Mono-institutional phase 2 study of innovative Stereotactic Body RadioTherapy targeting PArtial Tumor HYpoxic (SBRT-PATHY) clonogenic cells in unresectable bulky non-small cell lung cancer: profound non-targeted effects by sparing peri-tumoral immune microenvironment

Abstract

BackgroundRadiotherapy-induced lymphopenia may be limiting the success of therapy and could also negatively affect the ability of immune system in mediating the bystander (BE) and abscopal effects (AE). A novel SBRT-based PArtial Tumor irradiation of HYpoxic clonogenic cells (SBRT-PATHY) for induction of the tumoricidal BE and AE by sparing the peritumoral immune microenvironment and regional circulating lymphocytes has been developed to enhance the radiotherapy therapeutic ratio of advanced lung cancer. The aim of this retrospective review of prospectively collected mono-institutional phase 2 study was to compare the outcomes between unconventional SBRT-PATHY and standard of care in unresectable stage IIIB/IV bulky NSCLC.Materials and methodsSixty patients considered inoperable or unsuitable for radical radio-chemotherapy were enrolled and treated using the following 3 regimens: SBRT-PATHY (group I, n = 20 patients), recommended standard of care chemotherapy (group II, n = 20 patients), and institutional conventional palliative radiotherapy (group III, n = 20 patients).ResultsMedian follow-up was 13 months. The 1-year overall survival was 75, 60, and 20% in groups 1, 2 and 3, respectively (p = 0.099). The 1-year cancer specific survival was 90, 60, and 20% in groups 1, 2, and 3, respectively (p = 0.049). Bulky tumor control rate was 95% for SBRT-PATHY compared with 20% in the other two groups. BE and AE were seen by SBRT-PATHY in 95 and 45% of patients, respectively. Multi-variate analysis for cancer specific survival was significant for treatment effect with SBRT-PATHY (p < 0.001) independent of age, sex, performance status, histology, stage, treated bulky site and tumor diameter. SBRT-PATHY resulted in lower toxicity (p = 0.026), and improved symptom control (p = 0.018) when compared to other two treatment options.ConclusionSBRT-PATHY improved treatment outcomes in unresectable NSCLC and should be investigated in larger trials.Present study has been retrospectively registered on 8th of August 2019 by the ethic committee for Austrian region „Kärnten “in Klagenfurt (AUT), under study number A 31/19.

Time-synchronized immune-guided SBRT partial bulky tumor irradiation targeting hypoxic segment while sparing the peritumoral immune microenvironment

“…SBRT-PATHY target definition and radiotherapy technique have been previously described in detail [7]. We used a combination of CT and 18F-FDG-PET to define the hypovascularized (contrast-hypo-enhanced) and hypometabolic (SUV max < 3) tumor region representing the "hypoxic" segment between the centralnecrotic and the remaining peripheral-vascularized tumor segments, which was then irradiated with 10Gy × 3 to the 70%-isodose line (Fig.…”

“…The median follow-up was 11.8 months (range: [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. At the time of analysis, one patient (treated at "most favourable" time-position) had died 22 months after SBRT-PATHY because of causes other than cancer.…”

“…Our concept implied that for successful therapeutic immune modulation, the entire tumor volume may not need to be irradiated but only a part of the tumor. This should initiate antigen shedding, increase effector T cell activation and lead to favorable alterations in radiation-spared peritumoral immune environment [7].…”

Spatially fractionated radiotherapy (SFRT) targeting the hypoxic tumor segment for the intentional induction of non-targeted effects: An in silico study to exploit a new treatment paradigm

“…Based on the preclinical finding that irradiating the hypoxic fraction of the tumor may intentionally induce non targeted effects, they proposed a new irradiation technique that consists of stereotactic body radiotherapy for partial irradiation of bulky tumors (larger than 6 cm), targeting exclusively their central hypoxic segment (SBRT-PATHY) with high dose (10 Gy). With SBRT-PATHY, they recently observed impressive results in a small retrospective clinical series with local and abscopal response rate of more than 90 and 50%, respectively [2,3].…”

“…Tubin and colleagues used VMAT to deliver 1-3 fractions each of 10-12 Gy of SBRT-PATHY in lesions of more than 6 cm, with the aim of keeping the dose within the peritumoral tissue as low as reasonably achievable. The dose was prescribed to the 70% isodose-line, however there is no particular mention that this prescription method has been chosen to reduce the dose to the tumor periphery [2,3].…”