Experts express strong confidence in the effectiveness of radiation therapy for epithelioid sarcomas, noting the tumors are very sensitive to it. In difficult locally advanced cases, radiation is a key modality for gaining disease control and managing pain, with growing interest in combining it with immunotherapy to enhance its effects.
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Following high response rates to systemic therapies like EV Pembro, using radiation for bladder preservation is now questioned. It may constitute overtreatment by radiating a now cancer-free organ, while providing no benefit for the systemic micrometastases that are the primary driver of mortality.
Clinicians are concerned about the overuse of Stereotactic Body Radiation Therapy (SBRT) for oligoprogressive disease, a practice dubbed 'Pokemon' (gotta catch 'em all). This approach of sequentially radiating new lesions can delay the start of more effective systemic therapies and is not considered a standard of care.
Unlike traditional chemotherapy, radioligand therapy's toxicity may be inversely correlated with tumor volume. In low-burden disease, fewer cancer cells act as a 'sink' for the drug, potentially leading to higher radiation exposure and side effects in healthy, PSMA-expressing tissues like salivary glands.
A key investigational strategy for epithelioid sarcoma involves combining EZH2 inhibitors like tazometastat with checkpoint blockade immunotherapy. The biological rationale is that these drugs can alter the tumor microenvironment, potentially converting immunologically "cold" tumors to "hot" ones, making them more susceptible to immunotherapies.
A leading hypothesis for why adding immunotherapy to chemoradiation failed is that radiation, particularly for central tumors, destroys the very lymphocytes immunotherapy aims to activate. This biological mechanism suggests the radiation essentially canceled out the drug's intended effect.
For patients with very high-burden or symptomatic mesothelioma, clinicians may deviate from standard guidelines. They may choose chemo-immunotherapy to maximize the chance of a rapid response, viewing it as their single best opportunity to control the disease, especially if the patient's condition is precarious.
Frontline treatment selection hinges on histology. Non-epithelioid mesothelioma responds poorly to chemotherapy, making dual immunotherapy (Nivo/Ipi) the clear choice. For epithelioid cases, chemo-immunotherapy is a strong option, especially for symptomatic patients, due to its higher and faster response rate.
Dr. Radvanyi advocates for a paradigm shift: treating almost all cancers with neoadjuvant immunotherapy immediately after diagnosis. This "kickstarts" an immune response before standard treatments like surgery and chemotherapy, which are known to be immunosuppressive, can weaken the patient's natural defenses against the tumor.
For epithelioid sarcoma, the timeline of metastatic recurrence dictates treatment sequencing. Rapid progression (e.g., within three months of local therapy) indicates aggressive biology requiring fast-acting cytotoxic chemotherapy. The epigenetic drug tazometastat takes much longer to work and is better suited for slower-growing, asymptomatic disease.
Patients with technically stage IV but low-volume, oligometastatic gastric cancer may benefit from an aggressive approach. This involves powerful systemic therapy followed by reassessment and potential local consolidation, such as radiation to any remaining viable disease sites, challenging traditional palliative approaches.
