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

Two weeks prior to initiation of SBRT-PATHY, serial (7x) bloods were taken from each patient every second day and assayed for serum biomarkers such as High Sensitive C-Reactive Protein (HS-CRP), Lactate Dehydrogenase (LDH) and also Lymphocyte/Monocyte Ratio (LMR). Data from the assays were analysed to define cyclical fluctuations using high-order polynomial trend analysis. In order to determine each patient’s idiosyncratic immune cycle periodicity, the trend/periodicity analysis was performed to generate a standard sine wave of similar periodicity (over several cycles) and visually overlayed and aligned (peak & trough) on the generated polynomial trend graph. This alignment was done in order to project forward in time to the designated/putative treatment date(s) (Figs. 1 and 2). After the biomarker data analysis detected the immune fluctuations and related idiosyncratic immune cycle periodicity, we determined the “most favourable” and “least favourable” treatment time-positions in the immune cycle. As the biomarkers we used are known to rise and fall periodically over several days with the initiation and then homeostatic termination of the immune response [13, 17], we defined a pre-trough time-position as the “most favourable” treatment phase in the immune cycle, while a pre-peak region as the “least favourable” day for SBRT-PATHY. In order to evaluate the impact of an idiosyncratic immune cycle on treatment outcomes, our first consecutive four patients were treated on the “most favourable” while the remaining four on the “least favourable” day.

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 central-necrotic and the remaining peripheral-vascularized tumor segments, which was then irradiated with 10Gy × 3 to the 70%-isodose line (Fig. 3).

Eight patients with symptomatic, unresectable bulky tumors were prospectively treated between November 2017 and July 2019 with time-synchronized immune-guided SBRT-PATHY. All patients presented either distant metastases or regional metastatic lymph nodes that were not irradiated but followed for AE-induction. The treated patients’ main characteristics are summarized in Table 1. Two of eight patients previously received chemotherapy and immunotherapy, and both developed disease progression prior to SBRT-PATHY. No patient received any systemic treatment concomitant with SBRT-PATHY or before the second follow up after it. Two patients which previously received systemic treatment, continued with their treatment after 2 months post-SBRT-PATHY. The response evaluation was performed following the RECIST criteria at 1 month after the treatment by using CT and/or PET-CT, followed by repeated scans at month 2 and then every 3 months. Toxicity was evaluated using the CTCAE Criteria v5.0. All procedures performed in the present study were in accordance with the ethical standards. All the patients signed the informed consent. Present study has been registered by the local ethic committee under study number A 37/19.

The biomarker data analysis showed immune response fluctuations (Fig. 2) which were synchronized, following similar, regular frequency. The mean immune cycle duration was 7.3 days (range: 6.5–10). The average HS-CRP and LDH concentrations were 2.92 mg/dl (range: 0.13–7.35) and 492.8 (range: 163–1080), respectively.

The median follow-up was 11.8 months (range: 4–22). 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. A significant BE (defined as a 30% or greater regression of partially treated bulky tumor) was observed in all four patients treated at “most favourable” time-position (including those two previously being in progression under systemic treatment) with an average tumor shrinkage of 100% (three complete responses (CR), one 80% tumor regression), while among those treated at “least favourable” time-position in two patients with an average tumor shrinkage of 35% (one CR, one 50% tumor regression, two stable bulky tumors reduced for 25%). Significant AE was observed in three patients treated at “most favourable” time-position (in lung and lymph node metastases, and in primary breast cancer) (Fig. 4), while in one among those treated at “least favourable” time-position (in lymph node metastases). Two patients with CR (one from each treatment group) were submitted two months after SBRT-PATHY to surgery, which confirmed pathologic CR at the level of the partially treated bulky tumor but also regional unirradiated lymph node metastases in both patients. Six out of eight patients were free from progression among which all four which were treated at “most favourable” day. In all these four patients was also achieved the symptom relief while among those treated at “least favourable” day it was observed in three patients. Four patients (two from each treatment group) experienced fatigue grade 1. No patient reported any late toxicity.