Effect of simultaneous integrated boost concepts on photoneutron and distant out-of-field doses in VMAT for prostate cancer.

BACKGROUND: A simultaneous integrated boost (SIB) may result in increased out-of-field (DOOF) and photoneutron (HPN) doses in volumetric modulated arc therapy (VMAT) for prostate cancer (PCA). This work therefore aimed to compare DOOF and HPN in flattened (FLAT) and flattening filter-free (FFF) 6­MV and 10-MV VMAT treatment plans with and without SIB. METHODS: Eight groups of 30 VMAT plans for PCA with 6 MV or 10 MV, with or without FF and with uniform (2 Gy) or SIB target dose (2.5/3.0 Gy) prescriptions (CONV, SIB), were generated. All 240 plans were delivered on a slab-phantom and compared with respect to measured DOOF and HPN in 61.8 cm distance from the isocenter. The 6­ and 10-MV flattened VMAT plans with conventional fractionation (6- and 10-MV FLAT CONV) served as standard reference groups. Doses were analyzed as a function of delivered monitor units (MU) and weighted equivalent square field size Aeq. Pearson's correlation coefficients between the presented quantities were determined. RESULTS: The SIB plans resulted in decreased HPN over an entire prostate RT treatment course (10-MV SIB vs. CONV -38.2%). Omission of the flattening filter yielded less HPN (10-MV CONV -17.2%; 10-MV SIB -22.5%). The SIB decreased DOOF likewise by 39% for all given scenarios, while the FFF mode reduced DOOF on average by 60%. A strong Pearson correlation was found between MU and HPN (r > 0.9) as well as DOOF (0.7 < r < 0.9). CONCLUSION: For a complete treatment, SIB reduces both photoneutron and OOF doses to almost the same extent as FFF deliveries. It is recommended to apply moderately hypofractionated 6­MV SIB FFF-VMAT when considering photoneutron or OOF doses.

Local dose rate effects in implantable cardioverter-defibrillators with flattening filter free and flattened photon radiation.

PURPOSE: In the beam penumbra of stereotactic body radiotherapy volumes, dose rate effects in implantable cardioverter-defibrillators (ICDs) may be the predominant cause for failures in the absence of neutron-generating photon energies. We investigate such dose rate effects in ICDs and provide evidence for safe use of lung tumor stereotactic radioablation with flattening filter free (FFF) and flattened 6 Megavolt (MV) beams in ICD-bearing patients. METHODS: Sixty-two ICDs were subjected to scatter radiation in 1.0, 2.5, and 7.0 cm distance to 100 Gy within a 5â€¯× 5 cm2 radiation field. Radiation was applied with 6 MV FFF beams (constant dose rate of 1400 cGy/min) and flattened (FLAT) 6 MV beams (430 cGy/min). Local dose rates (LDR) at the position of all ICDs were measured. All ICDs were monitored continuously. RESULTS: With 6 MV FFF beams, ICD errors occurred at distances of 1.0 cm (LDR 46.8 cGy/min; maximum ICD dose 3.4 Gy) and 2.5 cm (LDR 15.6 cGy/min; 1.1 Gy). With 6 MV FLAT beams, ICD errors occurred only at 1 cm distance (LDR 16.8 cGy/min; 3.9 Gy). No errors occurred at an LDR below 7 cGy/min, translating to a safe distance of 2.5 cm (1.5 Gy) in flattened and 7 cm (0.4 Gy) in 6 MV FFF beams. CONCLUSION: A LDR in ICDs larger than 7 cGy/min may cause ICD malfunction. At identical LDR, differences between 6 MV FFF and 6 MV FLAT beams do not yield different rates of malfunction. The dominant reason for ICD failures could be the LDR and not the total dose to the ICD. For most stereotactic treatments, it is recommended to generate a planning risk volume around the ICD in which LDR larger than 7 cGy/min are avoided.

Effectivity and applicability of the German DEGRO/DGK-guideline for radiotherapy in CIED-bearing patients.

BACKGROUND AND PURPOSE: No evidence has been presented until now whether recommendations given in recently issued guidelines concerning CIED-bearing patients significantly decrease RT-related complications. MATERIALS AND METHODS: 160 RT-cases were prospectively treated with 3D-CRT, IMRT, SBRT using exclusively 6 MV photons (n = 146) and electrons (n = 14) according to the 2015 issued German DEGRO/DGK-guideline for CIED-bearing patients and compared to 40 RT-cases (3D-CRT, 10-23 MV photons (n = 39) and electrons (n = 1)) of CIED-bearing patients which were treated in concordance to the 1994 issued AAPM-guideline. RESULTS: With AAPM-recommendations, complications occurred in 7/39 (17.95%) photon-RT cases, one patient experienced inadequate defibrillation therapy. For all patients treated with photon energies between 6 and 23 MV, a relative risk for CIED failure if treated with > 6 MV was calculated to be 9.03 (95% CI 5.24-15.55). After implementation of the DEGRO/DGK guideline, no complications were noted in 147 cases treated with photons, even though CIED-doses were as high as 5.37 Gy. In 13 cases treated with electrons, one PM lost patient-related data in a patient receiving antiproliferative RT to mammary glands. CONCLUSIONS: Implementation of the German DEGRO/DGK-guideline effectively prevented radiation-associated CIED failures in patients treated with photons. Limitation of photon energy to 6 MV, suspension of defibrillation therapy in ICDs, surveillance of patients according to risk stratification and avoidance of direct irradiation of CIEDs should become standard of care.

Interaction between CIEDs and modern radiotherapy techniques: Flattening filter free-VMAT, dose-rate effects, scatter radiation, and neutron-generating energies.

BACKGROUND AND PURPOSE: Providing evidence for radiotherapy (RT)-induced effects on cardiac implantable electric devices (CIEDs) with focus on flattening filter free-volumetric modulated arc therapy (FFF-VMAT) at 6 and 10 MV as well as 3D-conformal radiotherapy (3D-CRT) at 18 MV. MATERIALS AND METHODS: 68 CIEDs (64 implantable cardioverter-defibrillators (ICDs) and 4 cardiac pacemakers (PMs)) were located on the left chest position on a slab phantom and irradiated under telemetrical surveillance either directly, or distant to 3D-CRT or FFF-VMAT, dose-rate 2500 cGy/min, and target dose of 150 Gy. Devices were placed within, close by (2.5 cm and 5 cm), and distant (35 cm) to the radiation field. Scatter radiation (SR) and photon neutrons (PN) were recorded. CIEDs were investigated in following groups: 1a) 18 MV 3D-CRT - 4 ICDs/4 PMs out of radiation field, 1b) 18 MV open field - 4 ICDs/4 PMs within radiation field, 2) 6 MV FFF-VMAT, 15 ICDs in 35 cm distance to VMAT, 3) 10 MV-FFF VMAT, 15 ICDs in 35 cm distance to VMAT, 4) 6 MV FFF-VMAT, 15 ICDs in 2.5 cm distance to VMAT, 5) 10 MV FFF-VMAT, 15 ICDs in 2.5 cm distance to VMAT. RESULTS: No incidents occurred at 6 MV FFF. 10 MV FFF-VMAT and 18 MV 3D-CRT resulted in data loss, reset, and erroneous sensing with inhibition of pacing (leading to inadequate defibrillation) in 8/34 ICDs and 2/4 PMs which were not located within radiation. Direct radiation triggered instantaneous defibrillation in 3/4 ICDs. CONCLUSIONS: 6 MV FFF-VMAT is safe even at high dose-rates of 2500 cGy/min, regardless whether CIEDs are located close (2.5 cm) or distant (35 cm) to the radiation beam. CIEDs should never be placed within radiation and energy should always be limited to 6 MV. At 6 MV, VMAT at high dose-rates can be used to treat tumors, which are located close to CIEDs.

Accelerated Partial Breast Irradiation in Clinical Practice.

Accelerated partial breast irradiation (APBI) has been under clinical investigation for more than 15 years. There are several technical approaches that are clinically established, e.g. brachytherapy, intraoperative radiotherapy (IORT), or external-beam radiotherapy. The understanding of the underlying biology, optimal technical procedures, patient selection criteria, and imaging changes during follow-up has increased enormously. After completion of several phase III trials using brachytherapy or IORT, APBI is currently increasingly used either in phase IV studies, registries, or in selected patients outside of clinical studies. Consensus statements about suitable patients are available from several international and national societies like ASTRO, ESTRO, and DEGRO. One may expect that 15-25% of patients undergoing breast-conserving surgery may qualify for APBI, i.e. patients with small invasive ductal breast cancer without clinical lymph node involvement.

DEGRO/DGK guideline for radiotherapy in patients with cardiac implantable electronic devices.

An increasing number of patients undergoing radiotherapy (RT) have cardiac implantable electronic devices [CIEDs, cardiac pacemakers (PMs) and implanted cardioverters/defibrillators (ICDs)]. Ionizing radiation can cause latent and permanent damage to CIEDs, which may result in loss of function in patients with asystole or ventricular fibrillation. Reviewing the current literature, the interdisciplinary German guideline (DEGRO/DGK) was developed reflecting patient risk according to type of CIED, cardiac condition, and estimated radiation dose to the CIED. Planning for RT should consider the CIED specifications as well as patient-related characteristics (pacing-dependent, previous ventricular tachycardia/fibrillation). Antitachyarrhythmia therapy should be suspended in patients with ICDs, who should be under electrocardiographic monitoring with an external defibrillator on stand-by. The beam energy should be limited to 6 (to 10) MV CIEDs should never be located in the beam, and the cumulative scatter radiation dose should be limited to 2 Gy. Personnel must be able to respond adequately in the case of a cardiac emergency and initiate basic life support, while an emergency team capable of advanced life support should be available within 5 min. CIEDs need to be interrogated 1, 3, and 6 months after the last RT due to the risk of latent damage.

Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP(5+).

With the goal to enhance the distribution of cationic Mn porphyrins within mitochondria, the lipophilic Mn(III)meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP(5+) has been synthesized and tested in several different model of diseases, where it shows remarkable efficacy at as low as 50 µg/kg single or multiple doses. Yet, in a rat lung radioprotection study, at higher 0.6-1 mg/kg doses, due to its high accumulation and micellar character, it became toxic. To avoid the toxicity, herein the pulmonary radioprotection of MnTnHex-2-PyP(5+) was assessed at 50 µg/kg. Fischer rats were irradiated to their right hemithorax (28 Gy) and treated with 0.05 mg/kg/day of MnTnHex-2-PyP(5+) for 2 weeks by subcutaneously-implanted osmotic pumps, starting at 2 h post-radiation. The body weights and breathing frequencies were followed for 10 weeks post-radiation, when the histopathology and immunohistochemistry were assessed. Impact of MnTnHex-2-PyP(5+) on macrophage recruitment (ED-1), DNA oxidative damage (8-OHdG), TGF-ß1, VEGF(A) and HIF-1α were measured. MnTnHex-2-PyP(5+) significantly decreased radiation-induced lung histopathological (H&E staining) and functional damage (breathing frequencies), suppressed oxidative stress directly (8-OHdG), or indirectly, affecting TGF-ß1, VEGF (A) and HIF-1α pathways. The magnitude of the therapeutic effects is similar to the effects demonstrated under same experimental conditions with 120-fold higher dose of ~5000-fold less lipophilic Mn(III)meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP(5+).

Pacemaker and radiotherapy in breast cancer: is targeted intraoperative radiotherapy the answer in this setting?

We present the case of an 83 year old woman with a cardiac pacemaker located close in distance to a subsequently diagnosed invasive ductal carcinoma of the left breast. Short range intraoperative radiotherapy was given following wide local excision and sentinel node biopsy. The challenges of using ionising radiation with pacemakers is also discussed.

Early and late administration of MnTE-2-PyP5+ in mitigation and treatment of radiation-induced lung damage.

Chronic production of reactive oxygen and nitrogen species is an underlying mechanism of irradiation (IR)-induced lung injury. The purpose of this study was to determine the optimum time of delivery of an antioxidant and redox-modulating Mn porphyrin, MnTE-2-PyP(5+), to mitigate and/or treat IR-induced lung damage. Female Fischer-344 rats were irradiated to their right hemithorax (28 Gy). Irradiated animals were treated with PBS or MnTE-2-PyP(5+) (6 mg /kg/24 h) delivered for 2 weeks by sc-implanted osmotic pumps (beginning after 2, 6, 12, 24, or 72 h or 8 weeks). Animals were sacrificed 10 weeks post-IR. Endpoints were body weight, breathing frequency, histopathology, and immunohistochemistry (8-OHdG, ED-1, TGF-beta, HIF-1alpha, VEGF A). A significant radioprotective effect on functional injury, measured by breathing frequency, was observed for all animals treated with MnTE-2-PyP(5+). Treatment with MnTE-2-PyP(5+) starting 2, 6, and 12 h but not after 24 or 72 h resulted in a significant decrease in immunostaining for 8-OHdG, HIF-1alpha, TGF-beta, and VEGF A. A significant decrease in HIF-1alpha, TGF-beta, and VEGF A, as well as an overall reduction in lung damage (histopathology), was observed in animals beginning treatment at the time of fully developed lung injury (8 weeks post-IR). The catalytic manganese porphyrin antioxidant and modulator of redox-based signaling pathways MnTE-2-PyP(5+) mitigates radiation-induced lung injury when given within the first 12 h after IR. More importantly, this is the first study to demonstrate that MnTE-2-PyP(5+) can reverse overall lung damage when started at the time of established lung injury 8 weeks post-IR. The radioprotective effects are presumably mediated through its ability both to suppress oxidative stress and to decrease activation of key transcription factors and proangiogenic and profibrogenic cytokines.

Comparison of two Mn porphyrin-based mimics of superoxide dismutase in pulmonary radioprotection.

Development of radiation therapy (RT)-induced lung injury is associated with chronic production of reactive oxygen and nitrogen species (ROS/RNS). MnTE-2-PyP5+ is a catalytic Mn porphyrin mimic of SOD, already shown to protect lungs from RT-induced injury by scavenging ROS/RNS. The purpose of this study was to compare MnTE-2-PyP5+ with a newly introduced analogue MnTnHex-2-PyP5+, which is expected to be a more effective radioprotector due to its lipophilic properties. This study shows that Fischer rats which were irradiated to their right hemithorax (28 Gy) have less pulmonary injury as measured using breathing frequencies when treated with daily subcutaneous injections of MnTE-2-PyP5+ (3 and 6 mg/kg) or MnTnHex-2-PyP5+ (0.3, 0.6, or 1.0 mg/kg) for 2 weeks after RT. However, at 16 weeks post-RT, only MnTE-2-PyP5+ at a dose of 6 mg/kg is able to ameliorate oxidative damage, block activation of HIF-1alpha and TGF-beta, and impair upregulation of CA-IX and VEGF. MnTnHex-2-PyP5+ at a dose of 0.3 mg/kg is effective only in reducing RT-induced TGF-beta and CA-IX expression. Significant loss of body weight was observed in animals receiving MnTnHex-2-PyP5+ (0.3 and 0.6 mg/kg). MnTnHex-2-PyP5+ has the ability to dissolve lipid membranes, causing local irritation/necrosis at injection sites if given at doses of 1 mg/kg or higher. In conclusion, both compounds show an ability to ameliorate lung damage as measured using breathing frequencies and histopathologic evaluation. However, MnTE-2-PyP5+ at 6 mg/kg proved to be more effective in reducing expression of key molecular factors known to play an important role in radiation-induced lung injury.

Low molecular weight catalytic metalloporphyrin antioxidant AEOL 10150 protects lungs from fractionated radiation.

The objective of this study was to determine whether administration of a catalytic antioxidant, Mn(III) tetrakis(N,N'-diethylimidazolium-2-yl) porphyrin, AEOL10150, reduces the severity of long-term lung injury induced by fractionated radiation (RT). Fisher 344 rats were randomized into five groups: RT+AEOL10150 (2.5 mg/kg BID), AEOL10150 (2.5 mg/kg BID) alone, RT+ AEOL10150 (5 mg/kg BID), AEOL10150 (5 mg/kg BID) alone and RT alone. Animals received five 8 Gy fractions of RT to the right hemithorax. AEOL10150 was administered 15 min before RT and 8 h later during the period of RT treatment (5 days), followed by subcutaneous injections for 30 days, twice daily. Lung histology at 26 weeks revealed a significant decrease in lung structural damage and collagen deposition in RT+AEOL10150 (5 mg/kg BID) group, in comparison to RT alone. Immunohistochemistry studies revealed a significant reduction in tissue hypoxia (HIF1alpha, CAIX), angiogenic response (VEGF, CD-31), inflammation (ED-1), oxidative stress (8-OHdG, 3-nitrotyrosine) and fibrosis pathway (TGFbeta1, Smad3, p-Smad2/3), in animals receiving RT+ AEOL10150 (5 mg/kg BID). Administration of AEOL10150 at 5 mg/kg BID during and after RT results in a significant protective effect from long-term RT-induced lung injury. Low dose (2.5 mg/kg BID) delivery of AEOL10150 has no beneficial radioprotective effects.

Using biological markers to predict risk of radiation injury.

Recent advances in our understanding of the molecular events leading to the development of normal tissue complications after radiotherapy has led to an effort to identify biological markers that could identify patients at increased or decreased risk for treatment related injury. The goal of this effort is to improve the therapeutic ratio and enable physicians to optimize therapy for individual patients. In radiotherapy of the thoracic region, the lung is one of the most critical dose-limiting organs. This review briefly introduces the mechanisms of radiation-induced lung injury and gives a summary of clinical research focused on evaluating changes in biological markers before, during, and after radiation therapy of the thorax.