Phase 2 trial: serial metastasis-directed therapy in oligometastatic clear-cell renal-cell carcinoma

Evidence before this study

We searched PubMed for all studies published in English from database creation to Feb 1, 2025, using the terms “renal cell carcinoma” or “kidney cancer”, “radiation” or “radiotherapy”, and “oligometastatic”. We identified two prospective studies that assessed definitive radiotherapy for oligometastatic renal-cell carcinoma without systemic therapy, one of which was our previously published feasibility study. An additional prospective study tested definitive radiotherapy with systemic therapy in oligometastatic renal-cell carcinoma. None of the prospective studies identified prognostic markers. At least ten retrospective reviews and one meta-analysis were also identified. Several baseline prognostic factors were identified in retrospective reviews, including time from metastasis diagnosis to radiotherapy, International Metastatic Renal Cell Carcinoma Database Consortium risk group, metastasis number, presence of brain or bone metastases, and non-clear-cell histology. An additional manual search to identify “all histology” registries investigating radiotherapy for oligometastatic disease and enrolling more than 1000 patients identified two registries. The UK National Health Service registry reported on 1422 patients, including 143 patients with renal-cell carcinoma, while the European Organisation for Research and Treatment of Cancer OligoCare registry reported on 1597 patients but did not specify the number of patients with renal-cell carcinoma. The current phase 2 trial was designed to test the efficacy of serial metastasis-directed therapy without systemic therapy for patients with clear-cell renal-cell carcinoma in a larger clinical trial. Given the observed absence of identified prognostic markers from prospective trials, we undertook an exploratory analysis to evaluate the prognostic ability of baseline clinical factors and circulating tumour DNA (ctDNA).

Added value of this study

To the best of our knowledge, this is the largest clinical trial with the longest follow-up to evaluate sequential metastasis-directed therapy without systemic therapy for oligometastatic renal-cell carcinoma. We found that this treatment strategy facilitated prolonged deferral of systemic therapy in addition to exhibiting promising progression-free survival and overall survival. This approach was associated with modest toxicity. In addition to the baseline clinical variables number of metastatic lesions and previous lines of systemic therapy, ctDNA at baseline and at the 3-month follow-up was associated with systemic therapy-free survival.

Implication of all the available evidence

The current study shows that serial metastasis-directed therapy can prolong systemic therapy-free interval while maintaining promising progression-free survival and preserving overall survival. We found that the baseline number of metastatic lesions and previous lines of systemic therapy in addition to ctDNA were prognostic and thus might help to guide personalised treatment selection. Ultimately, metastasis-directed therapy can enable meaningful treatment de-escalation in a subset of patients, potentially improving quality of life and reducing health-care costs.

Source: The Lancet Oncology