ESTRO 2020 Abstract Book

S25 ESTRO 2020

use of H-RT in elderly men and those with locally advanced PCa. PD-0061 Does the dose to penile bulb/internal pudendal arteries matter for erectile dysfunction post- SBRT? G. Lamanna 1 , S. Jorcano 2 , S. Bral 3 , C. Rubio 4 , A. Oliveira 5 , M. Bottero 1 , U. Abacioglu 6 , V. Achard 1 , H. Minn 7 , Z. Symon 8 , T. Zilli 1 , R. Miralbell 1,2 1 HUG, Radiotherapy, Genève, Switzerland ; 2 Teknon Oncologic Institute, Radiotherapy, Barcelona, Spain ; 3 Onze-Lieve-Vrouwziekenhuis- Aalst- Belgium, Radiotherapy, Aalst, Belgium ; 4 HospitalUniversitario HM Sanchinarro- Madrid- Spain, Radiotherapy, Madrid, Spain ; 5 Portuguese Institut of Oncology- Porto- Portugal, Radiotherapy, Porto, Portugal ; 6 Neolife Medical Center, Radiotherapy, Istanbul, Turkey ; 7 University Hospital Turku, Radiotherapy, Turku, Finland ; 8 Sheba Medical Center, Radiotherapy, Ramat Gan, Israel Purpose or Objective Stereotactic body radiotherapy (SBRT) is an emerging treatment option for localized prostate cancer(PCa) patients that,despite the overall low toxicity profile, lead to erectile dysfunction (ED) as a common side effect. The dose to the penile bulb (NTD 2Gy D 2% <50 Gy and D mean <20 Gy, Rasmusson et al. ASTRO 2019) and to the internal pudendal arteries (IPA)/crura (NTD 2Gy ≤ 36/30 Gy, Spratt DE et al. Eur Urol 2017) have been strongly correlated with ED. In this study we aimed to assess the correlation between the dose to the penile bulb and IPA with the development of ED after extreme hypofractionation as part of a phase II randomized trial of once-a-week (QW) versus every-other- day (EOD) urethra sparing prostate SBRT (NCT01764646). Material and Methods Between 2012 and 2015, 170 patients with localized PCa from 9 centers were randomized to receive 36.25Gy in 5 fractions (6.5Gy x 5 to the urethra) delivered either EOD (arm A, n=84), or QW (arm B, n=86) with 25% of them receiving 6 months of androgen deprivation therapy. At baseline, 87 patients aged between 50 and 80 yo (median 69) presented with grade 0-1 ED (CTCAE v4.0 grading scale). The penile bulb, the crura, and the IPA D mean and D 2% were recorded to find a correlation with an eventual development of ED.The impact on QoL ( i.e. , difficulty getting or maintaining an erection based on the EORTC PR- 25 questionnaire) was also assessed. Results After a median follow-up of 36 months (range 15-49), only 19.5% (n=17) of patients developed a grade 2-3 ED with no differences regarding age (years ≤ 65 vs. > 65) or penile base structure and prostate PTV volumes. D mean and D 2% of IPA were: 13.3 Gy vs . 13.9 Gy and 19.9 Gy vs. 21.7 Gy for grade 0-1 ED (ED-) vs. grade 2-3 ED (ED+), respectively; for the crura: 4.7 Gy vs. 4.8 Gy and 12 Gy vs. 14.1 Gy for ED- vs. ED+, respectively; and for the penile bulb: 6 Gy vs. 6.8 Gy and 21.4 Gy vs. 20.3 Gy, for ED- vs. ED+, respectively (p=NS). At last follow-up, 70% of the patients (n=44/63) reported moderate to high ED based on the EORTC PR-25 QoL patient self-evaluation questionnaire, with no dose- volume-effect correlations too. Conclusion ED rates following urethra sparing SBRT in our study seem to be promising. The low doses delivered to penile base structures, below published threshold constraints predictive of ED, may explain the minimal impact of SBRT on erectile function and the lack of dose-volume-effect correlation differences between patients with or without severe ED. Longer follow-up is needed to confirm these findings.

IPA

IPA Penile Bulb Penile Bulb Crura Crura

Dmean D2% Dmean

D2% 21.4 20.3

Dmean D2%

ED - 13.3 19.9 6 ED + 13.9 21.7 6.8

4.7 4.8

12

14.1 Table: Dmean and D2% (in Gy) to the internal pudendal arteries (IPA), the penile bulb, and the crura and erectile dysfunction (ED)

Poster discussion: Radiobiology

PD-0062 Clinical modulation of tumour immune infiltrates and plasma cytokines by ATR inhibition ± radiation M. Dillon 1 , M. McLaughlin 1 , E. Patin 1 , P. Malin 1 , C. Ragulan 1 , F. Elisa 1 , A. Wilkins 1 , A. Melcher 1 , K. Harrington 1 1 Institute of Cancer Research, Chester Beatty Laboratories, London, United Kingdom Purpose or Objective ATR is an apical kinase in the DNA damage response (DDR). ATR inhibitors (ATRi) are currently in phase I clinical studies as monotherapy and as novel radiosensitizers [1]. Our group has previously observed marked changes in the immune tumor microenvironment after combined ATRi and radiation therapy (RT) [2]. Material and Methods We analysed gene expression in paired tumor biopsies from 5 patients participating in the phase I study of the ATR inhibitor AZD6738 as monotherapy or in combination with palliative radiotherapy. Paired biopsies from three patients with RECIST partial response (PR) and 2 patients with stable disease (SD) after ATRi monotherapy (dose escalation 40 to 240 mg twice daily) were analysed, as well as paired plasma cytokine levels in 11 patients treated with ATRi and 5 with ATRi + RT (20-80 mg twice daily with 20 Gy in 10 fractions). Results Significant increases in plasma CCL2 and CCL3 were observed after 2 weeks of ATRi monotherapy. We observed variable cytokine responses to ATRi + RT. Generally, there was an increase in CCL2 and CCL3 and a decrease in CCL5 with combination therapy. Increased CCL3 had also been observed in the supernatant of cell lines treated with this combination. Modulation of immune-related gene transcripts after treatment with ATRi was noted in paired tumour biopsies. Large increases were seen in macrophage- related transcripts. Interestingly, the patients who had partial responses to ATRi appeared to have larger increases in macrophage-related transcripts than those who had stable disease. This parallels the significant increase in myeloid cells that was observed in the animal model treated with ATRi-RT. Conclusion This work provides evidence that immunomodulation by ATRi ± RT observed in animal models also occurs in patients. Ongoing work aims to characterize this further in a larger number of patients, and correlate with tumor response. The observation that responding patients appear to have increased macrophage infiltration warrants further investigation. Funding National Institute for Health Research RM/ICR Biomedical Research Centre, Cancer Research UK CRUKD/14/007 References 1. PATRIOT: A phase I study to assess the tolerability, safety and biological effects of a specific ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) as a single agent and in combination with palliative radiation therapy