!
Radioterapia e nuove molecole
biologiche: implicazioni cliniche
Carlo Greco
Radioterapia Oncologica
Università Campus Bio-Medico di Roma
Università Campus Bio-Medico di Roma - Via Álvaro del Portillo, 21 - 00128 Roma – Italia!
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DICHIARAZIONE
Come da nuova regolamentazione della Commissione Nazionale per la Formazione Continua del Ministero della Salute, è richiesta la
trasparenza delle fonti di finanziamento e dei rapporti con soggetti portatori di interessi commerciali in campo sanitario.
•  Posizione di dipendente in aziende con interessi commerciali in campo sanitario
•  Consulenza ad aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE)
•  Fondi per la ricerca da aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE)
•  Partecipazione ad Advisory Board (NIENTE DA DICHIARARE)
•  Titolarietà di brevetti in compartecipazione ad aziende con interessi commerciali in campo sanitario (NIENTE DA
DICHIARARE)
•  Partecipazioni azionarie in aziende con interessi commerciali in campo sanitario (NIENTE DA DICHIARARE)
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Increase tumor control
New technologies
Integrated
Therapies
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Dose escalation
Among current phase III trials for cancer,
only 46 (0.9%) examine a combination of
radiotherapy and molecular targeted therapy
Morris ZS, Harari PM, JCO 2014;32(28):2886-93
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Radiotherapy and new biological molecules:
clinical implications
Radiotherapy and targeted therapies
! 
Locally advanced disease
! 
Metastastic disease
Radiotherapy and Immunotherapy
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Recent advances in molecularly targeted therapies coupled with
technologic strides in radiotherapy have the potential to
improve outcomes for patients?
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Radiotherapy and new biological molecules:
clinical implications
Radiotherapy and targeted therapies
! 
Locally advanced disease
! 
Metastastic disease
Radiotherapy and Immunotherapy
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Inhibitors of EGFR signaling
"  Preclinical Rationale
"  Clinical Experience
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EGFR as a target for cancer treatment
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Tumors that overexpress EGFR are less responsive to Radiotherapy
colon
lung
Head and Neck
Esophageal
Glioma
NSCLC
Pancreatic
Colo-Rectal
80-100%
30–70%
60%
40-80%
30-89 %
25-77%
Head
and
Neck
vek K. Mehta Frontiers in Oncology 2012
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Radiotherapy and EGFR Inhibitors
Preclinical Evaluation of Mechanisms
!  Inhibition of DNA repair (#apoptosis)
!  Inhibition of cell cycle progression
!  Inhibition of clonogen repopulation
! Angiogenesis
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Radiosensitivity
Baumann M, Radiotherapy and Oncology, 2007; 14: 238-248
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Inhibitors of EGFR signaling
"  Preclinical Rationale
" 
Clinical Experience
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5y OS 45,6%!
5 y OS 36,4!
Bonner JA New Engl J Med 2006;354(6):567–78.2006/02/10.!
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The initial report of RTOG 0436: A phase III trial evaluating the addition of
cetuximab to paclitaxel, cisplatin, and radiation for patients with esophageal
cancer treated without surgery.
344 pts 2008-2013
cCR!
1 y OS!
2y OS!
56%!
64%!
44%!
No Cetuximab! 59%!
65%!
42%!
Cetuximab!
p=0,72!
p=0,7!
The addition of cetuximab to concurrent chemoradiation did not improves
OS and cCR
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RTOG 0617 !
A Randomized Phase III Comparison of Standard-Dose (60
Gy) versus High-Dose (74 Gy) Conformal Radiotherapy with
Concurrent and Consolidation Carboplatin/Paclitaxel +/Cetuximab in Patients with Stage IIIA/IIIB Non-Small Cell
Lung Cancer
Intergroup Partecipation:
RTOG, NCCTG, CALGB
Bradley JD, Lancet Oncol 2015; 16: 187-199
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RTOG 0617
RT Technique
1. 3D-CRT
2. IMRT
S
T
R
A
T
I
F
Y
Zubrod
1. 0
2. 1
PET Staging
1. No
2. Yes
Histology
1. Squamous
2. Non
Squamous
R
A
N
D
O
M
I
Z
E
Concurrent Treatment
Consolidation Treatment
Arm A
Concurrent chemotherapy*
RT to 60 Gy, 5 x per wk for 6
wks
Arm A
Consolidation chemotherapy*
Arm B
Concurrent chemotherapy*
RT to 74 Gy, 5 x per wk for 7.5
wks
Arm B
Consolidation chemotherapy*
Arm C
Concurrent chemotherapy* and
Cetuximab
RT to 60 Gy, 5 x per wk for 6
wks
Arm C
Consolidation chemotherapy*
and Cetuximab
Arm D
Concurrent chemotherapy* and
Cetuximab
RT to 74 Gy, 5 x per wk for 7.5
wks
Arm D
Consolidation chemotherapy*
and Cetuximab
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100
100
75
75
PFS Rate (%)
Survival Rate (%)
Cetuximab vs No Cetuximab
50
25
Cetuximab
No Cetuximab
Dead Total
128 237
123 228
HR=0.99 (0.78, 1.27)
0
0
Patients at Risk
Cetuximab
237
No Cetuximab 228
3
225
217
25
Cetuximab
No Cetuximab
p=0.4838
6
9
12
15
Months since Randomization
203
195
187
174
169
154
50
18
HR=0.96 (0.77, 1.19)
0
0
Patients at Risk
149
122
Cetuximab
237
144
120
No Cetuximab 228
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Fail
Total
176 237
164 228
3
222
212
p=0.3471
6
9
12
15
Months since Randomization
184
174
139
130
96
100
76
83
18
60
66
Summary of Adverse Events Definitely, Probably, or Possibly Related
to Treatment (CTCAE V3.0)
Concurrent Cetuximab
Cetuximab (n=237)
Grade
Worst nonhematologic
3
4
5
3
4
5
130
(54.9%)
26
(11.0%)
167 ( 70.5%)
11
(4.6%)
91
(40.1%)
18
(7.9%)
115 ( 50.7%)
6
(2.6%)
117
(49.4%)
74
(31.2%)
202 ( 85.2%)
11
(4.6%)
93
(41.0%)
57
(25.1%)
157 ( 69.2%)
7
(3.1%)
Combined*
Worst
overall
Combined*
No Cetuximab (n=227)
Grade
*p<0.0001
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TKIi and RT-CT
Salama and Vokes, JCO 2013; 31:1029-1038
N° pts
Concurrent
Tox G3-4
Median SVV
Notes
MD Anderson
(Komaki 2012)
48
Carbo-Taxol
NS
26 months
Response Rate
80%
CBM
(Ramella 2013)
60
2-8%
23.3 months
SCC: Gem+ Erl
NSCC:Pem+Erl
Gem/Pem
weekly DI ROMA!
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Recent advances in molecularly targeted therapies coupled with
technologic strides in radiotherapy have the potential to
improve outcomes for patients?
1.  Pre-clinical results interesting
2.  Clinical: disappointing results (no standard therapy)
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How we can improve the likelihood of
clinical success with target therapy?
Identify clinical variables and biomarkers that can be used for
patient selection (mutational status of K-Ras and EGFR)
The lack of biomarkers in many drug-radiotherapy studies has been a major
cause of trials failing to live up to expectations
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EGFR mutation causes conformational change
and increased activation
Wild-type EGFR
Mutant EGFR
Ligand
Extracellular domain
Trans-membrane domain
Tyrosine kinase domain
Tyrosine phosphorylation
Ras-Raf-MAPK
Proliferation
EGFR internalisation
Degradation / recycling
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Pi3K-AKT
Survival
EGFR signals for longer
at the cell membrane
EGFR- WT
The WT EGFR cell lines showed a
significant tolerance to radiation and
modest loss of colony-forming ability.
Mutated EGFR
The mutant EGFR-expressing NSCLC
cell lines exhibited high radiosensitivity
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RTOG 1306 : A RANDOMIZED PHASE II STUDY OF INDIVIDUALIZED
COMBINED MODALITY THERAPY FOR STAGE III NON-SMALL CELL
LUNG CANCER (NSCLC)
RTOG 1306, Version Date: 9/11/15
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Multicenter Randomized Phase II Clinical Trial Comparing Neoadjuvant
Oxaliplatin, Capecitabine, and Preoperative Radiotherapy With or Without
Cetuximab Followed by Total Mesorectal Excision in Patients With High-Risk
Rectal Cancer (EXPERT-C)
165 patients T3-T4
81 (44 Kras WT) neoadjuvant
CAPOX (4 cycles)
83 (46 Kras WT) neoadjuvant
CAPOX + Cetuximab (4 cycles)
RT-CT 50,4 Gy + Capecitabine +/- Cetuximab
Adjuvant CapeOx +/- Cetuximab
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OS in K-ras WT
P=0,034
Conclusion
Cetuximab led to a significant increase in RR and OS in patients with
KRAS/BRAF wild-type rectal cancer.
Dewdney et al.JCO May 2012
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RAS mutations and cetuximab in locally advanced rectal
cancer: results of the EXPERT-C trial.
Median FUP= 63.8 months
PAN-RAS WILD TYPE
78/149 pts (52%)
pCR (%)
5y PFS (%)
5y OS (%)
CAPOX
7.5
67.5
70
CAPOX-Cetuximab
15.8
75.5
83.8
p=0.31
p=0.20
p=0.20
CONCLUSIONS:
Given the small sample size, no definitive conclusions on the effect of additional
RAS mutations on cetuximab treatment in this setting can be drawn and further
investigation of RAS in larger studies is warranted.
SCLAFANI, Eur J Cancer. 2014 May;50(8):1430-6
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Radiotherapy and new biological molecules:
clinical implications
Radiotherapy and targeted therapies
! 
! 
Locally advanced disease
Metastastic disease
Radiotherapy and Immunotherapy
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Figure 2. Survival Comparisons
Patients with an oncogenic driver mutation who did and did not
receive targeted therapy, and patients without an ocogenic driver
The median survival:
3.5 YEARS for patients with an
oncogenic driver and genotype-directed
therapy
1.0
Survival Probability
B
0.8
No targeted
therapy
0.6
Targeted therapy
0.4
2.4 YEARS for patients with any
oncogenic driver(s) who did not receive
0.2 genotype-directed, p = .006).
No driver
Patients w
who recei
1.0
Survival Probability
A
0.8
0.6
0.4
0.2
Log-rank P<.001
0
0
1
Log-r
2
3
4
5
0
0
Years
No. at risk
Patients with
oncogenic
driver
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BIO-MEDICO DI ROMA!
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205
110
No targeted 318
therapy
Targeted
260
225
143
No. at risk by oncoge
EGFR(s) 136
EGFR(o)
23
64Kris MG, JAMA
43 2014; 311(19):1998-2006
20
ALK
49
KRAS
22
72
36
23
ESMO Consensus Guidelines: Non-small-cell lung cancer first-line/
second and further lines in advanced disease
For patients who are being treated with EGFR or ALK inhibition and
have oligometastatic progression
Recommendation 27: in case of oligometastatic
progression during TKI treatment, use a local
treatment (such as surgery or radiotherapy) and
continue/resume TKI.
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Author
Molecular subtype
(TKI)
N pts (mutation)
Radiation
Dose
PFS after initial
TKI (months)
Outcome with SABR
Weickhardt et al.
(2012)
EGFR (erlotinib);
ALK (crizotinib)
27 (EGFR);
38 (ALK)
15-54 Gy
10.3
6.2 months second PFS
after the initial progression
on TKI
Gan et al.
(2013)
ALK (crizotinib)
38
12-54 Gy
9.1 overall
14 for SABR
5.5 months second PFS
after the initial progression
on TKI
Yu et al.
(2013)
EGFR (erlotinib,
gefitinib)
184
45 Gy
12 overall
19 for SABR
10 months second PFS
after the initial progression
on TKI
In patients with metastatic disease, local control of isolated deposits of resistant
subclones might improve clinical outcome.
Zeng J, Lancet Oncol 2014;15:426-34
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Is radiation delivery safe if target
therapy is concurrently administered?
Few clinical data exist on the safety of combination of Radiotherapy
with many of the present targeted drugs, and most data are from small patient
series with relatively short follow up
The combination of RT and targeted therapies unfortunately might also
account for increased toxicity to normal tissue from the combination of the two
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MAP Kinase Pathway Targeting in Melanoma
cKIT, NRAS, BRAF mutated in ~ 70% of melanomas, usually mutually exclusive[1]
cKIT
NRAS
~42-55% melanomas
BRAF
MEK
BRAF inhibitors:
DABRAFENIB
VEMURAFENIB
ERK
Sosman JA, et al. ASCO 2011 Educational Book.
Arkenau HT, et al. Br J Cancer.
2011;104:392-398.
Thomas N, et al.
Cancer Epidemiol Biomarkers Prev.
2007;16:991-997.
Nikolaou VA, et al. J Invest Dermatol.
2012;132:854-863.
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Oncogenic cell proliferation and survival
Potenziamento della radiotossicità associata a Zelboraf® (vemurafenib)
Sintesi
• Casi severi di lesioni correlate a radiazioni, alcuni con esito fatale, sono stati riferiti in
pazienti sottoposti a radioterapia prima, durante o dopo il trattamento con Zelboraf
•  20 casi di lesioni da radiazioni diagnosticate come recall da radiazioni (n = 8 casi) e
sensibilizzazione alle radiazioni (n = 12 casi)
• La maggior parte dei casi è stata di natura cutanea, ma alcuni casi hanno coinvolto gli
organi viscerali
•  8 casi di recall da radiazioni hanno evidenziato un’infiammazione acuta confinata all’area
precedentemente irradiata, innescata dalla somministrazione di Zelboraf, 7 o più giorni dopo
il completamento della radioterapia.
Zelboraf deve essere usato con cautela quando è somministrato
prima, in concomitanza o in sequenza al trattamento radiante.
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Radiosensitization by BRAF inhibitor therapy – mechanism
and frequency of toxicity in melanoma patients
161 melanoma patients were evaluated for acute and late toxicity, of whom 70
consecutive patients received 86 series of radiotherapy with concomitant BRAF
inhibitor therapy
43% of acute or late toxicities
Hecht et al. Annals of Oncology Advance Access published March 11, 2015
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Figureis
2. Clinical
photographs taken 2 weeks after the completion of
latest
version
at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.49.0565
icities are the most frequent adverse effects,The
particularly
hyperkeratosis
radiotherapy showed clear evidence of extensive dry desquamation of the
(6% to 51% with vemurafenib), as well as cutaneous squamous cell
skin within the radiation field (Figs 3A and 3B). These changes were
carcinoma and keratoacanthoma (4.3% to 31%
with vemurafenib,
Published
Ahead
of Print on May 27, 2014 as 10.1200/JCO.2013.49.0565
unanticipated increased in-field radiation skin toxicity.
6% to 11% with dabrafenib).1 Photosensitivity
can occur
in 52% of is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.49.0565
The
latest
version
D I A G N O S I S I N O N C O L O G Y
patients treated with vemurafenib.1 OURNAL OF
LINICAL
NCOLOGY
Case 2
Radiation therapy plays an important role in the treatment of
A 39-year-old man with widespread metastatic melanoma inpatients with metastatic melanoma. In this report, we describe five
volving multiple
bony metastases was foundD
to have
BRAF
I Athe
GV600E
N O
S I S I N O N C O L O G Y
patients who experienced unanticipated
increased OF
in-field skin
toxicOURNAL
LINICAL
NCOLOGY
mutation
on
biopsy
of
a
rib
lesion.
The
patient
received
palliative
ity while undergoing radiotherapy with the concomitant use of
radiotherapy (8 Gy in a single fraction) to painful bony metastases in
BRAF inhibitors.
Pulvirenti et al
the left humerus, left ribs, and sacrum, resulting in reduction of pain.
After radiotherapy, he began receiving dabrafenib at a dose of 150 mg
Case 1
twice per day. After 8 weeks of treatment with dabrafenib, he develeral fields was used in
A 71-year-old man with widespread metastatic melanoma inforrib,
Research
Oncology
oped new painful metastases affecting the right second
right iliac and Treatment of Cancer/Radiation Therapy
performed for patient
volving a solitary asymptomatic brain
and
multiple
subcutaneous
and
ACUTE RADIATION SKIN TOXICITY ASSOCIATED WITH
3
crest, and right pubis. He underwent additional palliative
radiotherGroup
grade 2 radiation reaction in the form of an erythematous
treatmentmacufields, to che
nodal metastases was found to have the V600K BRAF mutation
BRAF on
INHIBITORS
for sites
Research
and disease,
Treatment of Cancer/Radiation Therapy Oncology a total dose of 20.8 to
apy (8 Gy in a single fraction) to these new
of metastatic
biopsy of a chest wall lesion. The
patient
was
enrolled
onto
the
phase
II
lar rash pattern with features of coalescence, as shown in Figures 1A and
ACUTE RADIATION SKIN TOXICITYconcurrently
ASSOCIATED
WITH There was no overlap
with dabrafenib.
with2his
previous reaction in the form of an erythematous macu- treatment, which corre
Group3 grade
radiation
GlaxoSmithKline BREAK MB study (A Study of BRAF
GSK2118436
in
INHIBITORS
1B.
After
nine fractions of treatment (27 Gy to the dose prescription
radiotherapy
fields.
All three patients
BRAF Mutant MetastaticIntroduction
Melanoma to the Brain [also known as study
lar rash pattern with features of coalescence, as shown in Figures 1A and
The patient developed a significant skin reactionpoint,
after this
second
18
Gy
to
skin),
the
erythema
became
more
intense
and
confluent
strated
in clinical pho
BRF113929]) of dabrafenib in BRAF-mutant metastatic melanoma
1B. After
nine fractions
of treatment (27 Gy to the dose prescription
BRAF
inhibitors,
vemurafenib
and
dabrafenib,
are
the
mainstay
2
course
of
radiotherapy
with
brisk
erythema,
desquamation,
and
hyIntroduction
whole-brain
radiothe
involving the brain. Disease progression in the left axilla was treated
with
features
of
early,
patchy,
dry
desquamation
posteriorly,
as
shown
in
point,
18 Gy to skin),
the erythema became more intense and confluent (Fig 5A), patient
perpigmentation
the irradiated field,
as demonstrated
in Figure
of treatment
BRAF-mutant
metastatic
melanoma.
Cutaneous
tox4 dev
with palliative radiotherapy
of 36 Gyinhibitors,
in 12for
fractions
without bolus for
BRAF
vemurafenib
and
dabrafenib,
are within
the mainstay
Figure
2. Clinical
photographs
taken
2 weeks
after the
completion
of
4, approximately 4 weeks after treatment.
Thefeatures
patient
did
not
develop
with
of
early,
patchy,
dry
desquamation
posteriorly,
as
shown
in
desquamation
(Fig
5B
increasing pain. Dabrafenib
was
continued
concurrently
with
radioare the
most frequentmetastatic
adverse effects,
particularly
hyperkeratosis
oficities
treatment
for BRAF-mutant
melanoma.
such an intenseCutaneous
reaction withtoxthe first course
of
radiotherapy.
thema
as
well
as
mul
radiotherapy
showed
clear
evidence
of
extensive
dry
desquamation
of
the
therapy. A thermoluminescent dosimeter placed at the center of the
(6%are
tothe
with
as cutaneous
squamousFigure
cell 2. Clinical photographs taken 2 weeks after the completion of treatment fields. In al
icities
most
frequent
adverse
particularly
hyperkeratosis
radiotherapy field demonstrated
a51%
total
dose
ofvemurafenib),
24 Gy
(2 Gy effects,
per as well
skin
within
theevidence
radiation
field (Figs
3A and 3B). ofThese
radiotherapy
showed
clear
of extensive
dry desquamation
the changes were
(6%
to course
51% with
vemurafenib),
as well (4.3%
asCases
cutaneous
squamous
cell
within 1 to 2 months
3, 4,
and
5
fraction) on skin for the
entire
ofand
treatment.
carcinoma
keratoacanthoma
to
31%
with
vemurafenib,
skin
within
the(patient
radiation
field (Figsin-field
3A andradiation
3B). Theseskin
changes
were after the completion
unanticipated
increased
toxicity.
1
A
39-year-old
woman
(patient
3),
a
41-year-old
man
4),
After only seven fractions
of
treatment
(21
Gy
to
the
dose
prescripcarcinoma
and
keratoacanthoma
(4.3%
to
31%
with
vemurafenib,
6% to 11% with dabrafenib). Photosensitivity can occur in 52%
of
increased
period of 3 to 4 mont
54-year-old man (patient 5),unanticipated
developed multiple
brainin-field radiation skin toxicity.
tion point, 14 Gy to skin), the patient developed a European Organisation
1
1 and a can
6%
to
11%
with
dabrafenib).
Photosensitivity
occur
in
52%
of
patients treated with vemurafenib.
detected in these pati
1
J
J
C
C
O
O
A 71-year-old man with widespread metastatic
melanoma
Disease progression in the axilla was treated
with palliative radiotherapy of 36 Gy in 12 fractions
and Vemurafenib.
patientsRadiation
treated withtherapy
vemurafenib.
Case 2
plays an important role in the treatment
of
Case 2
Radiation therapy plays an important role in the treatment of
A 39-year-old man with widespread metastatic melanoma
Discussion inpatients with metastatic melanoma. In this report, we describe five A 39-year-old
man with widespread metastatic melanoma inpatients
with metastatic melanoma. In this report,
we describe five
In these
five patien
Apatients
B
volving multiple bony metastases was found to have the V600E
BRAF
who experienced unanticipated increased in-field skin toxicvolving multiple bony metastases was found to have the V600E BRAF itors, the in-field skin r
patients who experienced unanticipated increased in-field skin toxicmutation
of aThe
rib patient
lesion. received
The patient
received
palliative
while
undergoing
radiotherapy
withconcomitant
the concomitant
of
in the first patient, oc
on biopsy on
of abiopsy
rib lesion.
palliative
ityitywhile
undergoing
radiotherapy
with the
use of usemutation
radiotherapy
(8
Gy
in
a
single
fraction)
to
painful
bony
metastases
in
BRAF
inhibitors.
radiotherapy (8 Gy in a single fraction) to painful bony metastases in relatively low palliative
BRAF
inhibitors.
scribed
here
does
the left left
humerus,
ribs, and
sacrum,
resultingofin
reduction of pain.not c
the left humerus,
ribs, andleft
sacrum,
resulting
in reduction
pain.
Fig 2.
mation that was obse
After radiotherapy,
he began
receiving
a dose
of 150
mgand
After radiotherapy,
began
dabrafenib
at adabrafenib
dose of 150at
mg
clinically
in skin
Case
27heGy
toreceiving
the
dose
prescription
Case
1 1
per 8day.
After
8 weeks of
treatment
with
he develtwice
day. After
weeks
of treatment
with
dabrafenib,
he dabrafenib,
devel- (eg, brain).
A 71-year-old
manman
with with
widespread
metastatic
melanoma
inA 71-year-old
widespread
metastatic
melanoma
in- per twice
point,
18
Gy
to
skin
The
mechanism
metastases
from
V600E
BRAF-mutant
metastatic
melanoma.
All
three
oped
painful
metastases
the affecting
right second
right
iliac rib, right
new
painful affecting
metastases
therib,
right
second
iliac u
volving
a solitary
asymptomatic
brainbrain
and multiple
subcutaneous
and
volving
a solitary
asymptomatic
and multiple
subcutaneous
and newoped
may be a result of all fi
patients received whole-brain radiotherapy at a dose of 30 Gy in 10
crest, andcrest,
right
pubis.
He underwent
palliative
radiotherandasright
Headditional
underwent
additional
palliative
radiothernodal
metastases
was was
found
to have
the V600K
BRAF mutation
on
tivity
to ionizing radiat
fractions
part ofpubis.
their disease
management. For
patients 3 and
4,
nodal
metastases
found
to have
the V600K
BRAF mutation
on
apy
(8
Gy
in
a
single
fraction)
to
these
new
sites
of
metastatic
disease,
previously
reported,4 a
vemurafenib
ataasingle
dose of 960
mg twice to
perthese
day wasnew
given sites
concurrently
biopsy
of
a
chest
wall
lesion.
The
patient
was
enrolled
onto
the
phase
II
apy
(8
Gy
in
fraction)
of
metastatic
disease,
biopsy
a chest
lesion.
The patient waspoint,
enrolled14
ontoGy
the phase
II
21
Gyofto
thewall
dose
prescription
to concurrently
skin
with
the
entire
course
of
whole-brain
radiotherapy.
For
patient
5,
However,
the
different
with
dabrafenib.
There
was
no
overlap
with
his
previous
GlaxoSmithKline
BREAK
MB study
(A Study
of GSK2118436
in
concurrently
with
dabrafenib.
There
was
no overlap
withsame
his dose
previous
GlaxoSmithKline
BREAK
MB study
(A Study
of GSK2118436
in
vemurafenib
was
commenced
halfway
through
whole-brain
radioof
radiother
radiotherapy
fields.
Pulvirenti
,J
Clinical Oncol Vol 32, 2014 that the exaggerated
BRAF Mutant Metastatic Melanoma toFigthe
Brain [also known as study
radiotherapy
fields.
therapy and was
given concurrently with the last five fractions of the
BRAF Mutant Metastatic Melanoma1. to the Brain [also known as study The patient
developed
a significant
skin reaction
after opposed
this second
BRF113929]) of dabrafenib in BRAF-mutant metastatic melanoma
radiotherapy.
Whole-brain
radiotherapy
using parallel
lat- after
cutaneous
toxicity of b
The
patient
developed
a significant
skin reaction
this second
of
dabrafenib
in
BRAF-mutant
metastatic
melanoma
2
Journal of Clinical Oncology, VolBRF113929])
32, 2014
©
2014
by
American
Society
of
Clinical
Oncology
1
course
of
radiotherapy
with
brisk
erythema,
desquamation,
and hyUNIVERSITA'
CAMPUS
BIO-MEDICO
DI treated
ROMA!
involving
the
brain.
Disease
progression
in
the
left
axilla
was
Downloaded from jco.ascopubs.org2 on June 4, 2014. For personal use only. No other uses without permission.course of radiotherapy with brisk erythema, desquamation, and hyinvolving
the
brain.
Disease
progression
in the
left
axilla
was
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perpigmentation within the irradiated field, as demonstrated in Figure
Copyright
© 2014 American
Oncology.
All rights
reserved.
with
palliative
radiotherapy
of 36Society
Gy
inof12Clinical
fractions
without
bolus
for treated
perpigmentation
the irradiated
as demonstrated
in Figure
Copyright
2014
by
American
Society
of
Clinical
Oncology
4,for
approximately
4 weeks afterwithin
treatment.
The patientfield,
did not
develop
with
palliative
radiotherapy
of
36
Gy
in
12
fractions
without
bolus
increasing pain. Dabrafenib was continued concurrently with radioA
B
4,
approximately
4
weeks
after
treatment.
The
patient
did
not
develop
such an intense reaction with the first course of radiotherapy.
increasing
pain. Dabrafenibdosimeter
was continued
therapy.
A thermoluminescent
placed atconcurrently
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the radio-
such an intense reaction with the first course of radiotherapy.
Published Ahead of Print on May 27, 2014 asD10.1200/JCO.2013.49.0565
I A G N O S I S I N O N C O L O G Y
JOURNAL
OF
CLINICAL
ONCOLOGY
The latest
version
is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.49.0565
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
I N
O N C O L O G Y
Diagnosis in Onc
for Research and Treatment of Cancer/Radiation Therapy Oncology
ACUTE RADIATION SKIN TOXICITY ASSOCIATED WITH
Group3 grade 2 radiation reaction in the form of an erythematous macuBRAF INHIBITORS
lar rash pattern with features of coalescence, as shown in Figures 1A and
for Research
and nine
Treatment
of Cancer/Radiation
Therapy
1B. After
fractions
of treatment (27
Gy toOncology
the dose prescription
ACUTE RADIATION SKIN TOXICITY ASSOCIATED WITH
3
Introduction
Group
grade
2
radiation
reaction
in
the
form
of
an
erythematous
macu-and confluent
RT 8 Gy to painful
bony
metastases
in
the
left
humerus,
left
BRAF INHIBITORS
point, 18 Gy to skin), the erythema became more intense
BRAF inhibitors, vemurafenib and dabrafenib, are the mainstay
lar rash pattern with features of coalescence, as shown in Figures 1A and
with features of early, patchy, dry desquamation posteriorly, as shown in
ribs,
and for
sacrum.After
radiotherapy,
heCutaneous
began toxreceiving
of
treatment
BRAF-mutant metastatic
melanoma.
1B. After nine fractions of treatment (27 Gy to the dose prescription
Introduction
Figure
2. Clinical photographs taken 2 weeks after the completion of
point,of
18 Gy
to skin), the erythema became more intense and confluent
icities
are the
most
frequent
adverse
effects,
particularly
dabrafenib.
He
underwent
8 Gy
toarethese
new sites
metastatic
BRAF
inhibitors,
vemurafenib
and
dabrafenib,
the hyperkeratosis
mainstay
radiotherapy
showeddry
clear
evidence ofposteriorly,
extensive as
dryshown
desquamation
of the
with features
of early, patchy,
desquamation
in
(6%
to 51%concurrently
with
vemurafenib),
as well
as cutaneous
squamous
cell
of treatment
for
BRAF-mutant
metastatic
melanoma.
Cutaneous
tox- was
disease,
with
dabrafenib.
There
no
overlap
skin
within
the radiation
(Figsafter
3A the
andcompletion
3B). Theseofchanges were
Figure 2.
Clinical
photographs
takenfield
2 weeks
carcinoma
(4.3%
with vemurafenib,
et alto 31% hyperkeratosis
icities are theand
mostkeratoacanthoma
frequent adverse Pulvirenti
effects,
particularly
unanticipated
increased
radiation
skin toxicity.of the
showed clear
evidencein-field
of extensive
dry desquamation
1
with
his
radiotherapy
fields.
6%
with
dabrafenib).
can
occur incell52% radiotherapy
of
(6%to
to11%
51% previous
with vemurafenib),
asPhotosensitivity
well as cutaneous
squamous
skin within the radiation field (Figs 3A and 3B). These changes were
1
carcinoma
and keratoacanthoma
(4.3%
to 31% with vemurafenib,
patients
treated
with vemurafenib.
unanticipated
in-field radiation skin toxicity.
A
B
1
Caseincreased
2
6% toRadiation
11% with therapy
dabrafenib).
Photosensitivity
in 52%
of
plays
an important can
roleoccur
in the
treatment
of
1
A 39-year-old man with widespread metastatic melanoma inpatients treated
with vemurafenib.
patients
with metastatic
melanoma. In this report, we describe five
Case
2
Radiation
therapy playsunanticipated
an important increased
role in thein-field
treatment
of toxicvolving multiple bony metastases was found to have the V600E BRAF
patients
who experienced
skin
A
39-year-oldon
man
with widespread
metastatic
inpatients
metastatic melanoma.
In this
report,
describe fiveuse of
mutation
biopsy
of a rib lesion.
The melanoma
patient received
palliative
ity
whilewith
undergoing
radiotherapy
with
the we
concomitant
volving
multiple
bony
metastases
was
found
to
have
the
V600E
BRAF
patients who experienced unanticipated increased in-field skin toxicradiotherapy (8 Gy in a single fraction) to painful bony metastases in
BRAF inhibitors.
mutation on biopsy of a rib lesion. The patient received palliative
ity while undergoing radiotherapy with the concomitant use of
the left humerus, left ribs, and sacrum, resulting in reduction of pain.
radiotherapy (8 Gy in a single fraction) to painful bony metastases in
BRAF inhibitors.
radiotherapy,
began resulting
receivingindabrafenib
a dose of 150 mg
Case 1
the left After
humerus,
left ribs, andhesacrum,
reduction ofatpain.
twice per day.
Afterreceiving
8 weeksdabrafenib
of treatment
withofdabrafenib,
he develAfter radiotherapy,
he began
at a dose
150 mg
CaseA171-year-old man with widespread metastatic melanoma inoped
affecting
the right he
second
twice per
day.new
Afterpainful
8 weeksmetastases
of treatment
with dabrafenib,
devel-rib, right iliac
volving
a solitary asymptomatic
brain and
multiplemelanoma
subcutaneous
A 71-year-old
man with widespread
metastatic
in- and
crest,
and metastases
right pubis.
He underwent
additional
palliative
oped new
painful
affecting
the right second
rib, right
iliac radiothernodal
was found brain
to have
V600K
BRAF mutation
volvingmetastases
a solitary asymptomatic
andthe
multiple
subcutaneous
and on
crest,
and
right
pubis.
He
underwent
additional
palliative
radiotherapy (8 Gy in a single fraction) to these new sites of metastatic disease,
nodal metastases
was found
have
the V600K
BRAF mutation
biopsy
of a chest wall
lesion.toThe
patient
was enrolled
onto theon
phase II
apy
(8
Gy
in a single fraction)
to these new
sites was
of metastatic
disease,
Fig
5.
with dabrafenib.
There
no overlap
with his previous
biopsy of a chest wallBREAK
lesion. The
patient
was(A
enrolled
onto
phase II
GlaxoSmithKline
MB
study
Study
ofofthe
GSK2118436
in10 concurrently
Whole-brain
radiotherapy
at
a
dose
30
Gy
in
concurrently
with
dabrafenib.
There
was
no
overlap
with
his
previous
GlaxoSmithKline
BREAK Melanoma
MB study (A
of GSK2118436
radiotherapy fields.
BRAF
Mutant Metastatic
to Study
the Brain
[also known in
as study
radiotherapy
fields.
Pulvirenti
,J Clinical Oncol Vol Fig32,
2014after this second
BRAF
Mutant Metastatic
Melanoma
to
the Brain
[alsoSJ,
known
as study
fractions
with
The
patient
reaction
4.
9. Heidornmetastatic
Milagre C, Whittaker
S, et al: Kinase-dead BRAF
and
onco- developed a significant skin
BRF113929])
of
dabrafenib
in
BRAF-mutant
melanoma
Stock Ownership: None
Honoraria: Alexconcurrent
Guminski,
Roche; Georgina
V. dabrafenib
The patient
a significant skin reaction after this second
genic RAS
cooperate to
drive tumor progression through
CRAF. Cell
140:209of dabrafenib
in BRAF-mutant
metastatic
melanoma
Long, Roche ResearchBRF113929])
Funding: None Expert
Testimony:
None
2
course
ofdeveloped
radiotherapy
with brisk erythema, desquamation, and hyinvolving
theOther
brain.
Disease
progression
in
the
left
axilla
was
treated
221,
2010
2
course
of
radiotherapy
with
brisk erythema, desquamation, and hyPatents, Royalties, and
Licenses:
None
Remuneration:
None
UNIVERSITA'
CAMPUS
DI treated
ROMA!
involving the brain.
Disease progression
inBIO-MEDICO
the
left
axilla
was
perpigmentation
10. Poulikakos PI, Zhang C, Bollag G, et al: RAF inhibitors
transactivate RAF within the irradiated field, as demonstrated in Figure
with
palliative radiotherapy
of 36 Gy indimers
12
fractions
without
bolus
for
without anyfield,
directas
molecular
interaction.
Given that there was no
www.unicampus.it!
perpigmentation
within the irradiated
demonstrated
in Figure
REFERENCES
and ERK
signalling
in cells
with wild-type
BRAF. Nature 464:427-430,
with palliative radiotherapy
of 36 Gy in 12 fractions
without
bolus
for
4,
approximately
4
weeks
after
treatment.
The
patient
did
not develop
evidence
of
significant
BRAF
inhibitor–related
cutaneous
reactions
1. Anforth R, Fernandez-Peñas
P, Long
GV: Dabrafenib
Cutaneous toxicities
of RAF
2010
increasing
pain.
continued
concurrently
with radio4, approximately 4 weeks after treatment. The patient did not develop
pain.
Dabrafenib
waswas
continued
concurrently
with radioinhibitors. Lancet Oncolincreasing
14:e11-e18, 2013
outside
of
the
radiotherapy
field
in
these
patients,
this
hypothesis
11. Oberholzer PA, Kee D, Dziunycz P, et al: RAS mutations
are
associated
such
an reaction
intense
reaction with the first course of radiotherapy.
therapy.
placed
at the
centersquamous
of the
such
intense
2. Long GV, Trefzer
U, Davies A
MA,thermoluminescent
et al: Dabrafenib in patientsdosimeter
with
with the
development
of cutaneous
cellan
tumors
in patients
treated with the first course of radiotherapy.
therapy. A thermoluminescent dosimeter placed at the center of the
Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-
with RAF inhibitors. J Clin Oncol 30:316-321, 2012
radiotherapy field demonstrated a total
dose of 24 Gy (2 Gy per
would seem unlikely.
In vitro experiments5 suggest that vemurafenib sensitizes BRAF-
mo
ocy
itat
see
stu
acti
app
adj
spe
the
Tri
Cro
Sou
An
The
Hos
Art
Cro
Univ
Dio
Can
Sou
An
Roy
Ale
The
Hos
Ca
The
Hos
Pet
Mel
New
Ge
Mel
Ric
Cro
for
Severe radiotherapy-induced EXTRACUTANEOUS
TOXICITY under vemurafenib.
The first patient, a female aged 32, treated with
vemurafenib for three months, presented a
steroid-dependent RADIONECROSIS after
brain stereotactic radiosurgery. Symptoms
persisted until her death six months later.
The second patient, a male aged 64 and treated
with vemurafenib for nineteen days, presented a
radiation-induced ANORECTITIS complicated
by diarrhoea, anorexia and weight loss following
the concomitant radiation of a primary rectal
tumour. A colostomy was needed after ten
months in order to improve local status and
general health.
Peuvrel L, Eur J Dermatol. 2013 Nov-Dec;23(6):879-81.
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Receptor tyrosine kinase inhibitor
UNIVERSITA' CAMPUS BIO-MEDICO DI ROMA!
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25 patients with
oligometastases
Reported a grade 5 gastrointestinal hemorrhage and a fatal bronchobiliary
fistula, possibly related to treatment.
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June 2012 | Volume 7 | Issue 6
MUTAZIONI SENSIBILIZZANTI, NUOVI TARGET E MODERNI TRATTAMENTI ONCOLOGICI
Inhibitor of mammalian target of rapamycin (mTOR)
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm254350.htm
"US FDA approves Novartis drug Afinitor for breast cancer". Reuters. 20 Jul 2012.
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TOTAL RECALL OF RADIOTHERAPY WITH MTOR
INHIBITORS: A NOVEL AND POTENTIALLY
FREQUENT SIDE EFFECT?
Pelvic RT 2007
4 weeks after the start of temsirolimus
(2010), she presented with a
subocclusive syndrome associated with
grade 2 colitis
RT for prostate cancer 2006
Temsirolimus for pancreatic cancer
2010
Bourgier C, Ann Oncol 2011
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Radiation-Induced Esophagitis exacerbated by Everolimus
ESOPHAGITIS 3 months after RT:
Breast Cancer Vertebral M+: RT D12 (30Gy/
10 fx)
Miura, Case Rep Oncol 2013; 6:320-324
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Attention to possible severe toxicities!!!
Questions that are important to investigate further
"  Timing of RT and target therapy
"  Doses of drugs when combined with radiotherapy
"  Optimization of fractionating and delivery technique and new dose constraints
"  Better patients selections (Anamnesis and collaboration with medical oncologists)!
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Radiotherapy and Immunotherapy
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CTLA-4
PD-1
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NIVOLUMAB
Presented By David Spigel at 2015 ASCO Annual Meeting
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Presented By David Spigel at 2015 ASCO Annual Meeting
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Dovedi et al., Cancer Research; 74 October 2014
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Formenti Journal of Translational Medicine 2015, 13(Suppl 1):K10
http://www.translational-medicine.com/content/13/S1/K10
KEYNOTE SPEAKER PRESENTATION
Open Access
Combining radiation therapy with immunotherapy:
clinical translation
Silvia C Formenti
From Melanoma
Bridgeradiotherapy
Meeting 2014
The novel
role
of
as a powerful adjuvant to
Naples, Italy. 03-06 December 2014
immunotherapy warrants more research to define the optimal
sMICA were 35
associated
with increased
expression
of
Ionizing radiation induces immunogenic
cell death ofcurrently
immunotherapy/RT
combinations:
TRIALS
OF
RT
tumors, an effect likely to contribute to the success asso- NKG2D in T and NK cells, and corresponded to
to treatment. Anti-sMICA antibodies and
ciated with radiotherapy of cancer [1]. Recent
discovery response
+IMMUNOTHERAPY
are
ongoing
in
USA.
suggests that radiotherapy can be applied as a powerful sMICA levels can be measured in serum with ELISA by
adjuvant to immunotherapy and, in fact, can contribute
to convert the irradiated tumor into an in situ vaccine,
resulting in specific immunity against metastases [2].
Preclinical models of syngeneic tumors have reliably predicted clinical success, in distinct tumor settings and
immunotherapy/radiation combinations [3-5]. As a first
proof of principle trial, we translated the preclinical evidence of a successful combination with Flt3 ligand and
RT [6] to a protocol of GM-CSF and RT, and demonstrated
out of field objective
in 27%
patients
UNIVERSITA'
CAMPUSresponses
BIO-MEDICO
DIofROMA!
with multiple
metastases
of
solid
tumors,
defined
as an
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abscopal effect [7]. Parallel mechanistic studies in the lab
in the syngeneic 4T1 mouse model of metastatic breast
cancer demonstrated at intratravital microscopy that RT
using recombinant MICA protein and anti-human MICA
monoclonal antibodies [10]. Since RT is known to upregulate MICA on the surface of tumor cells [11] biopsies
of tumors before and after radiotherapy and Ipilimumab
could also be tested for expression of MICA.The preclinical success of the combination of anti-CTLA-4 antibody
and RT was mirrored by abscopal responses in metastatic
melanoma and NSCLC patients irradiated to one lesion,
during Ipilimumab. This evidence inspired our current
trial testing radiotherapy with CTLA-4 blockade in metastatic melanoma. In this study patients with newly diagnosed metastatic melanoma eligible to first line
Ipilimumab are randomly assigned to Ipilimumab alone
or Ipilimumab and radiotherapy to one metastatic lesion.
Radiotherapy and Immunotherapy
There is a strong biological rationale in exploring feasibility and efficacy of
combining radiotherapy and immunotherapy
The diseases (melanoma, lung vs. prostate, breast) and setting (up-front in
metastatic disease, oligo-progressive only) where applying this combination
remains uncertain …as well as type of RT (optimal dose, SBRT vs standart
fractionation)
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Conclusions (1)
Improvements in our understanding of tumour and radiation biology have
identified multiple new strategies that may enable us to specifically render
tumours more sensitive to radiotherapy
Previous trials combining drugs with radiotherapy have failed to live up to
expectations due to :
"  the lack of reliable predictive biomarkers
"  failure to select the most appropriate patients for clinical studies
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Conclusions (2)
Novel drugs need to undergo more rigorous pre-clinical testing in order to
reduce the risk of producing negative trials and potentially discarding beneficial
treatments
If the arsenal of drugs now available to us is used in appropriately
selected patients, we may significantly improve clinical outcomes in the
future
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"Abbiamo una speranza senza fine,
non un fine senza speranza"
(E. Stein)
Grazie!!!
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