Low Dose Rate Research Articles

Proposed Priorities for Low-Dose Radiation Research and Their Relevance to the Practice of Radiology.

Because ionizing radiation is widely used in medical imaging and in military, industry, and commercial applications, programmatic management and advancement in knowledge is needed, especially related to the health effects of low-dose radiation. The U.S. Congress in partnership with the U.S. Department of Energy called on the National Academies of Sciences, Engineering, and Medicine (NASEM) to develop a long-term strategic and prioritized agenda for low-dose radiation research. Low doses were defined as dose amounts less than 100 mGy or low-dose rates less than 5 mGy per hour. The 2022 NASEM report was divided into sections detailing the low-dose radiation exposure and health effects, scientific basis for radiation protection, status of low-dose radiation research, a prioritized radiation research agenda, and essential components of a low-dose radiation research program, including resources needed and recommendations for financial recourse. The purpose of this review is to summarize this report and examine the recommendations to assess how these pertain to the practice of radiology and medicine.

Combined anticancer effects of neutron radiation and genistein on prostate cancer cells

Prostate cancer is the most frequent cancer in men and the second largest cause of cancer-related mortality after lung cancer. Today, studies on neutron radiation therapy show that this method alone is not able to prevent the progression of the disease in most patients with prostate cancer, so it is better to combine neutron radiation with an auxiliary antitumor such as genistein. We found that genistein has anticancer properties and few antioxidant capabilities and could cause the death of prostate cancer cells, mostly through triggering apoptosis. Here the purpose of this study was to evaluate the effect of very low dose rate neutron irradiation emitted from 241Am-Be neutron source as well as the effect of the combination of neutron irradiation and adding the optimal concentration of genistein (480 μM) on the attenuation of prostate cancer PC3 cells in 3D culture environment. MTT assay, Neutral red assay, NO assay, Catalase activity, Reduced glutathione (GSH), Cytochrome c releasing, and Comet assay were used to assess the effect and type of mortality caused by neutron radiation and also neutron and genistein combination in prostate cancer cells. The results of cytotoxicity test reveal that very low dose rate neutron radiation (0.6 mGy/h) with or without genistein at 5, 10, 15, and 20h reduced the survival of prostate cancer cells. Moreover, the rate of necrosis due to the neutron effect at different irradiation times enhanced with the increasing time. Despite significant anticancer effect of Genistein, it cannot be used simultaneously with neutron radiation for prostate cancer treatment.

Cancer and circulatory disease risks for the largest solar particle events in the space age

In this paper we use the NASA Space Cancer Risk (NSCR version 2022) model to predict cancer and circulatory disease risks using energy spectra representing the largest SPE's observed in the space age. Because tissue dose-rates behind shielding for large SPE's lead to low dose-rates (<0.2 Gy/h) we consider the integrated risk for several historical periods of high solar activity, including July–November, 1960 events and August–October 1989 events along with the February 1956 and August 1972 events. The galactic cosmic ray (GCR) contribution to risks is considered in predictions. Results for these largest historical events show risk of exposure induced death (REID) are mitigated to < 1.2 % with a 95 % confidence interval with passive radiation shielding of 20 g/cm2 aluminum, while larger amounts would support the application of the ALARA principle. Annual GCR risks are predicted to surpass the risks from large SPEs by ∼30 g/cm2 of aluminum shielding.

Aspects of thermoluminescence (TL) of quartz from metamorphic rocks of the Peloponnese (Greece) and its potential for geothermometry and thermochronometry

This pilot study explores the suitability of thermoluminescence (TL) of quartzites from exhumed metamorphic rocks of the Peloponnese (Greece) for thermometry and thermochronometry. Specifically, four quartz samples with very low radioelement content were extracted from large quartz lumps exposed at the surface of extensive quartzite rocks that make up the metamoprhic core of the central and southern Peloponnese The samples were submitted to a series of experiments and methods of analysis involving the sensitization of the 110 °C TL peak, fractional glow (via initial rise), TL-signal deconvolution, and characterization of signal response to large doses. The sensitization of the 110 °C TL trap was used to monitor the peak metamoprhic temperature of the quartzites. This is a novelty employed for the first time in this work. The sensitization of the 110 °C TL trap points to peak metamorphic temperatures which seem to be in agreement with independent thermometric data specific to these rocks. TL deconvolution analysis returned at least three traps which exhibit variable geological stabilities (lifetimes) but high saturation levels. Our studies demonstrate that TL from these rocks has the potential to be used for both thermometry and thermochronometry. Nevertheless, the very low dose rates associated with these quartzes qualify the here estimated equivalent doses for the estimation of maximum cooling ages only at this stage.

Ultrasensitive and Robust CsPbBr3 Single-Crystal X-ray Detectors Based on Interface Engineering.

Halide lead perovskites have shown great development in recent years for ionizing radiation detection. However, the bias-induced interfacial electrochemical reaction between the perovskite and electrode severely deteriorates detector performance. We report that BCP strongly interacts with Al and constructs a stable Al-BCP chelating interface, resulting in the suppression of a detrimental electrochemical reaction. The fabricated Au/Al/BCP/C60/CsPbBr3/Au detector shows a low dark current of 3 nA with a stable baseline at an extremely high bias of 100 V (∼100 V mm-1). The superior high-bias stability enables a high sensitivity of 7.3 × 104 μC Gyair-1 cm-2 at 100 V. Meanwhile, a low detection limit of 15 nGyair s-1 at 40 V is achieved due to the reduced noise. The outstanding performance of our device exceeds that of most advanced detectors based on CsPbBr3 single crystals. Besides, X-ray imaging with 1 mm spatial resolution is well demonstrated at a low dose rate of 200 nGyair s-1. The interfacial chelating strategy overcomes the technical limitation of bias-induced instability of perovskite radiation detectors and can be anticipated to operate under an extremely high electrical field.

Low dose rate radiation impairs early follicles in young mice

Low-dose radiation is generally considered less harmful than high-dose radiation. However, its impact on ovaries remains debated. Since previous reports predominantly employed low-dose radiation delivered at a high dose rate on the ovary, the effect of low-dose radiation at a low dose rate on the ovary remains unknown. We investigated the effect of low-dose ionizing radiation delivered at a low dose rate on murine ovaries. Three- and ten-week-old mice were exposed to 0.1 and 0.5 Gy of radiation at a rate of 6 mGy/h and monitored after 3 and 30 days. While neither body weight nor ovarian area showed significant changes, ovarian cells were damaged, showing apoptosis and a decrease in cell proliferation after exposure to 0.1 and 0.5 Gy radiation. Follicle numbers decreased over time in both age groups proportionally to the radiation dose. Younger mice were more susceptible to radiation damage, as evidenced by decreased follicles in 3-week-old mice after 30 days of 0.1 Gy exposure, while 10-week-old mice showed reduced follicles only following 0.5 Gy exposure. Primordial or primary follicles were the most vulnerable to radiation. These findings suggest that even low-dose radiation, delivered at a low dose rate, can adversely affect ovarian function, particularly in the early follicles of younger mice.

Dose and dose rate dependence of precipitation in a series of surveillance RPV steels under ion and neutron irradiation

Life extension of light water reactors requires robust models to predict the embrittlement of reactor pressure vessel (RPV) steels under long-term neutron irradiation. Embrittlement is due to nanoscale precipitation hardening by phases containing Cu, Mn, Ni, and Si, resulting in increases of the ductile to brittle transition temperature. Embrittlement data for low flux, high fluence extended life conditions, up to 80 years or more, are largely not available. Thus, higher flux, accelerated test reactor irradiations have been used to help develop models to predict low flux embrittlement at high fluence. Here flux, or dose rate, is expressed in units of displacements per atom per second (dpa/s). The dose rate can significantly influence precipitate evolution in a way that depends on fluence (dpa), temperature, and alloy composition, as well as flux itself. Here, we explore precipitation in surveillance steels with varying compositions at high fluxes (10−5–10−6 dpa/s) produced using 70 MeV Fe2+ ion irradiations. Atom probe tomography was used to characterize the dose dependence of precipitation at very high ion irradiation dose rates, and to evaluate corresponding similarities or differences compared to neutron irradiated steels at a much lower dose rate of ≈ 5 × 10−9 dpa/s. The data show that, on average, the ion irradiation precipitate volume fractions increase by factors of ∼ 1.5 to 2 between 0.3 dpa and 1.2 dpa. Limited data show that the major effect of neutron versus ion irradiation is the former has lower precipitate number densities and larger sizes. Otherwise, the precipitates are remarkably similar in composition and volume fraction.

High Gain Derived from Facile Carrier Dynamics Manipulation for Sensitive X‐ray Detection and Imaging

AbstractSignal amplification is vitally important for sensing low‐dose X‐rays in medical diagnosis by amplifying the generated electric read‐out signal. However, the complexity of external amplification circuits hampers device miniaturization and portability, while integrating amplification functionality directly into sensors or detectors remains a significant and formidable challenge. In this work, a direct high‐gain X‐ray detector with facile electron drift speed manipulation is reported in perovskite single‐crystal film (SCF). By employing laser‐assisted nucleation, high‐quality MAPbBr3 SCF is fabricated with precise control of thickness from ≈20 to ≈500 µm and the area up to 3 by 2 cm, while the architecture of ITO/MAPbBr3/Au is constructed to form the Schottky junction in opposite polarity. With the assistance of applied bias, the space electric field over MAPbBr3 SCF can be tunable, which ensures the manipulation of charge carrier drift speed to form recirculation for internal gain. The resultant photodetector exhibits an ultrahigh sensitivity of 1.44 × 105 µC Gy−1 cm−2 with a gain of 5.14 × 105, an ultralow detection limit of 39.8 nGy s−1, and the X‐ray array imaging is achieved at a low dose rate of 5 µGy s−1. These results confirm the advance of high‐gain detectors in constructing sensing arrays for practical safe medical diagnosis.

Retrospective analysis of tooth extraction and osteoradionecrosis after low-dose rate brachytherapy for patients with tongue cancer.

This study aimed to investigate the incidence of osteonecrosis of the jawbones (ORN) after tooth extraction in patients undergoing low-dose rate brachytherapy (LDR-BT) and assess its safety. This study retrospectively analyzed 145 patients with tongue cancer treated at Hiroshima University Hospital from 2007 to 2021 with LDR-BT using 192Ir or 198Au alone, LDR-BT and external beam radiotherapy (EBRT) with or without chemotherapy, and LDR-BT with chemotherapy. Patients' mandible and maxilla were protected with spacers. Forty-seven patients underwent tooth extraction, and the incidence, site, and relationship of ORN with tooth extraction were recorded. A subgroup of 26 patients received additional EBRT to the neck after dissection for late cervical lymph node metastases. Of 145 patients, six (4.1%) developed ORN on the same side of the mandible as LDR-BT, and EBRT was performed before and/or after LDR-BT on the sites where ORNs developed. Five of 47 (10.6%) patients who underwent tooth extraction after LDR-BT developed ORN. ORN incidence was 1.8% (2/109) in the LDR-BT and/or chemotherapy group and 11.1% (4/36) in the combination LDR-BT and EBRT and/or chemotherapy group for primary tongue cancer. Different irradiation methods (LDR-BT and/or chemotherapy and combination LDR-BT and EBRT and/or chemotherapy) and the presence or absence of tooth extraction showed significant differences (p = 0.0335 and p = 0.0139, respectively) with or without ORN. Mandibular tooth extraction should be avoided on the side of LDR-BT in combined EBRT cases. However, tooth extraction is feasible using a spacer in LDR-BT and/or chemotherapy.

Comparison of Low Dose Rate and High Dose Rate Brachytherapy Boost Techniques in Prostate Cancer: Evaluation of Toxicity.

The ASCENDE-RT trial has been criticized for higher rates of chronic severe toxicity (18% genitourinary (GU)) than expected with a low dose rate (LDR) boost technique. We compared clinical outcomes of LDR and high dose rate (HDR) boost in the acute and chronic setting from a large single institution experience over a continuous 20-year period, with a focus on GU and gastrointestinal (GI) toxicity during treatment of prostate cancer. We retrospectively reviewed patients treated with LDR boost (2003 - 2013) and HDR boost (2014 - 2018). Clinical and treatment-related prognostic factors including age, stage, androgen deprivation therapy (ADT), dosimetry details, and toxicity data were recorded. Toxicity was scored according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Multi-variable analysis (MVA) was performed to evaluate variables associated with toxicity. A total of 184 men were evaluated (87 LDR and 97 HDR) with a median follow-up of 7.1 years and 4.0 years, respectively. Most patients (92% LDR and 57% HDR) received ADT in addition to BT. The median EBRT dose was 46 Gy for LDR and 45 Gy for HDR (range 25 - 50 Gy). Prostate D90% was similar at 104% and 105% in the LDR and HDR groups, respectively. Urethra D10% and Rectum V100% were both higher with LDR compared to HDR with 155% vs 119% and 0.436% vs 0.073%, respectively. Severe (grade 3+) toxicity was rare (Table 1), with 3.4% of LDR patients experiencing grade 3 chronic GU toxicity. With HDR, 3.1% and 1% of patients experienced acute and chronic grade 3 GU toxicity, respectively. Although non-severe GU toxicity (grade 1-2) was similar between groups (95% LDR vs 89% HDR, p = 0.16), LDR patients experienced more grade 2 GU events (80.5% acute; 82.8% chronic) compared to HDR patients (45.4% acute; 57.7% chronic). There were no severe GI toxicities in the acute or chronic period. Non-severe acute GI toxicity was more common with HDR, while non-severe chronic GI toxicity was more common with LDR. On MVA, acute GU toxicity (any grade) was associated with short term ADT (p = 0.01) and Urethra D10% (p < 0.05); Chronic GU toxicity (any grade) was associated with age (p = 0.09) and Prostate V150cc (p = 0.07) but not BT boost technique. This comparative retrospective analysis of BT boost techniques reveals the overall rate of severe GU and GI toxicity to be low with both LDR and HDR. HDR boost appears to have a slightly more favorable ratio of Grade 1 to Grade 2 GU toxicity and improved urethra/rectum dosimetry. Our analysis suggests that the dosimetric advantages of HDR may deliver small reductions in GU toxicity.

Comparison of the Efficacy of Low Dose Tadalafil with Tamsulosin against Lower Urinary Tract Symptoms and Sexual Dysfunction after Low Dose Rate Prostate Brachytherapy.

Patients with clinically localized prostate cancer (PCa) can be curatively treated with different modalities, including low dose rate (LDR) prostate brachytherapy (PB). LDR-PB allows the patient a relatively short recovery time compared with other treatment modalities such as prostatectomy. However, PB might exert distinct impact on quality of life, lower urinary tract symptoms (LUTS) and sexual dysfunction (SD) are two major concerns. The aim of present study was to assess prospectively the efficacy of low dose tadalafil treatment on both SD and LUTS compared with tamsulosin treatment in patients treated PB for localized PCa. Patients scheduled for PB with I-125 seeds for low or intermediate-risk localized PCa at our institution were eligible for this study. The prescribed dose was set at 160 gray. Participants were randomized into two groups; those started treating with a daily use of 0.2 mg of tamsulosin hydrochloride or 5 mg of tadalafil just after PB. The duration of the study was 12 months and the patients were assessed for urinary and sexual function status at baseline, and 1, 3, 6, and 12 months after PB. The primary study endpoints were both changes from baseline in urinary and sexual function status. Between July 2015 and August 2020, 120 participants were enrolled in this study. The median age was 68 years with the median PSA of 6.5 ng/ml. A total 15 patients were excluded within 6 months after randomization. All subjective LUTS findings, including International Prostate Symptom Score (IPSS), and Over Active Bladder Symptom Score (OABSS), were significantly deteriorated at 1, 3, and 6 months after PB compared with baseline in both groups, respectively (p<0.05). Among objective LUTS findings, a significant decrease in maximum urinary flow rate (Qmax) was found at 1, 3, 6, and 12 months after PB compared with baseline in both groups, respectively (p<0.05). A significant increase in post void residual urine (PVR) was found at 1, 3, and 6 months after PB compared to baseline in tadalafil group, whereas no significant increase was seen in tamsulosin group. There were no statistically significant differences between the 2 groups in scores of the total International Index of Erectile Function (IIEF)-15 and Erection Hardness Score (EHS) before and at 1 month post PB. The EHS was significantly higher in tadalafil group compared with tamsulosin group at 3, 6 and 12 months (p = 0.001, p = 0.004, and p = 0.019, respectively). The EHS after PB in tadalafil group was not significantly decreased from baseline. After LDR-PB, tamsulosin treatment significantly decreased PVR compared with tadalafil. On the other hand, tadalafil contributed to maintain erection hardness compared with tamsulosin.

Development of a compact high-current repetitive pulsed x-ray system.

Pulsed x-rays are crucial for various applications such as radiography, biological effects, and the system-generated electromagnetic pulse effect. X rays with a higher dose rate and a higher total dose can generate more significant radiation effects and more effective radiography. However, most pulsed sub-100keV x-ray systems with high dose rates operate in the single pulse mode with limited total dose, and most repetitive pulsed x-ray systems have a low dose rate. This paper develops a compact high-current repetitive pulsed x-ray system with a low-impedance diode to generate high dose rate pulsed x-rays with an average energy below 100keV. A diode with a double-ring cathode is designed and tested to produce uniform pulsed x-rays. In order to investigate the x-ray intensity and the pulse number of repetitions for different anode thicknesses, five typical thicknesses are tested. The experimental results show that this system can operate stably at a repetitive rate of 0.2Hz with a peak voltage of about 200kV and a peak current of about 100kA. The dose rate is about 2.4 × 105 Gy(LiF)/s, and the average x-ray energy is about 55keV with the 40 µm thick tantalum anode. The x-ray uniformity is better than 2:1 over the measuring plane.

Initial Clinical Outcomes of a Phase II Trial of Focal Salvage LDR Brachytherapy for Local Recurrence of Prostate Cancer after External Beam Radiation Therapy.

To evaluate the clinical outcomes of focal salvage low dose rate brachytherapy (FSB) for biopsy proven local recurrence of prostate cancer after definitive external beam radiation therapy (EBRT). Patients with a Phoenix definition PSA recurrence (nadir + 2.0ng/dL) after definitive EBRT for localized prostate cancer and a negative metastatic work up were enrolled in a Phase II clinical trial. Patients first underwent MR-guided transperineal mapping biopsy of the prostate using a template grid. Patients with a pathologically confirmed recurrence underwent FSB using iodine-125 seeds to a prescription dose of 145 Gy. The brachytherapy planning target volume (PTV) was defined by the positions of the pathologically negative core biopsies adjacent to the positive core biopsies as recorded on the template grid during the biopsy procedure. An intraoperative treatment plan was then developed to cover the PTV with the 145 Gy isodose line. Follow up included assessment of genitourinary (GU) and gastrointestinal (GI) toxicities using Common Terminology Criteria for Adverse Events version 4.03 (CTCAEv4.03), patient reported outcomes using the International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index-26 (EPIC-26) forms, and serial PSA blood draws. Ten patients underwent FSB. The median prior EBRT dose was 7805 cGy (interquartile range IQR 7560-7920) and the median time from completion of EBRT to FSB was 81 months (IQR 68-134). The median PSA prior to FSB was 3.2 ng/dL (IQR 2.3 - 4.5). The median follow up after FSB was 32 months (IQR 18-57). Eight patients were free of Phoenix definition PSA failure at last follow up. Of the two patients who experienced a PSA failure, one developed distant metastases 5 months after FSB and the other a biopsy proven seminal vesicle recurrence 3 years after FSB. The median change in post FSB IPSS score compared to the pre-FSB IPSS score was an increase of 1.5 (IQR -1.5 to 8) at 3 month follow up and an increase of 3.5 (IQR 0.5 to 5.5) at last follow up (≥1 year). The median change in post FSB EPIC-26 urinary domain score compared to the pre-FSB score was -1 (IQR -26 to +14.5) at 3 month follow up and +2 (IQR -12.5 to +14.5) at last follow up (≥1 year). The median change in post FSB EPIC-26 bowel domain score compared to the pre-FSB score was -2 (IQR -9.5 to 0.0) at 3 month follow up and 0 (IQR -6.0 to +3.0) at last follow up (≥1 year). No patients experienced post FSB Grade 3 or higher GU or GI toxicities. High dose FSB for a local recurrence of prostate cancer after EBRT can be delivered with good biochemical control and a favorable toxicity profile. Further clinical trial enrollment and longer follow up will be needed to better assess long term outcomes.

A Phase I/II Dose-Escalation Study Evaluating the Safety of 21 Gy, 23 Gy, and 25 Gy for High Dose Rate (HDR) Prostate Brachytherapy: An Interim Toxicity Report.

Single-fraction high dose rate (HDR) prostate brachytherapy has shown improved actuarial biochemical control rates from 66% to 82% with dose escalation from 19 to 20.5 Gy, respectively, but is still inferior to the reported low dose rate brachytherapy control rates of over 90%. We aimed to identify whether dose escalation to 21, 23, and 25 Gy can be safely accomplished. Patients with previously untreated, pathologically confirmed, low-risk (cT1-T2a, Gleason ≤6, PSA <10 ng/mL) or favorable intermediate risk (Gleason 3+4, percentage of positive biopsy cores <50%, ≤1 NCCN intermediate risk factor) prostate adenocarcinoma were enrolled from a single institution. PSA and toxicity assessment were performed at baseline and at routine 6-month follow-ups. From May 9, 2018 to May 12, 2022, 18 patients were enrolled. None had received prior androgen deprivation therapy, 44% had low risk disease, and 61% were ECOG 0 at baseline. Median age was 68 years (total range: 43-79), and 83% were Caucasian. Eight patients received 21 Gy, nine patients received 23 Gy, and one patient received 25 Gy, with the 25 Gy cohort still accruing. The mean prostate size and range, determined by pre-operative prostate volume study on trans-rectal ultrasound, were as follows: 21Gy cohort (mean: 41.2cc; range: 21.9-63.1cc), 23Gy Cohort (mean: 41.2cc, range 28.3-71.7cc), 25Gy cohort (65.3cc). A median of 17 catheters (range: 16-20) were implanted. At a median follow-up of 35.7 months (range: IQR 4.4 - 50.2), only one grade 3 toxicity was reported, which was an ulcerative colitis (UC) flare noted in a patient whose UC was poorly controlled, requiring multiple courses of prednisone in the 6 months prior to his brachytherapy. Regarding toxicities attributable to therapy, fourteen and four patients experienced a grade 1 and 2 genitourinary toxicity respectively; four and four patients experienced a grade 1 and 2 reproductive system toxicity respectively; one patient experienced a grade 1 GI toxicity. Two patients needed foley catheters upon discharge, with neither requiring the foley long term. There were two treatment failures in the 21Gy cohort at 1.39 and 1.67 years from date of HDR brachytherapy; date of failure was defined by the first PSA 2.0ng/mL over nadir. Of these patients, one underwent focal salvage HDR, whilst the other underwent radical prostatectomy with only 1% of the volume involved by prostate cancer. Of note, there was seminal vesicle involvement on restaging prostate biopsy for the patient that underwent radical prostatectomy, however, this was not appreciated on the final prostatectomy specimen. Both patients have no evidence of disease currently. HDR brachytherapy appears well tolerated in patients with low to favorable intermediate risk prostate cancer at 21 and 23 Gy, with more accrual needed at 25Gy. Long-term follow-up needed to assess efficacy.

Health-Related Quality of Life after Combined External Beam and Either High Dose Rate (HDR) or Low Dose Rate (LDR) Brachytherapy: Does the Rectal Dose from the LDR Brachytherapy Make a Difference?

The recently reported randomized Phase III trial comparing health related quality of life (HRQOL) after combined external beam radiation therapy (EBRT) and either HDR or LDR brachytherapy (BT) found a significant decline in the EPIC Bowel domain HRQOL score at 24- 48 months after treatment in the LDR arm of the trial. As all patients in the trial received the same EBRT dose, and HDR rectal dose was strictly controlled to be <9.5 Gy to 1cc of rectal wall (RD1cc), we investigated whether the variable rectal dose from the LDR component of treatment was related to the decline in Bowel HRQOL for these patients. A total of 195 men with upper tier intermediate or high-risk prostate cancer were assigned by a random number generator to receive either an HDR (15 Gy, n = 108) or LDR (110Gy, n = 87) brachytherapy boost combined with 46Gy/23 fractions EBRT. All LDR patients had 1 month post implant quality assurance using CT-MRI fusion. The Expanded Prostate Cancer Composite (EPIC) questionnaire was used to evaluate HRQOL at baseline, q3 mo for 1 year, q6mo for 3 yr and then annually. A multivariate linear regression model was used to investigate the dose-response relationship between EPIC bowel domain score at 24- 48 months and RD1cc. With a median follow up of 48 months, the previous analysis confirmed the expected time course of acute bowel/urinary symptoms, with LDR showing more prolonged decline in HRQOL bowel domain at 3 and 6 months, but equivalence to HDR by 12 months. HRQOL urinary domain remained equivalent from 12-60 mo. The decline in the HRQOL bowel domain observed for LDR patients from 24-48 mo was analyzed for the 79 patients with sufficient data. The mean baseline HRQOL bowel domain score was 92 and fell on average to 85 at 24-48 mo. Mean RD1cc for the LDR patients was 82Gy (SD 22 Gy), with a maximum value of 129 Gy. In this range of rectal doses, a 20Gy increase in RD1cc, was associated on average with a 1.5-point decrease in EPIC HRQOL bowel domain score (p = 0.21). The rectal dose received by the LDR patients showed a non-significant dose-response with the EPIC Bowel domain HRQOL score. This confirms the accepted rectal dose constraints for LDR brachytherapy but does not explain the observed decline in bowel scores from 24-48 months.

Impact of Prostate Cancer Treatment with Low Dose Rate Brachytherapy on Testosterone: A Retrospective Analysis

Decrease in serum testosterone counts have been reported in the literature following external beam radiotherapy (EBRT), with a suggested association to low dose irradiation of the testes occurring with historical and modern external techniques. Low dose rate (LDR) brachytherapy has been described as exposing the testes to between 2 and 19 cGy compared with 196-220 cGy with EBRT. This decrease in excess dose is hypothesized to spare post-treatment testosterone decrease and subsequent change in patient-perceived quality of life. Here, we retrospectively evaluate LDR-treated prostate cancer patient testosterone change in a single-institution patient cohort. Patients with prostate cancer who had previously received LDR brachytherapy were identified, and patients with prior baseline total testosterone lab values as well as a lab value within one year post-treatment were identified. Patients receiving concurrent androgen deprivation therapy or EBRT were excluded. The closest baseline values prior to and after LDR treatment were used for before/after comparison. Samples were compared using the paired t-test. A total of 1,463 patients receiving LDR were identified with data available for analysis between 1998 and 2023; of these, 139 patients met the above criteria for analysis. Mean age was 66 (median 67; range: 47 - 79). 5 patients received 110 Gy, 2 received 120 Gy, and the remainder 145 Gy, all conducted with I-125. Total mCi delivered ranged from 20.3 mCi to 56.7 mCi (median 37.6 mCi). Approximately 57% were GS6, 42% G7, and < 1% G8. Approximately 80% of patients had T1c disease, with 19% T2 and < 1% T3a. All patients were cN0M0. Mean pre- and post-treatment testosterone were 385.5 ng/dL and 382.9 (SD: 170.9, 150.9; mean difference 2.65 [95% CI: -15.6, 20.9]), respectively, with no statistical change noted (p = 0.774). Testosterone levels have been reported to drop following definitive EBRT owing to excess dose delivery to the testes. On review of our institutional experience in definitive LDR brachytherapy for patients treated without ADT administration, no change in testosterone levels were noted.

Clinical Outcomes of Sidewall/Parametrial Simultaneous Integrated Boost for Patients with Cervical Cancer

In the treatment of cervical cancer, simultaneous integrated boost (SIB) is a common technique to deliver increased dose to gross disease in the para-aortic and pelvic nodal basins. However, SIB to the pelvic sidewall/parametria is not well characterized in the literature. We hypothesized that sidewall simultaneous integrated boost (SIB) in the treatment of cervical cancer is associated with acceptable levels of toxicity. From 1/2009-12/2018, patients who received concurrent chemoradiation with external beam radiation therapy, utilizing a sidewall SIB technique, followed by low dose rate or high dose rate brachytherapy treatment were retrospectively identified. Sidewall SIB was defined as treatment at 2.1-2.4Gy/fraction to the parametria-usually performed for those with disease width >4cm at time of treatment start. Acute and late toxicity grading was defined by the Common Terminology Criteria for Adverse Events Version 5.0. Overall survival (OS), local control, progression-free survival (PFS), and toxicity were analyzed utilizing the Kaplan Meier method. Potential associations between cumulative D2cc for bladder and rectum and time to toxicity were investigated using Cox regression. Fifty-six patients with IB2-IVB cervical cancer treated with sidewall SIB were identified, with a median follow up of 7.0 years (95% CI: 6.3, 8.3). Patients had a median age of 43 years (range: 26-68); 2 (3.6%) had FIGO stage I, 7 (12.5%) stage II, 46 (82.1%) stage III, and 1 (1.8%) stage IV disease. A majority had squamous cell histology (83.9%). Nearly all patients (96.4%) received concurrent cisplatin chemotherapy. Rates of acute grade ≥3 gastrointestinal (GI), genitourinary (GU), vaginal, and hematologic toxicity were 1.8%, 1.8%, 0%, and 15.9% respectively. Rates of late grade ≥3 GI, GU, and vaginal toxicity were 11.3%, 18.5%, and 11.1% respectively. OS and local control rates at five years were 0.61 (95% CI: 0.46, 0.73) and 0.95 (95% CI: 0.84, 0.98), respectively. Median PFS was 7.8 years (95% CI: 2.4, Not reached). Cumulative D2cc bladder was not significantly associated with time to Grade 2 or greater (HR 1.04, p = 0.33) or Grade 3 or greater (HR 1.02; p = 0.64) GU toxicity. Cumulative D2cc rectum was not significantly associated with time to Grade 2 or greater (HR 1.06, p = 0.06) or Grade 3 or greater (HR 1.08; p = 0.09) GI toxicity. Sidewall SIB is a feasible technique for dose escalation in the treatment of cervical cancer with rates of acute and late toxicity consistent with other reports.

Radiochemical Oxygen Depletion Depends on Chemical Environment and Dose-Rate: Implications for FLASH Effect

FLASH (dose rates > 40 Gy/s) radiotherapy (RT) protects normal tissues from radiation damage, compared with conventional RT (∼Gy/min). Radiation-chemical oxygen depletion (ROD) has been the leading and most-studied mechanism to explain FLASH. Previous studies have reported low ROD values of ∼0.35 µM/Gy, however, they do not accurately model (utilizing water or oxidized substrates such as albumin) the intracellular environment. It has been proposed that the intracellular environment may support higher ROD values due to its specific chemical makeup. As chemical reducing agents, which play a critical role in the cell, may promote ROD, we measured ROD for several well-known cellular reducing agents. Precision polarographic oxygen sensors were used to measure ROD over a ∼100-0 µM oxygen concentration range in solutions containing various types of intracellular reducing agents, either alone or combined with glycerol (1M; to simulate the intracellular hydroxyl-radical-scavenging capacity). A Cs irradiator and a research proton beamline were used for radiation beam generation over a 10,000-fold (0.0085 to 100 Gy/s) dose rate range. Reagents were grouped generally into primary free-radical scavengers (glycerol & lysozyme) and reducing agents (cysteamine, cysteine, glutathione, dextrin-conjugated linoleic acid, NAD(P)H, ascorbate and uric acid). Reducing agents at 1 mM significantly altered ROD values. ROD, at 0.1 Gy/s varied from greater than 1 µM/Gy for NADPH to less than 0.1 µM/Gy for uric acid. Even higher RODs were found at lower dose rates and/or higher reducing agent concentrations. Although most greatly increased ROD, ascorbate and uric acid decreased ROD and additionally imposed an oxygen dependence of ROD at low oxygen concentrations. Interestingly, all agents having high rates of ROD at low dose rates show a decrease at FLASH dose rates and this seems to be a proportional response (i.e., the greater the ROD at low dose rate, the greater the inhibition by FLASH). At FLASH dose rates our data for a simple mixture of glycerol and glutathione showed the same trend as recent studies that, in general, FLASH had ∼25% lower ROD rates than conventional demonstrating agreement between polarographic sensors and optical phosphorescence decay methods. ROD was greatly augmented by some intracellular reducing agents but others effectively reversed this effect. Ascorbate had its greatest impact at low oxygen concentrations. ROD decreased with increasing dose rate and in all cases was less than 1 µM/Gy at 100 Gy/s, potentially posing a fundamental limit of max ROD for FLASH.

Combined Radiotherapy Using a Method for Biologically Informed IMRT Planning

Radiotherapy (RT) regimens routinely employ multiple courses that vary by delivery modality and/or fractionation schedule as part of initial or follow up treatment. The combination of RTs ideally should consider the biological effect of the total composite dose distribution. Biological effect can be quantified by biological effective dose (BED) which is a function of the RT modality, dose fractionation, and tissue radiosensitivity. This work describes a method of optimizing a follow up intensity modulated RT (IMRT) plan that considers BED from prior RT. Required inputs for this method are the desired composite BED objectives (BEDref) for target volume(s) and organs at risk (OARs). First, the physical dose in each CT voxel from prior RT (Dprior) is converted to BED (BEDprior). The difference between BEDref and BEDprior gives the optimal BED distribution for the follow up IMRT plan (BEDIMRT). Next, the optimal physical dose (DIMRT) corresponding to BEDIMRT is calculated for each voxel as a function of the number of IMRT fractions (nIMRT). Commercial IMRT treatment planning systems require optimization objectives to be specified for contoured structures, not individual voxels, so a workaround is proposed: 1) for each structure, BEDref is converted to physical dose (Dopti) as a function of nIMRT, and 2) for each voxel, the difference of Dopti and DIMRT is calculated. The result is a "base dose distribution" (Dbase) that is used with standard inverse optimization tools to optimize an IMRT plan so that the sum of Dbase and the IMRT dose approaches Dopti for each voxel. This method was implemented using a custom software workflow to calculate Dbase as a function of Dprior and input BEDref values. Validation was performed by comparing the workflow output with hand calculated Dbase values at randomly selected points within clinically significant regions. Satisfactory agreement was considered to be within 5%. Feasibility of the method was demonstrated using an RT trial protocol for glioblastoma multiforme that combines permanent low dose rate brachytherapy (BT) using collagen tiles embedded with 131Cs seeds and follow-up IMRT (20 fractions). The Dbase distribution was obtained from the software as a function of the BT dose and BEDref for one patient model. Comparison of Dbase values from the software and hand calculated values resulted in agreement within 5% for 22/25 points and within 10% for 3/25 points. Discrepancies >5% (max 9.4%) were attributed to data precision resolution effects inherent in the DICOM standard. The resulting IMRT plan was deemed clinically acceptable and the composite dose distribution achieved dosimetric objectives for all target and OARs. A method for optimizing a follow up IMRT plan that considers dose from prior RT to produce a desired composite BED distribution was derived and proof of concept was successfully demonstrated. Further validation of this method with additional patients and multimodality RT protocols will be performed.

Impacts of Combining Pulsed Low Dose Rate Radiotherapy (PLDR) and Anti-PD-1 Antibody on Tumor Growth and Its Mechanism for Lung Cancer in Mice

As an emerging anti-tumor strategy, Immunotherapies has been approved for the treatment of a variety of tumors. Recent data suggest that the efficacy of radiotherapy in various cancers can be augmented when combined with immune checkpoint blockade. Then, pulsed low dose rate radiotherapy (PLDR) is a new radiotherapy segmentation method. Therefore, this study investigated the inhibitory effect of PLDR combined with anti-PD-1 antibody on lung cancer in mice and its impact on tumor immune microenvironment. By transplanting murine LLC cells into the right leg of C57BL/6 mice with immune activity, a transplanted subcutaneous tumor model was established. The mice were randomly divided into five groups: control, conventional radiotherapy (RT)±anti-PD-1 antibody (mAb),PLDR±anti-PD-1 antibody (mAb). RT was delivered as a dose of 5 × 2 Gy whereas PLDR involved delivering a dose of 2 Gy as 10 pulses of 0.2 Gy, each 3 minutes apart and lasting for 5 days. Anti-PD-1 antibody and isotype control were administered intraperitoneally once every three days at a dose of 5mg/kg, three times in total. The tumor, blood and tumor-draining lymph nodes (TDLNs) were harvested after treatment, and a single cell suspension was prepared for flow cytometry to analyze the changes in the immune microenvironment of the tumor tissue, the expression of PD-L1. PD-1 and the activated systemic immune response; Finally, this study explored a mechanism able to explain the observed synergy of combined therapy. PLDR combined with anti-PD-1 antibody can better inhibit the growth of tumor than RT,PLDR and RT combined group. Survival analysis demonstrated a statistically significant advantage for PLDR+anti-PD-1 than other groups. Median survival with PLDR+anti-PD-1mAb was 63d compared with 54d with RT+anti-PD-1mAb,41d with RT and 40d with PLDR and 33 with control. Meanwhile both RT and PLDR induced up-regulation of PD-L1 expression on tumor surface and PD-1 expression on lymphocytes. Then, the frequency of CD4+,CD8+T cells were higher in the PLDR combined treatment group in tumor blood and draining lymph nodes, and synergistically reduce the local accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs) than others. Finally, the main reason for the better tumor inhibition effect of PLDR combined group is that it upgrades the number and activity of CD8+T cells in tumor. PLDR combined with anti-PD-1 antibody can result in better tumor growth inhibition and significantly delay the survival time of mice, which was mainly through the cytotoxic T cell-dependent mechanism, meanwhile increasing the infiltration of CD4 + and CD8 +T-cells in tissues.