LONG TERM REMISSION: Challenges and controversies
How and until when to treat?
Christoph Thomssen Department of Gynaecology Martin-Luther-University Halle-Wittenberg Halle an der Saale / Germany
Thursday, 2 November 2017 Audit I. 14:30-14:45
ABC4AB
Conferences
treat
hristophDepartmMa
Potential Conflicts of Interest
• Amgen • Astra-Zeneca • Celgene • Genomic-Health • Lilly
• Nanostring • Novartis • Pfizer • Puma • Roche
Honoraria as compensation for lectures and advisory boards:
ABC4 Conference
A
ce
mic Heailly
• N
lecture
General law:
ferenc
• Long Term Remission: Definition, Frequency
ABC4 Conference
A
ce
ition, F
Long Term Remission after complete remission (CR) to chemotherapy
Greenberg PAC et al. J Clin Oncol 1996;14:2197-2205
N=263
5 years
CR 16.6% beyond 5 years
ABC4 Conference
A
cepy
er
=26
Conferenceerears
Long Term Remission – Definition (HER2 positive mBC, 1st-line trastzuzumab)
Definition (acc. median): • Beyond 3 to 5 years
(4 yrs lower 5%-limit PFS) Predictors: • Younger age (<50 y at
treatment start) • High Performance (ECOG 0) • Initially complete response • No treatment interruption
(trastuzumab)
Unselected (Yeo 2015): • 12% beyond 5 yrs
Witzel I et al. BMC Cancer 2014, 14:806 Yeo B et al. The Breast 24 (2015) 751-757
268 patients with HER2-positive inoperable LABC or mBC without progression after at least 2 yrs
ABC4 Conference
A
ceb)
COG 0sponse
nterruptionmab)
ected (Yeo 2
ABC2% beyon
onferencfe
I e
Long Term Remission - Definition
• Threshold: 5 yrs is reasonable • Relevance depends on
–Biology / subtypes (chemotherapy rarely >9m) –Selection –Performance status –Patients preferences
• Incidence:
Unselected <15% no progression >5 yrs
ABC4 C
A4 Conferencece
n
e
emotherap
ateferences
denceUnse
ER positive mBC
• Long term endocrine therapy • Maintenance endocrine therapy after
chemotherapy
ABC4 A
4 Conferencece
m endocrinance
hemothera
ER-positive disease (Luminal-like, HER2neg)
Endocrine therapy until progression
• High efficacy, low toxicity • Positive therapeutic index can be expected
for a long time interval • Clinical standard:
–Continous treatment as long as efficacy is given (LoE IV B)
–ET may maintain remission induced by CT
ABC4 Conference
A
ceressio
cityindex c
intervalndard:
ous reatIV
T may ma
References: Maintenance endocrine therapy after chemotherapy induced response 1. Sutherland S et al. Eur J Cancer. 2016 Dec;69:216-222. 2. Rossi S et al. Future Oncol. 2016 May;12(10):1299-307 (systematic review)
ReferencA1 Sut2
C4
Maintenance ET after response to capecitabine: A retrospective analysis
Median exposure to 1st-line Capecitabine: 6-8 courses à 3 weeks; Median F/U: 43 mths Chen XL et al. Chin J Cancer (2016) 35:39
N=138
N=59
N=79
ABC4 Conference
A
ceysis
BC4 Coferenc
onf
xposure o 1 linees à 3 weeks
an F/U: 43 mth
XL
Conclusions: Endocrine therapy in LONG TERM REMISSION
• Biological rationale for long term ET –ET downregulates tumor cell proliferation, but
does not destroy tumor cells • ET as long as possible (until PD) (LoE IIIB)
–With long term remission, any switch to chemotherapy can be postponed
–Interruption („drug holidays“): •Short term feasible (derived from adjuvant data) •Long term (e.g. for pregnancy): individual decision
• Maintenance after chemotherapy (LoE IIB) –Retrospective data support the concept (& 1 RCT)
ABC4 Conference
A
ceEToliferatio
l(until P
sion, anyan be postru h
feasible (dterm e.g.
ntenance–Retrospe
• HER2-positive mBC
• Two cases
ABC4 Conference
A
ce
o cases
Case 1: NB, 59 yrs
• 1999 BC, pT1c pN0 M0 G3 ER/PR-neg. HER2-pos. • 2001 proven metastases: sternal, parasternal,
lung; sternal/parasternal histologically proven; CT: disseminated lung metastases
• Paclitaxel / trastuzumab q1w 12 weeks, since then trastuzumab (q3w, now s.c.) and zoledronate (now q3m), meanwhile 190 months (>15 yrs !)
• Since 2002 clinically in complete remission (several CT scans); no toxicity (ECHO)
• Open question: Stop trastuzumab?
• Answer: The patient wants to continue
ABC4 Conference
A
ceHER2-al, parast
tologically pstases
q1w 12 , ow s.c )
nwhile 19clinically in
); n toxquestion S
Answer T
Discontinuation of trastuzumab feasible?
Retrospective analysis, n=108, >2 y trastuzumab for mBC, 61% non-visceral; CR 52.8%, median PFS 11.2 yrs
Niikura N et al. Breast Cancer Res Treat. 2017 Sep 11. doi: 10.1007/s10549-017-4489-9. [Epub ahead of print]
Interruption of Trastuzumab before PD (n=27)
Long term remission: 3 rec./17
ABC4 Conference
A
ceib
C4 Coonferenc
Retrospectiv61%
N00
m remission
LONG TERM REMISSION To stop or not to stop trastuzumab
PRO discontinuation • Substantially cardiotoxicity
(2% - 7%) • Long term remission after
discontinuation reported • Retrospective cohort
analyses favouring discontinuation – Niikura et al. 2017 (n=27) – Moilanen et al. 2017 (n=21)
CONTRA discontinuation • No prospective data / RCTs • Risk of selection bias in the
retrospective reports • Reports of early recurrence
after discontinuation • No predictors for relapse
after discontinuation • Reinduction – risk of
resistance • No reimbursement for re-
introduction (in some countries) ABC4 Conference
A
ceab
017 (n=27)al. 2017
ontinuaective a
f selectiretrospect
• ReportsafterN
Conclusion and Ontario Survey
Haq R et al. Curr Oncol. 2016 Apr;23(2):91-95
Conclusion: • To date, evidence does not support discontinuation
of trastuzumab in LONG TERM REMISSION (LoE IVC) • RCT based on world wide collaboration are needed Ontario Survey:
ABC4 Conference
A
ce
e
discontinMISSIO
laboratio
BC4 Confe
C4
Case 2: KJ, 37 yrs
• Invasive ductal BC (left upper inner quadrant) 2013/14 – cT2(3cm) pN1(1/1sn) G2 ER+(9/12) PR+(4/12) HER2+++ Ki-67 25 % – Isolated sternal metastasis M1 (OSS)
• Primary treatment: – ddEC q2wks*4 => docetaxel, Pertuzumab, Trastuzumab
q3wks*4 followed by– BCS with resection of the metastatic region of the sternum; – Radiotherapy incl. LAR/IMN and sternum
• Histopathology: – pCR breast, axilla and sternum (no tumour cells)
• Further therapy: – Pertuzumab / Trastuzumab + ET ABC4 Conference
A
cedrant) 2) HER2++
S)
Pertuzuma
the metastaAR/IMN an
:st, axilla an
r therapyuzumab /
Case 2 (de novo M1, HER2 pos.): Is the patient cured? Should she be considered as metastatic patient? How
long pertuzumab, how long trastuzumab?
Strong additional effect by pertuzumab
Weak additional effect by pertuzumab
Swain SM et al., Cleopatra Study Group. N. Engl J Med 2015; 372:724-34
ABAM
cecet? H?
ABC4 Conference
LONG TERM REMISSION with dual HER2-blockade: Conclusion
• In case of discussing discontinuation of
antiHER2-therapy, first consider pertuzumab to be discontinued for – Toxicity (diarrhea) – Possible reduced benefit after >3 yrs
(LoE: Expert opinion)
ABC4 Conference
A
cen
inuatioconsider
ontinue
ed benefi
xper opi
• Chemotherapy
ABC4 Conference
A
cece
LONG TERM REMISSION Chemotherapy: How and until when?
• Long term treatment often not feasible for acute toxicities – Combination regimen, docetaxel q3w – 6 to 9 courses recommended (as in the studies)
• Rather long tolerated regimen – Weekly regimen (paclitaxel, epirubicin, doxorubicin) up to
one year – Stop for cumulative cardiac toxicity or CIPN
• Well tolerated therapies –Daily regimen (e.g. capecitabine,
dose adjustment feasible) –Metronomic treatment (low dose cyclophos/mtx)
As long as therapeutic index is positive
ABC4 Conferenceceen?
te toxiciti
udies)
menepirubicin
cardia toxi
therapieen (e.g.
djustmenetronomic
Maintenance Chemotherapy yes or no
Sánchez-Muñoz A et al. Expert Rev. Anticancer Ther. 8(12), 1907–12 (2008)
ABC4 Conference
A
cer n
fefenfenfenfnf
z-
Maintenance Chemotherapy yes or no
Comments: • Combination chemotherapy is not state-of-the-art • Long term toxicity must be balanced against
reduction of cancer symptoms
• Alternatives of low dose incl. metronomic chemotherapy have not been sufficiently studied – Capecitabine – Cyclophosphamide/methotrexate – Paclitaxel weekly – PEG-liposomal doxorubicin (?) ABC4 Con
A
Conferencecer n
state obalanced agms
dose inclv ot be
osphamideel eek
G iposoma
Summary - Long term remission? How and until when to treat?
• Endocrine therapy: – Until progression. – Maintenance therapy (e.g. ET after CT)
• Reasonable, some encouraging retrospective data
• Anti HER2-therapy: – Trastuzumab: Permanently. – Pertuzumab in addition to trastuzumab: As long as possible,
at least 3 years, limited by diarrhea • Chemotherapy:
– Combination therapy, toxic single agent: 6 to 9 courses – Anthracyclines: until cumulative toxicity is reached
(individual variations, regimen depending) – Less toxic agents (e.g. capecitabine, PLD): until progression
ABC4 Conference
A
ceT)
ospective da
tly. tion o astu
mi by dy:
ation herahracyclines
ndividual var– Less toxic
General recommendation
• Treatment as long as therapeutic index is positive
(LoE: Expert opinion)
A
ces thera
: Expert
Halle an der Saale, Germany
Halle an der Saale, Market Place The bronze age celestial chart of Nebra as an early guideline example (app. 2000 yrs. BC)
Source::left: www.Wikipedia.de; right: Landesamt für Denkmalpflege und Archäologie Sachsen-Anhalt, Landesmuseum für Vorgeschichte ABC4 Conference
A
ce
an der Saale, Mar
Long term remissions: Challenges and controversies Management issues: How and until when to treat?
A
onferenceceons: Challe
snt issues: How
reat?