Background
Stereotactic ablative body radiotherapy (SABR) is a non-invasive therapy for inoperable primary renal cell carcinoma. However, long-term prospective clinical trial data are scarce. We aimed to use pooled data from two clinical trials (FASTRACK and FASTRACK II) to evaluate activity and safety of SABR in the long term.
Methods
In this pooled analysis, we used data from FASTRACK, a single-institutional, phase 1, prospective clinical trial conducted at the Peter MacCallum Cancer Centre (Melbourne, VIC, Australia), and FASTRACK II, an international, non-randomised, phase 2 clinical trial conducted in seven academic hospitals in Australia and one in the Netherlands. The treatment protocol, inclusion and exclusion criteria, and dose constraints were the same in both trials. Patients had primary renal cell carcinoma and were deemed medically inoperable or high-risk for surgery, were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 2 or less, tumours of 10 cm or less in maximal dimension, and N0–N1 disease. Tumours 4 cm or smaller in FASTRACK II and smaller than 5 cm in FASTRACK received a single fraction of 26 Gy and larger tumours received 42 Gy in three fractions 48 h apart. Local control (freedom from local progression) was the primary endpoint, assessed using Response Evaluation Criteria in Solid Tumours (version 1.1) criteria. The analyses were conducted only in patients who commenced protocol treatment. Safety was evaluated with the Common Terminology Criteria for Adverse Events in participants who started protocol treatment. A patient representative was involved in the study design and conduct of FASTRACK II. Both trials were registered with ClinicalTrials.gov (FASTRACK: NCT01676428; FASTRACK II: NCT02613819) and are both completed.
Findings
108 patients were enrolled between June 28, 2012, and Oct 17, 2014 (FASTRACK), and between July 28, 2016, and Feb 27, 2020 (FASTRACK II). Five patients did not receive treatment (one opted for surgery, three did not meet dose constraints and were withdrawn, and one died before treatment). Median age was 76·9 years (IQR 70·0–81·9). 74 (72%) of 103 patients analysed were male and 29 (28%) were female. Race and ethnicity data were not collected. The median follow-up was 5·0 years (IQR 2·3–6·0). Local control at 1 year was 100%, at 3 years was 98% (89–100), and at 5 years was 98% (89–100), with local progression occurring in only one patient who had both local and distant progression at 28 months. Eight (8%) patients had grade 3 adverse events: abdominal or flank pain (four [4%] patients), nausea or vomiting (two [2%]), colonic obstruction (two [2%]), fatigue (one [1%]), and colitis or diarrhoea (one [1%]). All grade 3 or worse adverse events occurred within 2 years of SABR delivery. No grade 4 adverse events or treatment-related deaths were reported.
Interpretation
This pooled analysis from two clinical trials of SABR in patients with larger primary kidney tumours unsuitable for surgery supports evidence of long-term local control and low rate of severe adverse events. These results support further investigation through a randomised trial comparing SABR with surgery in select operable patients.
For many years, radiotherapy played only a marginal role in renal cell carcinoma (RCC), largely because of the historical perception that RCC is a radioresistant tumour. In the last few years, a consistently increasing body of literature has explored the role of stereotactic ablative body radiotherapy (SABR) for metastasis-directed therapy and more recently also for primary kidney cancer.
The FASTRACK trials have contributed significantly to the latter, and the present pooled analysis with 5-year follow-up provides the strongest prospective evidence available so far on the role of SABR for primary RCC. The study includes 103 patients treated within the FASTRACK and FASTRACK II trials, most of whom were elderly, medically frail, and considered poor candidates for surgery. This is an important point because these patients are frequently encountered in clinical practice and often present a therapeutic dilemma. While active surveillance may not always be appropriate, surgery and even thermal ablation can be challenging because of tumour size, anatomical location, or competing comorbidities.
Included patients had primary RCC 10 cm or less, N0–N1, with an ECOG performance status of 2 or less, and considered medically inoperable, high risk, or declined surgery. Patients were treated with a single treatment of 26 Gy for primary RCC < 5 cm in the FASTRACK trial and < 4 cm in the FASTRACK II. For larger tumours, a dose of 42 Gy in three fractions was delivered on non-consecutive days, 48 h apart. After a median follow-up of five years, local control was 98%, with only a single local failure observed, and cancer-specific survival was also 98%. Additionally, severe adverse events were uncommon (8% of patients had grade 3 adverse events; no grade 4–5 adverse events), with no reported toxicity after two years from the treatment. Mean baseline renal function was suboptimal (mean eGFR was 60 ml/min) and declined during the first two years after treatment but subsequently stabilised, with only two patients starting dialysis after treatment.
The results of this pooled analysis confirmed the durability of tumour control achieved with this approach. Equally important is the safety profile. From a practical perspective, delivering potentially curative treatment in one or three outpatient sessions without general anaesthesia, hospital admission, or recovery time is an attractive proposition, particularly for elderly patients with multiple comorbidities. Considering the relatively poor baseline renal function of this cohort and the fact that many lesions were larger than those usually considered suitable for other non-surgical managements, the overall renal outcomes appear clinically acceptable.
What makes this study particularly relevant is that it moves the discussion beyond feasibility. We now have prospective evidence showing that SABR can achieve durable local control with limited toxicity. However, a direct comparison of these results with the existing literature on either partial nephrectomy or thermal ablation cannot be made, due to the lack of comparative studies and differences in inclusion/exclusion criteria for accessing treatment. Therefore, cross-study comparisons must be interpreted cautiously.
The next challenge for the field is obvious. Randomised comparisons will be required to determine whether the excellent local control achieved with SABR can translate into equivalent long-term oncological outcomes of both surgery and thermal ablation. Such studies will not be easy to conduct, but they are now justified.