Advanced Thoracic NET Clinical Cases:

PRRT in Lung NEN

Ulrike Garske-Román MD, PhD

ESMO Preceptorship Prague 2017

Bronchial carcinoidsCycle 1 March 2009 Cycle 7 Oct 2010

Ulrike Garske-Román

Cycle 1 2 3 45 6 7

TTP 71 MonthsSurvival 80+ Months

8e december 2012

Bronchial carcinoids: 13 patients with

advanced disease

Median time to

progression 44

months

Median overall

survival 44

months

Ulrike Garske-Román, Dissertation Uppsala University 2012

Bronchial carcinoids

! " #$%&' ( )*+&,*- '

. +- *" /0"12''

34&$)52' 3#6 "$'- *)1&'75)*+&, *-8'

9 " $54" /0"1+%': &-5" , -&'

33( '" $'( ; ! ''

9 &<+) , '! #$=+=)0'

! "#$%&"' (&)(#*(+, , - ((

+. ( ( ! /01( ( 23(45+. 6(73(+85+. (

997(- : (; <$)=>(?23@(

(

( . ( ( 2)"&A)<(B(: /1C(

( 73(. 5. ( ( (

( +( ( 2)"&A)<(B(D<E<"F%GHG$(

( 23(+5+( 997(I /- , (; <$)=>(

(

( I ( ( J G>A*#)G$F; (B(&)<A<>GD&((

( 7K(+5I 6(23(- 5I 6(73(: 5I (

997(L/I (?7K@(

(

( 8- ( +. (9J (4(MJ (

( 9(000(?+@((9(0N(?+O@(

( ( +: (; <$)=>(

P G")=(&)(#*(+, , 4(

- I ( I (9J (- , (MJ (

- O(DGQQ&"&$)("&' G; &$>R("&>A<$>&>(8(HG>A*#)G$F; /%#>&DR(- (A#H*G)#E&*(B(STK(

9(0T(?+@(9(000(?: @(9(0N(?- - @(

J =&; <(#*<$&(85- : (?+, U @R(G$(H<; %G$#)G<$(V G)=(STK(45- I (?- (J K6(8(7K@(

( M**(A#)G&$)>(W(+, (; <$)=>(

SX&%*#D(&)(#*(+, , . (

- 8( - , (9J ((8(MJ (

9&; <Y<*</; GD&(

MDZ#$H&D(DG>&#>&R(A"&ZG<F>()=&"#A[ (Q#G*&D(

7K(45- 8(?8- U @(23(45- 8(?8- U @(

\ Z&"#**(997(. (; <$)=>(

- L(; <$)=>(?>=<")(Q<**<V /FA@(

] G$D=<*; ((&)(#*(+, - - (

+8584(&Z#*F#%*&(#HH<"DG$' (()<(KS/J 029(

- , (9J (- 4(MJ (- , ( ^ (

9&; <Y<*</; GD&(

_ &)#>)#>)GHR(: , U (A"<' "&>>&D(<$(A"&ZG<F>()=&"#A[ (

7K(45+8((?- . U @(23(- - 5+8(?4I U @(73(I 5+8(?8: U @(

712(: : (5(+8(A#)G&$)>(

M**(A#)G&$)>W(84`+(; <$)=>((

0; =<Q(&)(#*(+, - - (

I 4( ( O, a/3\ 9M/9\ J (

_ &)#>)#)GH6(A"<' "&>>G<$(G$H*F>G<$(H"G)&"G#(

M$[ ()[ A&(+45I 4(?+I `LU @(

( _ &#$(>F"/ZGZ#*(4, (; <$)=>(?8- /: , (O: U (J 0@(

N#$(S>>&$(&)(#*(+, , . (

O( 4(9J (: (MJ (

- . . ] F/3\ 9M/<H)"&<)#)&6(4(H[H*&>(

9(000(+5O?++`+U @(((9(0N(. 5O(?. . I U @(

7K(: 5O(?: LU @((7K5_ K(L5O(?L. U @((

997(8- (; <$)=>(

(

7"&>&$)(D#)#(

- 8( 4(9J (: (MJ (4( ^ ((

- . . ] F/3\ 9M/<H)"&<)#)&6(D<>G; &)"[ (

9(0N(- 85- 8( : 5- 8(7K(?8I `O@6(#$[ ()[ A&(O5- 8(?LO+U @(

997(44(; <$)=>(712(8. (; <$)=>(

44(; <$)=>(

(

Bronchial carcinoids

Median Time to Progression 44 Months

Median Overall Survival 44 Months

Lung NET& PRRT• Sabet, Haug, Eiden et al JNM May 2014,

supplement 1, 394

• 22 patients Bronchial NETs G1&2: 177Lu-DOTA-

octreotate 4 cycles, intended 3 months interval,

mean activity 7,8 GBq

• PFS 31, median OS 42

This publication should have been

mentioned in this place:• Long-term results of PRRT in advanced bronchopulmonary

carcinoid

• Eur J Nucl Med Mol Imaging (2016) 43:441–452• Mariniello, A. Bodei, L, Tinelli, C, Baio, SM, Gilardi, L, Colandrea,

M, Papi, S, Valmadre, G, Fazio, N, Galetta, D, Paganelli, G, Grana, MC

• Retrospective analysis of 114 patients with advanced stages of BPC treated in Milan from 1997-2012, follow-up until 2014 with three different PRRT protocols

• 90Y-DOTATOC vs 177Lu-DOTATATE vs 90Y-DOTATOC+177Lu-DOTATATE

• Rating of objective responses, overall survival (OS) and andprogression-free survival (PFS)

Long-term results of PRRT in advanced bronchopulmonary carcinoidEur J Nucl Med Mol Imaging (2016) 43:441–452

continued

• Median OS (evaluated in 94 patients) 58.8 months

• Median PFS 28 months

• The 177Lu-DOTATATE protocol resulted in the highest 5-year OS (61.4 %). Morphological responses (partial responses+ minor responses) were obtained in 26.5 % of the cohort and were associated with longer OS and PFS.

• The 90Y- DOTATOC+177Lu-DOTATATE protocol provided the highest response rate (38.1 %).

• Adverse events were mild in the majority of patients. However, haematological toxicity negatively affected survival.

• Patients treated with 90Y- DOTATOC alone more frequently showed a mild/moderate decrease in renal function. In patients treated with chemotherapy before PRRT had a shorter OS and PFS, and a higher risk of developing nephrotoxicity.

Long-term results of PRRT in advancedbronchopulmonary carcinoid

Eur J Nucl Med Mol Imaging (2016) 43:441–452, continued

• Conclusion:

• PRRT proved to be promising in prolonging survival

and delaying disease progression

• Despite the potential selection biases, considering

the risk-benefit ratio, 177Lu-DOTATATE monotherapy

seems the best option for PRRT.

• Our results indicate that the use of PRRT in earlier

stages of the disease could provide a more

favorable outcome.

Leukemia and PRRT: Uppsala experience

• 485 patients with data (++)

• 6 leukemia (bony mets in at least 5)

• 1 ALL: Lung NET, BM mets +, previous temozolomide

• 1 CML: SI-NET(unconfirmed) G2/G3; BM mets +++

• previous temozolomide (4 mo)

• 4 AML:

• 1 Lung: Paraplatin Vepesid before, 3 yearsTemozolomide after PRRT,

• 2 SI-NET ( 1 no chemo; BM mets ++, 1 unknowntreatment),

• 1 EPT (Strepto/ 5FU: intolerance r//t declined kidneyfunction

• Absorbed BM doses: 0.2-0.5 Gy blood dose;

• 0.47-0.64 Gy total accumulated dose

This publication should have been mentioned in this place:

• Eur J Nucl Med Mol Imaging (2015) 42:5–19

• Long-term tolerability of PRRT in 807 patients with

neuroendocrine tumours: the value and limitations

of clinical factors• Bodei, L, Kidd, M, Paganelli, G, Grana, CM, Drozdov, I, Cremonesi, M,

Lepensky, C, Kwekkeboom, DJ, Baum, RP, Krenning, EP, Modlin, IM

• 807 patients studied at IEO Milan (1997-2013)

• 177Lu: 34.4%/ 90Y: 44.4%7 177Lu&90Ycombined (19.5%)/ 2% PRRT

combined with other agents

• Results: Treatment with 90Y and 90Y+177Lu was more likely to result in

nephrotoxicity than treatment with 177Lu alone (33.6 %, 25.5 % and

13.4 % of patients, respectively; p < 0.0001)

Eur J Nucl Med Mol Imaging (2015) 42:5–19continued

• Results: Nephrotoxicity (any grade), transient and persistent, occurred in 279 patients (34.6 %) and was severe (grade 3+4) in 12 (1.5 %).

• …..

• Myelodysplastic syndrome occurred in 2.35 % of patients…... Platelet toxicity grade (…..) and longer PRRT duration (…..) were relevant. Acute leukaemia occurred in 1.1 % of patients (….).

• Myelodysplastic syndrome occurred in 2.35 % of patients … Platelet toxicity grade ….and longer PRRT duration …….were relevant. Acute leukaemia occurred in 1.1 % of patients.

• Conclusion Identified risk factors provide a limited (<30 %) risk estimate even with target tissue dosimetry.

• These data strongly suggest the existence of unidentified individual susceptibilities to radiation-associated disease.

PRRT and chemotherapy• More data need to be collected regarding late

bone marrow toxicity

• Combination of especially alkylating agents or

cisplatinum and radiation (PRRT) reported

problematic

• Brieau et al 2016 (20% 4/20 3 MDS,1 AML) all had

had alkylating agents

• Kesavan et al 2014 (2/65 patients (3%) PRRT with

tem/cap) MDS

Risk factors and open questions

• Presence of BM mets: Can they increase the

stochastic risk? What about small volume disease in

skeleton?

• Early hematotoxicity after treatment: indicator ?

• Bone marrow absorbed doses? Blood doses?

Accumulated activity?

Getting back to PRRT in lung NETs……

• Promising

• A place for 1st line therapy in progressive patients

with advanced disease?

• A randomised study would be nice: against …..???

Open questions!

• The future is yours to ask the

right questions to provide

new concepts and to come

up with new ideas!

The aim of therapy

• Thank you for your attention!

• Hopefully, your stay in

Prague was fruitful!