Novel stereotactic body radiation therapy (SBRT)-based partial tumor irradiation targeting hypoxic segment of bulky tumors (SBRT-PATHY): improvement of the radiotherapy outcome by exploiting the bystander and abscopal effects

Abstract

BackgroundDespite the advances in oncology, patients with bulky tumors have worse prognosis and often receive only palliative treatments. Bulky disease represents an important challenging obstacle for all currently available radical treatment options including conventional radiotherapy. The purpose of this study was to assess a retrospective outcome on the use of a newly developed unconventional stereotactic body radiation therapy (SBRT) for PArtial Tumor irradiation of unresectable bulky tumors targeting exclusively their HYpoxic segment (SBRT-PATHY) that exploits the non-targeted effects of radiotherapy: bystander effects (local) and the abscopal effects (distant).Materials and methodsTwenty-three patients with bulky tumors received partial bulky irradiation in order to induce the local non-targeted effect of radiation (bystander effect). The hypoxic tumor segment, called the bystander tumor volume (BTV), was defined using PET and contrast-enhanced CT, as a hypovascularized-hypometabolic junctional zone between the central necrotic and peripheral hypervascularized-hypermetabolic tumor segment. Based on tumor site and volume, the BTV was irradiated with 1–3 fractions of 10–12 Gy prescribed to 70% isodose-line. The pathologic lymph nodes and metastases were not irradiated in order to assess the distant non-targeted effects of radiation (abscopal effect). No patient received any systemic therapy.ResultsAt the time of analysis, with median follow-up of 9.4 months (range: 4–20), 87% of patients remained progression-free. The bystander and abscopal response rates were 96 and 52%, respectively. Median shrinkage of partially irradiated bulky tumor expressing intensity of the bystander effect was 70% (range 30–100%), whereas for the non-irradiated metastases (intensity of the abscopal effect), it was 50% (range 30–100%). No patient experienced acute or late toxicity of any grade.ConclusionsSBRT-PATHY showed very inspiring results on exploitation of the radiation-hypoxia-induced non-targeted effects that need to be confirmed through our ongoing prospective trial.Present study has been retrospectively registered by the local ethic committee under study number A 26/18.

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

“…Our preclinical findings indicated that the hypoxic in respect to normoxic tumor cells, if selectively irradiated as inductor of BE/AE, show higher potential for the generation of BE/AE [3]. The subsequent translation of these findings to a clinic led to the introduction of a novel SBRT-based PArtial Tumor irradiation targeting HYpoxic clonogenic cells (SBRT-PATHY) showing promising BE/AE-response rates [2,4]. Recently, the Italian group confirmed efficacy of SBRT-PATHY in their initial experience [5].…”

“…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.…”

“…Recently, the Italian group confirmed efficacy of SBRT-PATHY in their initial experience [5]. Considering the immune-mediated nature of BE/AE and in order to further improve BE/AE response rate, SBRT-PATHY was upgraded in 2018 by the sparing of peritumoral immune microenvironment as a new OAR, defined by its own dose-constraints [4,6]. 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.…”

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].…”