Stereotaxic Body Irradiation of Oligometastase in Sarcoma (Stereosarc)
Status:
Recruiting
Trial end date:
2026-12-01
Target enrollment:
Participant gender:
Summary
Up to 50% of soft tissue sarcoma (STS) patients will develop metastases in the course of
their disease. Cytotoxic therapy is a standard treatment in this setting but yields average
tumor response rates of 25% at first line and ≤10% at later lines. It is also limited in the
number of lines and courses by tolerance issues. Trials include poly/oligometastases
indistinctively and suggest that consolidation ablation is used in ~20% of patients with
residual oligometastases refractory to chemotherapy. Oligometastases represent a stage of
disease between completely absent and widely metastatic, and which might be cured if the
limited numbers of metastatic sites are eradicated. Ablative strategies to treat patients
with oligometastases from sarcomas yield prolonged survival times and stereotactic body
radiation therapy (SBRT) is associated with excellent tolerance. Surgery may be offered in
selected metastatic cases. Alternatively and increasingly, SBRT yields high control rates at
treated sites (≥ 80%). The so-called radioresistance of sarcomas is overcome by the high
doses per fraction made possible owing to the high precision achieved with SBRT. SBRT is an
accepted treatment strategy provided that tumor burden remains limited in the number and size
of metastases. Systemic treatment can be combined with SBRT. SBRT may produce abscopal
effects where tumors outside the irradiation area also demonstrate tumor shrinkage in some
occurrences. SBRT produces systemic antitumoral immune response in certain conditions and
enhances radiation-induced tumor cell death compared to conventional lower dose irradiation.
Abscopal effects have been potentialized with SBRT/immunotherapy in several tumor models.
Sarcomas are a privileged target tumor given their high metastatic propensity.
Several potent immunomodulators that skew the tumor immune microenvironment toward a
proimmunity context are being investigated in STS either alone or in combination with
chemotherapy or targeted therapy. The PD-1 receptor is present within the tumor
microenvironment, and limits the activity of infiltrating cytotoxic T lymphocytes, thus
blocking effective immune responses. The action of PD-1 is triggered upon binding to its
ligands. PD-1 can stimulate the immunosuppressive function of regulatory T cells. Moreover,
blockade of PD-1 can stimulate anti-tumor immune responses. Significant responses have been
obtained in several sarcomas with acceptable tolerance. Preliminary clinical experience
suggests that immunotherapy can be efficient in refractory leiomyosarcomas. Several drugs
targeting the PD-1/PD-L1/2 axis are ongoing either as single agents or in combination with
ipilimumab, kinase inhibitors, or chemotherapy in STS subtypes. Combination of radiotherapy
with immunotherapy is included as a means of increasing tumor antigen release in metastatic
STS. Immunomodulated SBRT is a particularly attractive strategy, given the potential of
radiation to induce cytotoxicity in tumors and induce abscopal effects. A phase II radiation
trial showed increased apoptosis-, intra-tumoral dendritic cells and accumulation of
intratumoral T cells in STS with correlation with tumor-specific immune responses.
We here propose a randomized phase II study to prolong progression-free survival (PFS) with
the combination of SBRT/immunotherapy in oligometastatic STS patients.
SBRT is well-tolerated with hardly any severe toxicity (fewer than 5% acute and late grade 3
toxicities). It is performed in an ambulatory setting in only a few treatment fractions.
Associations between irradiation and immunomodulatory agents appear to be synergistic and
show favorable tolerance profiles. Immunomodulatory agents have a more favorable toxicity
profile than cytotoxic agents with about 65% overall acute toxicities. Immunotherapy
selectively binds to PD-L1 and competitively blocks its interaction with PD-1.
Compared with anti-PD-1 antibodies that target T-cells, immunotherapy targets tumor cells,
and is therefore may induce fewer side effects, including a lower risk of autoimmune-related
safety issues, as blockade of PD-L1 leaves the PD-L2 - PD-1 pathway intact to promote
peripheral self-tolerance.
Stereotactic irradiation is associated with an excellent tolerance with rates of grade 3 or
more toxicities below 5%.
Preliminary data of toxicity with the association of stereotactic irradiation and
immunotherapy show no cumulative toxicity in association with immunotherapy. However, their
incidence and characteristics are no different from that observed with stereotactic
irradiation alone. Moreover, intracranial metastases are exceptional in sarcomas.
The toxicity of the association for extracranial stereotactic irradiation does not seem to be
increased either.
Phase:
Phase 2
Details
Lead Sponsor:
Centre Antoine Lacassagne
Collaborators:
Centre Hospitalier Universitaire de Caen Centre Hospitalier Universitaire de Caen Normandie Roche Pharma AG