Milan inter-group consensus forum on adult soft tissue sarcomas Panel 1 Pathology Panel 2 Local treatment Panel 3 Systemic treatment Plenary discussion Consensus Teleconference EUR-US Milan, 1-2 February 2001

Adjuvant chemotherapy... surg + RT + CT surg + RT

EORTCopen trial with a “non-CT” arm (some center might avoid to include some pts) SSG“treatment protocol”: DOX+IFX x 6 in all high-risk pts (incl. visceral sarcomas) FSG/SORadjuvant CT is an “option” GEIShigh-risk pts receive adjuvant CT in many centers ISGopen trial with CT in both arms

Metastatic disease... DOX+IFX DOX

EORTCopen trials with single agent CT (some pts might not be included, but single agent CT is a “standard”) FSG/SORsingle agent CT is a “standard” SSGDOX+IFX in some pts GEISDOX in some pts ISGDOX+IFX in most pts

All these data would strongly suggest that adjuvant chemotherapy may be effective, especially in high risk presentations, but, as of today, there is no consensus on the adoption of adjuvant chemotherapy as standard practice in soft tissue sarcomas. Randomized trials with a no-treatment arm are still ongoing in Europe. Adjuvant chemotherapy may thus be considered investigational or suitable for individual clinical use in selected patients, on a type 2 level of evidence, i.e. in those with bad prognostic factors (high grade, tumour diameter 5-10 cm., deep location) within an individualized shared decision making with a fully informed patient. In other terms, the patient should be aware that standard treatment is surgery ± radiotherapy, without chemotherapy, but that there are strong suggestions that adjuvant chemotherapy might give some reduction (higher than or equal to 5-10% in absolute terms) of the risk of relapse (which averages 50% or more in high-risk soft tissue sarcomas, depending on the presentation). Chemotherapy could also be suitable for individual clinical use, on a type R basis. in those cases in which a high risk sarcoma could not be treated at best with surgery and radiotherapy, for instance a trunk high grade sarcoma which could not be treated with truly adequate surgery and full dose radiotherapy. Even in these cases no formal demonstration has been published of the effectiveness of adjuvant chemotherapy in terms of survival and disease free survival. There are some suggestions, however, from some of the published trials on adjuvant chemotherapy and to the meta-analysis, that the medical treatment might somewhat decrease the local risk of relapse.

The Community of European Sarcoma Groups… Milan, February 2001 Milan, June 2004 Trieste, May 2005

CONSENSUS STATEMENTS ON STATE-OF-THE-ART TREATMENT OF ADULT SOFT TISSUE SARCOMA AND GIST FROM THE COMMUNITY OF EUROPEAN SARCOMA GROUPS to be submitted for publication by end 2005 and released on the Web

GIST StandardIndividualizedInvestigational GI swellingBiopsy (endoscopic)Follow-up IF <1 cm Abdominal massCore needle biopsy OR Fine needle aspiration biopsy Laparoscopic biopsy Surgery Very low risk localized Surgery: Complete open excision (R0) Surgery: Complete open surgical excision (R1) Low risk localized Surgery: Complete open excision (R0) Surgery: Complete open surgical excision (R1) Intermediate / high risk localized Surgery: Complete open excision (R0) Surgery: Complete open surgical excision (R1) Surgery: Complete open surgical excision (R0-1) + Adjuvant Imatinib Localized not suitable for conservative surgery Mutilating surgery + Adjuvant Imatinib Imatinib + R0/R1 surgery Imatinib + Conservative surgery Metastatic / Locally unresectable non previously treated Imatinib 400 mg daily + Surgery/ablation of residual disease (generally after >6-12 mos) plus maintainance of Imatinib 400 mg daily Complete surgery + Imatinib Metastatic / Locally unresectable Resistant to Imatinib Primary resistanceFurther generation molecular targeted agents Secondary resistanceImatinib dose escalation up to 800 mg daily Surgery of “partially” progressive disease + Imatinib 800 mg daily Further generation molecular targeted agents

Localized resectablesurgery + RT surgery + RT  adjuvant CT CT  surgery + RT Recurrent localizedsurgery + RT surgery + RT  adjuvant CT CT  surgery + RT ILP  surgery + RT Localized unresectableCT + RT  surgery + RT ILP  surgery + RT Isolated lung metastasessurgery + CT* Extrapulmonary metastases /CT* / unop. / recurrentbest supportive care *CT = ADM+IFX, ET743 (lipos, lms), GEM+taxanes (lms), taxanes (angiosa), Phase II studies standard individualized investigational EUR Community SA Groups Consensus

Localized VLR, LRcomplete surgery Localized IR, HRcomplete surgery surgery  Imatinib Localized unresectablemutilating surgery conservativelyImatinib  R0/R1 surgery Imatinib  conservative surgery Metastatic / locally advancedImatinib (400mg) Imatinib (400mg)  surgery surgery  Imatinib Imatinib-resistantImatinib 800mg Surgery  Imatinib 800mg Further generation agents standard individualized investigational EUR Community SA Groups Consensus

Standard Investigational A third option…

Standard Individualized Investigational A third option…

A third option... standard investigational …acceptable within an individualized, patient-physician shared decision-making process

A “consensus” expert effort…

State of the art vs CPG...

An effort to prompt coordination of clinical research on STS/GIST in Europe…