1. Watchful waiting: Is it a choice? PRO
Marianne E. Pavel
Campus Virchow Klinikum, Charité, Berlin
DEBATES IN NEUROENDOCRINE TUMORS
Somatostatin analogs vs. watchful waiting in GEP NET
June 16, 2015

2. Overview Spontaneous tumor growth & life expectancy in NET
What is the impact of SSA ?
Impact of early vs. late treatment onset on overall survival
Impact on economic resources
NCCN/ UKI/ENETS guidelines recommendations
Tumor control- OR, PFS, OS
Unknown – start early or wait for progression in subtypes with proven efficacy; efficacy in smaller subsets of NET (rectal, gastric, lung )
Value of combination therapy and maintenance therapy (continue upon progression? Dose escalation- high dose therapy ? Maintenance _ SONNET; REMINET)
Future perspectives… novel analogs, novel formulations

3. Limitations to predict tumor progression by clinico-pathological parameters
Limitations of known prognostic factors in Stage IV disease
but G1 G2
Differentiation & Grading
Stage I
P<0.001
Proportion Alive
Stage II
Stage III
Stage IV
I (n = 44)
II (n = 44)
III (n = 34)
IV (n = 33)
Months
0.00
0.25
0.50
0.75
1.00 48 96
144
192
240
Diffuse liver metastases
Different growth pattern
Will there be tumor growth, and in which time frame?
Need for additional
prognostic biochemical markers!
Staging

4. Survival in Midgut/Hindgut NET German-French Cohort
Median OS 161
months
242 Midgut
20 Hindgut
173 stage IV
acquired data confirm the prognostic relevance of the proposed TNM-staging and
grading system and demonstrate the applicability of these classification tools. The TNMsystem
can therefore facilitate therapeutic stratification and comparison of data from different
(66%)
62%
32% 6%
n= 189
Jann et al, Cancer 2011

5. Prognosis of GEP-NET in comparison to other malignancies
Frilling et al, Lancet Oncol 2014

6. What is the impact of Somatostatin analogs?

7. Somatostatin analogs in gastro-entero-pancreatic NET
Low objective response rates !
No cure !
Review: Toumpanakis & Caplin Semin Oncol 2013

8. 84 patients with midgut NET 204 patients with entero-pancreatic NET
What is the added value of SSA ? Results from Placebo-controlled Trials
84 patients with midgut NET
PFS: months
204 patients with entero-pancreatic NET
PFS: + >9 months

9. What do we learn from the placebo arms of randomized trials?
62%
22%
50 % are stable without treatment for 18 mo.
22% are stable even for more than 27 mo.
PROMID Study:
37 % are stable without treatment for 12 mo.
Some are stable for more than 32 mo.

10. Lanreotide is active in G2 NET (-10% Ki67) and in patients with higher liver tumor burden
OLE study demonstrates that lanreotide is also active in progressive NET
Caplin et al NEJM 2014

11. Somatostatin Analogs Impact on overall survival ?
PROMID study
No survival benefit if treatment starts upon diagnosis or in stable diasease
p=0.77
CLARINET study
P=0.8791
Caplin et al NEJM 2014

12. Can the (Greek/ Global) Health System afford early medical treatment?
Impact of costs
Can the (Greek/ Global) Health System afford early medical treatment?
Physician treating a patient (Attic red-figure aryballos, 480–470 BC)

13. NET G1/G2- spontaneous tumor growth
54 year old female patient with midgut NET , GI Bleeding
Primary tumor removed; Ki-67 5%, NET G2
LM non-resectable, Ki-67 2%, low hepatic tumor load, non-functional
Pro_ PROMID
Against _ Spontaneous growth arrest in subgroup of patients may justify F/U q 3 months
MRI liver: multiple small lesions
MRI liver: 3 years later : SD
….we saved EUR to the German and EUR to the Greek Health System

14. Case of midgut NET with liver metastases
40 yr old patient, initial diagnosis of ileum NET in 1995
Primary tumor removal
Mild preoperative diarrhea
Synchroneous Liver metastases ->TAE
Started on sc. octreotide
Stable disease for 5 years
Non RECIST progression 2000
Developed 2 abdominal metastases 2010
Started Octreotide LAR 10 mg in 2000
Dose escalation 20 mg
Continues on Octreotide 30 mg since 2010
20 yrs of SSA treatment
accounts for > EUR

15. or Progressive disease
Whom to treat if you need to make a choice in a system with limited health care resources ?
Stable disease
or Progressive disease

17. Pan-NET-7

18. What do the UKI NETS Guidelines recommend?

20. Conclusions Pro: Watch & Wait
SSA do not cure
Objective response rates are low (<5%)
Stabilization of disease is best response in most patients
Prolongation of PFS in early treatment onset does not translate in survival benefit compared to patients with treatment start upon progression
Early use of SSA may produce tremendeous costs in patients who have SD for decades
Although tolerability is good, there may be side effects…
Molecular profiling is needed to preselect patients who might be „real“ candidates for early treatment

21. Thank you !