Abstract

Shankar Siva^1,2, Mathias Bressel³, Tao Mai⁴, Hien Le⁵, Shalini Vinod⁶, Harini de Silva⁷, Sean Macdonald⁷, Marketa Skala⁸, Nicholas Hardcastle⁹, Angela Rezo¹⁰, David Pryor⁴, Suki Gill¹¹, Braden Higgs⁵, Kassandra Wagenfuehr¹², Rebecca Montgomery¹², Raef Awad⁸, Brent Chesson¹³, Thomas Eade¹⁴, Wenchang Wong¹⁵, Giuseppe Sasso¹⁶, Richard De Abreu Lourenco¹⁷, Tomas Kron^9,2, David Ball^18,2, Paul Neeson^7,2

¹Peter MacCallum Cancer Centre, Radiation Oncology, Melbourne, Australia; ²The University of Melbourne, Sir Peter MacCallum Department of Oncology, Melbourne, Australia; ³Peter MacCallum Cancer Centre, Centre for Biostatistics and Clinical Trials, Melbourne, Australia; ⁴Princess Alexandra Hospital, Radiation Oncology Centre, Brisbane, Australia; ⁵Royal Adelaide Hospital, Department of Radiation Oncology, Adelaide, Australia; ⁶Liverpool Hospital, Cancer Therapy Centre, Sydney, Australia; ⁷Peter MacCallum Cancer Centre, Cancer Immunology Program, Melbourne, Australia; ⁸Royal Hobart Hospital, Radiation Oncology, Hobart, Australia; ⁹Peter MacCallum Cancer Centre, Department of Physical Sciences, Melbourne, Australia; ¹⁰Canberra Hospital, Radiation Oncology, Canberra, Australia; ¹¹Sir Charles Gairdner Hospital, Department of Radiation Oncology, Perth, Australia; ¹²Trans Tasman Radiation Oncology Group (TROG), Cancer Research, Sydney, Australia; ¹³Peter MacCallum Cancer Centre, Department of Radiation Therapy, Melbourne, Australia; ¹⁴Royal North Shore Hospital, Northern Sydney Cancer Centre, Sydney, Australia; ¹⁵Prince of Wales Hospital, Department of Radiation Oncology, Sydney, Australia; ¹⁶Auckland City Hospital, Radiation Oncology Department, Auckland, New Zealand; ¹⁷University of Technology Sydney, Centre for Health Economics Research and Evaluation, Sydney, Australia; ¹⁸Peter MacCallum Cancer Centre, Department of Radiation Oncology, Melbourne, Australia

There is no randomized evidence to guide the optimal approach for SABR in patients with pulmonary oligometastases. We conducted a randomized trial to determine whether single or multi-fraction SABR is optimal. We hypothesized that each arm had acceptable adverse events (AEs), efficacy and quality of life effects, but that single fraction SABR was cost-effective.

The TransTasman Radiation Oncology Group (TROG) 13.01 SAFRON II study was a multicenter unblinded randomized phase II trial across 13 centers in Australia and New Zealand. Enrolment was between 2015 and 2018, with a minimum patient follow-up of 2 years. Participants had 1–3 oligometastases of <5cm diameter to the lung from any non-haematological malignancy, located away from central airways, ECOG 0-1, and all primary and extrathoracic disease controlled with local therapy. The interventions were either a Single fraction of 28Gy (SF Arm) or four fractions of 12Gy (MF Arm) to each oligometastasis. The primary outcome was grade ³3 treatment related AEs (CTCAE v4.0) occurring within 1 year of SABR. Secondary outcomes were freedom from local failure (FFLF), overall survival (OS), disease free survival (DFS) and patient reported outcomes (MDASI-LC and EQ-5D VAS). Exploratory baseline and post-treatment peripheral blood was collected in a subset of participants from a single center for translational analysis. Health care resource use, including patient time, and EQ-5D-5L quality of life measures for the assessment of cost-effectiveness were prospectively collected.

90 participants were randomized, with n = 87 treated for 133 pulmonary oligometastases. Median follow-up was 36.5 months. Median age was 68 years, 64% were male. Grade ³3 AEs in the MF Arm and SF Arm were 3% [80% CI: 0-10] and 5% [80% CI: 1-13], p = 0.37. There was one grade 5 AE in the MF arm. There were no significant differences between the MF Arm and SF Arm for FFLF (HR 0.5, [95% CI: 0.2-1.3], p = 0.13), OS (HR 1.5 [95% CI: 0.6-3.7], p = 0.44), or DFS (HR 1.0, [95% CI: 0.6-1.6], p = 1.00). The areas under the curve for each of the MDASI-LC subscales and EQ-5D VAS were no different between arms (p-values 0.12-0.95). Both regimens induced changes in the frequency of immune cell subsets in peripheral blood with potentially altered function (expression of PD-1, TIGIT and CTLA-4 checkpoints) and plasma cytokine levels. Costs for radiotherapy delivery were A$4,943 for the SF Arm and A$6,320 for the MF Arm. For the within trial period, the average cost was estimated to be A$41,700 in the SF Arm and A$39,251 in the MF Arm, with 2.43 quality-adjusted life-years (QALYs) in the SF arm and 2.25 QALYs in the MF arm. The incremental cost-effectiveness ratio for SF SABR compared with MF SABR was A$13,597/QALY gained.

Neither arm demonstrated evidence of superior safety, efficacy or symptom burden. SF SABR is likely to be cost-effective at common thresholds of cost-effectiveness. Trial Registration: Clinicaltrials.gov ID:NCT01965223