I TUMORI RARI Sarcomi e GIST

I TUMORI RARI
Aviano, 5 Novembre 2015
Sarcomi e GIST
Percorsi Diagnostici e Terapeutici
Antonino De Paoli
UO Oncologia Radioterapica
Giulio Bertola
UO Oncologia Chirurgica
Centro di Riferimento Oncologico (CRO) – Aviano
Extremity Soft Tissue Sarcoma
Local Treatment
Conservative Surgery and RT
85 - 90 %
of local control
(<10% amputations)
…indeed, preop RT has some potential advantages
STS of the Limbs and Trunk Wall
ISG-GEIS Randomised Trial (High Risk)
Local
A -- Control
Treatment
B -- EPI-IFO
R EPI-IFO
x 3 cycles
x 2 cycles
EPI: 60 mg/mq days 1-2
IFO: 3 gr/mq days 1-3
GSF: 300 ug days +9 +16
Study Coordinators: S Frustaci CRO-Aviano
A Gronchi INT-Milano
M Mercuri IOR-Bologna
ISG-GEIS Trial
Local Treatment Options
Favourable Presentation
EI
x
3 cycles

SURG
+
RT boost

46-50 Gy + 14-16 Gy
EI
G-CSF
EI
22 Gy
G-CSF
22 + 16
Critical Presentation
EI
G-CSF
EI
G-CSF
EI
Control
G-CSF
SURG +
RT boost
22 Gy
22 Gy
RT boost: IORT or BRT or 3D-CRT
 EI x
2 cycles
Pleomorphic Sarcoma of the Thigh
By courtesy of Prof E Barbieri
G3 MFH, Preop EIx3+44Gy
3D-CRT
+IORT
CRO
Aviano
radical surgery included an high rate
of amputations
ISG-GEIS TRIAL
RADIATION THERAPY
N. Patients 300/328 (91%)
Preop-RT
160 Pts (53.4%)
8% Amputation
Postop-RT
140 Pts (46.6%)
Dose intensity
Table 1: PRE-OPERATIVE CT: median and range of relative dose-intensity
ARM A
ARM B
RT PRE YES
RT PRE NO
OVERALL
median
range
median
range
median
range
median
range
median
range
EPI
95.5
46.0-135.6
94.7
43.0-113.8
94.6
43.0-135.6
95.8
65.8-116.2
95.3
42.9-135.6
IFO
95.5
25.3-116.6
95.3
42.8-113.8
95.5
31.2-106.8
95.8
25.3-116.6
95.5
25.3-116.6
ARDI
95.5
38.6-116.4
95.0
42.9-113.8
95.2
38.6-113.0
95.5
45.6-116.4
95.3
38.6-116.4
90% completed preop CT in both arms,
Table 2: POST-OPERATIVE CT: median and range of relative dose-intensity
independently
of combination
with RTOVERALL
RT PRE YES
RT PRE NO
median
Range
median
range
median
range
EPI
88.1
43.5-103.5
96.6
24.9-102.9
91.7
24.9-103.5
IFO
86.8
33.1-103.5
97.7
34.6-102.4
95.5
33.0-103.5
70%
completed
postop
CT
in arm 92.9
B (67%
if
85.7
44.0-103.5
96.6
29.8-102.4
27.8-103.5
RT+ POST-OPERATIVE
in preop setting,
75%
not) dose-intensity
Table 3: PRE
CT: median and
range if
of relative
ARDI
RT PRE YES
RT PRE NO
OVERALL
median
range
median
range
median
range
EPI
90.6
64.1-103.5
93.6
42.6-102.1
92.0
42.6-103.5
IFO
90.4
64.1-103.4
95.5
49.5.103.7
93.3
49.5-103.7
ARDI
90.5
64.1-103.5
94.4
46.1-102.2
93.0
46.1-103.5
Abbreviation: ARDI, average relative dose intensity.
0.5
DM
Positive margins do notM-affect
local outcome after preop CT-RT
probability
0.4
0.3
M+
DM
M-
LR
0.2
0.1
0.0
0
12
24
36
months
48
M+
LR
60
Preop IMRT/Chemo, Resection-IORT
and Surgical recontruction
CRO
Aviano
Sarcoma of Extremity and S.Trunk
IORT in extension of surgical margins
Local Control analysis
Local Control
Local Control by Resection
WR: 5 yrs LC 90%
5 yrs LC: 86%
MR: 5 yrs LC 83%
Time (months)
p-value=0.43
Time (months)
De Paoli A et al, ISIORT 2010
Histotype-tailored neoadjuvant CT Phase III
Trial within an integrated approach
 High grade, spindle cell
 Limbs, superficial trunk
 >5 cm and/or local relapse
EI x 3 + Surg/RT +/- Boost
R
RT Boost:
ht CT x 3 + Surg/RT +/- Boost
IORT
BRT
EBRT





MFH, Pleomorphic
Syn Sa
LMS
Round Cell Lipo
MPNST
Gem/Tax
Ifx
Gem/Tax
ET743
Carbo/VP
RT Postop: Indicazione Convenzionale
RT Preop: Presentazioni meno favorevoli
BRT-IORT: Indicazioni Particolari
Retroperitoneal STS
Clinical problem
Resectability (difficult to achieve, high
incidence of local recurrences)
Safe radiation delivery (high dose,
critical structures)
Metastatic potential (high grade)
Retroperitoneal Sarcomas
Results from Surgical Series
Centre
N° Pts
Dalton,’89
Catton,’94
Lewis,’98
Karakousis
Gronchi,’04
Anaya,’09
Strauss,’10
116
104
231°
130
167
393
200
Complete
Resection
Local
Failure
54%
43%
80%
95%
88%
78%
85%
59%
22%
30%
44%
-
5 yrs
OS
59%
36%
54%
60%
54%
54%
69%
10 yrs
OS
LF >30%,10 year OS 30%
°primary tumours only
14%
35%
48%
27%
-
Patients 288
5-yr Loc Rec 48% vs 28%
Determinant Factors
MV analysis:
Histotype: Liposa
Grade: G1-2
Fig 1. Crude cumulative incidence
RT: yes
of local recurrences by period of
surgical resection at our institution
•Selection bias…
RPS - Liberal en-bloc visceral resections
Retroperitoneal Sarcomas
Post-op Radiation Therapy - Selected Series
Centre
N° Pts
Radiation
Dose
Local
Control
5 yrs
OS
MGH
23
24-69 Gy
54%
54%
PMH
36
20-50 Gy
28%
36%
FoxChase
21
36-61 Gy
72%
44%
CRO-Aviano 34
36-63 Gy
52%
42%
IMRT-Tomo 50.4Gy
for RPS
CRO
Aviano
G3-DDLS RPS
Resection +
R Nephrectomy
IVC +margim
IORT12Gy
CRO
Aviano
IFO
14 g/sqm
14 g/sqm
14 g/sqm
SURGERY
50.4 Gy / 28 fr.
RT
wks 0
2
4
6
8
10
14
+/-IORT
or
post-op
boost
16
Study Coordinators: A De Paoli CRO-Aviano
A Gronchi INT-Milano
83pts, 5yrs OS: 59%
(mFup 4.8yrs)
5yrs RFS: 44%
Post-surgical complications
17/79 (21%)
Retroperitoneal Sarcomas
Pre-op Radiation therapy - Selected Studies
Group
Design
RT
Dose
Local Control
5yrs
OS
5yrs
MGH
Retrosp.
27-50 Gy
59%
50%
PMH
Phase II
45 Gy
69%
70%
*MDAH Phase I-II 18-50 Gy
60%
61%
*ISG
63%
59%
Phase I-II
+/-BRT-IORT
50.4 Gy
*Concurrent Chemotherapy
256 patients
50.4Gy/28fxs
… in summary
 Pre or Postop RT can be safely combined with fulldose of adjuvant epirubicin and ifosfamide
(extremity/sup trunk sarcoma)
 Neoadjuvant CT and RT may be preferred for HRextremity STS (critical presentations)
 Histoype-tailored neoadj. chemotherapy could be
combined with new RT modalities (IMRT-IGRT/IORT)
in most HR-extremity STS (phase I-II studies for GemTax/RT are needed)
 More solid data on possible impact of RT +/- IORT on
tumor control and survival in RPS are available
(Strass Trial ongoing)
STRASS Trial
Standard Arm: Surgery alone
Operability Criteria
 Expected R0-R1 resection
 ASA score <-2
 Criteria for non-resectability
- SMA involvement
- or Aorta involvement
- or bone involvement
STRASS Trial
Investigational Arm: RT and Surgery
Preop Radiation Therapy
 Patient suitable for preop RT (CTscan/MRI, MDT
consultation)
 RT delivered with 3D-CRT or IMRT (EORTC QART
guidelines)
 RT should be performed in the same center as
surgery (no satellites centers allowed)
 RT start within 8 wks from random
STRASS Trial
Pt/Tumor selection criteria
 Age ³ 18 years; WHO PS <-2
 Normal bone marrow, renal, hepatic function
 Primary STS of retroperitoneal or infra-peritoneal space of
pelvis
 Histologically-proven RPS (no GIST, uterine or RMS, PNET
and other round cell sarcoma)
 No previous teatment
 Tumor both resectable (R0-R1) and suitable for RT (based on
CT scan/MRI on MDT consultation)
 Measurable disease (RECIST) by CT or MRI (28 days before
random)
 No mets disease
 Written informed consent/Option for traslational research
program
STRASS Trial
Recommended surgical procedures
 Surgery as soon as possible (<-4 wks from random)
 Medline laparotomy preferred
 Ideally, organs in proximity of tumor should be
resected (Kidney, spleen, colon, psoas m. or fascia)
 Duodenum, head pancreas,liver,stomach,major
abdominal vessels/nerves should be reseccted only
if directed infiltrated
Pre-op RT for RPS
Potential Advantages
 A RT dose of 45-50 Gy is expected to inactivate a large
percentage of tumour cells and to minimise the risk of
seeding during surgery (peritoneal sarcomatosis)
 Possible reductions in tumour size as well as thickening of
the pseudo-capsula favouring a complete resection
(increase in resection rate)
 Large tumours will usually displace the adjacent uninvolved
abdominal viscera, which can be excluded from the pre-op
RT volume (decreased risk of complications)
 Tumor in site allow better CTV and OARs delineation (More
appropriate RT pianification and treatment)