Aggiornamento in tema di Sarcomi delle Parti Molli e
GIST
Ha uno spazio la chirurgia
nella sarcomatosi retroperitoneale?
Carlo Riccardo Rossi
Unità Melanoma e Sarcomi
Clinica Chirurgica II - Università di Padova
Padova, 30 maggio 2008
Peritoneal sarcomatosis
DEFINITION
SPREAD OF SOFT TISSUE SARCOMAS (STS) OR GISTs
THROUGHTOUT THE ABDOMEN (WITHOUT DISTANT METASTASES)
Peritoneal sarcomatosis
RETROPERITONEAL SARCOMAS
LOCAL RECURRENCE AND SURVIVAL
Author
Year
Local
Recurrence (%)
5 yrs Survival (%)
Lewis JJ et al
1998
24
54
Stoeckle E et al
2001
48
46
Gilbeau L et al
2002
51
60
Gronchi A et al
2004
44
54
Ballo MT et al
2006
43
44
Peritoneal sarcomatosis
GISTs
LOCAL RECURRENCE AND SURVIVAL
Before Imatinib advent
Author
Year
Local
5 yrs Survival
Recurrence (%)
Eilber FC et al
2000
48
31
De Matteo RP et al
2000
40
54
Crosby JA et al
2001
43
41
Pierie JP et al
2001
60
42
Peritoneal sarcomatosis
TREATMENT:
STATE OF THE ART
•Systemic
•Locoregional
Peritoneal sarcomatosis
STANDARD TREATMENT
(SYSTEMIC CHEMOTHERAPY + SURGERY)
Retroperitoneal Sarcomas
Response rate: 20-40%
•
Antracyclin +/- ifosfamide
Median survival 12-24 mos
•
Gemcitabine +/- docetaxel leiomyosarcoma
•
Trabectedine (ET-743)
liposarcoma
leiomyosarcoma
GISTs
Response Rate: 50-85%
•
Imatinib
Overall 2 yr survival: 71%
Peritoneal sarcomatosis
SYSTEMIC CHEMOTHERAPY + PALLIATIVE
SURGERY
MD ANDERSON CANCER CENTER EXPERIENCE
N° of pts:
Recurrence rate:
Median Survival:
51
72 %
22 mos
Bilimoria et al., Cancer 2001
Peritoneal sarcomatosis
LOCOREGIONAL TREATMENT
Barriers to
effective
treatment
Aggressive
Cytoreductive
Surgery ±
Postoperative adhesions
Low drug penetration 1-3mm
EPIC
HIPEC
(Early Post-operative IntraPeritoneal
Chemiotherapy)
(Hyperthermic IntraPeritoneal
Chemotherapy)
Peritoneal sarcomatosis
CYTORIDUCTIVE SURGERY
Peritoneal sarcomatosis
INTRAPERITONEAL CHEMOTHERAPY
RATIONALE
Body
Vd, [drug]
K
Clearance
Intercompartmental
Transport (IT)
Peritoneal cavity
Vd, [drug]
High MW
K > IT = ADVANTAGE
High Syst Cl
Peritoneal sarcomatosis
HIPEC TECHNIQUE
Peritoneal sarcomatosis
LOCOREGIONAL TREATMENT: EPIC/HIPEC
THE WASHINGTON CANCER INSTITUTE
N° of pts:
Recurrence rate:
Median Survival:
43
100%
20 months
Berthet B et al. Eur J Cancer, 1999
Peritoneal sarcomatosis
LOCOREGIONAL TREATMENT: EPIC
UCLA MEDICAL CENTER
N° of pts:
Recurrence rate:
Median Survival:
35
48%
24 mos
Eilber FC et al, Ann Surg Oncol, 1999
Peritoneal sarcomatosis
LOCOREGIONAL TREATMENT: EPIC
INSTITUT GUSTAVE ROUSSY
N° of pts:
38
Recurrence rate: 100%
Overall Survival: 29 months
Bonvalot S et al, EJSO, 2005
Peritoneal sarcomatosis
LOCOREGIONAL TREATMENT: HIPEC
PADOVA UNIVERSITY
Cytoreductive Surgery and Hyperthermic
Intra-Peritoneal Chemotherapy
(Phase I study)
RESULTS
DOXO:
15.25 mg/l
CDDP:
43.00 mg/l
Rossi CR et al, Cancer 2002
Peritoneal sarcomatosis
LOCOREGIONAL TREATMENT (HIPEC):
PHARMACOKINETICS OF DOXO
perfusate
plasma
Open symbols = DOXO
Filled symbols = CDDP
Rossi et al, Cancer 2002
Peritoneal sarcomatosis
LOCOREGIONAL TREATMENT (HIPEC):
PHARMACOKINETICS OF DOXO
PERITONEUM MUSCLE
FAT
TUMOR
Rossi et al., Cancer 2002
Peritoneal sarcomatosis
LOCOREGIONAL TREATMENT (HIPEC):
SITILO* EXPERIENCE
(Phase II study)
PTS:
HISTOL:
60
LIPO
14
OTHER 13
GRADING:
68%
32%
MORB
MORT
33%
0%
MEAN FU
28 mo
20
UTERUS 13
GIST
CC0
CC1
G1
23
G2-3
37
* ITALIAN SOCIETY FOR LOCOREGIONAL TREATMENT OF CANCER
Peritoneal sarcomatosis
LOCOREGIONAL TREATMENT (HIPEC):
SITILO EXPERIENCE
(Phase II study)
N° of pts:
Recurrence rate:
Overall Survival:
60
52%
34 months
Rossi et al, Cancer 2004
Peritoneal sarcomatosis
RESULTS OF THE DISEASE CONSENSUS VOTING
• PREOPERATIVE EVALUATION
• ELEGIBILITY
• METHODOLOGY
• FOLLOW – UP
• FUTURE INVESTIGATIONS
5th International Workshop on Peritoneal Surface Malignancy, Milano 2006
Peritoneal sarcomatosis
Results of the disease consensus voting
ELIGIBILITY
With regard to the non-GIST sarcomas,
may we foresee a role for HIPEC in the era
of molecularly targeted therapies?
YES
66,67%
NO
33,33%
With regard to the GIST model, may we
foresee a role for HIPEC in the era of
molecularly targeted therapies?
YES
50,00%
NO
50,00%
With regard to the GIST model, may we
foresee a role for HIPEC in patient non
responsive to targeted therapies?
YES
66,67%
NO
33,33%
5th International Workshop on Peritoneal Surface Malignancy, Milano 2006
Peritoneal sarcomatosis
Results of the disease consensus voting
ELIGIBILITY
Referring to retroperitoneal sarcomas,
pelvic sarcomas, GIST, is there any clinical
presentation in which abdominal
sarcomatosis could be treated today with
HIPEC outside a clinical study? In other
words, as of today, should we consider
HIPEC:
As of today's knowledge, which is the
selective contribution of cytoreductive
surgery, antiblastic perfusion and
hyperthermia to the potential efficacy of
HIPEC, if any, in abdominal
sarcomatosis?
With regard to non-GIST sarcomas,
which timing for HIPEC may we
foresee within combined approaches
incorporating pre/post-operative
chemotherapy?
Investigational only
58,33%
Suitable for individual clinical use in
selected patients
41,67%
Only for palliation
33,33%
For Locoregional Control
66,67%
For Improvement on survival
0,00%
At the time of primary tumor
treatment
At the time of recurrence
72,73%
Both
18,18%
9,09%
5th International Workshop on Peritoneal Surface Malignancy, Milano 2006
Peritoneal sarcomatosis
Results of the disease consensus voting
STATE OF THE ART OF METHODOLOGY
1-SURGERY: Definition of
Complete Cytoreductive
Surgery
cc-0:
Yes
No
100,00%
0,00%
• Is there a role for maximal palliative
cytoreduction in not amenable to radical
surgery?
• Is it sufficient a limited peritonectomy to the
affected area?
• Is it indicated a complete parietal
peritonectomy even in case of limited
affected area?
2- HIPEC: Role of HIPEC in Palliative/inoperable
cc-1:
Yes
No
62,50%
37,50%
YES
25,00%
NO
75,00%
YES
91,67%
NO
8,33%
YES
25,00%
NO
75,00%
YES
27,27%
NO
72,73%
5th International Workshop on Peritoneal Surface Malignancy, Milano 2006
Peritoneal sarcomatosis
Results of the disease consensus voting
STATE OF THE ART OF METHODOLOGY
Would you consider
single agent or
combination HIPEC
best?
What drugs would be
best to use HIPEC
combination agent
Single
0,00%
Combination
100,00%
1 cisplatin+mitomycin-C
0,00%
2 cisplatin+doxorubicin
100,00%
3 other
0,00%
5th International Workshop on Peritoneal Surface Malignancy, Milano 2006
Peritoneal sarcomatosis
Results of the disease consensus voting
FUTURE INVESTIGATIONS SHOULD BE DIRECTED
AT
Do you think it is necessary to
perform a large trial in order
to identify the role of CRS +
HIPEC in patients with
Peritoneal Sarcomatosis?
Should the patients be
randomized to CRS+HIPEC
vs. CRS alone
YES
91,67%
NO
8,33%
YES
91,67%
NO
8,33%
5th International Workshop on Peritoneal Surface Malignancy, Milano 2006
Peritoneal sarcomatosis
CONCLUSIONS
•
Chemotherapy +/- surgery +/- radiotherapy is the standard
palliative treatment for sarcomatosis and locally advanced
GISTs
•
Median survival after standard treatment is 12-24 months
for sarcomatosis before Imatinib (including GISTs)
•
Imatinib improves median survival up to 58 months in GISTs
(locoregional treatment excluded at present)
•
There is no sufficient evidence supporting the locoregional
treatment of sarcomatosis with surgery associated to
EPIC/HIPEC
•
Cytoreductive surgery and HIPEC should be further
investigated in sarcomatosis confined to the peritoneum or
imatinib resistant GISTs