Advanced Thoracic NET Clinical Cases: PRRT in Lung NEN. Ulrike Garske-Román MD, PhD ESMO Preceptorship Prague 2017

Transcription

1 Advanced Thoracic NET Clinical Cases: PRRT in Lung NEN Ulrike Garske-Román MD, PhD ESMO Preceptorship Prague 2017

2 Bronchial carcinoids Cycle 1 March 2009 Cycle 7 Oct 2010 Ulrike Garske-Román

3 Cycle TTP 71 Months Survival 80+ Months

4 8e december 2012

5 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

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ronchial?23@( carcinoids ( 9(000(?+@(( 9(0N(?+O@( - O(DGQQ&"&$)( 9(0T(?+@( "&' G; &$>R( "&>A<$>&>(8( 9(0N(?- HG>A*#)G$F; / %#>&DR(- ( A#H*G)#E&*(B( STK( 9&; <Y<*</ ; GD&( 9&; <Y<*</ ; GD&( I 4( ( O, a/3\ 9M/ 9\ J ( O( 4(9J ( : (MJ ( - 8( 4(9J ( : (MJ ( 4(^ ^ (( -.. ] F/3\ 9M/ <H)"&<)#)&6(4( H[ H*&>( -.. ] F/3\ 9M/ <H)"&<)#)&6( D<>G; &)"[ ( ( 73(. 5. ( ( ( ( 23(+5+( 997(I / -, ( ( 7K(+5I 6(23( - 5I 6(73(: 5I ( MDZ#$H&D( DG>&#>&R( A"&ZG<F>( )=&"#A[ (Q#G*&D( _ &)#>)#>)GHR( :, U ( A"<' "&>>&D(<$( A"&ZG<F>( )=&"#A[ ( _ &)#>)#)GH6( A"<' "&>>G<$( G$H*F>G<$( H"G)&"G#( 9(000( (9(0N(. 5O(?.. `I 9(0N(- 85-8( 997(L/I (?7K@( ( ( +: ( J =&; <(#*<$&( ( M**( 85- : (?+, A#)G&$)>(W( G$( +, ( H<; %G$#)G<$( V G)=(STK( 45- I (?- (J K6(8( 7K@( 7K(45-8(?8- 23(45-8(?8- 7K(45+8((?-. 23( (?4I 73(I 5+8(?8: M$[ ()[ A&( +45I 4(?+I 7K(: 5O(?: 7K5_ K(L5O(?L. : 5-8(7K(?8I `O@6(#$[ ( )[ \ Z&"#**( 997(. ( 712(: `: ( 5(+8( A#)G&$)>( ( ( ( - L(?>=<")( Q<**<V / FA@( M**( A#)G&$)>W( 84`+( ( ( _ &#$(>F"/ ZGZ#*(4, (?8- /:, ( O: U (J 0@( 997(8- ( 997(44( 712(8. ( ( 44( Bronchial carcinoids Median Time to Progression 44 Months Median Overall Survival 44 Months

7 Lung NET& PRRT Sabet, Haug, Eiden et al JNM May 2014, supplement 1, patients Bronchial NETs G1&2: 177 Lu-DOTAoctreotate 4 cycles, intended 3 months interval, mean activity 7,8 GBq PFS 31, median OS 42

8 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: 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 , follow-up until 2014 with three different PRRT protocols 90 Y-DOTATOC vs 177 Lu-DOTATATE vs 90 Y-DOTATOC+ 177 Lu- DOTATATE Rating of objective responses, overall survival (OS) and and progression-free survival (PFS)

9 Long-term results of PRRT in advanced bronchopulmonary carcinoid Eur J Nucl Med Mol Imaging (2016) 43: continued Median OS (evaluated in 94 patients) 58.8 months Median PFS 28 months The 177 Lu-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 90 Y- DOTATOC+ 177 Lu-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 90 Y- 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.

10 Long-term results of PRRT in advanced bronchopulmonary carcinoid Eur J Nucl Med Mol Imaging (2016) 43: , continued Conclusion: PRRT proved to be promising in prolonging survival and delaying disease progression Despite the potential selection biases, considering the risk-benefit ratio, 177 Lu-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.

11 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 years Temozolomide after PRRT, 2 SI-NET ( 1 no chemo; BM mets ++, 1 unknown treatment), 1 EPT (Strepto/ 5FU: intolerance r//t declined kidney function Absorbed BM doses: Gy blood dose; Gy total accumulated dose

12 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 ( ) 177Lu: 34.4%/ 90Y: 44.4%7 177Lu&90Ycombined (19.5%)/ 2% PRRT combined with other agents Results: Treatment with 90 Y and 90 Y+ 177 Lu was more likely to result in nephrotoxicity than treatment with 177 Lu alone (33.6 %, 25.5 % and 13.4 % of patients, respectively; p < )

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

14 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

15 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?

16 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..???

17 Open questions! The future is yours to ask the right questions to provide new concepts and to come up with new ideas!

18 The aim of therapy

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20 Thank you for your attention! Hopefully, your stay in Prague was fruitful!