Based on this, our team conducted NCT03388619, a phase I trial of post-prostatectomy radiotherapy to evaluate the safety of increasingly hypofractionated radiotherapy. This trial had two arms. The first, previously published, profiled hypofractionated PORT in patients without evidence of local recurrence on imaging (Patel et al., Adv Radiat Oncol. 2022. PMID: 36420197). The second, reported here, profiled a novel radiation technique termed “risk-volume-adapted” PORT, which allows for the intensification of treatment to the gross tumor volume (GTV) while simultaneously de-intensifying treatment to the remainder of the operative bed. Figure 1 shows a comparative example of this technique in a patient with disease identified on both PET/CT (Figure 1A) and MRI (Figure 1B). Here, a standard treatment plan (Figure 1D) is compared with risk-volume-adapted PORT (Figure 1C), and the dosimetric advantage of risk-volume-adapted radiotherapy on regional normal tissues such as the rectum (Figure 1E, brown) and the bladder (Figure 1E, yellow) is demonstrated.
In this phase I trial, we utilized a standard 3+3 design to test 3 increasingly hypofractionated, isoeffective dose schedules (DS1: 20 fractions, DS2: 15 fractions, DS3: 10 fractions). Dose-limiting toxicity (DLT) was defined as CTCAE grade (G) 3 toxicities lasting >4 days within 21 days of PORT or grade 4 gastrointestinal (GI) or genitourinary (GU) toxicities thereafter. We did not observe any DLTs, and, thus, DL3 (10 fractions) was considered the maximum tolerated hypofractionated dose schedule. The cumulative incidence of grade 3 GI and GU toxicity was 7% and 9% at 24 months. Biochemical PFS was 91% at both 24- and 60-months. No significant change in quality of life (QOL) attributable to PORT was noted from baseline at 24 months.
In conclusion, in this trial, we profile a novel form of postoperative radiotherapy and evaluate the safety of three increasingly hypofractionated dose schedules. The 10-fraction regimen (36.4Gy to the operative bed and 47.1Gy to the GTV) was determined to be the maximum tolerated hypofractionated dose schedule. Disease control outcomes were favorable as compared to historical comparators. This treatment has the potential to maintain efficacy while reducing toxicity, although further trials are required prior to the adoption of this 10-fraction, risk-volume-adapted PORT paradigm.
Figure: Example case demonstrating the advantage of risk-volume-adapted radiotherapy. Panels A and B demonstrate a PSMA-based PET/CT (A) and MRI (B) showing a local recurrence after prostatectomy. Panels C and D compare risk-volume-adapted radiotherapy (C) and a standard plan (D) for this patient. In panel C, a representative axial (top) and sagittal (bottom) slice from the treatment plan is shown with corresponding labels for the PTVProstateBed field and PTVTumor treatment volumes. In panel D, corresponding axial (top) and sagittal (bottom) slices from a standard-of-care treatment plan are shown for purposes of comparison. In the standard treatment plan (panel D), the entire prostate bed is treated to the same dose, whereas in the risk-volume-adapted regimen (panel C), a risk-volume-adapted approach is utilized. A comparison of these two strategies on a dose volume histogram (DVH; panel E) depicts the clear dosimetric advantage of the prescription regimen utilized in this study with significantly lower doses to both the bladder (yellow) and rectum (brown) which appears to enable the safe delivery of hypofractionated post-operative radiotherapy as demonstrated in this trial.
Written by: Krishnan R. Patel, MD, & Deborah E. Citrin, MD, Radiation Oncology Branch, National Cancer Institute, NIH, Bethesda, MD
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