Padova, 30 maggio 2008 Carlo Riccardo Rossi Unità Melanoma e Sarcomi Clinica Chirurgica II -...

Padova, 30 maggio 2008

Carlo Riccardo RossiUnità Melanoma e Sarcomi

Clinica Chirurgica II - Università di Padova

Ha uno spazio la chirurgia Ha uno spazio la chirurgia nella sarcomatosi retroperitoneale?nella sarcomatosi retroperitoneale?

Aggiornamento in tema di Sarcomi delle Parti Molli e Aggiornamento in tema di Sarcomi delle Parti Molli e GISTGIST

SPREAD OF SOFT TISSUE SARCOMAS (STS) OR GISTs

THROUGHTOUT THE ABDOMEN (WITHOUT DISTANT METASTASES)

DEFINITIONDEFINITION

Peritoneal sarcomatosis

RETROPERITONEAL SARCOMASLOCAL RECURRENCE AND SURVIVAL

Author Year LocalRecurrence (%)

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


GISTs

LOCAL RECURRENCE AND SURVIVAL

Author Year LocalRecurrence (%)

5 yrs Survival

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

Before Imatinib advent


TREATMENT:STATE OF THE ART

•Systemic

•Locoregional


• Antracyclin +/- ifosfamide

• Gemcitabine +/- docetaxel leiomyosarcoma

• Trabectedine (ET-743) liposarcomaleiomyosarcoma

• Imatinib

STANDARD TREATMENT (SYSTEMIC CHEMOTHERAPY + SURGERY)

Response rate: 20-40%

Median survival 12-24 mos

Response Rate: 50-85%

Overall 2 yr survival: 71%

Retroperitoneal Sarcomas

GISTs


SYSTEMIC CHEMOTHERAPY + PALLIATIVE SURGERY

MD ANDERSON CANCER CENTER EXPERIENCE

Bilimoria et al., Cancer 2001

N° of pts: 51

Recurrence rate: 72 %

Median Survival: 22 mos


AggressiveCytoreductiveSurgery ±

LOCOREGIONAL TREATMENT

EPIC

HIPEC

Postoperative adhesionsLow drug penetration 1-3mm

Barriers to effective treatment

(Early Post-operative IntraPeritonealChemiotherapy)

(Hyperthermic IntraPeritoneal Chemotherapy)


CYTORIDUCTIVE SURGERYCYTORIDUCTIVE SURGERY


BodyVd, [drug]

Peritoneal cavityVd, [drug]

ClearanceK

Intercompartmental

Transport (IT)

K > IT = ADVANTAGEHigh MW

High Syst Cl

INTRAPERITONEAL CHEMOTHERAPYINTRAPERITONEAL CHEMOTHERAPY

RATIONALERATIONALE


HIPEC TECHNIQUEHIPEC TECHNIQUE


LOCOREGIONAL TREATMENT:EPIC/HIPEC

THE WASHINGTON CANCER INSTITUTE

N° of pts: 43Recurrence rate: 100%Median Survival: 20 months

Berthet B et al. Eur J Cancer, 1999


Eilber FC et al, Ann Surg Oncol, 1999

UCLA MEDICAL CENTER

N° of pts: 35Recurrence rate: 48%Median Survival: 24 mos

LOCOREGIONAL TREATMENT: EPIC


INSTITUT GUSTAVE ROUSSY

Bonvalot S et al, EJSO, 2005

N° of pts: 38

Recurrence rate: 100%

Overall Survival: 29 months

LOCOREGIONAL TREATMENT: EPIC


LOCOREGIONAL TREATMENT: HIPEC

Rossi CR et al, Cancer 2002

DOXO: 15.25 mg/l

CDDP: 43.00 mg/lRESULTS

PADOVA UNIVERSITY

Cytoreductive Surgery and Hyperthermic Intra-Peritoneal Chemotherapy

(Phase I study)


perfusate

plasma

Open symbols = DOXO

Filled symbols = CDDP

Rossi et al, Cancer 2002

LOCOREGIONAL TREATMENT (HIPEC):PHARMACOKINETICS OF DOXO


LOCOREGIONAL TREATMENT (HIPEC): PHARMACOKINETICS OF DOXO

Rossi et al., Cancer 2002

PERITONEUM MUSCLE FAT TUMOR


LOCOREGIONAL TREATMENT (HIPEC):SITILO* EXPERIENCE

(Phase II study)

CC0CC1

68%32%

MORBMORT

33%0%

MEAN FU 28 mo

PTS: 60

HISTOL: LIPO 20

UTERUS 13

GIST 14

OTHER 13

GRADING: G1 23

G2-3 37

* ITALIAN SOCIETY FOR LOCOREGIONAL TREATMENT OF CANCER


N° of pts: 60

Recurrence rate: 52%

Overall Survival: 34 months

Rossi et al, Cancer 2004

LOCOREGIONAL TREATMENT (HIPEC):SITILO EXPERIENCE

(Phase II study)


• PREOPERATIVE EVALUATION

• ELEGIBILITY

• METHODOLOGY

• FOLLOW – UP

• FUTURE INVESTIGATIONS

RESULTS OF THE DISEASE CONSENSUS VOTING


5th International Workshop on Peritoneal Surface Malignancy, Milano 2006

YES 66,67%

NO 33,33%

YES 50,00%

NO 50,00%

With regard to the non-GIST sarcomas, may we foresee a role for HIPEC in the era of molecularly targeted therapies?

With regard to the GIST model, 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 patient non responsive to targeted therapies?

Results of the disease consensus votingELIGIBILITY



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%

Results of the disease consensus votingELIGIBILITY

At the time of primary tumor treatment

9,09%

At the time of recurrence 72,73%

Both 18,18%

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?



cc-0:

Yes No

100,00% 0,00%

cc-1:

Yes No

62,50% 37,50%

YES 25,00%

NO 75,00%

Results of the disease consensus votingSTATE OF THE ART OF METHODOLOGY

YES 91,67%

NO 8,33%

YES 25,00%

NO 75,00%

YES 27,27%

NO 72,73%

1-SURGERY: Definition of Complete Cytoreductive Surgery

• 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



Single 0,00%

Combination 100,00%

1 cisplatin+mitomycin-C 0,00%

2 cisplatin+doxorubicin 100,00%

3 other 0,00%

Would you consider single agent or combination HIPEC best?

What drugs would be best to use HIPEC combination agent

Results of the disease consensus votingSTATE OF THE ART OF METHODOLOGY



YES 91,67%

NO 8,33%

Results of the disease consensus votingFUTURE INVESTIGATIONS SHOULD BE

DIRECTED AT

YES 91,67%

NO 8,33%

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



• 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

CONCLUSIONS


Padova, 30 maggio 2008 Carlo Riccardo Rossi Unità Melanoma e Sarcomi Clinica Chirurgica II -...

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