 
4. 3. 1.  P ot e nti al m o d es of s u bj ect i d e ntific ati o n  
T o i d e ntif y p ot e nti all y eli gi bl e p ati e nts f or i n vit ati o n i nt o t h e N E T-P R O st u dy, e nr olli n g sit es will 
m a n u ally r e vi e w - a n d/ or, us e a N E T c o m p ut a bl e p h e n ot y p e ( pr o vi d e d by t h e UI C C) t h at is r u n a g ai nst - 
existi n g E M R, r es e arc h w ar e h o us e, a n d / or o nc ol o gy r es e arc h d at a b as e or c a nc er r e gistry d at a.  
 
4. 4.  D e v el o p m e nt of a N E T C o m p ut a bl e P h e n ot y p e  
S p ecific c o d es f or G E P -N E Ts will i ncl u d e 2 0 9. 0 0 -2 0 9 . 2 7, 1 5 7. 4, 1 5 6. 2 (I C D-9) a n d C 7 A. 0 1 -C 7 A. 0 9 6, C 2 4. 1 
a n d C 2 5. 4 (I C D -1 0) , a n d f or l u n g -N E Ts  will  i ncl u d e 2 0 9. 2 1 (I C D-9) a n d C 7 A. 0 9 0 (I C D -1 0). T h e c urr e nt 
al g orit h ms w e h av e d ev el o p e d ar e si mil ar t o t h at us e d b y A D A P T A BL E f or i d e ntifyi n g p ati e nts wit h a 
hist o r y of at h er oscl er otic c ar di o v asc ul ar dis e as e [ 4 6].  
 
Q u er y l o gic  a n d c o d es will b e pr ovi d e d wit h e n o u g h d oc u m e nt ati o n t h at it will b e e asy t o a d o pt by sit es.  
A n ex a m pl e of t h e  t ec h nic al s p ecific ati o ns a n d S A S c o d e f or a hi g h P P V a n d a hi g h s e nsiti vit y c o m p ut a bl e 
p h e n ot y p e  is s h o w n i n A p p e n di x B . W e h a v e als o i ncl u d e d a p h e n ot y p e t h at us es d at a fr o m i nstit uti o n al 
t u m or r e gistri es. All b ut t h e hi g h s e nsitivity p h e n ot y p e ar e i nt e n d e d f or a ‘l o w -t o uc h’ m et h o d of 
r ecr uit m e nt. T h e l u n g-N E T Hi g h  P P V p h e n oty p e h a d a P P V of 9 2 %, a n d t h e G E P -N E T Hi g h P P V p h e n oty p e 
h a d a P P V of 9 0 -9 8 % w h e n c o m p ar e d wit h c h art r evi e w at T h e U niv ersit y of I o w a.   T h e esti m at e d 
s e nsiti vit y w as 5 9. 0 % a n d 4 5. 2 %, r es p ectiv ely. T h e hi g h s e nsiti vit y p h e n oty p e (f or us e w h e n r es o urc es 
c a n c o nfir m eli gi bilit y first i. e.: c h art r evi e w or i n -p ers o n cli nic r ecr uit m e nt), r es ult e d i n a s e nsitivit y of 

 
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8 4. 6 % f or l u n g -N E Ts, a n d 8 9. 2 % f or G E P -N E Ts A p p e n di x B . W e will  diss e mi n at e t h e p h e n oty p e  t o all 
c oll a b or ati n g sit es a n d vi a P C O R n et w e bi n ars t o e nc o ur a g e its a m e n d m e nt a n d us e i n ot h er dis e as e 
s etti n gs. T h e c o m p ut a bl e p h e n oty p e will b e o p e nl y d e p osit e d o n a p u blic p h e n oty p e  d at a b as e (i. e.: 
P h e K B)  a n d p ost e d o n t h e P C O R n et i M e et C e ntr al sit e.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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5.  R E C R UI T M E N T , E N R OLL M E N T A N D S T U D Y A C TI VI TI E S 
5. 1.  O v er vi e w  
T h e UI C C will pr o vi d e s u p p ort f or e nr olli n g sit es t o i d e ntif y a n d i m pl e m e nt m ulti pl e m o d es of 
a p pr o ac hi n g a n d r ecr uiti n g p ati e nts.  R ecr uit m e nt m at eri als will dir ect p ati e nts t o t h eir assi g n e d st u dy 
w e bsit e acc o u nt.  A d diti o n al acc o m m o d ati o ns will b e m a d e f or p ati e nts wit h o ut i nt er n et acc ess or w h o 
d o n ot f e el c o mf ort a bl e usi n g t h e st u dy w e bsit e (s e e S ecti o n 5. 5. 3  f or d et ails). O nc e l o g g e d i n, t h e 
w e bsit e will dir ect p ati e nts t hr o u g h t h e e nr oll m e nt pr oc ess, a n d i nf or m ati o n o n l oc al sit e c o nt acts f or 
q u esti o ns will b e a v ail a bl e o n t h e w e bsit e.  S e e Fi g ur e 3 f or a sc h e m atic of st u dy r ecr uit m e nt a n d 
e nr oll m e nt activiti es.  
 
All sit es r el yi n g o n t h e U niv ersit y of I o w a I R B as t h e I R B of R ec or d will b e pr o vi d e d wit h  I R B a p pr ov e d 
t e m pl at es as a p pr o pri at e f or r ecr uit m e nt a n d e nr oll m e nt m at eri als ( e. g., I nf or m e d C o ns e nt D oc u m e nt, 
i nvit ati o ns, br oc h ur es).  T h es e m at eri als will b e t ail or e d t o sit e  n e e ds a n d r e q uir e m e nts b as e d o n r evi e w 
of t h e l oc al c o nt ext d oc u m e nts s u p pli e d by r elyi n g sit es.  
 
5. 2.  R ol es a n d r es p o nsi biliti es of e nr olli n g sit es a n d UI C C  
E nr olli n g sit es will b e r es p o nsi bl e f or p ati e nt c o nt acts u p t hr o u g h a n d i ncl u di n g p artici p a nt e nr oll m e nt 
d efi n e d as  c o m pl eti o n of c o ns e nt a n d c o nt act i nf or m ati o n  ( St e p 4 of e nr oll m e nt [S ecti o n 5. 7 b el o w ]). I n 
s o m e i nst a nc es, s uc h as t h os e t h at i nv olv e n o n -el ectr o nic e nr oll m e nt i n w hic h p artici p a nt c o nt act 
i nf or m ati o n is n ot av ail a bl e b y t h e UI C C, sit es m ay b e r es p o nsi bl e f or p ati e nt c o nt acts u p t hr o u g h a n d 
i ncl u di n g c o m pl eti o n of S urve y # 1.  T h e UI C C will b e r es p o nsi bl e f or p ati e nt c o nt acts r el at e d t o f oll o w -u p 
d at a c oll ecti o n fr o m p ati e nts dir ectly ( i. e.: b as eli n e/ 6/ 1 2/ 1 8 m o nt h s urv e ys).  H o w e v er, b ot h e nr olli n g 
sit es a n d t h e UI C C m ay b e c o nt act e d b y p ati e nts at a n y p oi nt i n t h e st u dy a n d s h o ul d b e p ositi o n e d t o 
a d dr ess p ati e nt q u esti o ns acc or di n gl y.  
 
5. 2. 1.   U ni v ersit y  of I o w a C o or di n ati n g C e nt er ( UI C C) r ol es a n d r es p o nsi biliti es  
 
1)  C o or di n at e all as p ects of t h e st u dy c o n d uct acr oss cli nic al sit es  
2)  T r ai n sit e st aff o n i m pl e m e nt ati o n of t he r es e arc h pr ot oc ol  
3)  Tr ac k e nr oll m e nt st at us of p ati e nts w h o visit t h e P H R w e bsit e or r et ur n p a p er st u dy p ac k ets  
a n d c o m m u nic at e t his p ati e nt-l e v el i nf or m ati o n t o sit es 
4)  C o m m u nic at e I nstit uti o n al R e vi e w B o ar d (I R B) a p pr o v als, c o nti n ui n g r e vi e ws, a n d 
m o dific ati o ns t o sit es 
5)  Pr ovi d e  t e m pl at es f or all st u dy m at eri als 
6)  Pr ovi d e  h ar d c o py m at eri als w h e n n e e d e d a n d as a p pr o pri at e (i. e.: t o s u p p ort p a p er -b as e d 
e nr oll m e nt by sit es).  
7)  A ns w er  p ati e nt q u esti o ns pr e - a n d p ost -e nr ol l m e nt 
8)  A d mi nist er  t h e st u dy w e bsit e ( P H R) 
9)  M ai nt ai n  s ec urit y a n d i nt e grit y of c oll ect e d d at a 
 
5. 2. 2.  E nr olli n g sit e r ol es a n d r es p o nsi biliti es  
1)  R u n q u eri es t o i d e ntif y p ot e nti all y eli gi bl e p ati e nts  i niti ally, a n d t h e n ev er y 2 -4 w e e ks  (i. e.: usi n g 
l oc al d at a s o urc es/w ar e h o us e or  C D M)  as a p pr o pri at e b as e d o n r at e of p ot e nti ally eli gi bl e 
p ati e nt accr u al  
2)  Scr e e n a n d r ecr uit p ati e nts t o t h e st u dy   
3)  Pr ovi d e missi n g c o nt act i nf or m ati o n f or e nr oll e d s u bj ects (I. e.: p h o n e n u m b er, m aili n g a d dr ess, 
e m ail a d dr ess)  

 
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4)  C oll ect m e dic al r ec or d d at a o n e nr oll e d s u bj ects a n d r et ur n t h os e d at a t o t h e UI C C  (s e e 6. 1 
b el o w)  
5)  A ns w er p ati e nt  q u esti o ns pr e -a n d p ost -e nr oll m e nt  
6)  M ai nt ai n a tr ac ki n g d at a b as e ( R E D C a p) of eli gi bl e a n d a p pr o ac h e d p ati e nts , i ncl u di n g 
m ai nt e n a nc e of t h e li n k b et w e e n  UI C C -assi g n e d P A R TI CI P A N TI D a n d C D M P A TI D  
7)  Pr ovi d e m o nt hly e nr oll m e nt r e p orts t o t h e UI C C  
8)  P o p ul at e t h e P C O R n et T RI AL t a bl e f or e nr oll e d p ati e nts 
 
5. 3.  I d e ntif yi n g p ati e nts f or r ecr uit m e nt at p artici p ati n g sit es   
D at a gr o u ps at e ac h sit e will r u n t h e c o m p ut a bl e p h e n ot y p e a g ai nst t h eir E M R, r es e arc h w ar e h o us e, a n d 
/ or o nc ol o gy r es e arc h d at a b as e or c a nc er r e gistr y d at a ev ery t w o t o f o ur w e e ks t o i d e ntif y i nci d e nt a n d 
r ec e ntly di a g n os e d N E T p ati e nts usi n g t h e a p pr o ac h es o utli n e d i n 4. 3  a n d 4. 4 a b ov e.  
 
5. 3. 1.  D at a el e m e nts us e d t o i d e ntif y p ot e nti al s u bj ects f or r ecr uit m e nt  
T h e f oll o wi n g d at a el e m e nts will b e us ef ul fi el ds f or cli nic al sit es t o ai d i d e ntific ati o n/ i niti al c o nt act wit h 
p ot e nti al st u dy p artici p a nts. T h es e  v ari a bl es  will n ot b e s h ar e d wit h t h e UI C C  pri or t o e nr oll m e nt .  
 
i. 
N a m e(s) (s ur n a m e a n d f or e n a m e)  
ii. 
M R N ( M e dic al R ec or d N u m b er)   
iii. 
D at e of birt h  
i v. 
A d dr ess  
v.  
C o nt act n u m b er(s) ( h o m e/ m o bil e/ b ot h) , a n d c o nt act pr ef er e nc es  
vi. 
E -m ail a d dr ess  
vii.  
E M R d at a ( di a g n osis c o d es ( s e e A p p e n dix A), t ests a n d pr oc e d ur es, m e dic ati o ns a n d e nc o u nt ers)  
viii. 
Vit al st at us  
 
5. 4.  Assi g ni n g a n d m ai nt ai ni n g u ni q u e I Ds a n d P H R cr e d e nti al  li n k a g e t o p ati e nts 
T h e UI C C will pr o vi d e sit es wit h a  u ni q u e P A R TI CI P A N TI D  a n d cr ed e nti als f or p ati e nts t o acc ess t h e st u dy 
w e bsit e a n d t o est a blis h li nk a g es t o p ati e nts i n t h eir C D M d at a m art. T h e P A R TI CI P A N TI D will i nc or p or at e 
sit e i d e ntifyi n g i nf or m ati o n ( e. g.: 1 5 X X X X = U ni v ersity of I o w a). P ati e nt w e bsit e cr e d e nti als will i ncl u d e 
( 1) a t e m p or ary us er n a m e a n d p ass w or d, a n d ( 2) a u ni q u e U RL.   
 
O nc e eli gi bl e p ati e nts  ar e i d e ntifi e d (s e e 5. 3 ), sit es will li nk p ati e nt i nf or m ati o n wit h a P A R TI CI P A N TI D 
a n d cr e d e nti als pr ovi d e d by UI C C.  T h e UI C C will  s et u p a R E D C a p tr ac ki n g d at a b as e f or sit es t o us e. F or 
sit es t h at d o n ot wis h t o us e t h e R E D C a p d at a b as e s et u p b y t h e UI C C,  a t e m pl at e will b e pr ovi d e d f or 
sit es t o us e t o s et u p a l oc al v ersi o n of a R E D C a p tr acki n g d at a b as e.  Sit e st aff will b e as k e d t o u p d at e  
p ati e nt acti viti es  i n t h e UI CC  R E D C a p pr oj ect .  T his i nf or m ati o n will h el p g ui d e n ext st e ps f or p ati e nt 
e nr oll m e nt c o nt acts . 
 
5. 5.  P ati e nt r ecr uit m e nt a n d r ecr uit m e nt m at eri als  - i niti al c o nt acts 
O nc e t h e li n k a g e b et w e e n p ati e nt c o nt act i nf or m ati o n a n d UI C C -pr ovi d e d i nf or m ati o n is est a blis h e d i n 
R E D C a p, i niti al p ati e nt c o nt acts by l oc al sit e p ers o n n el c a n b e gi n. Sit es ar e e nc o ur a g e d t o o pti miz e 
r ecr uit m e nt str at e gies  b as e d o n av ail a bl e r es o urc es, i nstit uti o n al f act ors a n d/ or st u dy t e a m pr ef er e nc es.  
 
Sit es m a y i niti all y c o nt act p ot e nti ally eli gi bl e p ati e nts by e m ail, dir ect -t o-p ati e nt m ess a gi n g ( e. g., 
M y C h art, E M R m ess a gi n g f e at ur es, etc.), or gr o u n d m ail ; sit es m a y als o a p pr o ac h p ati e nts dir ectly i n-
p ers o n i n a priv at e s etti n g d uri n g a cli nic visit/c o ns ult ati o n (i. e.: a n ex a m r o o m). At t h at ti m e, t h e 
r es e arc h t e a m m e m b er m ay pr ovi d e t h e p ati e nt wit h i nf or m ati o n a b o ut t h e st u dy per a l ett er 

 
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( d escri b e d a b o v e), e m ail, dir ect -t o-p ati e nt m ess a gi n g (li k e M y C h art),  or st u dy p ac k et, d e p e n di n g o n 
p ati e nt pr ef er e nc e.  ( D ir ect-t o-p ati e nt m ess a gi n g (lik e M y C h art) will n ot t a k e pl ac e at UI H C b ut m a y 
occ ur at ot h er r el yi n g sit es.)  
 
UI C C m ay  als o pr o vi d e a st u dy br oc h ur e or si mil ar m at eri als t o b e us e d d uri n g t h e r ecr uit m e nt pr oc ess 
by sit es as a p plic a bl e or a p pr o pri at e. F or ex a m pl e, t h es e m at eri als m a y b e pr es e nt e d t o eli gi bl e p ati e nts 
d uri n g a n i niti al i n -cli nic visit t o pr ovi d e i ntr o d uct ory i nf or m ati o n a b o ut t h e N E T-P R O st u dy b ef or e a 
st u dy i n vit ati o n ( or st u dy p ac k et) is ext e n d e d. 
I d e all y, all r ecr uit m e nt m at eri als will b e p ers o n aliz e d wit h t h e i nstit uti o n l o g os/l ett er h e a ds of t h e 
r ecr uiti n g sit e t o f ost er sit e affili ati o n wit h t he N E T -P R O st u dy a n d pr ovi d e f a mili arit y a n d l oc al  sit e 
c o nt act d et ails. 
 
5. 5. 1.  E -m ail  
A n e -m ail i nvit ati o n  is s e nt by t h e sit e c o or di n at or dir ectl y t o t h e p ati e nt. T h e e-m ail b o dy 
i ncl u d es a bri ef st u dy s u m m ar y a n d u ni q u e N E T -P R O w e bsit e cr e d e nti als a n d/ or a li n k t h at 
t a k es r eci pi e nts dir ectl y t o t h eir st u dy w e bsit e acc o u nt . 
 
5. 5. 2.  Dir ect -t o-p ati e nt c o m m u nic ati o n ( e. g., M y C h art , ot h er E M R m ess a gi n g, etc.) 
A n  el ectr o nic i nvit ati o n is s e nt b y t h e sit e r es e arc h t e a m m e m b er dir ectly  t o t h e p ati e nt, i n 
acc or d a nc e wit h l oc al p olici es a n d pr oc e d ur es . T h e c o nt e nt of t h e c o m m u nic ati o n will b e 
i d e ntic al t o t h at of a n e m ail c o m m u nic ati o n. 
 
5. 5. 3.  Lett er   
A r es e arc h t e a m m e m b er c a n  m ail a n i nvit ati o n l ett er t o p ati e nts. T h e l ett er will c o nt ai n t h e 
st u dy w e bsit e a n d u ni q u e cr e d e nti als f or acc essi n g t h e st u dy P H R.   
 
5. 5. 4.  St u d y p ac k ets  
Sit es c a n el ect t o pr o vi d e or s e n d p ati e nts a “st u dy p ac k et” as a n o n -i nt er n et-b as e d o pti o n f or 
 
p ati e nts w h o ex pr ess diffic ult y or disc o mf ort wit h usi n g t h e st u dy w e bsit e.  St u dy p ac k ets will 
 
c o nt ai n: 
•  
A c ov er l ett er  
•  
A c o py  of t h e c o ns e nt s u m m ar y a n d t w o c o pi es of t h e i nf or m e d c o ns e nt d oc u m e nt ( o n e 
t o r et ur n t o t h e UI C C, o n e t o k e e p) 
•  
S ur v e y # 1  
•  
A  b usi n ess r e ply e nv el o p e ( B R E) a d dr ess e d t o t h e UI C C  r es e arc h t e a m ( n ot t h e st u dy 
sit e) 
 
T h e UI C C will pr o vi d e c o pi es of all p ac k et m at eri als exc e pt f or t h e c ov er l ett er, as t h e c o v er 
 
l ett er will n e e d t o i ncl u d e t h e p ati e nt s n a m e a n d a d dr ess.  Sit e c o or di n at ors will writ e or m ail 
 
m er g e t h e P A R TI CI P A N TI D  o n t h e fr o nt of t h e s urv ey s o t h e UI C C c a n i d e ntify t h e p ati e nt  
 
if/ w h e n a s ur v e y is r et ur n e d t o t h e UI C C usi n g t h e pr ovi d e d B R E. Aft er e nr oll m e nt t o t h e st u dy  
 
a n d c o m pl eti o n of S ur v e y # 1 , t h e UI C C will ass u m e r es p o nsi bilit y f or d at a c oll ecti o n.  
 
5. 6.  P ati e nt r ecr uit m e nt c o nt acts a n d r ecr uit m e nt m at eri als –  f oll o w-u p c o nt acts  
F oll o wi n g t h e i niti al c o nt acts, s it e r es e arc h t e a m m e m b ers c a n m a k e u p t o a n a d diti o n al  fi v e (5 ) c o nt act 
att e m pts t o p ot e nti all y eli gi bl e p ati e nts .A ft er i niti al el ectr o nic , m ail or i n-p ers o n c o nt acts ar e m a d e, a n d 
if all o w a bl e p er sit e p olicy, sit es m ay c o nt act p ati e nts by p h o n e (i ncl u d e d i n t h e m ax of 6 c o nt acts)  t o 
f oll o w u p wit h t h e i niti al i nvit ati o n a n d a d dr ess a n y q u esti o ns p ati e nts m a y h av e a b o ut t h e st u dy .  

 
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Si mil arly, sit es m a y a p pr o ac h p ati e nts i n -p ers o n w h o w er e pr e vi o usl y i nvit e d t o p artici p at e i n t h e st u dy. 
Sit es ar e e nc o ur a g e d t o v ary a p pr o ac h es t o m axi miz e p ati e nt e nr oll m e nt.   
 
P ati e nts w h o d o n ot w a nt t o p artici p at e a n d d o n ot w a nt t o b e c o nt act e d f urt h er c a n n otify t h e r es e arc h 
t e a m i n a v ari et y of w a ys: 
1.  B y c alli n g or e m ail i n g t h e l oc al st u dy t e a m  
2.  B y c alli n g or e m ail i n g t h e UI C C N E T P R O t e a m (c o nt act i nf or m ati o n will b e pr ovi d e d o n t h e st u dy 
w e bsit e)  
3.  Af t er r evi e wi n g t h e c o ns e nt d oc u m e nt o nli n e, b y s el ecti n g t h e ‘ n ot i nt er est e d’ o pti o n. 
4.  B y r et ur ni n g t h e st u dy p ack et bl a nk t o t h e UI C C (f or  p ati e nts w h o w er e s e nt a st u dy p ac k et)  
 
T h e UI C C will i ncl u d e d at es of all n otific ati o n s by p ati e nts t h at t h e y ar e d ecli ni n g p artici p ati o n i n t h e 
u p d at es pr ovi d e d t o sit es  t o eli mi n at e t h e p ossi bility of s u bs e q u e nt c o nt acts. 
 
5. 7.  E nr oll m e nt vi a N E T -P R O P H R  r es e arc h p ort al 
P ati e nts w h o r ec eiv e i nvit ati o ns t o visit t h e st u dy w e bsit e will pr oc e e d s e q u e nti all y t hr o u g h fi v e st e ps 
aft er l o g gi n g i nt o t h eir st u dy acc o u nt:  
St e p 1 - A ns w er eli gi bilit y st at e m e nt (s e e 5. 7. 1  b el o w)  
St e p 2 - R evi e w t h e c o ns e nt s u m m ary a n d c o ns e nt d oc u m e nt, a n d el ectr o nic all y si g n t h e 
c o ns e nt d oc u m e nt 
 
St e p 3 - Cr e at e  n e w l o gi n cr e d e nti als f or t h eir P H R st u dy acc o u nt 
 
St e p 4  - E nt er c o nt act i nf or m ati o n  
 
St e p 5  - C o m pl et e S urv ey # 1  
 
5. 7. 1.  P ati e nt -R e p ort e d El i gi bilit y Crit eri a  
Gi v e n t h e diffic ulty of s p ecif yi n g a c o m p ut a bl e p h e n oty p e i n a r ar e dis e as e lik e N E T (i. e.: p ot e nti al f or 
f als e p ositi v es), a n d t h at t h e no m e ncl at ur e f or N E Ts c a n b e u nc ert ai n , p ati e nt s elf -r e p ort will b e us e d to 
v erify t h e  p ati e nt ’s b eli ef t h at t h ey h a v e b e e n di a g n os e d wit h a N E T ( a n d t o e ns ur e p ati e nts ar e n ot 
distr ess e d by r ec eivi n g t h e st u dy i n vit ati o n if t h ey d o n ot t hi n k t h ey h av e a t u m or ). T h e l a n g u a g e b el o w 
h as b e e n dr aft e d f or r evi e w by t h e p ati e nt a dvis ory c o m mitt e e a n d cli nici a n gr o u p f or us e i n t h e 
i nvit ati o n t o p artici p at e: 
 
“ Y o u ar e r ec ei vi n g t his st u dy p ac k et b ec a us e y o ur m e dic al r ec or ds i n dic at e t h at y o u w er e e v al u at e d i n 
cli nic f or a p ossi bl e n e ur o e n d ocri n e c o n diti o n. If t h e n e ur o e n d ocri n e c o n diti o n y o u w er e e v al u at e d f or  
w as di a g n os e d as a n e ur o e n d ocri n e/c arci n oi d t u m or, y o u m ay b e eli gi bl e t o p artici p at e i n t his st u dy. T o 
b e eli gi bl e, y o u m ust h a v e b e e n di a g n os e d wit h a n e ur o e n d ocri n e t u m or of t h e l u n g or br o nc h us a n d/ or 
g astr oi nt esti n al tr act (i. e.: st o m ac h, d u o d e n u m, j ej u n u m, il e u m, c ol o n, p a ncr e as, r ect u m or a p p e n dix) 
o n or aft er J a n u ar y 1, 2 0 1 9. I n a d diti o n, y o u m ust h a v e b e e n 1 8 y e ars of a g e or ol d er at t h e ti m e of 
di a g n osis.  If t h e a b ov e crit eri a d o es n ot a p pl y t o y o u or y o u f e el y o u’v e r ec ei v e d t his p ac k et i n err o r, 
pl e as e acc e pt o ur a p ol o gi es. I n a d diti o n, pl e as e c h ec k t h e b ox a n d r et ur n t h e bl a n k p ac k et i n t h e 
e ncl os e d p ost a g e p ai d e n v el o p e.”  
 
5. 7. 2.  Eli gi bilit y o utc o m es  
P ati e nts w h o r e m ai n eli gi bl e aft er att esti n g t o  t h e eli gi bilit y crit eri a a b o v e i n t h e st u dy w e bsit e will b e 
dir ect e d t o St e p 2 (r e vi e w / si g n c o ns e nt) o n t h e w e bsit e.  P ati e nts w h o ar e i n eli gi bl e will b e t a k e n t o a 
scr e e n th at t h a nks t h e m f or t h eir ti m e a n d i nf or ms t h e m t h e y ar e i n eli gi bl e.  
 

 
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5. 7. 3.  R e vi e w a n d Si g ni n g I nf or m e d C o ns e nt D oc u m e nt  
Aft er r evi e wi n g t h e i nf or m e d c o ns e nt d oc u m e nt, b ut b ef or e b ei n g as k e d t o si g n it, p ati e nts will h av e t h e 
a bilit y t o d o w nl o a d a n d pri nt it o ut a n d disc uss t h eir p ot e nti al p artici p ati o n wit h ot h ers. F oll o wi n g 
r e vi e w of t h e c o ns e nt d oc u m e nt, p ati e nts will b e as k e d if t h e y w a nt t o j oi n t h e st u dy. If t h ey a gr e e, t h ey 
will b e pr o m pt e d t o el ectr o nic all y si g n t h e i nf or m e d c o ns e nt d oc u m e nt o nli n e by e nt eri n g t h eir first a n d 
l ast n a m e. T h e d at e of e-si g n at ur e will b e a ut o-g e n er at e d b y t h e st u dy w e bsit e  a n d m ai nt ai n e d by t h e 
UI C C . A n el ectr o nic c o py of t h e si g n e d a n d d at e d i nf or m e d c o ns e nt d oc u m e nt will t h e n b e av ail a bl e f or 
e nr oll e es t o acc ess.  
 
P ati e nts will h a v e a n o pti o n b ot h t o d ecli n e p artici p ati o n a n d f or m or e ti m e t o c o nsi d er e nr oll m e nt.  
 
5. 8.  E nr oll m e nt vi a St u d y P ac k et  
Sit e c o or di n at ors will h av e writt e n or pri nt e d t h e P A R TI CI P A N TI D assi g n e d by t h e UI C C o n t h e st u dy 
p ac k et b ef or e s e n di n g/ pr ovi di n g it (i. e. , i n-p ers o n) t o p ati e nts.  
 
P ati e nts w h o w er e pr ovi d e d a st u dy p ac k et will att est t o t h e p ati e nt -r e p ort e d eli gi bilit y st at e m e nt 
o utli n e d i n 5. 7. 1 a b ov e .  If t h e y ar e i n eli gi bl e, or d ecli n e t o p artici p at e, t h e y will b e as k e d t o r et ur n t h e 
st u dy p ac k et bl a nk t o t h e UI C C usi n g t h e pr o vi d e d B R E.  If t h ey ar e eli gi bl e, t h e y will b e i nstr uct e d t o 
r e vi e w t h e c o ns e nt s u m m ar y a n d i nf or m e d c o ns e nt d oc u m e nt, a n d if i nt er est e d i n j oi ni n g t h e st u dy, will 
b e i nstr uct e d t o si g n a n d d at e o n e of t h e i ncl u d e d c o pi es a n d t o r et ai n a c o py f or t h e ms el v es. 
I n a dv ert e ntly r et ur n e d d u plic at e c o pi es of c o ns e nt d oc u m e nts will b e m ail e d b ack t o s u bj ects usi n g t h e 
a d dr ess i nf or m ati o n pr o vi d e d. R ec ei pt of a c o m pl et e d c o ns e nt d oc u m e nt t o t h e UI C C  will d e n ot e 
c o ns e nt t o p artici p at e i n t h e st u dy. T h e UI C C, or sit e r es e arc h t e a m i n c o ns ult ati o n wit h t h e UI C C, will 
c o nt act p ers o ns w h o di d n ot c o m pl et e t h e c o ns e nt d oc u m e nt (t o as k t h e m t o c o m pl et e a n d r et ur n it) if 
o nl y a c o m pl et e d s urv ey w as r et ur n e d.  
 
5. 9.  E nr oll m e nt M o nit ori n g  a n d R e p orti n g  
E nr olli n g sit e st aff will r ec or d all p ati e nt c o nt acts a n d st at us u p d at es ( e. g., d ecli n e d, d ec e a s e d, etc.) i n 
th e UI C C R E D C a p pr oj ect .  T h e UI C C R E D C a p pr oj ect  will est a blis h  t h e li n k a g e b et w e e n p ati e nt 
i d e ntif yi n g i nf or m ati o n at t h e cli nic al sit e a n d UI C C-pr o vi d e d P A R TI CI P A N TI D a n d cr e d e nti als a n d  will 
pr o vi d e r e al -ti m e u p d at es o n p ati e nt P H R acc ess a n d us e t o sit e st aff.  Sit es h a v e t h e o pti o n t o st a n d u p 
t h eir o w n, a d diti o n al c o py if pr ef err e d, a n d UI C C will n ot h av e acc ess t o t h es e sit e l oc al R E D C a p  
i nst a nc es ( asi d e fr o m UI O W A’s).  
 
As t h e UI C C is r e q uir e d t o u p d at e t h e P ati e nt C e nt er e d O utc o m es R es e arc h I nstit ut e (P C O RI ) o n 
e nr oll m e nt activiti es by  all sit es, sit es will b e as k e d t o m ai nt ai n c as e tr ac ki n g i nf or m ati o n i n t h e UI C C 
R E D C a p pr oj ect i ncl u di n g i nf or m ati o n r el at e d t o: 
•  
H o w eli gi bilit y w as ass ess e d  
•  
Invit ati o n c o nt acts t o eli gi bl e p ati e nts 
•  
P ati e nt d ecli n es/ wit h dr a w als  
•  F or d ec e as e d p ati e nts , t h e d at e a n d (if k n o w n) c a us e of d e at h 
 
UI C C will pr o vi d e t e m pl at es f or / acc ess t o t h e a b ov e. 
 
 
5. 1 0.  
P ost -c o ns e nt st u d y pr oc e d ur es  
 

 
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5. 1 0. 1.  B as eli n e s ur v e y  
5. 1 0. 1. 1.  
P artici p ati o n vi a t h e  N E T -P R O P H R  
Aft er t h e s u bj ect si g ns t h e i nf or m e d c o ns e nt d oc u m e nt, t h ey will b e pr o m pt e d t o cr e at e t h eir st u dy 
acc o u nt by c h a n gi n g t h eir us er n a m e a n d p ass w or d.  T h er e aft er, t h ey will b e i nvit e d t o c o m pl et e t h e first 
st u dy s urv e y, w hic h will t ak e a p pr oxi m at el y 4 0 mi n utes t o c o m pl et e. T his s ur v e y as ks a b o ut c urr e nt a n d 
p ast h e alt h c o n diti o ns a n d tr e at m e nts, sy m pt o ms, h e alt h b e h avi ors, f e eli n gs, c o nc er ns, a n d g e n er al 
pr ef er e nc es a b o ut h e alt h a n d h e alt h c ar e, p hysic al a n d m e nt al h e alt h, a n d b asic i nf or m ati o n (li k e 
m arit al st at us, a n d h ei g ht a n d w ei g ht). T h er e ar e als o a f e w q u esti o ns t o ass ess c o mf ort wit h a n d 
u n d erst a n di n g of h e alt h i nf or m ati o n. O nc e c o m pl et e d, s u bj ects will b e i n vit e d t o ex pl or e t h e st u dy 
w e bsit e w hic h c o nt ai ns a w a y t o vi e w t h eir s ur v e y r es p o ns es, c o ns e n t d oc u m e nt, t h eir st u dy st at us, a n d 
ot h er N E T r es o urc es.  
 
5. 1 0. 1. 2.  
P artici p ati o n vi a p a p er st u d y p ac k et  
Aft er t h e s u bj ect si g ns a n d d at es t h e i nf or m e d c o ns e nt d oc u m e nt, t h ey will b e i nvit e d t o c o m pl et e 
S ur v e y # 1  ( w hic h will b e p art of t h e pr o vi d e d p ac k et). O nc e c o mpl et e d, t h ey will r et ur n t h e st u dy p ac k et 
- w hic h i ncl u d es a c o py of t h e si g n e d/ d at e d c o ns e nt a n d t h e c o m pl et e d S urv ey # 1  - t o t h e UI C C usi n g a 
pr e -p ai d B R E.   
 
O nc e r ec eiv e d, a UI C C r es e arc h t e a m m e m b er will e nt er s u bj ect s ur v e y r es p o ns es i nt o t h e st u dy 
w e bsit e.  
5. 1 0. 2.  UI C C R e mi n d er C o nt acts  
S u bj ects w h o pr o vi d e c o ns e nt a n d c o nt act i nf or m ati o n b ut d o n ot c o m pl ete  S ur v e y # 1 , will b e c o nt act e d 
by e m ail, l ett er a n d/ or p h o n e aft er 7 d ays as a r e mi n d er t h at t h eir s urv ey is n ot c o m pl et e. A m axi m u m 
of 6 r e mi n d er c o nt acts will b e m a d e. E nr olli n g sit es will  b e as k e d t o  pr o vi d e s u bj ect c o nt act i nf or m ati o n 
t o t h e UI C C if t he s u bj ect h as n ot pr ovi d e d it ( or it w as n ot v ali d) i n t h e st u dy w e bsit e ( St e p s 3 a n d 4) t o 
e n a bl e t h es e r e mi n d er c o nt acts.  
 
5. 1 0. 3.  F oll o w -u p s ur v e ys  
A p pr oxi m at ely six m o nt hs aft er s u bj ects c o m pl et e t h e first s urv ey, t h e UI C C will s e n d i n vit ati o ns f or 
s u bj ects to c o m pl et e t h e 6 -m o nt h s urv e y vi a e m ail (f or st u dy w e bsit e e nr oll e es) or m ail (f or m ail 
e nr oll e es). C o nt e nt f or t his a n d t h e r e m ai ni n g f oll o w -u p s ur v eys ( at 1 2 a n d 1 8 m o nt hs) ar e si mil ar t o t h e 
S ur v e y # 1 ( b as eli n e), exc e pt t h ey d o n ot i ncl u d e q u esti o ns a b o ut c hr o nic c o n diti o ns, d e m o gr a p hics, 
t h o u g hts o n c a nc er di a g n os es a n d tr e at m e nt d ecisi o ns, or h e alt h lit er acy.  
 
If t h e s u bj ect h as n ot c o m pl et e d t h e 6-m o nt h s urv ey wit hi n 7 d ays of t h e i n vit ati o n, a r e mi n d er e m ail, 
m ail, or p h o n e i nvit ati o n will b e s e nt/ m a d e. T h es e r e mi n d ers will b e a ut o m at e d  by t h e UI C C or P H R , as 
a p plic a bl e.  T his pr oc ess will b e r e p e at e d ( e v er y 7 d ays) f or a m axi m u m of six c o nt acts u ntil t h e s u bj ect 
c o m pl et es t h e s ur v e y or d ecli n es t o c o m pl et e it.  I d e ntic al i n vit ati o n a n d n o nr es p o ns e pr oc e d ur es  will 
b e i m pl e m e nt e d f or t h e 1 2 - a n d 1 8 -m o nt h s urv e ys. (S e e A p p e n dix C f or d et ails o n pr e - a n d p ost -c o ns e nt 
c o nt acts.) 
 
If t h e UI C C is u ns ucc essf ul at c o nt acti n g s u bj ects usi n g t h e i nf or m ati o n pr o vi d e d b y t h e s u bj ect ( e. g., 
d at a e nt er e d err o n e o usl y o n t h e P H R), t h e UI C C will c o m m u nic at e wit h t h e e nr olli n g sit e t o r e vi e w t h e 
p ati e nt m e dic al r ec or d t o att e m pt t o fi n d a n d s h ar e u p d at e d c o nt act i nf or m ati o n wit h t h e UI C C.  
 
S u bj ects will b e a bl e t o acc ess t h eir st u dy acc o u nts ( P H R w e bsit e) at l e ast t hr o u g h t h e e n d of 2 0 2 5. A 
UI C C r es e arc h t e a m m e m b er or t h e P H R will b e us e d t o s e n d a ut o m at e d r e mi n d ers t o p ati e nts f or 

 
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s u bs e q u e nt c o m pl eti o n of t h e 6-, 1 2- a n d 1 8 -m o nt h f oll o w -u p q u esti o n n air es (c alc ul at e d fr o m t h e d at e 
of t h eir b as eli n e q u esti o n n air e c o m pl eti o n).  
 
5. 1 0. 4.  S u bj ect C o m p e ns ati o n  
R e g ar dl ess of t h e e nr oll m e nt m e a ns, s u bj ects will b e c o m p e ns at e d $ 4 0  f or c o m pl eti n g S ur v ey # 1, a n d 
$ 2 0  f or c o m pl eti n g e ac h s u bs e q u e nt s ur v e y (i. e.: S ur v e ys # 2 -4) , f or a t ot al of $ 1 0 0. 0 0. C h ecks will b e 
s e nt by t h e UI C C t o t h e a d dr ess pr o vi d e d by t h e s u bj ect o n t h eir P H R r e gistr ati o n p a g e or m ail e d 
q u esti o n n air e ( usi n g p ers o n al d at a c oll ect e d p ost c o ns e nt).  
 
5. 1 1.  
P ost -e nr oll m e nt m o nit ori n g  
T h e UI C C will r ec or d all s u bj ect c o nt acts a n d st at us u p d at es a n d will s h ar e t his i nf or m ati o n as n e e d e d 
wit h e nr olli n g sit es.  
 
I n s o m e c as es, it m ay b e n ec ess ary f or a n e nr olli n g sit e or t h e UI C C t o c o nfir m t h e i d e ntiti es of e nr oll e d 
p ers o ns a n d/ or t o c o nf ir m t h at t h e li n k a g e b et w e e n p ers o n a n d assi g n e d cr e d e nti als is c orr ect. 
I nf or m ati o n c oll ect e d fr o m s u bj ects p ost-e nr oll m e nt m a y b e s h ar e d b et w e e n a sit e a n d t h e UI C C t o 
r es olv e a ny s uc h discr e p a nci es.  
 
5. 1 2.  
P o p ul ati o n of C D M P C O R n et _ T RI AL t a bl e  
UI C C will pr o v i d e g ui d a nc e t o sit es o n p o p ul ati n g t h e P C O R n et _ T RI AL t a bl e.  T his is n ec ess ar y as t h e 
o utc o m es q u ery pr o vi d e d t o sit es will  r ef er e nc e t his t a bl e.  Sit es will n e e d t o p o p ul at e t h e t a bl e pri or t o 
r u n ni n g t h e o utc o m es q u ery. T h e UI C C will s h ar e a list of all p ers o ns w h o e nr oll e d i n t h e st u dy as a 
c h ec k a g ai nst sit e r ec or ds t o c o nfir m t h at t h e P C O R n et _ T RI AL t a bl e is p o p ul at e d c orr ectl y at all sit es.  
 
5. 1 3.  
D at a Cr oss w al ks  
As ill ustr at e d i n Fi g ur e 3, it is n ec ess ar y t o est a blis h a n d m ai nt ai n  t h e f oll o wi n g d at a cr oss walks  t o 
e ns ur e t h e i nt e grity of d at a li n k a g es acr oss s o urc es:  
 
R es p o nsi bl e 
p art y  
Li n k a g e of … 
T o …  
N ot es  
UI C C  
P A R TI CI P A N TI D  
St u dy W e bsit e 
Cr e d e nti als  
UI C C will est a blis h t his li n k a g e a n d m ai nt ai n it 
i n t h e st u dy d at a b as e ( S QL) 
Sit es  
P A R TI CI P A N TI D a n d 
St u dy W e bsit e 
Cr e d e nti als  
C D M P A TI D  
Est a blis h li n k a g e i n R E D C a p as eli gi bl e p ati e nts 
ar e i d e ntifi e d fr o m y o ur s o urc e E M R d at a. UI C C 
t o pr o vi d e P A R TI CI P A N TI D a n d St u dy W e bsit e 
Cr e d e nti als  
Sit es  
C D M P A TI D  
M R N or si mil ar I D  
Sit es s h o ul d a lr e a dy h a v e a w a y t o li n k C D M 
P A TI D t o M R N or si mil ar I D t h at c a n b e us e d t o 
dir ectl y i d e ntif y p ati e nts.  T his will b e n e e d e d 
f or c h art r evi e w activiti es. 
 
 
 
 
 
 
 
 

 
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Fi g ur e 3 : N E T-P R O st u d y e nr oll m e nt w or kfl o w  

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
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7.  S T U D Y O U T C O M E S  
T a bl e 4  s u m m ariz es t h e pri m ar y a n d s ec o n d ar y o utc o m es of t h e N E T-P R O st u dy by pr oj ect ai ms.  
7. 1.  Pri m ar y O utc o m e s 
1)  E ur o p e a n Or g a niz ati o n f or R es e arc h a n d Tr e at m e nt of C a nc er - Q u alit y of Lif e Q u esti o n n air e 
(E O R T C QL Q -C 3 0 ). T h e E O R T C QL Q -C 3 0 is o n e of t h e m ost wi d el y us e d H R Q oL q u esti o n n air es i n 
c a nc er r es e arc h. A v ali d at e d t o ol, it c o nsists of 3 0 q u esti o ns wit h a 4 -p oi nt Lik ert sc al e (fr o m “ n ot 
at all” t o “ v ery m uc h”) i nc or p or ati n g fi v e f u nct i o n al sc al es ( p hysic al, r ol e, c o g nitiv e, e m oti o n al, 
a n d s oci al), t hr e e sy m pt o m sc al es (f ati g u e, p ai n, a n d n a us e a a n d v o miti n g), a gl o b al h e alt h st at us / 
Q oL sc al e, a n d a n u m b er of si n gl e it e ms ass essi n g a d diti o n al sy m pt o ms c o m m o nl y r e p ort e d b y 
c a nc er p ati ents ( dys p n e a, l oss of a p p etit e, i ns o m ni a, c o nsti p ati o n a n d di arr h e a) a n d p erc ei v e d 
fi n a nci al i m p act of t h e dis e as e. R es p o ns es t o t h e QL Q -C 3 0 will b e li n e arl y tr a nsf or m e d t o a 0 -1 0 0 
sc al e usi n g E O R T C g ui d eli n es, a hi g h er sc or e r e pr es e nts a hi g h er (" b ett er") l ev el of f u ncti o ni n g, or 
a hi g h er (" w ors e") l e v el of s y m pt o ms.  A m e a n diff er e nc e of 1 0 p oi nts ( p ositiv e or n e g ati v e) h as 
b e e n wi d ely acc e pt e d as t h e mi ni m al cli nic all y i m p ort a nt diff er e nc e ( M CI D) f or t h e E O R T C QL Q -
C 3 0 [ 5 8]. A s p ecific M CI D f or c arci n oi d s y n dr o m e a n d N E T h as n ot b e e n i d e ntifi e d. H o w ev er a 
r ec e nt st u dy i n a dv a nc e d c ol or ect al c a nc er h as i n dic at e d M CI Ds f or i m pr ov e m e nt ( d et eri or ati o n) 
r a n g e d fr o m 6 t o 1 8 (-1 1 t o -5) p oi nts f or wit hi n -gr o u p c h a n g e a n d 5 t o 1 5 ( -1 0 t o -4) f or b et w e e n -
gr o u p c h a n g e f or t h e E O R T C QL Q -C 3 0, wit h s u m m ariz e d MI C Ds (i n a bs ol ut e v al u es) p er sc al e 
m ostl y r a n gi n g fr o m 5 t o 1 0 p oi nts [ 5 9]. A n M CI D w as n ot i d e ntifi e d i n t h e lit er at ur e f or t h e QL Q -
GI .N E T 2 1 m o d ul e.   
[ Ti m e Fr a m e: C h a n g e i n m e a n sc or e acr oss b as eli n e, 6, 1 2, a n d 1 8 m o nt h ti m e p oi nts.]  
2)  E ur o p e a n Or g a niz ati o n f or R es e arc h a n d Tr e at m e nt of C a nc er - Q u alit y of Lif e Q u esti o n n air e - 
N e ur o e n d ocri n e C arci n oi d M o d ul e  ( E O R T C QL Q-GI. N E T 2 1) T h e E O R T C  QL Q -C 3 0 c a n b e us e d i n 
c o nj u ncti o n wit h t h e E O R T C QL Q -GI. N E T 2 1 s p ecific q u esti o n n air e, w hic h c o m pris es a t ot al of 2 1 
it e ms: f o ur si n gl e-it e m ass ess m e nts r el ati n g t o m uscl e a n d/ or b o n e p ai n ( M B P), b o dy i m a g e ( BI), 
i nf or m ati o n (I N F) a n d s ex u al f u ncti o ni n g (S X), t o g et h er wit h 1 7 it e ms or g a niz e d i nt o fiv e pr o p os e d 
sc al es: e n d ocri n e sy m pt o ms ( E D; t hr e e it e ms), GI sy m pt o ms ( GI; fiv e it e ms), tr e at m e nt -r el at e d 
s y m pt o ms ( T R; t hr e e it ems), s oci al f u ncti o ni n g ( S F 2 1; t hr e e it e ms) a n d dis e as e-r el at e d w orri es 
( D R W; t hr ee it e ms). R es p o ns es t o t h e QL Q -GI N E T 2 1 will b e li n e arly tr a nsf or m e d t o a 0 -1 0 0 sc al e 
usi n g E O R T C g ui d eli n es, wit h hi g h er sc or es r efl ecti n g m or e s e v er e sy m pt o ms.  
[ Ti m e Fr a m e: C h a n g e i n m e a n sc or e acr oss b as eli n e, 6, 1 2, a n d 1 8 m o nt h ti m e p oi nts.] 
3)  S e q u e nci n g  of tr e at m e nt r e gi m e ns fr o m el ectr o nic m e dic al r ec or ds. T his will i n v ol v e i d e ntif yi n g 
w hic h tr e at m e nts a p ati e nt  us e d d uri n g t h eir f oll o w -u p , a n d als o i n w h at or d er t h e y r ec eiv e d 
tr e at m e nt. D at es a n d t y p es of t h er a py i niti at e d will b e p ull e d fr o m e ac h p ati e nts E M R  i n r ef er e nc e 
t o t h e p ati e nt’s i n d ex d at e ( d at e of di a g n osis). W e will als o b e as ki n g p ati e nts a b o ut t h eir 
tr e at m e nts (s elf-r e p ort e d) i n t h e b as eli n e s ur v e y t o asc ert ai n p ot e nti al miss e d t h er a pi es i n t h e 
E M R . W e will b e c o m p ari n g t h e fr e q u e ncy ( N) a n d pr o p orti o n  ( %) of us e of a v ari et y of t h er a pi es 
(i. e.: S S As, b ev aciz u m a b, cyt ot oxic c h e m ot h er a py, ev er oli m us, I nt erf er o n al p h a, e m b oliz ati o n, 
P R R T, s m all m ol ec ul e T KIs) a n d t h e eff ects of t h eir or d eri n g/s e q u e nci n g  o n o utc o m es of s y m pt o m 
b ur d e n a n d H R Q oL .  
[ Ti m e Fr a m e: U p t o 5 y e ars, b as eli n e t o e n d of f oll o w-u p]  
4)  R e n al f u ncti o n.  Gl o m er ul ar filtr ati o n r at e ( G F R) is t h e b est o v er all i n d ex of ki d n e y f u ncti o n. 
N or m al G F R d ecli n es wit h a g e, a n d v ari es acc or di n g t o s ex, r ac e a n d b o dy siz e. W e will c alc ul at e  
cr e ati ni n e cl e ar a nc e l oss [ 5 4] by c o m bi ni n g i n di vi d u al l e v el C D M a n d e nr oll m e nt q u esti o n n air e 
d at a o n s ex, r ac e, h ei g ht, w ei g ht a n d s er u m cr e ati ni n e m g/ dl l a b or at or y v al u es  at r e g ul ar i nt erv als 
b ef or e a n d aft er P R R T c ycl es u ntil t h e e n d of f oll o w-u p.   
[ Ti m e Fr a m e: C h a n g e i n e G F R fr o m b as eli n e t o e n d of f oll o w-u p.]  
 

 
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7. 2.  S ec o n d ar y O utc o m es  
1)  N orf ol k C arci n oi d S y m pt o m Sc or e. T h e C arci n oi d S y m pt o m Sc or e  [ 4 9]] c o nt ai ns 1 3 q u esti o ns, 
w h er e q u esti o n 1 h as 3 q u eri es a b o ut fl us hi n g, wit h a m axi m u m of 3 p oi nts; q u esti o n 3 h as 4 it e ms 
i n q uiri n g a b o ut r es pir at or y s y m pt o ms, wit h a m axi m u m sc or e of 4. T h er e ar e 3 q u esti o ns a b o ut 
g astr oi nt esti n al sy m pt o ms f or a t ot al of 3 p oi nts, 3 q u esti o ns r el at e d t o p hysic al f u ncti o ni n g f or a 
t ot al of 3 p oi nts, a n d 3 q u esti o ns r el at e d t o c ar di o v asc ul ar dis e as e f or a t ot al of 3 p oi nts; t h e 
r e m ai ni n g 2 q u esti o ns ar e a b o ut f a mily a n d p ers o n al m e dic al hist ory. T h e a ns w ers t o t h e q u esti o ns 
ar e q u a ntifi e d as ‘‘ 0’’ ( n o sy m pt o m) a n d ‘‘ 1’’ (sy m pt o m  pr es e nt), s o t h e hi g h er t h e sc or e t h e w ors e 
is t h e sy m pt o m b ur d e n, fr o m a sc or e of ‘‘ 0’’ t o ‘‘ 1 8.’’ 
[ Ti m e Fr a m e: C h a n g e i n sc or e acr oss b as eli n e, 6, 1 2, a n d 1 8 m o nt h ti m e p oi nts.] 
2)  E x p eri e nc es wit h c a nc er c ar e (fr o m C A N C O R S) . 1 3 it e ms ass es s p ati e nts' ex p eri e nc es wit h 
i nt er p ers o n al as p ects of c a nc er c are [ 5 3], i ncl u di n g p hysici a n c o m m u nic ati o n (fi v e it e ms), n ursi n g 
c ar e (t w o it e ms), a n d c o or di n ati o n a n d r es p o nsi v e n ess of c ar e (six it e ms ). T h e sc or es i n e ac h d o m ai n 
ar e  c o nv ert e d t o 1 0 0-p oi nt sc al es, wit h 0 r e pr es e nti n g t h e w orst p ossi bl e c ar e a n d 1 0 0 r e pr es e nti n g 
o pti m al c ar e. P ati e nts c a n als o r at e t h e o v er all q u alit y of t h eir h e alt h c ar e si nc e c a nc er w as 
di a g n os e d o n a 5 -p oi nt sc al e r a n gi n g fr o m exc ell e nt t o p o or .  
[ Ti m e Fr a m e: C h a n g e i n sc or e acr oss b as eli n e, 6, 1 2, a n d 1 8 m o nt h ti m e p oi nts.] 
3)  Pr o gr essi o n -fr e e s ur vi v al ( P F S). Ti m e t o ev e nt d at a will b e c alc ul at e d fr o m t h e i n d ex d at e ( d at e of 
di a g n osis) t o t h e e arli est of dis e as e pr o gr essi o n , d e at h fr o m a n y c a us e  or e n d of st u dy f oll o w-u p 
( 1 2/ 3 1/ 2 0 2 3). Ack n o wl e d gi n g t h at p ati e nts m a y h av e m or e t h a n o n e pr o gr essi o n ov er t h e st u dy 
p eri o d e n d p oi nts of m e di a n ti m e t o first pr o gr essi o n (ti m e fr o m i niti a ti o n of first-li n e t h er a py t o 
pr o gr essi o n) a n d ti m e t o s ec o n d pr o gr essi o n (ti m e fr o m s ec o n d -li n e t h er a py i niti ati o n t o 
pr o gr essi o n) will b e o bs erv e d fr o m t ar g et e d c h art r e vi e ws at a n n u al i nt erv als. I n c oll a b or ati o n wit h 
o ur cli nici a n gr o u p  w e h a v e disc uss e d t h e v ari o us li mit ati o ns of t h e a p plic ati o n of t h e R E CI S T 1. 1 
crit eri a i n N E Ts. T h es e li mit ati o ns i ncl u d e a n ov er e m p h asis o n t u m or pr o gr essi o n ( gi v e n t h e l o w 
pr olif er a ti o n r at e of G E P-N E Ts, m o nit ori n g c h a n g es i n t u m or siz e is s u b o pti m al), a n d R E CI S T 1. 1 
crit eri a d o n ot r efl ect ov er all t u m or l o a d or r es p o ns e t o t h er a py i n m et ast atic p ati e nts (i. e.: iss u es 
wit h cli nic al si g nific a nc e of r a di ol o gic pr o gr essi o ns).  O pti mizi n g  t h e m a n a g e m e nt of N E T p ati e nts 
t h er ef or e r e q uir es c o nsi d eri n g cli nic al, bi ol o gic al, a n d p at h ol o gic al as p ects of t h e t u m or. W e h a v e  
t h er ef or e c h os e n t o c at e g oriz e dis e as e pr o gr essi o n as DI S E A S E C O N T R OL (c o m pl et e or p arti al 
r es p o ns e & st a bl e dis e as e), P R O G R E S SI O N ( wit h n o tr e at m e nt c h a n g e), P R O G R E S SI O N ( wit h 
tr e at m e nt c h a n g e), a n d I N D E T E R MI N A T E. T his cli nici a n -a nc h or e d a p pr o ac h h as b e e n f o u n d t o  b e a n 
o pti m al a n d v ali d m et h o d (v ers us R E CI S T 1. 1) f or e v al u ati n g r e al -w orl d t u m or b ur d e n e n d p oi nts fr o m 
E M R d at a [ 5 5].  
[ Ti m e Fr a m e: m e di a n ti m e t o pr o gr essi o n, ass ess e d a n n u all y vi a c h art r e vi e w] 
4)  O v er all S ur vi v al ( O S). Ti m e t o e v e nt d at a wi ll b e c alc ul at e d fr o m t h e d at e of di a g n osis (i n d ex d at e) 
t o t h e d at e of d e at h fr o m a ny c a us e, or e n d of st u dy f oll o w-u p ( 1 2/ 3 1/ 2 0 2 3). D e at h a n d v it al st at us 
( d e at h d at e, c a us e of d e at h) will b e p ull e d fr o m t h e d e at h t a bl e, a n d d e at h c a us e t a bl e i n t h e C D M.  
T his d at a m a y b e s u p pl e m e nt e d fr o m sit e li nk a g e t o t h e s oci al s ec urit y d e at h i n d ex or c a nc er 
r e gistr y s o urc es ( w h er e p ossi bl e). Gi v e n t h e pr os p ectiv e n at ur e of t h e st u dy w e als o h av e p ot e nti al 
f or p assiv e s urv eill a nc e/f oll o w-u p wit h p artici p a nt/ n ext of ki n wit h i nf or m ati o n c oll ect e d o n o ur 
f oll o w-u p q u esti o n n air es.  
[ Ti m e Fr a m e: U p t o 5 y e ars] 
5)  A d v ers e t o xiciti es. W e will ass ess  inci d e nt ac ut e r e n al f ail ur e, di alysis a n d li v er f ail ur e  d uri n g st u dy 
f oll o w-u p (fr o m di a g n osis c o d es i n t h e C D M). T h e occ urr e nc e of t h es e e v e nts will b e c o m p ar e d i n 
r ef er e nc e t o t h e tr e at m e nt r e gi m e ns r ec eiv e d.  
[ Ti m e Fr a m e: U p t o 5 y e ars] 
 
T a bl e 4 : O v er vi e w of Pri m ar y a n d S ec o n d ar y o utc o m es  f or N E T-P R O  b y pr o j ect ai ms 
 

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
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N A: N ot a p plic a bl e  
 
 
 

 
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8.  C O M P A R A T O R S  
T his s ecti o n d et ails t h e m ai n i n d e p e n d e nt v ari a bl es t h at will b e us e d t o c o m p ar e o utc o m es of H R Q oL, 
s e q u e nci n g of tr e at m e nt r e gi m e ns a n d ki d n e y f u ncti o n.  
I n all 3 st u dy ai ms w e will b e c o m p ari n g b ot h t h e fr e q u e nc y of us e of first, s ec o n d a n d t hir d li n e a n d 
b e y o n d  t h er a pi es ( S S As, b ev aciz u m a b, c yt ot oxic c h e m ot h er a py, ev er oli m us, I nt erf er o n al p h a, 
e m b oliz ati o n, P R R T, s m all m ol ec ul e T KIs) a n d t h e eff ects of t h eir or d eri n g/s e q u e nci n g  o n ot h er 
s ec o n d ary o utc o m es (i. e.: sy m pt o m b ur d e n, s urvi v al a n d a d v ers e t oxic ity). T h es e i nt er v e nti o ns h av e 
b e e n s el ect e d as t h e y ar e list e d as p ot e nti al bi ol o gic al t h er a pi es, liv er dir ect e d t h er a pi es or 
c h e m ot h er a pi es t h at ar e r o uti n el y av ail a bl e t o N E T p ati e nts, a n d f or w hic h t h er e is n o cl e ar c o ns e ns us 
as t o t h e eff ecti v e n ess of  t h eir or d eri n g ( or c o nc o mit a nt us e). 
8. 1.  Ai m 1 ( Fr e q u e nc y of tr e at m e nt r e gi m e ns)  
I n t his ai m w e will d escri b e t h e fr e q u e nci es of tr e at m e nt r e gi m e ns b y li n e of t h er a py a n d m ulti-li n e 
s e q u e nc es.  I nf or m ati o n fr o m Ai m 1 will als o b e us e d –  wit h i n p ut fr o m t h e P ati e nt A dv oc acy C o m mitt e e 
( P A C) a n d Cli nici a n Gr o u p –  t o fi n aliz e t h e c o m p ar at ors f or Ai ms 2 a n d 3. 
8. 2.  Ai m 2 ( Tr e at m e nt s el ecti o n a n d o utc o m es)  
Wit h i n p ut fr o m t h e P ati e nt A dv oc acy C o m mitt e e  ( P A C) a n d Cli nici a n Gr o u p w e will ex a mi n e pr e dict ors 
of tr e at m e nt s el ecti o n a n d o utc o m es of o v er all s urvi v al a n d dis e as e pr o gr essi o n usi n g c h os e n 
c o m p ar at ors fr o m ai m 1. T o d o t his w e will n e e d t o c ar ef ully p ull i n di vi d u al p ati e nt l e v el d at a fr o m t h e 
C D M a n d c o n d uct t ar g et e d c h art r evi e ws of e ac h p ati e nt ’s E M R. 
8. 3.  Ai m 3  ( C o mp ar ati v e eff ecti v e n ess of P R R T r e gi m e ns)  
C o m p ar at ors will b e P R R T wit h vs. wit h o ut a d mi nistr ati o n of ot h er s yst e mic t h er a pi es a n d P R R T b ef or e 
vs. aft er e m b oliz ati o n t h er a py a n d c h e m ot h er a py.  C o m p aris o ns will b e wit h r es p ect t o r e n al t oxicit y, 
dis e as e pr o g r essi o n, p ati e nt-r e p ort e d sy m pt o ms, a n d H R Q oL.  H et er o g e n eity of tr e at m e nt eff ects will 
b e ass ess e d f or t h es e c o m p ar at ors i n s u b gr o u ps d efi n e d b y t u m or gr a d e a n d t y p e ( G E P or l u n g N E Ts).  
 
 
 

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
3 7  
9.  S T A TI S TI C AL A N AL Y SI S PL A N  
9. 1.  G e n er al St atistic al A p pr o ac h  
C o nti n u o us  v ari a bl es will b e s u m m ariz e d usi n g d escri pti v e st atistics s uc h as m e a n, st a n d ar d d e vi ati o n, 
m e di a n, mi ni m u m a n d m axi m u m. C at e g oric al v ari a bl es will b e s u m m ariz e d by c o u nt a n d p erc e nt a g e. 
Gr o u p c o m p aris o ns will b e ass ess e d usi n g c hi -s q u ar e d or Fis h er’s ex act t ests f or c at e g oric al v ari a bl es, 
a n d a n a n al ysis of v ari a nc e or Kr usk al -W allis t ests f or c o nti n u o us v ari a bl es w h er e a p pr o pri at e. 
A dj ust m e nt f or c o v ari at es list e d i n T a bl es 2 a n d 3  will b e ex pl or e d f or e ac h a n al ysis as n e e d e d t o 
acc o u nt f or p ot e nti al c o nf o u n di n g eff ects. Ti m e -d e p e n d e nt c o v ari at es will b e i nc or p or at e d t o c a pt ur e 
c h a n g es i n c o v ari at es acr oss ti m e, as n ec ess ary. I ncl usi o n of r a n d o m eff ects t o acc o u nt f or p ot e nti al 
cl ust eri n g of p ati e nts tr e at e d at t h e s a m e st u dy sit e will b e ex pl or e d. D e p e n di n g o n t h e r at e a n d p att er n 
of missi n g d at a, m ulti pl e i m p ut ati o n m et h o ds m a y b e c o nsi d er e d t o acc o u nt f or d at a missi n g at r a n d o m 
or attri b ut a bl e t o n o n -i g n or a bl e dr o p-o ut [ 5 6]. Pl a n n e d st u dy o utc o m es a r e s u m m ariz e d i n T a bl e 4. 
 
9. 1. 1.  Ai m 1  
Mix e d eff ects r e gr essi o n m o d els will b e utiliz e d t o ass ess c h a n g es i n H R Q oL a n d s y m pt o ms wit hi n a n d 
b et w e e n gr o u ps  (i. e.: diff er e nt tr e at m e nt r e gi m e ns) ov er ti m e.  R a n d o m eff ects will b e e m pl o y e d t o 
acc o u nt f or t h e l o n git u di n ally c orr el at e d n at ur e of r e p e at e d q u esti o n n air e m e as ur e m e nts. S h o ul d 
c o m pl eti o n of q u esti o n n air es d evi at e fr o m t h e pl a n n e d ass ess m e nt ti m e p oi nts, a s p ati al p o w er 
c o v ari a nc e str uct ur e will b e i ncl u d e d t o acc o u nt f or t h e u n e q u al ti m e s p aci n g b et w e e n ass ess m e nts 
wit hi n a p ati e nt.   
 
9. 1. 2.  Ai m 2  
M ulti n o mi al l o gistic r e gr essi o n m o d els will b e us e d t o i d e ntif y w hic h p ati e nt, c li nic al, a nd t u m or 
c h ar act eristics ( T a bl e 2), a n d p ati e nt attit u d es a n d b eli efs ( T a bl e 3) i nfl u e nc e s el ecti o n of tr e at m e nt 
r e gi m e ns f or e ac h li n e of tr e at m e nt. T h e c o n diti o n al C ox r e gr essi o n m o d el pr o p os e d b y Pr e ntic e, 
Willi a ms, a n d P et ers o n ( P W P) will b e us e d t o si m ult a n e o usl y m o d el t h e g a p ti m es b et w e e n i niti al 
di a g n osis a n d first pr o gr essi o n a n d b et w e e n s u bs e q u e nt pr o gr essi o ns as a f u ncti o n of t h e pr o g n ostic 
f act ors of i nt er est f or pr o gr essi o n-fr e e s urvi v al. T h e b as eli n e h az ar d is ex p ect e d t o diff er f or first-li n e 
t h er a py a n d f or s u bs e q u e nt li n es of t h er a py, t h us ev e nt-s p ecific esti m at es will b e o bt ai n e d. A r o b ust 
s a n d wic h esti m at or will b e us e d t o acc o u nt f or p ot e nti al d e p e n d e nci es wit hi n p ati e nts. Ov er all s urviv al 
will b e e v al u at e d usi n g a C ox r e gr essi o n m o d el.  
 
9. 1. 3.  Ai m 3  
St atistic al a n al ys es f or Ai m 3 will mi mic t h os e o utli n e d i n Ai ms 1 a n d 2, b ut wit h a s p eci al i nt er est i n 
e v al u ati n g t h e eff ectiv e n ess of P R R T r e gi m e ns o n e ac h of t h e o utc o m es. P R R T r e gi m e ns t o b e ev al u at e d 
i ncl u d e: P R R T al o n e, P R R T ± ot h er bi ol o gic al t h er a py, P R R T ± pri or e m b oliz ati o n. A d diti o n ally, t h e P R R T 
is ot o p e us e d ( 1 7 7L u vs 9 0-Y) will b e ev al u at e d.  
 
9. 2.  S a m pl e Siz e a n d P o w er  
F or t his pr os p ecti v e a n al ysis w e will h av e a n esti m at e d s a m pl e siz e of 3, 0 1 0 p ati e nts. T h e s a m pl e siz e is 
c o m p ut ed f or t h e p o p ul ati o n wit h mi ni m u m r e pr es e nt ati o n i n t h e t ot al s a m pl e. 2 0 1 9 r at es of P R R T w er e 
1 5 % i n t his p o p ul ati o n. Usi n g a c o ns er v ati v e esti m ati o n of 1 0 % P R R T a d mi nistr ati o n, a n d erri n g o n t h e 
si d e of c a uti o n, o ur s a m pl e siz e a n d p o w er j ustific ati o n is b as e d o n a p pr oxi m at ely 3 0 0 s u bj ects 
( excl u di n g H R Q oL q u esti o n n air e c o m pl eti o n r at es). B y t h e l a w of t h e mi ni m u m, all ot h er tr e at m e nt 
s u b gr o u ps wit h r e pr es e nt ati o n a b o v e 1 0 % will yi el d gr e at er s a m pl e siz e a n d c o ns e q u e ntl y hi g h er 
p o w ers f or t h e b el o w -st at e d diff er e nc es  
9. 2. 1.  Ai m 1  
T h e pri m ar y o bj ecti v e of Ai m 1 is t o e v al u at e c h a n g es i n H R Q oL o v er ti m e f or e ac h tr e at m e nt. 
C alc ul ati o ns ar e b as e d o n usi n g t h e E O R T C QL Q -C 3 0 as t h e pri m ar y H R Q oL m e as ur e. C o ns er v ati v el y 

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
3 9  
a ut oc orr el ati o n of 0. 5 fr o m o n e ti m e p oi nt t o t h e n ext a n d a st a n d ar d d evi ati o n of 5 mL/ mi n/ 1. 7 3 m 2. 
S h o ul d t h e st a n d ar d d e vi ati o n b ec o m e u nr e as o n a bl y hi g h i n t h e or d er of 1 5 mL/ mi n/ 1. 7 3 m 2, o ur sa m pl e 
siz e is l ar g e e n o u g h t o ac hi e v e 9 9 % p o w er u n d er t h e s a m e p ar a m et er s etti n gs. I n or d er t o t est 
B o nf err o ni -c orr ect e d p air wis e diff er e nc es, t h e i n di vi d u al t ests will ac hi e v e 9 9. 6 % p o w er t o d et ect a 
cl e ar a nc e l oss of 2 mL/ mi n/ 1. 7 3 m 2  b et w e e n t w o ti m e p oi n ts. T h e B o nf err o ni-c orr ect e d t ests will b e s et 
at a si g nific a nc e l ev el of 0. 0 5/ 6.  
 
9. 3.  A d dr essi n g c o nf o u n di n g  
Wit h a l ar g e, pr o p os e d s a m pl e siz e of a p pr oxi m at el y 3, 0 0 0 p ati e nts, w e will mi ni miz e t h e eff ects of 
c o nf o u n di n g o n tr e at m e nt eff ect esti m at es by a dj usti n g f or f act ors ass oci at e d wit h tr e at m e nt s el ecti o n 
wit hi n t h e c o nt ext of m ulti v ari a bl e m o d els. K n o w n a n d h y p ot h esiz e d f act ors ass oci at e d wit h tr e at m e nt 
s el ecti o n i ncl u d e b ut ar e n ot li mit e d t o t h e f oll o wi n g: s oci o d e m o gr a p hic ( a g e, s ex, r ac e, et h nicit y,  
m arit al st at us, i nc o m e), h e alt h st at us ( B MI, s m oki n g hist ory, c o m or bi diti es), dis e as e (sit e, st a g e, gr a d e, 
n o d al st at us), pri or t h er a py us e ( P R R T, ev er oli m us, s u niti ni b, li v er -dir ect e d t h er a pi es,  c h e m ot h er a py, 
s ur g er y), a n d p ati e nt-r e p ort e d pr ef er e nc es, attit u d es, b eli efs a n d ex p eri e nc e of c ar e. D et er mi n ati o n of 
c o nf o u n di n g f act ors t h at m a y w arr a nt a dj ust m e nt will b e g ui d e d b y t h e r es ults fr o m t h e m ulti n o mi al 
l o gistic r e gr essi o n m o d els e v al u ati n g f act ors ass oci at e d wit h s el ecti o n of tr e at m e nt r e gi m e ns ( Ai m 2). 
F urt h er m or e, t h e us e of ti m e -d e p e n d e nt v ari a bl es f or tr e at m e nt a n d p ot e nti al c o nf o u n d ers ( w h er e 
a p pr o pri at e) will mi ni miz e t h e eff ects of s ur viv or tr e at m e nt s el ecti o n bi as.  
As a n ov el pr oj ect ai m e d t o e v al u at e t h e c o m pl ex i nt er pl a y b et w e e n p ati e nt, d is e as e, a n d tr e at m e nt 
f act ors o n t oxicity, H R Q oL , a n d s ur vi v al o utc o m es, t h e st atistic al a n al ysis pl a n will b e r efi n e d o nc e 
d escri pti v e i nf or m ati o n fr o m Ai ms 1 a n d 2 is av ail a bl e f or c o ns e nt e d p ati e nts. F or ex a m pl e i n Ai m 3, 
P R R T sits a m o n gst a gr o wi n g n u m b er of t h er a p e utic o pti o ns i n m et ast atic w ell -diff er e nti at e d N E Ts, 
i ncl u di n g p h ar m ac ol o gic al (i. e.: m T O R i n hi bit or e v er oli m us a n d t h e tyr osi n e ki n as e i n hi bit or s u niti ni b), 
h or m o n al a n d liv er -dir ect e d t h er a pi es (i. e.: e m b oliz ati o n  ( bl a n d, c h e m o, r a di o)), a nd s ur gic al 
a p pr o ac h es. T h er ef or e , w e n e e d t o b e mi n df ul of t his m ulti m o d al tr e at m e nt al g orit h m w h er ei n p ati e nts 
m a y u n d er g o a v ari ety of tr e at m e nt o pti o ns at t u m or pr o gr essi o n(s).  
9. 4.  A d dr essi n g cl ust eri n g of sit e  
P ati e nts s e e n at t h e s a m e st u dy sit e a n d b y t h e s a m e pr o vi d er ar e at i ncr e as e d lik eli h o o d t o b e tr e at e d 
m or e si mil arly. R a n d o m eff ects will b e i ncl u d e d i n t h e m ulti v ari a bl e m o d els t o acc o u nt f or cl ust eri n g 
wit hi n t h e 1 4 st u dy sit es a n d wit hi n pr ovi d er ( ass u mi n g a s uffici e nt n u m b er of p ati e nts ar e s e e n b y e ac h 
pr o vi d er).  
9. 5.  H a n dli n g missi n g d at a  
T o mi ni miz e t h e eff ect of missi n g d at a o n o ur a bility t o a dj ust f or c o nf o u n di n g f act ors , any cli nic al 
v ari a bl e f o u n d t o b e i ns uffici e ntl y p o p ul at e d i n t h e C D M u p o n e v al u ati o n of s u b mitt e d c o h ort 
c h ar act eriz ati o n d at a , will b e a bstr act e d vi a c h art r evi e w f or c o ns e nt e d p ati e nts.  M or e ov er , all 1 4 
p artici p ati n g sit es h a v e a gr e e d t o pr o vi d e t u m or c h ar act eri stics a n d N A A C C R  r e q uir e d v ari a bl es i. e.: 
t u m or gr a d e, st a g e, n o d al st at us etc. ) as i m p ort a nt pr o g n ostic c ov ari at es. T his t u m or r e gistry d at a will 
b e p o p ul at e d i n e ac h sit es  C D M  t u m or t a bl es, a n d sit es will h av e t h e o p p ort u nity t o e n g a g e i n d at a 
q u alit y c ur ati o n usi n g s a m pl e scri pts d e v el o p e d b y t h e G P C n et w or k i nf or m aticists ( e n h a ncin g f ut ur e 
utiliz ati o n of c a nc er r e gistry  v ari a bl es i n t h e C D M), s e e 1 0 . 2 b el o w.  
 
 
 

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
4 0  
1 0.  D A T A M O NI T O RI N G & Q U ALI T Y C O N T R OL  
1 0. 1.  
M et h o ds t o est a blis h v ali dit y of t h e N E T C o m p ut a bl e P h e n ot y p e  
W e h av e  ex a mi n e d t h e pr o p orti o ns of N E T p ati e nts i d e ntifi e d t hr o u g h us e of o ur I C D -9/ 1 0 c o di n g 
cl assific ati o ns a n d t h e pr o p orti o ns of c as es d oc u m e nt e d b y t h e U ni v ersity of I o w a H os pit als a n d Cli nics 
( UI H C) i nstit uti o n al t u m or r e gistr y usi n g I C D-O -3 sit e/ hist ol o gy c o d es. T h e UI H C t u m or r e gistry i d e ntifi es 
a n d d escri b es c a nc er c as es  usi n g st a n d ar ds d e v el o p e d by N A A C C R , w hic h r e q uir e t h at c as es b e 
d oc u m e nt e d by c ertifi e d a bstr act ors, a n d t h e r es ulti n g d at a c o m pris es a ‘g ol d st a n d ar d ’ f or c o m p aris o n 
t o o ur p h e n ot y p e.  
 
F or G E P -N E Ts t h e I C D -9/ 1 0 c o d es al o n e i d e ntifi e d ov er 7 0 % of G E P -N E T p ati e nts i d e ntifi e d b y t h e UI H C 
r e gistr y. T h e m ost c o m m o n I C D-c o d e f or t h e 7 0 p ati e nts w h o w er e n ot i d e ntifi e d, w as C 7 A. 8, a n o n -
s p ecific bill a bl e I C D-1 0 -C M c o d e f or “ ot h er m ali g n a nt n e ur o e n d ocri n e t u m ors” . L u n g N E Ts acc o u nt f or 
o nl y 2 0 % of all di a g n os e d N E Ts. Of t h e 8 2 UI H C l u n g N E T c as es asc ert ai n e d b y t h e t u m or r e gistry 
b et w e e n 2 0 1 1 -2 0 1 6, 6 5 % w er e i d e ntifi e d wit h t h e I C D c o d es al o n e. F or t h e 2 9 p ati e nts ( 3 5 %) w h o w er e 
n ot i d e ntifi e d wit h o ur ori gi n al I C D c o d e cl assific ati o ns, t h e m ost c o m m o n n o n -N E T l u n g c o d es f ell i nt o 
t h e C 3 4. X gr o u pi n g t h at i n dic at es m ali g n a nt n e o pl as m of br o nc h us a n d l u n g ( excl u di n g s m all c ell l u n g 
c a nc er). T h e n o n-s p ecific N E T c o d e C 7 A. 8 f o u n d f or t h e G E P-N E T p ati e n ts w as als o oft e n f o u n d f or t h es e 
l u n g N E T p ati e nts. T h er ef or e, w e will i m pr o v e o ur G E P a n d l u n g -N E T p h e n ot y p es by i ncl u di n g C 7 A. 8 a n d 
C 3 4. X i n f ut ur e d at a s p ecific ati o ns, usi n g c a uti o n t o e ns ur e i ncl usi o n of t h es e l ess s p ecific N E T c o d es ar e  
n o t als o i d e ntifyi n g n o n G E P a n d l u n g N E T p h e n oty p es. F urt h er t esti n g of t h es e m o dific ati o ns at cli nic al 
sit es b ey o n d I o w a will b e i m p ort a nt. 
 
Ulti m at el y, o ur g o al is t o c o nstr uct a  c o m p ut a bl e p h e n ot y p e t h at r eli es o n str uct ur e d d at a fr o m billi n g 
a n d el ectr o nic m e dic al  r ec or d d at a. W e d o h av e a n ot h er p er m ut ati o n of t h e al g orit h m t h at t a k es P P V  u p 
t o 6 2 % ( b ut at a c ost, s e nsiti vity g o es d o w n t o 5 2 %) usi n g a d diti o n al pr oc e d ur e/tr e at m e nt c o d es. W e 
ar e i nt er est e d i n ass essi n g w h at t h e r e al P P V  w o ul d b e  f or t his v ersi o n (i. e.: t h at w hic h w o ul d b e 
o bt ai n e d fr o m a c h art r evi e w, r at h er t h a n usi n g t h e t u m or r e gistry as a st a n d ar d). I R B a p pr ov al ( #: 
2 0 2 1 0 7 3 8 3) h as b e e n o bt ai n e d at I o w a t o v ali d at e t h es e c o m p ut a bl e p h e n ot y p es a g ai nst c h art r evi e ws, 
str uct ur e d d at a a n d t u m or r e gistry s o urc es. T h e UI C C will t est a n d v ali d at e t his p h e n oty p e at t h e 
U ni v ersity of I o w a cli nic al sit e a n d ot h er e arl y a d o ptiv e sit es as a bl e.  
 
T h e i nst a nc e m a y aris e w h e n a pr ovi d er e nc o u nt ers a p ati e nt w h o a p p e ars eli gi bl e f or t h e N E T -P R O  
st u dy b ut w h o w as n ot i d e ntifi e d b y t h e N E T c o m p ut a bl e p h e n oty p e. S uc h p ati e nts s h o ul d still b e giv e n 
t h e o p p ort u nity t o e nr oll i n t h e N E T -P R O  st u dy (vi a a ny of t h e m et h o ds d escri b e d i n 5. 5 a b ov e), a n d a 
n ot e of t h eir miss e d i d e ntific ati o n  r ec or d e d i n t h e l oc al R E D C a p tr acki ng d at a b as e a n d  als o r e p ort e d  
b ac k t o t h e UI C C. T his will b e es p eci ally i m p ort a nt i n t h e e arl y p h as es of e nr oll m e nt w h e n t h e N E T 
p h e n ot y p e is still b ei n g v ali d at e d a n d t est e d.  
 
1 0. 2.  
D et ails o n p o p ul ati o n of t u m or t a bl e d at a  
All 1 4 p artici p ati n g sit es i ncl u d e t h e g ol d-st a n d ar d, N A A C C R-f or m att e d i nstit uti o n al t u m or r e gistr y d at a 
i n t h eir r es e arc h w ar e h o us e. O ur r es e arc h pl a n a n d sc h e d ul e of w or k wit h e ac h sit e i ncl u d es p o p ul ati o n 
of t h eir C D M t u m or t a bl e a n d p artici p ati o n i n d at a q u alit y c ur ati o n usi n g s cri pts d e v el o p e d b y G P C 
n et w or k i nf or m atici a ns. H avi n g t h e P C O R n et t u m or t a bl e at t h es e sit es will pr o vi d e ric h, hi g h -q u alit y 
d at a (i ncl u di n g t u m or gr a d e, st a g e, n o d al st at us, a n d ot h er p at h ol o gic al c h ar act eristics). It will als o 
pr o vi d e t h e o p p ort u nit y t o  f urt h er r efi n e a n d v ali d at e t h e I C D-b as e d N E T c o m p ut a bl e p h e n oty p es w hic h 
w o ul d f acilit at e p ot e nti al f ut ur e ex p a nsi o n t o sit es t h at d o n’t h a v e t u m or r e gistry d at a.   
 
It is r ec o g niz e d t h at m ost p artici p ati n g sit es h a v e n ot y et p o p ul at e d t h e P C O R n et C D M T u mor T a bl e. T o 
f ulfill Ai m 4 w hic h r el at es t o b uil di n g t h e P C O R n et i nfr astr uct ur e, w e r e q u est t h at sit es h av e t h eir t u m or 
t a bl es p o p ul at e d d uri n g 2 0 2 3. Pri or t o t h at ti m e, as n e e d e d f or i nt eri m p a p ers or f or t u ni n g t h e 

 
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1 1.  N E T -P R O TI M ELI N E  
T h e N E T -P R O st u dy p eri o d is t hr e e y e ars  ( 0 7/ 0 1/ 2 0 2 1 t o 0 6/ 3 0/ 2 0 2 4), wit h a o n e-y e ar p e er r e vi e w 
p eri o d. T o d at e t h e UI C C  st u dy t e a m h as f oc us e d c o nc ert e d eff orts o n t h e a d mi nistr ati v e a n d r e g ul at ory 
u n d er pi n ni n gs of t h e pr oj ect i ncl u di n g i niti al I R B a p pr o v al at UI O W A, a n d s u bc o ntr act ex ec uti o n. W e 
h a v e o bt ai n e d P C O R N E T st u dy d esi g n ati o n, a n d will s o o n b e i n t h e pr oc ess of c o m m e nci n g t h e I R B 
r eli a nc e pr oc ess a n d d at a s h ari n g a gr e e m e nts wit h c oll a b or ati n g sit es s o t h at r ecr uit m e nt c a n b e 
u n d ert a k e n. M uc h eff ort h as g o n e i n t o t h e fr o nt -e n d P H R r e pr o gr a m mi n g a s st u dy e nr oll m e nt, c o ns e nt 
a n d q u esti o n n air e c o m pl eti o n hi n g e o n t his d ev el o p m e nt.  
 
Fi g ur e 4 pr o vi d es a hi g h -l e v el o v ervi e w of k e y mil est o n es a n d d eliv er a bl es f or t h e N E T-P R O st u dy. A 
m or e d et ail e d pr oj ect ti m eli n e i n r el ati o n t o pr e -a gr e e d mil est o n es/ pr o gr a m d eliv er a bl es wit h t h e st u dy 
s p o ns or ( P C O RI) is o utli n e d i n T a bl e 8. D eli v er a bl es hi g hli g ht e d i n li g ht gr e e n i n dic at e c o m pl et e d t asks, 
t h os e i n li g ht or a n g e ar e c urr e ntl y i n pr o gr ess, t h os e i n li g ht r e d ar e d el a y e d, a n d t h os e n ot c ol or c o d e d 
a w ait f ut ur e  c o m pl eti o n. A d diti o n ally, mil est o n es hi g hli g ht e d i n bl u e i n dic at e k ey d eli v er a bl es r el e v a nt 
t o t h e d at a i nf or m atics t e a ms, w hilst mil est o n es hi g hli g ht e d i n p ur pl e d e n ot e k ey d eliv er a bl es a n d 
mil est o n es r el e v a nt t o p ati e nt e nr oll m e nt a n d r ecr uit m e nt.  
 

 
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1 2.  E n g a g e m e nt a n d s h ari n g of r e s ults c ust o miz e d t o l oc al s etti n gs of c ar e 
T his pr oj ect will pr ovi d e n e w i nf or m ati o n i n a r ar e dis e as e p ati e nt p o p ul ati o n w hic h h as a n u m b er of 
tr e at m e nt r e gi m e ns av ail a bl e b ut littl e evi d e nc e r e g ar di n g t h eir r el ativ e eff ecti v e n ess or s af ety. C ar e 
c ust o mizati o n is a n i m p ort a nt as p ect of q u alit y i n h e alt hc ar e –  ev ery p ati e nt w a nts t o f e el t h at t h ey ar e 
g etti n g t h e c ar e t h at is t ail or e d t o t h eir p artic ul ar n e e ds. T h e 1 4 p artici p ati n g sit es i n t his pr o p os e d st u dy 
ar e r efl ectiv e of t h e di v ers e cli nic al e n vir o n m e nts acc essi bl e t o N E T p ati e nts i ncl u di n g a mixt ur e of hi g h 
v ol u m e m ulti disci pli n ary s p eci alist N E T cli nics (i. e.: U niv ersity of I o w a, V a n d er bilt U ni v ersity M e dic al 
C e nt er, U ni v ersit y of N ort h C ar oli n a , M ay o Cli nic a n d O hi o St at e U niv ersit y) vs. s o m e l ess s p eci aliz e d 
h e alt hc ar e s yst e ms ( e. g. Alli n a H e alt h ), e n a bli n g t h e ex a mi n ati o n of t h e r e al-w orl d ex p eri e nc es a n d 
o utc o m es of c ar e acr oss a v ari ety of pr actic e s etti n gs. It is t h er ef or e i m p ort a nt t h at w e c o nsi d er o ur 
r es e arc h fi n di n gs i n t h e c o nt ext of c urr ent h e alt h c ar e d eli v er y at t h e p art n eri n g sit es i nv ol v e d i n t his 
a p plic ati o n.  
As st u dy r es ults b e gi n t o accr u e, st ak e h ol d ers (i. e.: p ati e nts, p ati e nt a dv oc at es, cli nici a n gr o u ps, etc.) will 
b e i nvit e d t o br ai nst or m p ot e nti al diss e mi n ati o n t ar g ets a n d p ot e nti al m o d es of pr o vi di n g t h at 
i nf or m ati o n, i ncl u di n g i d e as f or o pti m ally c o m m u nic ati n g r es ults t ail or e d t o diff er e nt st ak e h ol d er 
gr o u ps w hic h m ay h a v e diff er e nt m ess a gi n g n e e ds. Diss e mi n ati o n will b e gi n wit h a diss e mi n ati o n pl a n , 
d e v el o p e d b y t h e st a k e h ol d ers d uri n g t h e first y e ar of t h e st u dy.  I niti al st e ps of t his will i ncl u d e 
i d e ntif yi n g a d diti o n al st a k e h ol d ers (i. e.: i nf or m al c ar e gi v ers, c a nc er c e nt er dir ect ors, h e alt h syst e m 
m ar k eti n g a n d c o m m u nic ati o n, pr of essi o n al s oci eti es etc.) a n d h o w t o  e n g a g e t h e m. O ur t e a m will elicit 
f e e d b ac k fr o m st a k e h ol d ers t o a d vis e o n i m pl e m e nti n g o pti m al c o m m u nic ati o n r u brics t h at will s u p p ort 
e n g a g e m e nt of all p arti es. W e will ex pl or e a n d a d o pt a div ersit y of c o m m u nic ati o n m o d aliti es as 
i nf or m e d b y o ur st a k e h old er gr o u ps. W e will li k e wis e ass ess t h e s ucc ess of a n d i d e ntif y ar e as f or 
i m pr ov e m e nt of e n g a g e m e nt activiti es. W e will als o e n g a g e wit h t h e P C O R n et C o or di n ati n g C e nt er f or 
i n p ut a n d g ui d a nc e o n pri orit y diss e mi n ati o n t ar g ets, a n d t o e ns ur e w e ar e t aki n g full a d v a nt a g e of t h e 
e n g a g e m e nt t o ols, e n g a g e m e nt r u bric, a n d e n g a g e m e nt str at e gi es alr e a dy i n pl ac e wit hi n P C O R n et. T his 
will i ncl u d e us e of t h e P C O R n et r es o urc es  f or s h ari n g of us er-fri e n dl y c o m m u nic ati o n t o ols acr oss o ur 
st a k e h ol d er gr o u ps. W e will w ork wit h p ati e nt p art n er or g a niz ati o ns t o pr o m ot e t h e st u dy fi n di n gs usi n g 
t h eir w e bsit e a n d o nli n e pl atf or ms ( F ac e b o ok/ T witt er/I nst a gr a m etc.), e m ail lists, a n d/ or n e wsl ett ers, 
a n d p ati e nt e d uc ati o n c o nf er e nc es a s a p pr o pri at e t o c o m m u nic at e st u dy r es ults.  
 
 
 

 
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1 3.  S T U D Y G O V E R N A N C E A N D P OLI CI E S  
1 3. 1.  
St u d y l e a d ers hi p a n d M a n a g e m e nt  
Dr. O’ R or k e , as pri nci p al i nv esti g at or ( PI) of t h e N E T -P R O st u dy , ass u m es t h e ov er all r es p o nsi bility f or 
t h e st u dy c o n d uct, a n d is t h er ef or e r es p o nsi bl e f or e ns uri n g t h at: 
•  
H e pr ovi d es s uffici e nt ov ersi g ht ov er all st u dy activiti es a n d t as ks d el e g at e d t o ot h ers t o e ns ur e 
t h at t h e r es e arc h is c o n d uct e d i n c o m pli a nc e wit h all a p plic a bl e R e g ul ati o ns, P olici es a n d 
Pr oc e d ur es s et f ort h b y t h e S p o ns or ( P C O RI) a n d t h e I nstit uti o n al R evi e w B o ar d (I R B)  
•  
T h e st u dy pr ot oc ol a n d p ati e nt m at eri al r ec ei v e r evi e w by st a k e h ol d ers, a n d a p pr o v al b y t h e 
pr oj ect st e eri n g c o m mitt e e  
•  
I R B a p pr ov al is o bt ai n e d b ef or e a sit e st arts e nr olli n g s u bj ects 
•  
Aft er t h e r es e arc h is a p pr ov e d, all r e q uir e d r e p orts i ncl u di n g: pr o gr ess r e p orts, m o nt hly 
r ecr uit m e nt u p d at es, pr ot oc ol d evi ati o ns - ar e s u b mitt e d t o t h e I R B, a n d t h e r el e v a nt 
s p o ns or/f u n di n g a g e nc y as p er t h eir r e q uir e m e nts  
•  
N o c h a n g es ar e m a d e t o t h e r es e arc h wit h o ut first s u b mitti n g a r e q u est t o t h e I R B t o a m e n d t h e 
st u dy a n d r eceivi n g s u bs e q u e nt I R B a p pr o v al  
•  
A n al ys es a n d st u dy r e p orts a d h er e t o t h e pr e -pl a n n e d pr ot oc ol a n al ysis pl a n a n d ar e c o n d uct e d 
i n acc or d a nc e wit h acc e pt e d st atistic al pri nci pl es a n d g ui d eli n es f or r e p orti n g o bs er v ati o n al 
st u di es (S T R O B E St at e m e nt ) 
 
1 3. 2.  
U ni v ersit y of I o w a C o or di n ati n g C e nt er ( UI C C) R ol es a n d R es p o nsi biliti es  
T h e U ni v ers ity of I o w a s erv es as t h e c o or di n ati n g c e nt er ( UI C C) f or t h e N E T-P R O st u dy. T h e UI C C pl a ys a 
critic al r ol e i n k e e pi n g all pr oj ect t asks o n tr ac k, a n d i m pl e m e nti n g a n d s u p ervisi n g m ost of t h e fi el d 
m et h o ds e m pl o y e d. T h e UI C C m ust b e r es p o nsiv e t o t h e f e e d b a ck of t h e N E T-P R O St e eri n g C o m mitt e e. 
T h e UI C C is t h er ef or e r es p o nsi bl e f or:  
 
1)  C o or di n ati n g all as p ects of t h e st u dy c o n d uct acr oss cli nic al sit es  
2)  T r ai ni n g sit e st aff o n i m pl e m e nt ati o n of t h e r es e arc h pr ot oc ol 
3)  Tr ac ki n g e nr oll m e nt st at us of p ati e nts w h o visi t t h e P H R w e bsite or r et ur n p a p er st u dy 
p ac k ets, a n d c o m m u nic ati n g t his p ati e nt -l e v el i nf or m ati o n t o sit es 
4)  C o m m u nic ati n g I nstit uti o n al R evi e w B o ar d (I R B) a p pr o v als, c o nti n ui n g r e vi e ws, a n d 
m o dific ati o ns t o sit es  
5)  Pr ovi di n g  t e m pl at es f or all st u dy m at eri als 
6)  Pr ovi di n g  h ar d c o py m at eri als w h e n n e e d e d a n d a p pr o pri at e (i. e.: t o s u p p ort p a p er -b as e d 
e nr oll m e nt by sit es).  
7)  A ns w eri n g  p ati e nt q u esti o ns pr e - a n d p ost -e nr oll m e nt  
8)  A d mi nist eri n g  t h e st u dy w e bsit e ( P H R) 
9)  M ai nt ai ni n g  s ec urit y a n d i nt e grit y of c oll ect e d d at a 
 
1 3. 3.  
N E T -P R O St e eri n g C o m mitt e e  
T h e St e eri n g C o m m itt e e f or t h e N E T-P R O st u dy is r es p o nsi bl e f or t h e dir ecti o n, c o or di n ati o n, o v ersi g ht, 
f e asi bilit y a n d s ucc essf ul c o m pl eti o n of t h e N E T -P R O st u dy. T h e st e eri n g c o m mitt e e is c o -c h air e d b y t h e 
PI ( Dr. O’ R or k e), Mr. M ail m a n (l e a d p ati e nt a d v oc at e), a n d a n a n n u al r ot ati n g c o -c h air fr o m a n o n-G P C 
sit e (i. e.: O n e Fl ori d a, P a T H, a n d S T A R). T h e St e eri n g C o m mitte e m e m b ers hi p i ncl u d es t h e c h air of e ac h 
st a k e h ol d er gr o u p, a n d all of t h e p artici p ati n g P C O R n et p art n er sit e PI s ( or r e pr es e nt ativ es) ( Fi g ur e 5).  
 
1 3. 3. 1.  Pri m ar y f u ncti o ns of t h e St e eri n g C o m mitt e e  
T h e st e eri n g c o m mitt e e m e m b ers a d vis e o n l o n g -t er m str at e gi es i n s u p p ort of pr o gr a m o bj ectiv es, 
e ns uri n g pr o gr a m o bj ectiv es ar e b ei n g a d e q u at ely a d dr ess e d, a n d t h at t h e pr oj ect r e m ai ns u n d er 
c o ntr ol. I n pr actic e t h es e r es p o nsi biliti es ar e c arri e d o ut by p erf or mi n g t h e f oll o wi n g f u ncti o ns:  

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
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•  
R e vi e wi n g a n d pr o vi di n g fi n al si g n -off o n m aj or pr oj ect el e m e nts s uc h as k e y st u dy d oc u m e nts, 
i ncl u di n g b ut n ot li mit e d t o, t h e pr ot oc ol, sit e m at eri als (i. e.: p ati e nt m at eri als, c o ns e nt 
d oc u m e nt ati o n, n e wsl ett ers a n d u p d at es t o st u dy p art n ers etc.), D at a M a n a g e m e nt Pl a n, t h e 
St atistic al A n alysis Pl a n, a n d t h e st u dy accr u al a n d r et e nti o n m etrics i n c o m pli a nc e wit h S p o ns or 
r e q uir e m e nts 
•  
Pri oritiz ati o n of pr oj ect o bj ecti v es a n d o utc o m es as i d e ntifi e d i n t h e st u dy pr ot oc ol  
•  
M o nit ori n g a n d r evi e w of pr oj ect st at us, i ncl u di n g ov e rsi g ht of pr oj ect mil est o n es ov er t h e 
c o urs e of t h e st u dy t o e ns ur e pr o gr ess o n s p ecific ai ms, o bj ectiv es a n d d eli v er a bl es ar e b ei n g 
m et  
•  
E ns uri n g t h at str at e gi es t o a d dr ess p ot e nti al t hr e ats t o t h e pr oj ect's s ucc ess h a v e b e e n 
i d e ntifi e d, a n d a m eli or at e d, an d t h at t h es e ris ks ar e r e g ul arl y ass ess e d (i. e.: pr oj ect 
m a n a g e m e nt a n d q u alit y ass ur a nc e pr actic es, st u dy accr u al, r et e nti o n a n d attriti o n, as p ects of 
d at a q u alit y, d at a tr a nsf ers  a n d s af e g u ar di n g of t h e s a m e)  
•  
Pr ovi di n g assist a nc e t o t h e pr oj ect w h e n r e q uir e d i ncl u di n g r es ol uti o n of pr oj ect c o nflicts a n d 
dis p ut es, r ec o ncili n g diff e r e nc es of o pi ni o n a n d a p pr o ac h 
•  
E ns uri n g st a k e h ol d er c o m mitt e e e n g a g e m e nt i n ess e nti al st u dy f u ncti o ns  
•  
R e vi e wi n g j oi nt acti viti es, l e v er a gi n g l ess o ns l e ar n e d, a n d pl a n ni n g diss e mi n ati o n acti viti es  
•  
R e vi e wi n g a n d a p pr ovi n g fi n al dr aft m a n uscri pts pri or t o s u b missi o n t o p e er -r evi e w j o ur n als 
Fi g ur e 5 : O v er all g o v er n a nc e str uct ur e of t h e N E T-P R O st u d y  

 
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N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
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1 3. 7.  
R es ol uti o n of dis p ut es  
T h e St e eri n g C o m mitt e e will f acilit at e a n y dis p ut es arisi n g fr o m ot h er st a k e h ol d er gr o u ps. If dis p ut es 
aris e wit hi n t h e St e eri n g C o m mitt e e, all m e m b ers will h a v e t h e o p p ort u nit y t o a d dr ess t h eir c o nc er ns 
a n d if a d ecisi o n c a n n ot b e m ut u all y a gr e e d t o, t h e St e eri n g C o m mitt e e will v ot e.  If a dis p ut e aris es i n 
a ny of t h e st a k e h ol d er gr o u ps, t h es e dis p ut es will b e c o m m u nic at e d t o t h e St e eri n g C o m mitt e e f or 
disc ussi o n.  A ny m e m b er of t h e st a k e h ol d er gr o u p c a n pr es e nt t h eir c o nc er ns t o t h e St e eri n g 
C o m mitt e e, w h o will v ot e  o n t h e iss u e as a p pr o pri at e.   
 
 
 

 
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1 4.  S T U D Y R E S P O N SI BILI TI E S  
1 4. 1.  
I n v esti g at or R es p o nsi bilit y/ P erf or m a nc e  
T h e UI C C a gr e es t o b e r es p o nsi bl e f or i m pl e m e nti n g a n d m ai nt ai ni n g q u alit y c o ntr ol a n d q u alit y 
ass ur a nc e syst e ms t o e ns ur e t h at all w or k i nci d e nt al t o t his pr ot oc ol is c o n d uct e d a n d d at a ar e 
g e n er at e d, d oc u m e nt e d, a n d r e p ort e d i n c o m pli a nc e wit h t h e pr ot oc ol; acc e pt e d st a n d ar ds of  G o o d 
Cli nic al Pr actic e  (G C P ); a n d all a p plic a bl e f e d er al, st at e, a n d l oc al l a ws, r ul es, a n d r e g ul ati o ns r el ati n g t o 
t h e c o n d uct of t his pr os p ecti v e c o h ort st u dy. T h e UI C C will pr ovi d e c urr e nt c o pi es of t h e st u dy pr ot oc ol 
t o all cli nic al sit es a n d ot h er sit e p ers o n n el r es p o nsi bl e f or st u dy c o n d uct.  
1 4. 2.  
Sit e c o m m u nic ati o ns  
T h er e will b e m o nt hly  writt e n c o m m u nic ati o ns  ( N E T-P R O n e wsl ett er)  a n d a m o nt hl y Z o o m c all b et w e e n 
st u dy sit e i nv esti g at ors, t h e UI C C st u dy c o or di n at or a n d PI, a n d ot h er r el ev a nt p ers o n n el. T h es e  sit e 
m e eti n gs will b e i n p ar all el wit h o ur q u art erly st e eri n g c o m mitt e e c alls a n d w e e kly UI C C m e eti n gs.  
1 4. 3.  
St u d y d oc u m e nt ati o n  
St u dy d oc u m e nt ati o n i ncl u d es all el ectr o nic a n d p a p er f or ms, d at a e ntry a n d m o nit ori n g f or ms (i. e.: 
R E D C a p pr o f or m a or b as eli n e s u r v ey), s p o ns or-i nv esti g at or c orr es p o n d e nc e, a n d r e g ul at ory d oc u m e nts 
(i. e.: si g n e d pr ot oc ol a n d a m e n d m e nts, I R B c orr es p o n d e nc e a n d a p pr ov al, i nv oic es a n d b u d g et r ec or ds).  
B y si g ni n g t h e pr ot oc ol, t h e PI ack n o wl e d g es t h at, wit hi n l e g al a n d r e g ul at or y r estr icti o ns a n d 
i nstit uti o n al a n d et hic al c o nsi d er ati o ns, st u dy d oc u m e nt ati o n will b e pr o m ptly a n d f ull y discl os e d t o UI 
a p pr o pri at e p arti es by t h e UI C C i nv esti g at or u p o n r e q u est. It will als o b e m a d e av ail a bl e at t h e 
i nv esti g at or’s sit e b y UI C C u p o n r e q u est for i ns p ecti o n, c o pyi n g, r evi e w, a n d a u dit at r e as o n a bl e ti m es 
by r e pr es e nt ativ es of UI C C or r es p o nsi bl e g ov er n m e nt a g e nci es as r e q uir e d b y l a w.  
1 4. 4.  
Pr ot oc ol D e vi ati o ns  
A pr ot oc ol d evi ati o n is d efi n e d as a n ev e nt w h er e t h e i nv esti g at or or sit e p ers o n n el di d n ot  c o n d uct t h e 
st u dy acc or di n g t o t h e i nv esti g ati o n al pl a n. 
I nv esti g at ors ar e r e q uir e d t o o bt ai n a p pr ov al fr o m t h e UI PI b ef or e i niti ati n g d e vi ati o ns fr o m t h e 
i nv esti g ati o n al pl a n or pr ot oc ol. S uc h a p pr ov al will b e d oc u m e nt e d i n writi n g a n d m ai nt ai n e d i n st udy 
fil es. N o d e vi ati o ns fr o m t h e pr ot oc ol of a ny ty p e will b e m a d e wit h o ut c o m pl yi n g wit h all t h e I R B’s 
est a blis h e d pr oc e d ur es. Pl a n n e d d e vi ati o ns will b e r e p ort e d t o t h e UI C C a n d I R B 
a m e n d m e nts/ m o dific ati o ns s o u g ht as a p pr o pri at e.   
1 4. 5.  
P u blic ati o n p olici es  
T h e P C O R n et P u blic ati o ns P olicy a p pli es t o all sci e ntific p u blic ati o ns b as e d o n d at a fr o m t h e P C O R n et 
C D M. As s uc h, t his p olicy  will b e a p pli e d t o t h e N E T -P R O  st u dy a n d all p u blic ati o ns, a bstr acts, a n d 
pr es e nt ati o ns ass oci at e d wit h t h e pr oj ect. All a ut h ors m ust m e et t h e crit eri a f or a ut h ors hi p as o utli n e d 
by t h e  I nt er n ati o n al C o m mitt e e of M e dic al J o ur n al E dit ors (I CJ M E). First a n d l ast a ut h ors will b e 
d et er mi n e d b ef or e a n y w or k b e gi ns o n t h e p a p er. A ny st u dy m a n uscri pt t h at mi g ht als o b e c o nsi d er e d a 
f o u n d ati o n al or P C O R n et-wi d e p u blic ati o n will b e s h ar e d wit h t h e P C O R n et St e eri n g C o m mitt e e i n 
a dv a nc e, a n d m e m b ers i nvit e d t o j oi n as c o -a ut h ors.  
1 4. 5. 1.  G e n er al g ui d a nc e f or t h e assi g n m e nt of a ut h ors hi p:  
• F or p a p ers t h at i ncl u d e b ot h cli nic al a n d d at a ex p ertis e,  e ac h sit e will g et t o s el ect o n e c o ntri b uti n g 
a ut h or a n d o n e c oll a b or at or  
• P a p ers t h at ar e d at a -f oc us e d will i ncl u d e o n e a ut h or p er sit e (t h e sit e I nf or m atics l e a d or ot h er 
s el ect e d d at a p ers o n n el) 
 
 
 

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
5 8  
1 5.  P R O T E C TI O N O F H U M A N S U BJ E C T S  
W e will f oll o w t h e D e p art m e nt of H e alt h a n d H u m a n S er vic es ( D H H S) r e g ul ati o ns f or t h e Pr ot ecti o n of 
H u m a n R es e arc h S u bj ects b as e d o n est a blis h e d, i nt er n ati o n ally r ec o g niz e d et hic al pri nci pl es, t o 
s af e g u ar d t h e ri g hts a n d w elf ar e of p artici p a nts i n t h e N E T-P R O st u dy.  
1 5. 1.  
R is k t o H u m a n S u bj ects  
1 5. 1. 1.  St u d y Pr oc e d ur es, M at eri als a n d P ot e nti al Ris ks  
A p ot e nti al ris k t o s u bj ects is t o t h eir priv acy a n d c o nfi d e nti alit y s h o ul d o ur eff orts t o pr ot ect t his b e 
i n a dv ert e ntl y br e ac h e d. T h er e is t h e p ot e nti al t h at p artici p a nts will ex p eri e nc e s o m e disc o mf ort fr o m 
r es p o n di n g t o q u esti o ns a b o ut t h eir h e alt h a n d h e alt h c ar e. A ny u n a ut h oriz e d discl os ur e of i d e ntifi a bl e 
d at a m ay als o i n d uc e t h e f e eli n g of distr ess. H o w ev er, t his is n ot a n i nt erv e nti o n st u dy, a n d st u dy 
s u bj ects m ay c h o os e t o n ot a ns w er a ny q u esti o ns or wit h dr a w fr o m t h e st u dy at a ny ti m e.  
1 5. 1. 2.  A d e q u at e Pr ot ecti o n a g ai nst Ris ks  
S e v er al a p pr o ac h es t o mi ni mizi n g ris ks t o s u bj ects will b e i m pl e m e nt e d:  
T o miti g at e a g ai nst f e eli n g of disc o mf ort w h e n r es p o n di n g t o s urv e y q u esti o ns:  
•  
S u bj ects will b e a dvis e d t h at t h ey ar e fr e e t o ski p a n y s urv ey q u esti o ns t h e y pr ef er n ot t o 
a ns w er ( o nli n e s urv ey q u esti o ns als o h av e a r a di al ‘r es et’ b utt o n, s o r es p o n d e nts c a n c h a n g e 
t h eir mi n d, a n d r e m ov e/c h a n g e t h eir r es p o ns e f or a n y p artic ul ar q u esti o n). 
•  
S u bj ects ar e f r e e t o wit h dr a w fr o m t h e st u dy at a ny ti m e.  
•  
S u bj ects will b e pr o vi d e d ti m e t o r e a d t h e c o ns e nt f or m f ull y, a n d disc uss a ny q u esti o ns wit h t h e 
r es e arc h st aff, t h eir f a mily a n d t h eir d oct or.   
T o miti g at e a g ai nst u n a ut h oriz e d discl os ur es:  
•  
All i nv esti g at ors ar e c o m mitt e d t o t h e pr ot ecti o n of c o nfi d e nti alit y a n d priv acy i n all st u di es a n d 
d at a m a n a g e m e nt f u ncti o ns.  
•  
All sit es a p pr eci at e t h e u ni q u e as p ects of r ar e dis e as es t h at r e q uir e extr a att e nti o n i n pr ot ecti n g 
t h e c o nfi d e nti ality of s u bj ects as r el at e d s p ecific ally t o t h eir d at a. 
•  
T h e st u dy P H R p ort al is s ec ur e d wit h a c ertific at e iss u e d b y I T S. P ort al acc o u nts ar e o nly 
acc essi bl e wit h u ni q u e cr e d e nti als.  
•  
All p ort al d at a ar e st or e d i n a I T -m a n a g e d d at a b as e, o nl y acc essi bl e t o I T a d mi nistr at ors a n d 
s el ect m e mb ers of t h e r es e arc h t e a m w h o n e e d s uc h acc ess  
•  
St u dy d at a will b e m ai n t ai n e d o n p ass w or d pr ot ect e d I T m a n a g e d d at a b as es a n d n et w or k driv es 
a n d r es e arc h st aff will b e dir ect e d t o n ot d o w nl o a d d at a o nt o a ny l a pt o ps or m o bil e d e vic es.  
•  
D at a s h ari n g b et w e e n t h e  UI C C a n d st u dy sit es will occ ur vi a a n i nstit uti o n ally s u p p ort e d s ec ur e 
pl atf or m (li k e O n e Driv e).  
1 5. 1. 3.  P ot e nti al B e n efits t o P ati e nts  
T h er e is n o dir ect b e n efit t o t h e p artici p a nts of t h e st u dy. H o w e v er, t h e r es ults of t his st u dy will  p er mit 
t h e d ev el o p m e nt of c o m p ar ati v e eff ects of diff er e nt tr e at m e nt r e gi m e ns  ( a n d c o m bi n ati o ns) f or 
p ati e nts wit h N E Ts , a n d m ay  hi g hli g ht  o pti m al c ar e  p at h w a ys  fr o m t h e p ati e nt’s p ers p ectiv e. T his 
e vi d e nc e is c urr e ntl y l ac ki n g. D at a fr o m t his pr oj ect will t h er ef or e est a blis h t h e p ati e nt p ers p ectiv e o n 
m a n a gi n g N E Ts, a n d pr ovi d e cli nici a ns h el pf ul i nf or m ati o n t o g ui d e tr e at m e nt r ec o m m e n d ati o ns o n 
w hic h tr e at m e nts t o us e first , a n d h o w t h at  m a y aff ect  f ut ur e tr e at m e nt o pti o ns, a n d t h eir c o m p ar ati v e 
eff ectiv e n ess i n r e a l-w orl d c ar e s etti n gs; all of w hic h h a v e b e e n d e e m e d i m p ort a nt by p ati e nts.  
1 5. 1. 4.  R e pr es e nt ati v e n ess of t h e di v ersit y of t h e p ati e nt p o p ul ati o n  
T h e S ur v eill a nc e E pi d e mi ol o gy a n d E n d R es ults ( S E E R) d at a b as e c urr e ntl y pr ovi d es t h e m ost 
r e pr es e nt ati v e, p o p ul ati o n-b as e d, d e m o gr a p hic d at a o n N E Ts i n t h e U nit e d St at es. A r ec e nt 
r etr os p ectiv e a n alysis fr o m t his d at a b as e ex a mi ni n g t h e g e o gr a p hic (r ur al vs ur b a n) a n d 
s oci o d e m o gr a p hic f e at ur es of 5 3, 0 3 4 N E T p ati e nts ( all a g es a n d st a g es) di a g n os e d b et w e e n 1 9 7 3 t o 
2 0 1 5 [ 6 1]  i d e ntifi e d t h at 9 0 % ( 4 7, 5 1 7) of t h es e i n di vi d u als r esi d e d i n ur b a n vs r ur al ar e as. T h e m e a n a g e 
of p ati e nts at di a g n osis w as 5 8 y e ars ( 6 0 y e ars a m o n gst r ur al p ati e nts) a n d t h e m aj ority ( 3 4, 9 6 3/ 6 6 %) 

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
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R E F E R E N C E S  
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N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
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3 4.  
B o d ei, L., et al., L o n g -t er m e v al u ati o n of r e n al t oxicity aft er p e pti d e r ec e pt or r a di o n ucli d e 
t h er a py wit h 9 0 Y-D O T A T O C a n d 1 7 7L u -D O T A T A T E: t h e r ol e of ass oci at e d risk f act ors. E ur J N ucl 
M e d M ol I m a gi n g, 2 0 0 8. 3 5 ( 1 0): p. 1 8 4 7 -5 6.  
3 5.  
O' D orisi o, T. M., A. G. H arris, a n d M. S. O' D orisi o, Ev ol uti o n of N e ur o e n d ocri n e T u m or T h er a py.  
S ur g O nc ol Cli n N A m, 2 0 2 0. 2 9 ( 2): p. 1 4 5-1 6 3.  
3 6.  
B er gs m a, H., et al., P ersist e nt H e m at ol o gic Dysf u ncti o n aft er P e pti d e R ec e pt or R a di o n ucli d e 
T h er a p y wit h ( 1 7 7)L u -D O T A T A T E: I nci d e nc e, C o urs e, a n d Pr e dicti n g F act ors i n P ati e nts wit h 
G astr o e nt er o p a ncr e atic N e ur o e n d ocri n e T u m ors. J N ucl M e d, 2 0 1 8. 5 9 ( 3): p. 4 5 2-4 5 8.  
3 7.  
G o nc alv es, I., et al., C h ar act eristics a n d o utc o m es of t h er a py -r el at e d m y el oi d n e o pl as ms aft er 
p e pti d e r ec e pt or r a di o n ucli d e/c h e m or a di o n ucli d e t h er a py ( P R R T/ P R C R T) f or m et ast atic 
n e ur o e n d ocri n e n e o pl asi a: a si n gl e -i nstit uti o n s eri es. E ur J N ucl M e d M ol I m a gi n g, 2 0 1 9. 4 6 ( 9): 
p. 1 9 0 2 -1 9 1 0.  

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
6 2  
3 8.  
B er gs m a, H., et al., S u b ac ut e h a e m at ot oxicity af t er P R R T wit h ( 1 7 7)L u-D O T A -octr e ot at e: 
pr o g n ostic f act ors, i nci d e nc e a n d c o urs e. E ur J N ucl M e d M ol I m a gi n g, 2 0 1 6. 4 3 ( 3): p. 4 5 3-6 3.  
3 9.  
Riff, B. P., et al., P e pti d e R ec e pt or R a di o n ucli d e T h er a py -I n d uc e d H e p at ot oxicity i n P ati e nts Wit h 
M et ast atic N e ur o e n d oc ri n e T u m ors. Cli n N ucl M e d, 2 0 1 5. 4 0 ( 1 1): p. 8 4 5-5 0.  
4 0.  
K a d erli, R. M., et al., T h er a p e utic O pti o ns f or N e ur o e n d ocri n e T u m ors: A Syst e m atic R evi e w a n d 
N et w or k M et a -a n al ysis. J A M A O nc ol, 2 0 1 9. 5 ( 4): p. 4 8 0-4 8 9.  
4 1.  
S h ar m a, N., et al., P e pti d e R ec e pt or R a di o n ucli d e T h er a py O utc o m es i n a N ort h A m eric a n 
C o h ort Wit h M et ast atic W ell -Diff er e nti at e d N e ur o e n d ocri n e T u m ors. P a ncr e as, 2 0 1 7. 4 6 ( 2): p. 
1 5 1 -1 5 6.  
4 2.  
Bri g hi, N., et al., T h er a p e utic o pti o ns i n l u n g n e ur o e n d ocri n e t u m ors: b et w e e n est a blis h e d 
c o nc e pts a n d n e w h o p es. A ntic a nc er Dr u gs, 2 0 1 9. 3 0 ( 7): p. e 0 7 8 4. 
4 3.  
Pr as a d, V., et al., L ess o ns fr o m a m ultic e ntr e r etr os p ecti v e st u dy of p e pti d e r ec e pt or 
r a di o n ucli d e t h er a py c o m bi n e d wit h l a nr e oti d e f or n e ur o e n d ocri n e t u m o urs: a n e e d f or 
st a n d ar dis e d pr actic e. E ur J N ucl M e d M ol I m a gi n g, 2 0 2 0. 
4 4.  
C ar n a h a n, R. M., et al., Ex pl or ati o n of P C O R n et D at a R es o urc es f or Ass essi n g Us e of M ol ec ul ar -
G ui d e d C a nc er Tr e at m e nt. J C O Cli n C a nc er I nf or m, 2 0 2 0. 4 : p. 7 2 4-7 3 5.  
4 5.  
Pl etc h er, M.J., C. B. F orr est, a n d T. W. C art o n, P C O R n et's C oll a b or ativ e R es e arc h Gr o u ps.  P ati e nt 
R el at O utc o m e M e as, 2 0 1 8. 9 : p. 9 1-9 5.  
4 6.  
A h m a d, F. S., et al., C o m p ut a bl e P h e n oty p e I m pl e m e nt ati o n f or a N ati o n al, M ultic e nt er 
Pr a g m atic Cli nic al Tri al: L ess o ns L e ar n e d Fr o m A D A P T A BL E. Circ C ar di ov asc Q u al O utc o m es, 
2 0 2 0. 1 3 ( 6): p. e 0 0 6 2 9 2. 
4 7.  
Vi ni k, E., et al., D ev el o p m e nt of t h e N orf olk q u alit y of lif e t o ol f or ass essi n g p ati e nts wit h 
n e ur o e n d ocri n e t u m ors. P a ncr e as, 2 0 0 9. 3 8 ( 3): p. e 8 7-9 5.  
4 8.  
F orti n, M., J. Al mir all, a n d K . Nic h ols o n, D e v el o p m e nt of a r es e arc h t o ol t o d oc u m e nt s elf-
r e p ort e d c hr o nic c o n diti o ns i n pri m ary c ar e. J C o m or b, 2 0 1 7. 7 ( 1): p. 1 1 7-1 2 3.  
4 9.  
W e eks, J. C., et al., R el ati o ns hi p b et w e e n c a nc er p ati e nts' pr e dicti o ns of pr o g n osis a n d t h eir 
tr e at m e nt pr ef er e nc es. J a m a, 1 9 9 8. 2 7 9 ( 2 1): p. 1 7 0 9-1 4.  
5 0.  
H a wl e y, S. T., et al., D ecisi o n i n v olv e m e nt a n d r ec ei pt of m ast ect o m y a m o n g r aci ally a n d 
et h nic all y div ers e br e ast c a nc er p ati e nts. J N atl C a nc er I nst, 2 0 0 9. 1 0 1 ( 1 9): p. 1 3 3 7-4 7.  
5 1.  
D e g n er, L. F., J. A. Sl o a n, a n d P.  V e nk at es h, T h e C o ntr ol Pr ef er e nc es Sc al e.  C a n J N urs R es, 1 9 9 7. 
2 9 ( 3): p. 2 1-4 3.  
5 2.  
P o w e, B. D., F at alis m a m o n g el d erl y Afric a n A m eric a ns. Eff ects o n c ol or ect al c a nc er scr e e ni n g. 
C a nc er N urs, 1 9 9 5. 1 8 ( 5): p. 3 8 5-9 2.  
5 3.  
A y a ni a n, J. Z., et al., P ati e nts' ex p eri e nc es wit h c ar e f or l u n g c a nc er a n d c ol or ect al c a nc er: 
fi n di n gs fr o m t h e C a nc er C ar e O utc o m es R es e arc h a n d S ur v eill a nc e C o ns orti u m. J Cli n O nc ol, 
2 0 1 0. 2 8 ( 2 7): p. 4 1 5 4-6 1.  
5 4.  
C oc kcr oft, D. W. a n d M. H. G a ult, Pr e dicti o n of cr e ati ni n e cl e ar a nc e fr o m s er u m cr e ati ni n e.  
N e p hr o n, 1 9 7 6. 1 6 ( 1): p. 3 1-4 1.  
5 5.  
Griffit h, S. D., et al., G e n er ati n g R e al -W orl d T u m or B ur d e n E n d p oi nts fr o m El ectr o nic H e alt h 
R ec or d D at a: C o m p aris o n of R E CI S T, R a di ol o gy -A nc h or e d, a n d Cli nici a n -A nc h or e d A p pr o ac h es 
f or A bstr acti n g R e al-W orl d Pr o gr essi o n i n N o n -S m all C ell L u n g C a nc er. A dv T h er, 2 0 1 9. 3 6 ( 8): p. 
2 1 2 2 -2 1 3 6.  
5 6.  
B u ur e n, S. V., Fl exi bl e I m p ut ati o n of Missi n g D at a . 2 n d E diti o n e d. 2 0 1 8, B oc a R at o n: C R C Pr ess. 
4 4 4.  
5 7.  
G os ai n, R., et al., G e o gr a p hic a n d d e m o gr a p hic f e at ur es of n e ur o e n d ocri n e t u m ors i n t h e U nit e d 
St at es of A m eric a: A p o p ul ati o n -b as e d st u dy. C a nc er, 2 0 2 0. 1 2 6 ( 4): p. 7 9 2-7 9 9.  
5 8.  
Z or n os a, C. C., et al., B as eli n e d e m o gr a p hics of n e ur o e n d ocri n e t u m or p ati e nts pr es e nti n g t o 
s e v e n N ati o n al C o m pr e h e nsi v e C a nc er N et w or k ( N C C N) i nstit uti o ns: D ev el o p m e nt of a m ulti -
i nstit uti o n al o utc o m es d at a b as e. J o ur n al of Cli nic al O nc ol o gy, 2 0 1 2. 3 0 ( 1 5 _s u p pl): p. e 1 4 5 5 1-
e 1 4 5 5 1.  

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
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A P P E N DI X A: N E T di a g n osis c o d es (I C D -9/ 1 0), I C D -O -3 c o d es, a n d hist ol o g y c o d es  
 
I C D-O -3 Sit e C o d es  
SI T E  
C O D E  
D E S C RI P TI O N  
G E P  
C 1 6. 0  
C ar di a, N O S  
G E P  
C 1 6. 1  
F u n d us of st o m ac h  
G E P  
C 1 6. 2  
B o dy of st o m ac h  
G E P  
C 1 6. 3  
G astric a ntr u m  
G E P  
C 1 6. 4  
P yl or us  
G E P  
C 1 6. 5  
L ess er c urv at ur e of st o m ac h N O S 
G E P  
C 1 6. 6  
Gr e at er c ur v at ur e of st o m ac h N O S  
G E P  
C 1 6. 8  
O v erl a p pi n g l esi o n of st o m ac h  
G E P  
C 1 6. 9  
St o m ac h, N O S  
G E P  
C 1 7. 0  
D u o d e n u m  
G E P  
C 1 7. 1  
J ej u n u m 
G E P  
C 1 7. 2  
Il e u m 
G E P  
C 1 7. 3  
M eck els div ertic ul u m  
G E P  
C 1 7. 8  
O v erl a p pi n g l esi o n of s m all i nt esti n e  
G E P  
C 1 7. 9  
S m all i nt esti n e, N O S 
G E P  
C 1 8. 0  
C ec u m  
G E P  
C 1 8. 1  
A p p e n dix  
G E P  
C 1 8. 2  
Asc e n di n g c ol o n  
G E P  
C 1 8. 3  
H e p atic fl ex ur e of c ol o n  
G E P  
C 1 8. 4  
Tr a ns v ers e c ol o n  
G E P  
C 1 8. 5  
S pl e nic fl ex ur e of c ol o n  
G E P  
C 1 8. 6  
D esc e n di n g c ol o n  
G E P  
C 1 8. 7  
Si g m oi d c ol o n  
G E P  
C 1 8. 8  
O v erl a p pi n g l esi o n of c ol o n  
G E P  
C 1 8. 9  
C ol o n, N O S  
G E P  
C 1 9. 9  
R ect osi g m oi d j u ncti o n  
G E P  
C 2 0. 9  
R ect u m, N O S  
G E P  
C 2 5. 0  
H e a d of p a ncr e as  
G E P  
C 2 5. 1  
B o dy of p a ncr e as  
G E P  
C 2 5. 2  
T ail of p a ncr e as  
G E P  
C 2 5. 3  
P a ncr e atic d uct  
G E P  
C 2 5. 4  
Isl ets of L a n g er h a ns 
G E P  
C 2 5. 7  
Ot h er s p ecifi e d p arts of p a ncr e as  
G E P  
C 2 5. 8  
O v erl a p pi n g l esi o n of p a ncr e as  
G E P  
C 2 5. 9  
P a ncr e as, N O S  
G E P  
C 2 6. 0  
I nt esti n al tr act, N O S 
G E P  
C 2 6. 8  
O v erl a p pi n g l esi o n of di g esti v e s yst e m  
G E P  
C 2 6. 9  
G astr oi nt esti n al tr act, N O S  
L U N G 
C 3 4. 0  
M ai n br o nc h us  
L U N G 
C 3 4. 1  
U p p er l o b e, l u n g  
L U N G 
C 3 4. 2  
Mi d dl e l o b e, l u n g  

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
6 4  
L U N G 
C 3 4. 3  
L o w er l o b e, l u n g 
L U N G 
C 3 4. 8  
O v erl a p pi n g l esi o n of l u n g  
L U N G 
C 3 4. 9  
L u n g, N O S 
 
I C D-O -3 Hist ol o gy C o d es  
C O D E  
D E S C RI P TI O N  
8 1 5 0  
P a ncr e atic e n d ocri n e t u m or, m ali g n a nt  
8 1 5 1  
I ns uli n o m a, m ali g n a nt 
8 1 5 2  
Gl uc a g o n o m a, m ali g n a nt  
8 1 5 3  
G astri n o m a, m ali g n a nt  
8 1 5 5  
Vi p o m a, m ali g n a nt  
8 1 5 6  
S o m at ost ati n o m a, m ali g n a nt  
8 1 5 7  
E nt er o gl uc a g o n o m a, m ali g n a nt  
8 2 4 0  
C arci n oi d t u m or, N O S  
8 2 4 1  
E nt er oc hr o m affi n c ell c arci n oi d 
8 2 4 2  
E nt er oc hr o m affi n -li k e c ell t u m or, m ali g n a nt 
8 2 4 6  
N e ur o e n d ocri n e c arci n o m a, N O S  
8 2 4 9  
At y pic al c arci n oi d t u m or  
 
I C D-9 a n d -1 0 C o d es  
T Y P E  
SI T E  
C O D E  
D E S C RI P TI O N  
I C D-9  
G E P  
2 0 9. 0 0  
M ali g n a nt c arci n oi d t u m or of t h e s m all i nt esti n e, u ns p ecifi e d 
p orti o n  
I C D-9  
G E P  
2 0 9. 0 1  
M ali g n a nt c arci n oi d t u m or of t h e d u o d e n u m  
I C D-9  
G E P  
2 0 9. 0 2  
M ali g n a nt c arci n oi d t u m or of t h e j ej u n u m  
I C D-9  
G E P  
2 0 9. 0 3  
M ali g n a nt c arci n oi d t u m or of t h e il e u m  
I C D-9  
G E P  
2 0 9. 1 0  
M ali g n a nt c arci n oi d t u m or of t h e l ar g e i nt esti n e, u ns p ecifi e d 
p orti o n  
I C D-9  
G E P  
2 0 9. 1 1  
M ali g n a nt c arci n oi d t u m or of t h e a p p e n dix  
I C D-9  
G E P  
2 0 9. 1 2  
M ali g n a nt c arci n oi d t u m or of t h e c ec u m  
I C D-9  
G E P  
2 0 9. 1 3  
M ali g n a nt c arci n oi d t u m or of t h e asc e n di n g c ol o n  
I C D-9  
G E P  
2 0 9. 1 4  
M ali g n a nt c arci n oi d t u m or of t h e tr a nsv ers e c ol o n  
I C D-9  
G E P  
2 0 9. 1 5  
M ali g n a nt c arci n oi d t u m or of t h e d esc e n di n g c ol o n  
I C D-9  
G E P  
2 0 9. 1 6  
M ali g n a nt c arci n oi d t u m or of t h e si g m oi d c ol o n  
I C D-9  
G E P  
2 0 9. 1 7  
M ali g n a nt c arci n oi d t u m or of t h e r ect u m  
I C D-9  
G E P  
2 0 9. 2 3  
M ali g n a nt c arci n oi d t u m or of t h e st o m ac h  
I C D-9  
G E P  
2 0 9. 2 5  
M ali g n a nt c arci n oi d t u m or of f or e g ut, n ot ot h er wis e s p ecifi e d  
I C D-9  
G E P  
2 0 9. 2 6  
M ali g n a nt c arci n oi d t u m or of mi d g ut, n ot ot h er wis e s p ecifi e d  
I C D-9  
G E P  
2 0 9. 2 7  
M ali g n a nt c arci n oi d t u m or of hi n d g ut, n ot ot h er wis e s p ecifi e d  
I C D-9  
G E P  
1 5 7. 4  
M ali g n a nt n e o pl as m of isl ets of l a n g er h a ns  
I C D-1 0  
G E P  
C 7 A. 0 1  
M ali g n a nt c arci n oi d t u m ors of t h e s m all i nt esti n e  
I C D-1 0  
G E P  
C 7 A. 0 1 0  
M ali g n a nt c arci n oi d t u m or of t h e d u o d e n u m  
I C D-1 0  
G E P  
C 7 A. 0 1 1  
M ali g n a nt c arci n oi d t u m or of t h e j ej u n u m  
I C D-1 0  
G E P  
C 7 A. 0 1 2  
M ali g n a nt c arci n oi d t u m or of t h e il e u m  

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
6 5  
I C D-1 0  
G E P  
C 7 A. 0 1 9  
M ali g n a nt c arci n oi d t u m or of t h e s m all i nt esti n e, u ns p ecifi e d 
p orti o n  
I C D-1 0  
G E P  
C 7 A. 0 2 0  
M ali g n a nt c arci n oi d t u m or of t h e a p p e n dix  
I C D-1 0  
G E P  
C 7 A. 0 2 1  
M ali g n a nt c arci n oi d t u m or of t h e c ec u m  
I C D-1 0  
G E P  
C 7 A. 0 2 2  
M ali g n a nt c arci n oi d t u m or of t h e asc e n di n g c ol o n  
I C D-1 0  
G E P  
C 7 A. 0 2 3  
M ali g n a nt c arci n oi d t u m or of t h e tr a nsv ers e c ol o n  
I C D-1 0  
G E P  
C 7 A. 0 2 4  
M ali g n a nt c arci n oi d t u m or of t h e d esc e n di n g c ol o n  
I C D-1 0  
G E P  
C 7 A. 0 2 5  
M ali g n a nt c arci n oi d t u m or of t h e si g m oi d c ol o n  
I C D-1 0  
G E P  
C 7 A. 0 2 6  
M ali g n a nt c arci n oi d t u m or of t h e r ect u m  
I C D-1 0  
G E P  
C 7 A. 0 2 9  
M ali g n a nt c arci n oi d t u m or of t h e l ar g e i nt esti n e, u ns p ecifi e d 
p orti o n  
I C D-1 0  
G E P  
C 7 A. 0 9 2  
M ali g n a nt c arci n oi d t u m or of t h e st o m ac h  
I C D-1 0  
G E P  
C 7 A. 0 9 4  
M ali g n a nt c arci n oi d t u m or of t h e f or e g ut, u ns p ecifi e d  
I C D-1 0  
G E P  
C 7 A. 0 9 5  
M ali g n a nt c arci n oi d t u m or of t h e mi d -g ut, u ns p ecifi e d  
I C D-1 0  
G E P  
C 7 A. 0 9 6  
M ali g n a nt c arci n oi d t u m or of t h e hi n d g ut, u ns p ecifi e d  
I C D-1 0  
G E P  
C 2 5. 4  
M ali g n a nt n e o pl as m of e n d ocri n e p a ncr e as  
I C D-9  
L U N G 
2 0 9. 2 1  
M ali g n a nt c arci n oi d t u m or of t h e br o nc h us a n d l u n g  
I C D-1 0  
L U N G 
C 7 A. 0 9 0  
M ali g n a nt c arci n oi d t u m or of t h e br o nc h us a n d l u n g  
I C D-9  
A M BI G U O U S  
2 0 9. 2 0  
M ali g n a nt c arci n oi d t u m or of u nk n o w n pri m ar y sit e  
I C D-9  
A M BI G U O U S  
2 0 9. 2 9  
M ali g n a nt c arci n oi d t u m or of ot h er sit es  
I C D-9  
A M BI G U O U S  
2 0 9. 3 0  
M ali g n a nt p o orl y diff er e nti at e d n e ur o e n d ocri n e c arci n o m a, a n y 
sit e 
I C D-1 0  
A M BI G U O U S  
C 7 A. 0 0  
M ali g n a nt c arci n oi d t u m or of u ns p ecifi e d sit e  
I C D-1 0  
A M BI G U O U S  
C 7 A. 0 9 8  
M ali g n a nt c arci n oi d t u m ors of ot h er sit es  
I C D-1 0  
A M BI G U O U S  
C 7 A. 1  
M ali g n a nt p o orl y diff er e nti at e d n e ur o e n d ocri n e t u m ors  
I C D-1 0  
A M BI G U O U S  
C 7 A. 8  
Ot h er m ali g n a nt n e ur o e n d ocri n e t u m ors  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
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A P P E N DI X B: N E T C o m p ut a bl e P h e n ot y p e  –  t ec h nic al s p ecific ati o n ( S A S c o d e) 
 
N E T -P R O C o m p ut a bl e P h e n ot y p es a n d A p pr o ac h es f or R ecr uit m e nt  
 
O v er vi e w  
T h e N E T -P R O r ecr uit m e nt a p pr o ac h is si mil ar t o t h e A D A P T A BL E  pr a g m atic cli nic al tri al. T e a ms at e ac h 
sit e will c o nt act p ot e nti all y eli gi bl e p ati e nts by el ectr o nic/ gr o u n d m ail or will a p pr o ac h t h e m i n p ers o n 
a t t h e cli nic. U n d erst a n d a bl y, e ac h sit e m a y h av e a pr ef er e nc e f or a p artic ul ar f or m of c o nt act t h at will 
o pti miz e t h eir e nr oll m e nt.  
I n or d er t o acc o m m o d at e t h es e v ari e d a p pr o ac h es, w e h a v e d ev el o p e d a m ulti-pr o n g e d a p pr o ac h t h at 
l e v er a g es existi n g d at a s ourc es t o i d e ntif y p ot e nti al e nr oll e es. T h ey i ncl u d e:  
● P h e n ot y p es t h at us e di a g n osis c o d es i n  el ectr o nic h e alt h r ec or d ( E H R) d at a i n cli nic al d at a 
r es e arc h w ar e h o us es or m ost r ec e nt P C O R n et C o m m o n D at a M o d el ( C D M) r efr es h. 
○ A p h e n oty p e is pr ovi d e d f or usi n g t h es e d at a f or l o w-t o uc h r ecr uit m e nt: ‘ Hi g h p ositi v e 
pr e dicti v e v al u e p h e n ot y p e’  
○ A p h e n oty p e is pr ovi d e d f or us e w h e n r es o urc es c a n c o nfir m eli gi bilit y first, e. g. c h art 
r e vi e w or i n cli nic r ecr uit m e nt: “ Hi g h s e nsitivity p h e n ot y p e” 
 
● P h e n ot y p es t h at us e d at a fr o m i nstit uti o n al t u m or r e gistri es 
○ T h es e d at a h a v e a t y pic al l a g ti m e of o n e y e ar ( d e p e n di n g o n t h e i nstit uti o n), b ut a n 
exc ell e nt p h e n ot y p e is pr ovi d e d f or usi n g t his d at a s o urc e as p art of a l o w -t o uc h 
r ecr uit m e nt str at e g y 
 
T his d oc u m e nt d escri b es t h e a dv a nt a g es a n d dis a dv a nt a g es of e ac h d at a s o urc e a n d pr o vi d es t ec h nic al 
s p ecific ati o ns f or c o m p ut a bl e p h e n oty p es t h at ar e a p pr o pri at e f or diff er e nt r ecr uit m e nt str at e gi es. F or 
ex a m pl e, st u dy sit es t h at pl a n t o r ecr uit fr o m t h eir cli n ics or c o n d uct c h art r evi e ws b ef or e r ecr uiti n g m a y 
fi n d it m ost eff ectiv e t o us e a hi g hl y s e nsiti v e p h e n ot y p e t o i d e ntify p ot e nti al p artici p a nts a n d v erif y 
eli gi bilit y t hr o u g h c h art r e vi e w or i n t h e c o nt ext of a cli nic visit; st aff c o ul d scr e e n o ut t h e f al s e p ositi v es 
t h at w o ul d b e fl a g g e d wit h s uc h a p h e n ot y p e. Sit es t h at pl a n t o r ecr uit by ‘l o w-t o uc h’ vi a e-m ail or 
gr o u n d m ail wit h o ut pri or c h art r evi e w t o c o nfir m eli gi bility , h o w e v er, will n e e d a p h e n ot y p e wit h hi g h 
p ositi v e pr e dicti v e v al u e ( P P V) t o m ax i miz e t h e p ossi bilit y t h at c o nt act e d p ati e nts act u ally h a v e a 
n e ur o e n d ocri n e/c arci n oi d t u m or ( N E T) di a g n osis. ( T h er e is g e n er ally a tr a d e -off b et w e e n P P V a n d 
s e nsiti vit y; hi g h er P P V is ass oci at e d wit h l o w er s e nsitivit y a n d hi g h er s e nsiti vity is ass oci at e d wit h l o w er 
P P V.)  
T h e v ali dit y of e ac h c o m p ut a bl e p h e n ot y p e is als o disc uss e d. W h er e av ail a bl e, r es ults fr o m v ali d ati o n 
st u di es p erf or m e d at t h e U ni v ersity of I o w a C o or di n ati n g C e nt er ( UI C C) ar e pr o vi d e d. E ac h sit e is 
e nc o ur a g e d t o c o n d uct its o w n v ali d ati o n st u di es, a n d t h e UI C C c a n pr o vi d e assist a nc e f or t his b as e d o n 
its ex p eri e nc e. 
It is us ef ul t o r e m e m b er t h at pr os p ectiv e e nr oll e es will c o nfir m t h eir eli gi bilit y b y r es p o n di n g t o 
eli gi bilit y q u esti o ns e arl y i n t h e e nr oll m e nt pr oc ess. T his will s er v e as a  fi n al c h ec k i n c as e t h e p h e n oty p e 
mist ak e nl y i d e ntifi es s o m e o n e as h a vi n g a q u alifyi n g N E T. T h e r ecr uiti n g m at eri als h av e b e e n w or d e d 
c ar ef ull y t o mi ni miz e t h e p ossi bilit y t h at a p ot e nti al e nr oll e e is al ar m e d t o b e c o nt act e d f or a st u dy 
f oc us e d o n N E Ts. 
F oll o wi n g t h e A D A P T A BL E ex a m pl e, t h e UI C C will c o nti n u e t o d e v el o p a n d r efi n e t h es e c o m p ut a bl e 
p h e n ot y p es t o m axi miz e t h eir p erf or m a nc e. T his will h a p p e n t hr o u g h t h e lif e of t h e pr oj ect.  
P h e n ot y p es t h at us e di a g n osis c o d es i n  el ectr o nic h e alt h r ec or d ( E H R)  d at a (r es e arc h w ar e h o us e or 
C D M)  

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
6 7  
M a ny r es e arc h i nstit uti o ns m ai nt ai n m e dic al r ec or d a n d billi n g d at a i n a cli nic al r es e arc h d at a 
w ar e h o us e ( C R D W) t h at c o nt ai ns str uct ur e d i nf or m ati o n o n di a g n os es a n d pr oc e d ur es. T h e P C O R n et 
C o m m o n D at a M o d el ( C D M) is oft e n p o p ul at e d b y t his s o urc e d at a. C o m p ut a bl e p h e n oty p es c a n b e 
a p pli e d t o t h e C D M or t h e u n d erl yi n g C R D W ( w hic h m a y b e u p d at e d m or e fr e q u e ntl y t h a n t h e C D M).  
A n a d v a nt a g e of C R D W d at a is t h at p ati e nt d at a ar e str uct ur e d by cli nic al or billi n g st aff i n r e al -w orl d 
s etti n gs usi n g t h e I nt er n ati o n al Cl assific ati o n of Dis e as es (I C D) syst e m ( 9 t h a n d 1 0 t h e diti o ns). W hil e d at a 
ar e g e n er ally hi g h q u alit y, err ors c a n occ ur. Als o, di a g n os es c a n c h a n g e or b e r efi n e d ov er ti m e, a n d 
t h es e c h a n g es ar e n ot al w ays cl e arl y d oc u m e nt e d. S o m e I C D c o d es ar e a m bi g u o us wit h r e g ar d t o t u m or 
sit e (s e e t h e I C D c o d es l a b el e d A M BI G U O U S i n t h e A p p e n dix). It is als o i m p ort a nt t o n ot e t h at t h e d at e a  
c a nc er I C D di a g n osis c o d e first a p p e ars o n a n e nc o u nt er c a n n ot n ec ess arily b e c o nsi d er e d t o  b e t h e d at e 
of c a nc er di a g n osis; it g e n er all y l a gs b e hi n d t h e tr u e di a g n osis d at e. T h at l a g i n ti m e c a n b e s u bst a nti al, 
es p eci ally if a p ati e nt w as ori gi n ally di a g n os e d or tr e at e d at a n ot h er i nstit uti o n.  
P h e n ot y p e f or l o w -t o uc h r ecr uit m e nt ( wit h o ut pri or c h art r evi e w or cli nic visit): ‘ Hi g h p ositi v e pr e dicti v e 
v al u e p h e n ot y p e’  
● T his p h e n oty p e w as d esi g n e d t o m axi miz e p ositi v e pr e dicti v e v al u e s o it w o ul d b e a p pr o pri at e 
f or r ecr uit m e nt vi a el ectr o nic or gr o u n d m ail wit h o ut pri or c o nfir m ati o n of eli gi bilit y t hr o u g h 
c h art r evi e w or cli nic visit. 
● T h e p h e n ot y p e i d e ntifi es p ati e nts wit h at l e ast o n e I C D c o d e i n t h eir el ectr o nic m e dic al r ec or d 
( E M R)/ billi n g r ec or ds t h at s p ecifi es a G E P or l u n g N E T. T o miti g at e t h e eff ect of i nci d e nt al c o di n g 
err ors, at l e ast t w o N E T c o d es ( w hic h m ay or m a y n ot s p ecif y t h e sit e of t h e N E T; s e e c o d e 
d escri pti o ns i n t h e A p p e n dix) m ust b e pr es e nt, a n d t h e p ati e nt’s first a n d l ast N E T c o d e m ust b e 
m or e t h a n 3 0 d a ys a p art.  
● T h e first N E T c o d e f or a p ati e nt is pr es e ntly r e q uir e d t o b e d at e d o n or aft er 0 1J A N 2 0 1 9. T his 
i ncr e as es t h e lik eli h o o d t h at t h e p ati e nt’s N E T di a g n osis will b e i n t h e r e q uir e d 2 0 1 9-2 0 2 3 st u dy 
wi n d o w.  
● T his p h e n oty p e s h o ul d b e a p pli e d f or all p ati e nts w h o ar e n ot k n o w n t o h a v e di e d.  
● T h e l u n g N E T Hi g h P P V p h e n ot y p e h a d a P P V of 9 2 % a n d t h e G E P N E T Hi g h P P V p h e n oty p e h a d a 
P P V of 9 0 -9 8 % w h e n c o m p ar e d wit h c h art r e vi e w at T h e U ni v ersit y of I o w a.  T h e esti m at e d 
s e nsiti vit y w as 5 9. 0 % a n d 4 5. 2 %, r es p ectiv ely (s e e T ec h nic al D et ails B ox 1 f or f urt h er 
i nf or m ati o n) 
 
T ec h nic al D et ai ls B o x 1. P erf or m a nc e of P h e n ot y p es t h at us e Di a g n osis C o d es i n E H R D at a (r es e arc h 
w ar e h o us es or C D M)  
1.  Hi g h P P V P h e n ot y p e  
Esti m ati n g t h e P ositiv e Pr e dicti v e V al u e of t h e Hi g h P P V P h e n ot y p e  
T h e U ni v ersity of I o w a ( UI) t e a m c o n d uct e d a c h art r evi e w t o v ali d at e a 1 5 % r a n d o m s a m pl e of c as es 
i d e ntifi e d wit h t his p h e n oty p e o v er a fiv e-y e ar p eri o d. T his w as d o n e s e p ar at ely f or l u n g ( N = 1 3) a n d 
G E P N E Ts ( N = 5 1).  
● Of t h e 1 3 c as es i d e ntifi e d by t h e p h e n oty p e as h a vi n g l u n g N E Ts, 1 2 h a d di a g n os es t h at w er e 
u n e q ui v oc ally c o nfir m e d o n c h art r evi e w (i. e., t h e c h art d escri b e d p at h ol o gic al c o nfir m ati o n 
of a l u n g N E T). T his c orr es p o n ds t o a P P V of 9 2 %. T h e si n gl e c as e t h at w as n ot c o nfir m e d h a d 
a p a ncr e atic N E T.  
● Of t h e 5 1 c as es i d e ntifi e d by t h e p h e n oty p e as G E P N E Ts, 4 6 h a d di a g n os es t h at w er e 
u n e q ui v oc ally c o nfir m e d o n c h art r evi e w. T his c orr es p o n ds t o a P P V of 9 0 %. T h er e w er e t w o 
ot h er c as es t h at h a d p at h ol o gic al evi d e nc e of a N E T wit h a n u n k n o w n pri m ary l oc ati o n. A n 
a d diti o n al t w o c as es h a d a s us p ect e d N E T wit h  n o p at h ol o gic al c o nfir m ati o n o n t h e c h art. If 
t h es e f o ur c as es ar e c o nsi d er e d “ hits”, P P V i ncr e as es t o 9 8 %. F or t h e o n e r e m ai ni n g c as e, t h e 
c h art c o nt ai n e d c o ntr a dict or y a n d a m bi g u o us i nf or m ati o n a b o ut t h e p ati e nt’s t u m or.  

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
6 8  
Esti m ati n g t h e S e nsitivit y of t h e Hi g h P P V P h e n oty p e  
T h e UI t e a m us e d t h e U niv ersit y of I o w a H os pit als a n d Cli nics ( UI H C) i nstit uti o n al t u m or r e gistr y t o 
i d e ntif y c o h orts of p ati e nts wit h c o nfir m e d G E P a n d l u n g N E Ts ( N = 1 6 6 a n d N = 3 9, r es p ectiv ely). 
T h es e c as es w er e di a g n os e d o v er a t w o -y e ar p eri o d. T h e p h e n oty p e w as a p pli e d t o t h es e c o h orts t o 
o bt ai n a m e as ur e of s e nsitivit y.  
● Of t h e 3 9 c as es wit h l u n g N E Ts, 2 3 c as es w er e i d e ntifi e d wit h t h e p h e n ot y p e. T his 
c orr es p o n ds t o s e nsitivit y of 5 9. 0 %. 
● Of t h e 1 6 6 c as es wit h G E P N E Ts, 7 5 c as es w e r e i d e ntifi e d wit h t h e p h e n ot y p e. T his 
c orr es p o n ds t o s e nsitivit y of 4 5. 2 %. 
 
2.  Hi g h S e nsiti vit y P h e n ot y p e  
Esti m ati n g t h e S e nsitivit y of t h e Hi g h S e nsitivity P h e n ot y p e  
As a b ov e, t h e UI t e a m us e d t h e UI H C i nstit uti o n al t u m or r e gistr y t o i d e ntif y s e p ar at e c o h or ts of 
p ati e nts wit h c o nfir m e d G E P a n d l u n g N E Ts ( N = 1 6 6 a n d N = 3 9, r es p ectiv ely). T h e hi g h s e nsitivity 
p h e n ot y p e w as a p pli e d a g ai nst t h es e c o h orts t o o bt ai n a m e as ur e of s e nsitivit y.  
● Of t h e 3 9 c as es wit h l u n g N E Ts, 3 3 c as es w er e i d e ntifi e d wit h t h e p h e n o t y p e. T his 
c orr es p o n ds t o s e nsitivit y of 8 4. 6 %. 
● Of t h e 1 6 6 c as es wit h G E P N E Ts, 1 4 8 c as es w er e i d e ntifi e d wit h t h e p h e n ot y p e. T his 
c orr es p o n ds t o s e nsitivit y of 8 9. 2 %. 
 
I m pl e m e nt ati o n f or hi g h P P V p h e n ot y p e 
 
D efi niti o ns  
%L E T G E P C O D E S 1 0 = 
' C 7 A. 0 1',' C 7 A. 0 1 0',' C 7 A. 0 1 1',' C 7 A. 0 1 2',' C 7 A. 0 1 9',' C 7 A. 0 2 0',' C 7 A. 0 2 1',' C 7 A. 0 2 2',' C 7 A. 0 2 3', 
' C 7 A. 0 2 4',' C 7 A. 0 2 5',' C 7 A. 0 2 6',' C 7 A. 0 2 9',' C 7 A. 0 9 2',' C 7 A. 0 9 4',' C 7 A. 0 9 5',' C 7 A. 0 9 6',' C 2 5. 4'; 
%L E T G E P C O D E S 0 9 = ' 2 0 9. 0 0',' 2 0 9. 0 1',' 2 0 9. 0 2',' 2 0 9. 0 3',' 2 0 9. 1 0',' 2 0 9. 1 1',' 2 0 9. 1 2',' 2 0 9. 1 3',' 2 0 9. 1 4',  
' 2 0 9. 1 5',' 2 0 9. 1 6',' 2 0 9. 1 7',' 2 0 9. 2 3',' 2 0 9. 2 5',' 2 0 9. 2 6',' 2 0 9. 2 7',' 1 5 7. 4'; 
 
%L E T L U N G C O D E S 1 0 = ' C 7 A. 0 9 0';  
%L E T L U N G C O D E S 0 9 = ' 2 0 9. 2 1';  
 
%L E T a m bi g u o us N E T 1 0 = ' C 7 A. 0 0',' C 7 A. 0 9 8',' C 7 A. 1',' C 7 A. 8';  
%L E T a m bi g u o us N E T 0 9 = ' 2 0 9. 2 0',' 2 0 9. 2 9',' 2 0 9. 3 0';  
 
Crit eri o n  
L o gic/ N ot es 
D efi n e d  
1. At l e ast o n e 
I C D c o d e t h at 
s p ecifi es a G E P 
or l u n g N E T  
B asis: C D M 
DI A G N O SI S 
t a bl e or s o urc e 
d at a e q ui v al e nt  
At l e ast o n e r ec or d f or e ac h p ati e nt:  
 
L u n g N E Ts 
( D X _ T Y P E = ' 0 9' A N D ( D X I N ( &L U N G C O D E S 0 9)))  
O R  
( D X _ T Y P E = ' 1 0' A N D ( D X I N ( &L U N G C O D E S 1 0))); 
 
G E P N E Ts  
( D X _ T Y P E = ' 0 9' A N D ( D X I N ( & G E P C O D E S 0 9))) 
O R  
( D X _ T Y P E = ' 1 0' A N D ( D X I N ( & G E P C O D E S 1 0))); 

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
6 9  
2. P ati e nt’s  first 
N E T c o d e d at e d 
o n or aft er 
0 1J A N 2 0 1 9  
B asis: C D M 
DI A G N O SI S 
t a bl e or s o urc e 
d at a e q ui v al e nt  
 
 
D efi n e first _ n et _ dt:  
 
L u n g N E Ts 
[s et of l u n g/ a m bi g u o us sit e N E T r ec or ds] → 
( D X _ T Y P E = ' 0 9' A N D ( D X I N 
( &L U N G C O D E S 0 9, & a m bi g u o us N E T 0 9))) 
O R  
( D X _ T Y P E = ' 1 0' A ND ( D X I N 
( &L U N G C O D E S 1 0, & a m bi g u o us N E T 1 0))); 
 
G E P N E Ts  
[s et of G E P/ a m bi g u o us sit e N E T r ec or ds] → 
( D X _ T Y P E = ' 0 9' A N D ( D X I N 
( & G E P C O D E S 0 9, & a m bi g u o us N E T 0 9))) 
O R  
( D X _ T Y P E = ' 1 0' A N D ( D X I N 
( & G E P C O D E S 1 0, & a m bi g u o us N E T 1 0))); 
 
first _ n et _ dt = of t h e s et of l u n g/ G E P N E T r ec or ds f or e ac h 
p ati e nt, mi n( a d mit _ d at e)  
 
* * *  
 
first _ n et _ dt > = ‘ 0 1J A N 2 0 1 9’ d 
 
 
3. D ays 
b et w e e n 
p ati e nt’s first 
a n d l ast N E T 
c o d e is gr e at er 
t h a n 3 0 d a ys 
B asis: C D M 
DI A G N O SI S 
t a bl e or s o urc e 
d at a e q ui v al e nt  
 
D efi n e first _ n et _ dt a n d l ast _ n et _ dt:  
 
L u n g N E Ts 
[s et of l u n g/ a m bi g u o us sit e N E T r ec or ds] → 
( D X _ T Y P E = ' 0 9' A N D ( D X I N 
( &L U N G C O D E S 0 9, & a m bi g u o us N E T 0 9))) 
O R  
( D X _ T Y P E = ' 1 0' A N D ( D X I N 
( &L U N G C O D E S 1 0, & a m bi g u o us N E T 1 0))); 
 
G E P N E Ts  
[s et of G E P/ a m bi g u o us sit e N E T r ec or ds] → 
(D X _ T Y P E = ' 0 9' A N D ( D X I N 
( & G E P C O D E S 0 9, & a m bi g u o us N E T 0 9))) 
O R  
( D X _ T Y P E = ' 1 0' A N D ( D X I N 
( & G E P C O D E S 1 0, & a m bi g u o us N E T 1 0))); 
 
first _ n et _ dt = of t h e s et of l u n g/ G E P N E T r ec or ds f or e ac h 
p ati e nt, mi n( a d mit _ d at e)  
l ast _ n et _ dt = of t h e s et of l u n g/ G E P N E T r ec or ds f or e ac h 
p ati e nt, m ax( a d mit _ d at e)  
 
* * *  

 
N E T -P R O Pr ot oc ol v 1. 3                                                                                                     A pril 2 0 2 2  
7 0  
 
if i ntc k(' d a y',first _ n et _ dt,l ast _ n et _ dt) > 3 0 
 
 
P h e n ot y p e f or us e w h e n r es o urc es c a n c o nfir m eli gi bilit y first, e. g. c h art r evi e w or i n cli nic r ecr uit m e nt: 
“ Hi g h s e nsitivity p h e n ot y p e” 
● T his p h e n oty p e w as d esi g n e d t o m axi miz e s e nsiti vit y s o it w o ul d b e a p pr o pri at e f or cli nic 
r ecr uit m e nt or c h art c o nfir m ati o n pri or t o e-m ail or gr o u n d m ail r ecr uit m e nt.  
● T h e p h e n ot y p e r el ax es t h e crit eri a d escri b e d a b o v e a n d i d e ntifi es p ati e nts wit h at l e ast o n e I C D 
c o d e i n t h eir E M R/ billi n g r ec or ds t h at s p ecifi es a N E T (s e e c o d es i n t h e A p p e n dix). 
● R el axi n g t h e n u m b er of c o d es r e q uir e d r es ult e d i n a s e nsiti vity of 8 4. 6 % (l u n g) a n d 8 9. 2 % 
( G E P)( S e e T ec h nic al D et ails B ox 1).  
 
I m pl e m e nt ati o n f or hi g h s e nsitivity p h e n oty p e 
Crit eri o n  
L o gic/ N ot es 
D efi n e d  
1. At l e ast o n e I C D c o d e t h at 
s p ecifi es a N E T 
B asis : C D M DI A G N O SI S t a bl e 
or s o urc e d at a e q ui v al e nt  
 
At l e ast o n e r ec or d f or e ac h p ati e nt:  
 
L u n g N E Ts 
( D X _ T Y P E = ' 0 9' A N D ( D X I N 
( &L U N G C O D E S 0 9, & a m bi g u o us N E T 0 9))) 
O R  
( D X _ T Y P E = ' 1 0' A N D ( D X I N 
( &L U N G C O D E S 1 0, & a m bi g u o us N E T 1 0))); 
 
G E P N E Ts  
( D X _ T Y P E = ' 0 9' A N D ( D X I N 
( & G E P C O D E S 0 9, & a m bi g u o us N E T 0 9))) 
O R  
( D X _ T Y P E = ' 1 0' A N D ( D X I N 
( & G E P C O D E S 1 0, & a m bi g u o us N E T 1 0))); 
2.  P ati e nt’s first N E T c o d e 
d at e d o n or aft er 
0 1J A N 2 0 1 9  
 
L u n g N E Ts 
[s et of l u n g/ a m bi g u o us sit e N E T 
r ec or ds] → 
( D X _ T Y P E = ' 0 9' A N D ( D X I N 
( &LU N G C O D E S 0 9, & a m bi g u o us N E T 0 9)))  
O R  
( D X _ T Y P E = ' 1 0' A N D ( D X I N 
( &L U N G C O D E S 1 0, & a m bi g u o us N E T 1 0))); 
 
G E P N E Ts  
[s et of G E P/ a m bi g u o us sit e N E T 
r ec or ds] → 
( D X _ T Y P E = ' 0 9' A N D ( D X I N 
( & G E P C O D E S 0 9, & a m bi g u o us N E T 0 9))) 
O R  
( D X _ T Y P E = ' 1 0' A N D ( D X I N 
( & G E P C O D E S 1 0, & a m bi g u ous N E T 1 0)));