Stereotaxic Body Irradiation of Oligometastase in Sarcoma (Stereosarc)

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.