Onkologioppdatering med
hovedfokus på
klinisk onkologi/diagnostikk og
kortere om behandling"
.
Halfdan Sorbye
Medical Oncologist
Professor, Dept of Oncology
Haukeland Univ Hospital
Bergen, Norway
1
Cancer by the numbers
• The WHO projects: new cancer diagnoses will
reach 22 million per year in the next two
decades, up from 14 million in 2012.
• Cancer-related deaths may increase by as
much as 70%.
• Seven of 10 deaths resulting from cancer
occur in Africa, Asia, and Central and South
America, regions of the world with limited
access to cancer screening and treatment
2
The good news
• For most people, a diagnosis of cancer is not
as grim as it used to be.
• Today, 68% of adults and 81% of children with
cancer will be alive at least 5 years after a
diagnosis.
• This is a big improvement from the 1970s,
when only 50% of adults and 62% of children
were surviving 5 years
3
Antall krefttilfeller øker
• Kreftregisteret har anslått at antall
krefttilfeller i Norge vil å øke med 42 % for
menn og 27 % for kvinner fram mot 2030.
Denne økningen er forventet og skyldes at
befolkningen vokser og at andelen eldre
øker.
4
5
• Antall tilfeller av prostatakreft og tykktarmskreft
er beregnet å øke med godt over 40 % blant menn.
Antallet tilfeller av lungekreft hos menn vil
sannsynligvis være rundt 20 % høyere enn i dag.
• For kvinner vil det sannsynligvis være i overkant
av 25 % flere tilfeller av lungekreft og
tykktarmskreft, mens det er beregnet en økning på
20 % i antall tilfeller av brystkreft.
• Flere kvinner enn menn med lungekreft.
6
7
Nytt innen diagnostikk
• Screening
• Molekulær-genetisk testing av tumorvev før
valg av behandling.
• Nyere PET-tracere
8
Screening
• Prostata cancer
– Ser ut til å redusere metastaser
– Ikke nasjonalt, gjøres av fastleger regelmessig
– MR oppfølgning lavgradige forstader?
• Colorectal cancer
– Ferre død av colorectalcancer etter screening, men
ingen økt overlevelse.
– Vedtatt skal starte
– Fra 55 år
– Coloskopi eller fekal test?
9
Precision Medicine
• Pinpoint key molecular changes in the
tumor or free-floating cancer DNA in the
blood that allow cancers to grow and
spread.
• Changes can be matched to either existing
targeted treatments or experimental
treatments that are being tested in clinical
trials.
10
Molecular testing
• I biopsi eller operert tumorvev
Recommended upfront before start of chemotherapy;
prognosis, treatment strategy and selection of 1-line treatment.
–
–
–
–
BRAF
RAS
MEK
MSI, microsattelitt instabilitet
11
Role of BRAF
•
RAF proteins participate in signal transduction through the
MAPK pathway, which stimulates cell growth and survival
•
MAPK signaling is activated following the binding of
growth factors and cytokines to cell surface receptors
such as EGFR
•
BRAF lies downstream of EGFR and RAS proteins in this
pathway
•
Mutations in BRAF (most commonly V600E) lead to
constitutive activation of the kinase and thus sustained
MAPK signaling, which can contribute to oncogenesis
Ligand
EGFRinh
EGFR
RAS
BRAF
MEK1/2
ERK1/2
Proliferation, survival
MAPK, mitogen-activated protein kinase;
12 non-small cell lung cancer
NSCLC,
• The VE600E is caused by a CTG to CAG point
mutation; constitutive activation of
RAS/RAF/MER/ERK pathway effecting
– cell growth
– proliferation
– differentiation
– cell migration
– apoptosis
– survival (HIPPO pathway)
13
Medikamentell behandling ved metastatisk colorektalcancer (Hdir sept 2016)
Studie:
BRAF +
MEK
hemmer
1. linje
2. linje
mut BRAF
FOLFOXIRI±bev
Intensified treatment
WT-RAS
FOLFIRI
(FLIRI)
+ EGFR-hemmer
FLIRI
FOLFIRI
FOLFOX (FLOX/CAPOX)
± bevacizumab
FOLFIRI
(FLIRI) +
bevacizumab
FLOX/CAPOX
FOLFOX
Studie
Sequencial treatment
(elderly/fragile)
FLOX/CAPOX
FOLFOX
Flv/Capecitabine/
S-1 (Nordic9)
±bevacizumab
FLIRI
FLOX/CAPOX
Irinotecan
FLIRI/
FOLFIRI
Cetuximab/panitumumab ± irinotecan
3. linje
MSI-H
Palliativ intensjon
WT-RAS
Regorafenib
3/4 .linje
TAS-102
14
Molecular alterations deciding
treatment
• Malignt melanom ofte BRAF muterte.
BRAF pos: BRAF-hemmer
BRAF neg: immunterapi
• Approximately 3% to 7% of Non-small cell
lung cancer are carry a genetic change
known as anaplastic lymphoma kinase ALK
(ALK): treatment to specifically target
ALK-positive tumors.
15
Cell free tumor DNA (in blood)
FDG-PET
• Glucose tracer
• Utelukke avansert sykdom…….
• Ikke cancer spesifikk
• Kan ikke skille fra inflammasjon
17
Nano medisin
18
19
20
Pfeifer, J Nucl Med 2013
21
22
Key peculiarities of pancreatic cancer
and resulting consequences
•
•
•
Early molecular complexity
Intense desmoplatic reaction
Hypovascular, hypoxic, but non-necrotic
tumour
Biological and clinical aggressiveness
•
•
•
•
•
•
•
No early detection
Low resectability
Early relapse
Early metastases
Short overall survival
Severe symptoms and poor QOL
Treatment resistance
Pancreatic ductal adenocarcinoma characterized by low tumor cellularity and prominent
loose intratumoral stroma (S). Coexisting scattered islet cell nests (I) are noted.
A renewed model of pancreatic cancer evolution based on genomic
rearrangement patterns. Notta F, et al Nature. 2016 538(7625):378382
Canadian researchers have found that the genetic alterations believed
to cause the disease may all occur at once.
Rather than follow a gradual and accepted mutation order, the events
are more simultaneous rather than sequential, and they may also
include an outpouring of rapid and complicated rearrangements to the
tumor genome.
Has to be diagnosed at a pre-neoplastic phase.
Early is too late
25
MDT møter sentral plass
• Multidisiplinære møter ukentlig
• Alle nye cancer pasienter diskuteresbehandlingsplan
• Onkolog, kirurg, radiolog, patolog
• Video konferanse: Voss, Førde, Stavanger,
Haugesund.
• Frankrike: ingen refusjon uten…
26
Strategy for treating mCRC
MDT very important
mCRC
Resectable
“Solitary“
LM
Resectable
after response
LiM or LuM
Never resectable
Palliative CT
Adjuvant ?
Neoadjuvant ?
Preop CT
Symptoms No symptoms
Triple or double+TT
Double±TT
Single
Resection ?
27
Slide 51
28
Presented By Suzanne Topalian at 2015 ASCO Annual Meeting
Immunotherapy
• Immune checkpoints are specialized proteins
that act as brakes on the immune system,
ensuring that immune defenses are engaged
only when they are needed and for as long
as they are needed.
• They prevent the immune system from
becoming overactive, which can lead to
excessive inflammation or autoimmune
disease.
29
Immunterapi:
De mest suksessrike så langt
•
•
•
•
•
Melanom
Lunge kreft
Nyrekreft
Blærekreft
Noen
lymfekreftformer
• MSI tumores
•
•
•
•
Kjente karcinogener
Mange mutasjoner
Mange epitoper
Kaotiske svulster
30
Slide 31
Presented By Suzanne Topalian at 2015 ASCO Annual Meeting
31
Slide 3
32
Slide 4
33
34
Biologic Rationale for Combined PD-1 and CTLA-4 Blockade
35
Slide 38
Presented By Suzanne Topalian at 2015 ASCO Annual Meeting
36
Slide 44
Presented By Suzanne Topalian at 2015 ASCO Annual Meeting
37
<br />
Presented By Suzanne Topalian at 2015 ASCO Annual Meeting
38
39
40
Survival End Points.
Robert C et al. N Engl J Med 2015;372:320-330.
Proportion alive
4-year follow up in the 024: Efficacy
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Ipilimumab + DTIC
Placebo + DTIC
HR (95% CI): 0.72 (0.59–0.87)
Median OS: 11.2 vs 9.1 months
P value: 0.0009
0
1
2
Years
3
4
Estimated survival rate, % (95% CI)
1 year
2 year
3 year
4 year
Ipilimumab + DTIC n=250
47.3
28.5
21.2
19.0
Placebo + DTIC n=252
36.3
17.9
12.1
9.6
Maio et al. ESMO 2012
Robert C, et al. N Engl J Med 2011;364:2517–2526
Maio M, et al. Presented at ESMO 2012 (1127P)
42
Slide 10
Presented By Jedd Wolchok at 2015 ASCO Annual Meeting
44
A thought experiment:<br />
Presented By Leonard Saltz at 2015 ASCO Annual Meeting
45
Protonbehandling



Ser svært lovende ut, etablering i Norge
Stråling konsentrert i tumor, stråledosen økes med
mindre risiko for bivirkninger.
72 Gy HCC: lokal kontroll rate 87% etter 5 år
Selective intra-arteriell
radiotherapy = SIRT.
Gis i leverarterie, radioaktiv 90Yttrium ,
mikropartikler av glass
HUS/RH 2016
HCC
NET (SRI negative)
mCRC
Fase III data kommer
.
Radioaktiv isotopbehandling
Peptide reseptor radionukleotide terapi
(PRRT).
 Kobler på en radioaktiv 177-Lutetium på
octreotide (nanomedisin).
 Behandles i Uppsala eller København

Peptid Reseptor Radionukleotide Therapy = PRRT
SA + Chelator + Radioisotope =
90Y-DOTATOC
177Lu-DOTATOC
SSR
NET cell
49
Progression-Free Survival
Presented By Jonathan Strosberg at 2016 ASCO Annual Meeting
Prostate specific membrane antigen
(PSMA)
• PSMA prostata
51
Molecular directed treatment
• Breast cancer: hormon therapy
• Palbociclib blocking two molecules
involved in breast cancer resistance to
hormone therapy: cyclin-dependent kinase 4
(CDK4) and CDK6.
• CDK4/6 inhibitors are a new class of
targeted treatments that may have a role in
many different types of cancer in the future.
52
Future challenges
1956
2006
2050
53
Christensen K et al. Lancet 2009
54
The
Silver
Tsunami
55
Benefit
Harm
Improved
survival
Toxicity
Reduced
symptoms
Inconvenience
Limited available data. Elderly in trial not representative
Papamichael D, et al. Ann Oncol 2015;26:463–76.
NB-NPS-954-0316-126537
When is the balance tipped between treatment
benefit and harm in older cancer patients?
57
Impact of age on inferior cancer
survival
• Factors beyond older patients having
competing morbidity and mortality.
– Less use of chemotherapy and surgery of
metastases.
– Elderly patients often given monotherapy, less
often combination chemotherapy.
– 50% of elderly patients diagnosed with cancer
received dose-intensity less than 85% of
standard.
58
Possible explanations
Polypharmacy
Co-morbidity
Patients wish
Older oncologic patients
Social
support
Age-related changes in
Doctors attitude
pharmacokinetics
59
Daily Vitamin B Reduces
Skin Cancer Risk
• Non-melanoma skin cancer is the most
common type of cancer in fair-skinned
populations worldwide, rarely fatal.
• In a clinical trial of people with a history of
non-melanoma skin cancers, the rate of new
skin cancer diagnoses was 23% lower among
people who took the vitamin twice a day for a
year.
60
Onkologi
• Flere pasienter med kreft
• Mere behandling å tilby
• Pasienter med uhelbrederlig kreft lever mye
lengre
• Immunterapi en revolusjon
61