Partial Tumor Irradiation Exploiting the Bystander and Abscopal Effects

Abstract

We have previously proved for the first time that high-single-dose irradiation of hypoxic tumor cells results in significant radiation-hypoxia-induced bystander (R-H-IBE) and abscopal effects (R-H-IAE). Our preclinical findings were recently translated to clinic leading to development of a novel radiotherapy technique for partial tumor irradiation (PTI) that exploits R-H-IBE and R-H-IAE. We hypothesized that irradiating exclusively the hypoxic tumor segment with high-single dose will generate a strong abscopal tumor-signaling leading to significant regression of partially targeted tumor (bystander effects) and non-targeted (metastatic) tumor sites (abscopal effect). The aims of this study were to assess the safety and feasibility of PTI and analyze its impact on induction of R-H-IBE and R-H-IAE. Our novel technique has been applied to hard to treat large (bulky) tumors. The primary endpoint was to assess a neoadjuvant potential of PTI to downsize bulky tumors by inducing a strong R-H-IBE converting in that way a palliative into a potentially curative treatment. Twenty oligometastatic patients with hypoxic bulky tumors were included in a presenting study. The targeted hypoxic tumor segment, a so-called “bystander tumor volume (BTV)”, was defined by using PET/CT (SUVmax cut-off value of 3). Exclusively the BTV (no additional margins were added to the BTV) was irradiated with 10 or 12Gy SBRT in a single fraction to the 70% isodose line (Dmax: 14.5 or 18 Gy, respectively). Treatment was delivered by 6MV flattening filter free photon beams. SBRT plan was calculated on Monaco treatment planning system. Before each treatment was performed, a kilovoltage cone-beam CT was carried out. No patient received chemotherapy or immunotherapy. Among 20 patients treated with PTI, in 95% a significant R-H-IBE (bulky shrinkage) and in 55% also R-H-IAE (regression of un-treated distant metastases) was observed. On an average, BTV corresponded to about 30% of bulky tumor mass (mean bulky volume 215 cc, mean diameter 9.1 cm). After a mean time of 3 weeks, average bulky shrinkage induced by the bystander effect was 60% (range: 40-100%) and mean reduction of the metastases was 50% (range: 50-100%). Disease-specific survival was 85%. None of the patients experienced acute or late toxicity of any grade. Median follow-up was 8 months (range: 4-20). PTI of bulky tumors was feasible, effective and without any toxicity. The results confirmed our hypothesis since in almost all cases unresectable partially irradiated bulky tumors were significantly down-sized and converted to radically treatable lesions. In addition, in a majority of cases regression of un-treated metastases was also induced. This 1-day neoadjuvant approach can improve therapeutic ratio and cost-effectiveness profile offering a very safe basis for further (re-)irradiation.