Abstract
Simple SummaryDespite the large use of inhibitors of Poly-ADP ribose polymerase (PARP-I), the feasibility and safety of their combination with radiotherapy (RT) are unclear. The combination may be particularly interesting in the oligometastatic setting in which patients may benefit from local RT during the treatment with PARP-I. The aim of the current review was to evaluate the outcome and the toxicity in patients with newly diagnosed or recurrent tumors treated with a combination of PARP-I and RT. A total of 12 clinical studies met the inclusion criteria and, despite the heterogeneity of the evaluated patient populations and tumor types, this review suggests that a combination approach is feasible even though the efficacy profile remains unclear.Background: Despite the large use of inhibitors of Poly-ADP ribose polymerase (PARP-I), the feasibility and safety of their combination with radiotherapy (RT) is unclear. Aim: We conducted a literature analysis with the aim to evaluate the efficacy and safety profile of a combination with RT and PARP-I. Method: The key issues for the current review were expressed in two questions according to the Population, Intervention, Control, Outcome (PICO) criteria: 1. What is the outcome and 2. What is the toxicity in patients treated with a combination of PARP-I and RT for a newly diagnosed or recurrent tumors? Results: A total of 12 clinical studies met the inclusion criteria including seven single-arm dose-escalation phase I studies, two phase II (two- and three-arms controlled trials) trials, one parallel-arm phase I study, and two phase I/II studies published between 2015 and 2021. RT was performed with photon beams and several schedules according to the clinical situation. The acute toxicity ≥ grade 3 ranged between 25% and >96%, which was divided into hematological or non-hematological adverse events. Conclusions: despite the heterogeneity of the evaluated patient populations and tumor types, and the limited number of the studies, this review suggests that a combination approach is feasible even though the efficacy profile remains unclear.
Highlights
IntroductionPARP-1 (a member of the family PARP enzymes, which plays an important role as DNA discontinuity sensors as well as in single-strand breaks (SSB) repair Base ExcisionRepair (BER)) does not directly contribute to the repair of double-strand breaks (DSB), but when DSB reparation mechanisms are deficient, such as the homologous recombination (HR) pathway, PARP-1 inhibition can lead to cell death [2,7]
According to the Population, Intervention, Control, Outcome (PICO) method [9,10], we defined two research questions (Table 1) that were the cornerstone of literature research in the main databases (PubMed, Web of Science, Google Scholar and Scopus) through the ensuing matched keywords: “Parp-inhibitor”, “Poly-ADP-ribose polymerase inhibitors (PARP-I)”, “Poly-ADP ribose polymerase”, “Radiotherapy”, “Radiation”, “Hadrontherapy”, “Radiosensitizer”, “Synthetic Lethality”, “Toxicity”, “Stereotactic radiotherapy”, pluralization and US English/UK English spelling variations and suffixes/prefixes
Concerning the key questions examined in the current analysis according to the PICO approach (Table 1), it emerges that: (Queries 1 and 2) the combination of PARP-I and RT is feasible and safe, with a range in terms of survival and local control that it is different in the series according to the histology
Summary
PARP-1 (a member of the family PARP enzymes, which plays an important role as DNA discontinuity sensors as well as in SSB repair BER) does not directly contribute to the repair of DSB, but when DSB reparation mechanisms are deficient, such as the homologous recombination (HR) pathway, PARP-1 inhibition can lead to cell death [2,7]. This process is called synthetic lethality and is one of the most thrilling indicators of progress in oncology in recent years. Conclusions: despite the heterogeneity of the evaluated patient populations and tumor types, and the limited number of the studies, this review suggests that a combination approach is feasible even though the efficacy profile remains unclear
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