Poly(ADP-ribose) polymerase (PARP) inhibitors represent one of the successful novel approaches to targeted cancer treatment. Indeed, the US Food and Drug Administration (FDA) has recently approved PARP inhibitors for the treatment of breast and ovarian cancers. Despite the proven efficacy of these agents, certain challenges remain with their use. Among the most important are primary and secondary resistance. Here, we review the mechanism of action of PARP inhibitors and their ability to exploit certain inherent deficiencies among malignant cells to improve cell killing, with a focus on deficiencies in homologous recombination among cells with BRCA1 and BRCA2 mutations. Moreover, we discuss the different mechanisms of resistance including development of secondary resistance and strategies to overcome them. Finally, we discuss the limitations of novel therapeutic interventions and possible future studies to exploit biochemical pathways in order to improve therapeutic efficacy of PARP inhibitors.

Robust optimization generates scenario‐based plans by a minimax optimization method to find optimal scenario for the trade‐off between target coverage robustness and organ‐at‐risk (OAR) sparing. In this study, 20 lung cancer patients with tumors located at various anatomical regions within the lungs were selected and robust optimization photon treatment plans including intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) plans were generated. The plan robustness was analyzed using perturbed doses with setup error boundary of ±3 mm in anterior/posterior (AP), ±3 mm in left/right (LR), and ±5 mm in inferior/superior (IS) directions from isocenter. Perturbed doses for D99, D98, and D95 were computed from six shifted isocenter plans to evaluate plan robustness. Dosimetric study was performed to compare the internal target volume‐based robust optimization plans (ITV‐IMRT and ITV‐VMAT) and conventional PTV margin‐based plans (PTV‐IMRT and PTV‐VMAT). The dosimetric comparison parameters were: ITV target mean dose (Dmean), R95(D95/Dprescription), Paddick's conformity index (CI), homogeneity index (HI), monitor unit (MU), and OAR doses including lung (Dmean, V20 Gy and V15 Gy), chest wall, heart, esophagus, and maximum cord doses. A comparison of optimization results showed the robust optimization plan had better ITV dose coverage, better CI, worse HI, and lower OAR doses than conventional PTV margin‐based plans. Plan robustness evaluation showed that the perturbed doses of D99, D98, and D95 were all satisfied at least 99% of the ITV to received 95% of prescription doses. It was also observed that PTV margin‐based plans had higher MU than robust optimization plans. The results also showed robust optimization can generate plans that offer increased OAR sparing, especially for normal lungs and OARs near or abutting the target. Weak correlation was found between normal lung dose and target size, and no other correlation was observed in this study.

HT-GRID therapy demonstrates a significant therapeutic advantage over uniform dose from an open field irradiation for the same tumor cell kill. TR increases with the radioresistance of the tumor cells and with prescription dose.

Introduction:Radiation Therapy Oncology Group (RTOG) report #0813 and 0915 recommends using D2cm and R50% as plan quality metrics for evaluation of normal tissue sparing in stereotactic body radiation therapy (SBRT) of lung lesion. This study introduces dose falloff gradient (DFG) as a tool for analyzing the dose beyond the planning target volume (PTV) extending into normal tissue structures. In ascertaining the impact of PTV size and SBRT planning techniques in DFG, this study questions the independence of the RTOG recommended metrics.Materials and Methods:In this retrospective study, 41 RapidArc lung SBRT plans with 2 or 3 complete or partial arcs were analyzed. PTV volumes ranged between 5.3 and 113 cm3 and their geographic locations were distributed in both lungs. 6MV, 6 MV-FFF, 10 MV, or 10 MV-FFF energies were used. RTOG-0915 metrics conformity index, homogeneity index, D2cm, R50%, and HDloc were evaluated. DFG was computed from the mean and maximum dose in seven concentric 5 mm wide rings outside the PTV. DFG was investigated against the volume of normal lung irradiated by 50% isodose volume. Treatment plans with alternate energy and couch rotations were generated.Results:The dose falloff beyond PTV was modeled using a double exponential fit and evaluated for relationship with intermediate lung dose. Photon energy and beam configuration had a minimal impact on the dose falloff outside. The product of normalized D2cm and R50% was estimated to have a slowly varying value.Conclusions:Dose falloff outside PTV has been studied as a function of radial distance and ascertained by intermediate dose to normal lung. DFG can serve as a complementary plan quality metric.

This study questions the independence of the two RTOG recommended metrics, R50% and D2cm in lung SBRT plans, and suggests that noncoplanar beams may provide better normal tissue sparing by reducing the intermediate dose falloff.