Dose Limit Research Articles

Correlation between hippocampal radiation doses and psychological condition for patients with stage T1-2 nasopharyngeal carcinoma

Background and purposeThe study aimed to investigate the correlation between radiation doses to the hippocampi and the psychological status of patients with stage T1-2 nasopharyngeal carcinoma (NPC) undergoing intensity modulated radiotherapy (IMRT) and recommend proper hippocampal dose limits for preserving patients’ psychological well-being. Materials and methodsA retrospective study was conducted involving 152 newly diagnosed NPC patients. The patients' psychological status was assessed using the Hospital Anxiety and Depression Scale (HADS) before and after radiotherapy. The hippocampi were manually delineated on treatment planning images, and dosimetric parameters were obtained from dose-volume histograms. Logistic regression analysis was performed to identify influential dosimetric factors associated with anxiety and depression. ResultsThe results showed that several dosimetric parameters to the hippocampi were significantly associated with anxiety but not depression. The optimal cut-off value for the independent predictor of anxiety was determined as D40 to hippocampi > 1500 cGy.Patients with D40 to hippocampi > 1500 cGy showed a higher probability for anxiety after radiotherapy. ConclusionThis study provides insights into the relationship between radiation doses to the hippocampi and the psychological status of stage T1-2 NPC patients undergoing IMRT. It suggests the importance of hippocampal protection for preserving patients' psychological well-being. Further studies are needed to validate these results.

Effect of the New Italian Legislative Measures on the Eye Lens Protection of Radioexposed Workers

Introduction: Legislative Decree no. 101, published on 31 July 2020 in the Italian Official Gazette, the official journal of the Italian Government, sets out the provisions of Directive 2013/59/Euratom, which establishes the basic safety rules for protection against the risks arising from occupational exposure to ionizing radiation. Methods: The main purpose of the legislator was to improve the safety of workers exposed to radiation, updating the previous laws adopted by the Italian government 25 years earlier. Many strategies have been attempted in the past to increase the level of protection of these categories of workers. Still, it is too early to evaluate the effectiveness of the proposed measures. Results: Medical professionals play a leading role among other figures involved in the field of occupational radiation protection. To achieve a reliable and detailed evaluation of the risk assessment, which in Italy must be reported in a specific mandatory report called the “Risk Assessment Document”, the legislator has assigned differentiated but coordinated tasks to all the actors involved with different responsibilities in radiation protection. Conclusion: The drastic reduction of the dose limits for the crystalline lens is a tool for more effective protection of workers against exposure to ionizing radiation.

К вопросу об интерпретации терминов «предел дозы» и «радиационная авария» при разработке новых норм радиационной безопасности

Purpose: To analyze the existing in NRB-99/2009 and proposed in the journal “Medical Radiology and Radiation Safety” interpretations of the terms “dose limit” and “radiation accident” when developing a new version of this regulatory document. Material and methods: The features of the interpretation of these terms are considered both in NRB-99/2009 and in a number of domestic and international reference books and glossaries on radiation safety, including proposals published in No. 4 of the journal “Medical Radiology and Radiation Safety” for 2023. Results: The interpretation of the numerical values of the dose limits proposed in the indicated journal seems to be poorly substantiated, while their traditional interpretation remains more preferable. The addition of the concept of a radiation accident with the term “emergency” with its own explanation by the authors of the article contradicts the recommendations of the IAEA. The necessity of taking into account the specifics of radiation accidents in medicine when interpreting the term “radiation accident” is shown. Conclusions: 1. There is no need to revise the traditional interpretation of the numerical values of dose limits. 2. It is expedient to replace the wording of the concept of a radiation accident existing in NRB-99/2009 with the wording of the same concept from the IAEA glossary on radiation safety. 3. Taking into account the need for a correct interpretation of the concept of a radiation accident in medicine, the terms “radiation incident”, “unintentional (accidental) medical exposure” and “radiation accident” with their corresponding interpretations should be added to the new version of the NRB.

Comments on Pet Care and Dose Limits.

Comments on Pet Care and Dose Limits.

Whole body occupational exposure in industrial radiography in Cameroon (2012–2022)

Whole body doses records of industrial radiography workers in Cameroon were analyzed in this study. Average annual effective dose and collective effective dose were estimated from dose records of 2012 to 2022. The average annual effective dose for monitored workers in the periods 2012–2022 and 2020–2022 were respectively equal to 1.28 mSv and 0.41mSv, and the average annual effective dose for measurably exposed workers in the periods 2012–2022 and 2020–2022 were respectively equal to 1.61 mSv and 0.66 mSv. The average annual effective dose for monitored workers in the period 2020–2022 is lower than the global value of 1.10 reported by the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR 2020/2021 Report). The highest collective effective doses were obtained in 2013 and 2014 and were equal to 0.131 man.Sv and 0.126 man.Sv respectively. Many cases of high exposures and one case of effective dose limit exceeded were recorded during the period 2012–2022. Investigations carried out showed that high exposures were mainly caused by high workloads, working in elevated levels, failure to follow operational procedures, equipment malfunction or defect.

Breast Cancer: Clinical-Epidemiological Profile and Toxicities of Women Receiving Treatment with Taxanes in the Amazon Region.

Breast cancer is the most common malignant disease and the leading cause of mortality among women worldwide. Antineoplastic chemotherapy is one of its primary treatments, typically based on the class of drugs known as taxanes. Despite their proven therapeutic efficacy, these drugs can induce severe toxicities, leading to dose limitations or even treatment discontinuation. The objective of this study was to describe the clinical-epidemiological profile, risk factors, and toxicities of taxane-based chemotherapy treatment in women with breast cancer in the Amazon region. This is a cross-sectional, quantitative, and descriptive study conducted with 300 women diagnosed with breast cancer undergoing taxane treatment. Most patients were in the 40-49 age range, of brown ethnicity, and had completed elementary school. The majority of patients had risk factors such as alcoholism and a sedentary lifestyles. Most women had their first pregnancy between the ages of 18 and 21, breastfed their children, had menarche between the ages of 12 and 13, and were pre-menopausal and with a family history of cancer. The most frequent histological type was non-special invasive carcinoma and the Luminal B subtype. Most participants in this study showed taxane toxicity, with neurotoxicity being the most frequent. These findings reveal the importance of early detection, comprehensive risk factors, and effective management of treatment toxicities to improve patient outcomes in breast cancer care in the Amazon region.

Effect of Segmental Abutting Esophagus-Sparing Technique to Reduce Severe Esophagitis in Limited-Stage Small-Cell Lung Cancer Patients Treated with Concurrent Hypofractionated Thoracic Radiation and Chemotherapy

To evaluate the effect of segmental abutting esophagus-sparing (SAES) radiotherapy to reduce severe (G3+) acute esophagitis from 20% to 5% in patients with limited-stage small cell lung cancer (LS-SCLC) treated with concurrent chemoradiotherapy. Patients with a clinical target volume (CTV) ≤1 cm close to the esophagus were enrolled in the experimental arm (45 Gy in 3 Gy daily fractions in 3 weeks) of an ongoing phase III randomized clinical trial (NCT02675088), which enrolled patients with histologically confirmed SCLC and clinically staged as LS or I-IIIB (AJCC 7th). This trial was designed to determine whether HYPO TRT (45 Gy in 3 Gy QD, experimental arm) has the same efficacy as CF TRT (60 Gy in 2 Gy QD, controlled arm) in patients with LS-SCLC. The whole esophagus was divided into the involved esophagus and abutting esophagus (AE) to receive different dose limitations according to the distance from the edge of the CTV. The primary endpoint was grade ≥ 3 acute esophagitis. From 1 May 2021 to 30 April 2022, 30 patients were enrolled and completed four cycles of planned chemotherapy and radiotherapy. Our patient population was predominantly male (66.7% men vs. 33.3% women), with a median age of 62 years. A majority of patients presented with Stage N2-3 (90.0%) and T2-4 (76.7%), in which 4 patients had ultracentral-located primary tumors. With the SAES technique, all dosimetric parameters were significantly reduced for the whole esophagus and AE. The maximal and mean dose of the esophagus (47.4±1.9 Gy and 13.5 ± 5.8 Gy, respectively) and AE (42.9±2.3 Gy and 8.6 ± 3.6 Gy, respectively) in the SAES plan were significantly lower than those (esophagus 48.0±1.9 Gy and 14.7± 6.1 Gy, AE 45.1±2.4 Gy and 9.8± 4.2 Gy, respectively) in the non-SAES plan. After the follow-up of more than 7 months (range, 7.0-18.1 months) for all patients, only one patient (3.3%, 95% CI 0.1%-17.2%) experienced grade 3 acute esophagitis and no grade 4-5 acute esophagitis happened (Table 3). For late toxicities, one patient suffered sustained grade 1 late esophagitis and all others had no symptoms of esophagitis. The rate of radiation pneumonitis was very low, with one grade 3 event and no grade 4-5 event. Twelve (40.0%) patients had G3+ hematologic toxic events, including 2 patients with febrile neutropenia. The 1-year OS, LRFS, DMFS and PFS was 96.4%, 88.7%, 78.4% and 64.3%, respectively. No patient developed local recurrence in the abutting esophagus-sparing region. SAES radiotherapy has significant dosimetric advantages compared with standard radiotherapy, which are successfully translated into clinical benefits for patients with LS-SCLC treated with 45 Gy in 3 Gy daily fractions. This may facilitate dose escalation for TRT in LS-SCLC patients.

Proton Single-Energy Bragg-Peak FLASH Using Clinical Systems Can Achieve IMPT-Equivalent Plan Quality for Breast and Prostate Cancers

Most current proton FLASH-RT studies focus on transmission proton techniques. In this study, we propose a novel method for achieving FLASH dose rate in hypofractionated proton radiotherapy using the Bragg peak of a single-energy proton beam. The dosimetric characteristics using this novel technique for proton pencil beam scanning (PBS) stereotactic body radiation therapy (SBRT) of prostate and breast cancers were first investigated based on the clinically available cyclotron beam parameters. This novel approach uses the distal tracking technique that enables PBS Bragg-peak of the highest proton energy to adapt to the target distally. Positioning of the Bragg peak at different depths is achieved using a universal range shifter and range compensator. To investigate the feasibility of this approach, we developed an in-house treatment planning platform for intensity-modulated proton therapy (IMPT) delivery and performed dosimetric studies on prostate and breast SBRT cases previously treated with conventional proton PBS technique. FLASH plans were generated using a similar clinical beam arrangement to deliver 40 Gy (RBE) in 5 fractions. Dose metrics were compared between the clinical and FLASH plans. Dose-rate volume histograms (DRVH) were also calculated to investigate the 40 Gy/s coverage (V40 Gy/s) of organs-at-risk (OARs) for FLASH plans. The distal tracking can precisely stop the Bragg peak at the target distal edge, and Bragg peak plans achieved tumor coverage and dose conformality equivalent to IMPT plans. The clinical IMPT plans yielded slightly superior target dose uniformity -CTV Dmax of FLASH plans was 10% higher for prostate and 2% higher for breast. There was no significant difference between the clinical and FLASH plans in dose metrics for major OARs, including rectum, large bowel, heart, and lung. Higher maximal doses to femoral heads (∼2 Gy) and urethra (∼6 Gy) were observed in prostate FLASH plans than in the clinical plans but were still within clinically accepted dose limits. The V40 Gy/s for OARs were >90% for prostate FLASH plans and >76.5% for breast FLASH plans. The proposed single-energy Bragg-peak FLASH technique eliminates exit dose associated with transmission proton FLASH and can still yield comparable plan quality and OAR sparing while preserve sufficient FLASH dose rate coverage for prostate and breast proton SBRT. This study demonstrates the potential application of Bragg peaks for highly conformal FLASH-RT using clinical cyclotron systems to treat prostate and breast cancer patients, which moves towards clinical application.

A Comparison of Two Plan Optimization Methods in Three-Dimensional Brachytherapy for Cervical Cancer

To compare dose distributions created by using two Inverse Planning Simulated Annealing (IPSA) and Hybrid Inverse Planning Optimization (HIPO) in three-dimensional (with CT image guidance) brachytherapy planning for cervical cancer. Brachytherapy plans for thirty patients with cervical cancer were created using the IPSA and HIPO algorithms (The IPSA algorithm is calculated based on the anatomical structure, and the simulated annealing algorithm is used to optimize the residence time, and the HIPO algorithm is the optimization and replacement for the IPSA). To obtain a HIPO plan, a manually optimized post-loading treatment plan was applied to these 30 patients, and then the treatment plan was reoptimized using the HIPO algorithm based on the original image information. Individual patients will consider interpolation therapy according to the needs of their condition. The types of plans were compared based on a variety of dose volume parameters, including the mean dose covering 90% of high-risk clinical target volume (D90 for HR-CTV), the mean dose to 2 cm3 volume (D2cc) for bladder, rectum, intestine and sigmoid, and average treatment time were compared and analyzed. Compared with the two groups of plans, mean value of HR-CTV D90 for the HIPO plans was (585 cGy), which was significantly higher than that for the IPSA plans (567 cGy. This difference is statistically significant (P<0.05). The HIPO plans had mean D2cc 422±47 cGy for bladder, 403±38 cGy for rectum, which were lower than those from the SA plans, i.e., 446±42 cGy for bladder and 427±31 cGy for rectum; These differences were statistically significant (t = 5.125, 4.729, P <0.05). There was no statistically significant difference in the sigmoid D2cc doses between the two algorithms. The treatment times for delivering the two types of plans were not significant different. Depending on patient's condition, whether conventional brachytherapy therapy or interpolation therapy is used, the use of the HIPO algorithm to design the treatment regimen without additional treatment time can provide a higher target dose than the manually optimized brachytherapy regimen. Meanwhile, the bladder and rectum doses can be reduced to a certain extent under the premise of ensuring that the target dose met the treatment requirements. There is some increasement for the intestine dose with HIPO planning group, but the dose limits required by the guidelines are still met clinical requirement.

Identification and Dosimetric Analysis of Axillary Substructures Associated with Breast Cancer Related Lymphedema

It has been hypothesized that substructures in the axillary region may be involved in the development of upper limb lymphedema in breast cancer patients. We aimed to compare dosimetric parameters of different substructures to identify risk regions and dose indicators related to the development of lymphedema. A total of 486 patients with breast cancer treated with axillary node dissection (ALND) and regional node irradiation (RNI) between 2017 and 2020 were analyzed. Ten axillary substructures were retrospectively contoured, and dose-volume histogram (DVH) parameters (maximum dose [Dmax], Dmean, Dmin, V5 Gy, V10 Gy, V15 Gy, V20 Gy, V25 Gy, V30 Gy, V35 Gy, V40 Gy, V45 Gy and V50 Gy) were evaluated. EQD2 using α/β = 3 was applied for hypofractionation. The cumulative incidence of lymphedema was 32.5% during the median follow-up of 25 month (IQR 15-35). Higher BMI (≥21.77 kg/m2, hazard ratio [HR]1.6, 95% CI 1.1-2.3, p = 0.019) and higher number of dissected lymph nodes (≥13, HR 1.8, 95% CI 1.1-3.0, p = 0.026) were baseline risk factors associated with breast cancer related lymphedema (BCRL). A cohort of 196 patients was obtained by 1:1 propensity score matching based on the above two factors (154 treated with 50 Gy/25 fractions [Fx] and 42 with 40.05 Gy/15Fx). The optimal metric was axillary-lateral thoracic vessel juncture (ALTJ) Dmean ≥36.84 Gy (HR 3.7, 95% CI 1.6-8.6, p = 0.002). Other significant risk factors are Medial of Axillary Nodes level I(ALN-I-M) Dmin <9.19 Gy (HR 2.3, 95% CI 1.4-3.7, p = 0.001) and Posterior of Axillary Nodes level II(ALN-II-P) Dmax <52.75 Gy (HR 2.0, 95% CI 1.2-3.5, p = 0.015). A nomogram incorporated the above three parameters was created to predict the risk of lymphedema with reasonable accuracy confirmed by both self-training (area under curve [AUC], 0.76; 95% CI, 0.67-0.84) and internal validation (AUC 0.66; 95% CI, 0.50-0.80). A mean dose of 36.84 Gy of ALTJ may be a suggested dose limit for patients indicated RNI after ALND, especially when patients with higher BMI and higher dissected nodes. Ideally, avoidance of ALTJ may be realized without compromising dose coverage to high-risk nodal region. Confirmation of this finding in future prospective studies is needed.

Adaptive Radiotherapy with Dose Fractionation Painting

Efficacy of dose fractionation is dependent on tumor radiosensitivity. However, due to intra-tumoral dose response heterogeneity, the advantage of fractionation cannot be fully utilized. FDG-PET/CT has been used to assess intra-tumoral dose response during the treatment course. Thus, radiosensitivity of different sub-volumes within the individual tumors can be assessed and used to design dose fractionation. For each patient, the pre-treatment FDG-PET/CT and a feedback FDG-PET/CT obtained within the 3rd week of the chemo-radiotherapy for HN cancer were used to construct tumor voxel dose response matrix, DRM. Biologically equivalent dose EQD2 was determined using the DRM and assuming relative stability of the radiation double-hit effect, meanwhile normal tissue EQD2 was determined assuming the corresponding α/β = 3.0. Tumor voxel EQD2 ratio was calculated with a given limitation of normal tissue EQD2 and used to determine tumor voxel fractionation (Table). Tumor was divided into few sub-volumes based on ranges of the tumor voxel DRM value. Different fractionation doses, but same number of fractions, were selected to ensure that the planning dose distribution can be simultaneously delivered. Table shows the EQD2 of tumor voxel DRM for each given fractionation and normal tissue dose limitation. The treatment dose efficiency increases exponentially as increasing dose per fraction for those of resistant tumor voxels, i.e., DRM > = 0.7. The 2 Gy per fraction was used within the first 3 treatment weeks before tumor voxel dose response assessed. After the 15 fractions, tumor voxel dose fractionation will be adjusted with respect to its DRM and the expected treatment dose. Typically, 3 sub-volumes for each resistant tumor were segmented and designed with 3 fractionation regimens. With respect to normal tissue EQD2 constraint < = 70 Gy, the corresponding EQD2 was 55 ∼ 73 Gy for tumor sub-volume with DRM = 0.1 ∼ 0.6; 77 ∼ 90 Gy for tumor sub-volume with DRM = 0.65 ∼ 0.75; > 101 Gy for tumor sub-volume with DRM > = 0.8 respectively. For very resistant tumor cells i.e., DRM > 0.9, the EQD2 > 160 Gy can be achieved or > 244 Gy if the normal tissue EQD2 constraint can be relaxed to 90 Gy for the small resistant tumor sub-volume. For the study patients, tumor sub-volume with DRM > 0.9 = 0.128 ∼ 7.4cc. Adaptive dose fractionation painting can be achieved followed by the dose response assessment. Dependent on the size and location of resistant tumor sub-volumes, tumor EQD2 could be largely improved without increasing normal tissue dose.

Dosimetric Study of Total Marrow and Lymphoid Irradiation on a Ring Gantry-Based Medical Linac with a Two-Layer Multi-Leaf Collimator

In this study, we aimed to evaluate dosimetric quality of total marrow and lymphoid irradiation (TMLI) plans for a ring gantry-based medical Linac with a two-layer multi-leaf collimator. We retrospectively retrieved treatment planning CT images, structure sets, and plan dose for four adult patients, two male and two female, who previously received TMLI treatments on helical tomotherapy (HT) at our institution. TMLI plans were optimized for a ring gantry-based medical Linac with a two-layer multi-leaf collimator (Halcyon, Varian Medical Systems, Inc., Palo Alto, CA). A prescription dose of 12 Gy in 8 fractions was prescribed to the skeletal bones from the skull to mid-thigh, spleen, spinal canal, and lymphoid volume. Five or six isocenters were placed with equal spacing along the patient's longitudinal direction in each TMLI plan with two 6-MV flattening filter-free volumetric modulated arc therapy (VMAT) fields at each isocenter. Isocenter separation ranged from 15 cm to 16.5 cm. Each VMAT field has a field size of 28 cm to 28 cm with the collimator at 90° and a full gantry rotation. The nominal dose rate was 800 MU/minute, and the maximum gantry rotation speed was 24°/sec. Institutional dosimetric constraints were used for optimization including a mean lung dose limit of less than 8 Gy. All the plans were normalized so that 85% the primary planning target volume received the prescription dose. The average mean doses to the target volumes ranged from 12.2 to 12.6 Gy in the Halcyon TMLI plans, while they ranged from 12.1 to 12.5 Gy in the HT TMLI plans. Relative to the prescription dose, the average mean dose for normal organs ranged from 21.3% to 56.6% in the Halcyon TMLI plans, while it ranged from 10.1% to 68.4% in the clinical HT plans. The difference in the average mean dose to normal organs was less than 0.5 Gy except two organs between the Halcyon and HT TMLI plans. The average median dose for normal organs ranged from 18.2% to 48.8% relative to the prescription dose in the Halcyon TMLI plans. The mean lung dose (MLD) in the Halcyon TMLI plans met the institutional limit with an average dose of 6.75±0.42 Gy (range: 6.44 - 7.36 Gy), while the average MLD was 6.54±0.77 Gy (range: 6.24 - 7.22 Gy) in the HT plans (p-value = 0.71 in the paired t-test). The average total monitor unit in the Halcyon TMLI plans was 4,425±906 MU (range: 3,470 - 5,575 MU) with an average beam-on time of 5.1±1.3 minutes (range: 4.1 - 7.0 minutes), which excludes isocenter setup time, while the average beam-on time was 22.2±3.2 minutes (range: 19.6 - 26.1 minutes) with the HT plans. Halcyon TMLI plans met our institutional dosimetric constraints with adequate normal organ sparing and target dose coverage. The beam-on time with the Halcyon plans was significantly shorter than that with the HT plans, which could lead to shorter treatment time and increased patient comfort. This study showed the feasibility of TMLI treatments on the Halcyon machine. The same method could be used for total body irradiation on Halcyon.

An Intrapatient Dosimetry Comparison of 177Lu-rhPSMA-10.1 and 177Lu-PSMA-I&T in Patients with Metastatic Castration-Resistant Prostate Cancer.

As the use of radioligand therapy moves earlier in the prostate cancer timeline, minimizing the absorbed dose to normal organs while maintaining high tumor radiation doses becomes more clinically important because of the longer life expectancy of patients. We performed an intrapatient comparison of pretherapeutic dosimetry with the novel radiohybrid prostate-specific membrane antigen-targeting radiopharmaceutical 177Lu-rhPSMA-10.1, along with 177Lu-PSMA-I&T, in patients with metastatic castration-resistant prostate cancer. Methods: Four consecutive patients with advanced histologically proven metastatic castration-resistant prostate cancer who were scheduled for radioligand therapy were evaluated. Before undergoing therapy, each patient received 1.06 ± 0.05 GBq of 177Lu-rhPSMA-10.1 and 1.09 ± 0.02 GBq of 177Lu-PSMA-I&T at least 7 d apart. For dosimetric assessment, whole-body planar scintigraphy was performed after 5 min, 4 h, 1 d, 2 d, and 7 d. In addition, SPECT/CT images were acquired over the thorax and the abdomen, 4 h, 1 d, 2 d, and 7 d after injection. Dosimetry of the whole body and salivary glands was based on the evaluation of the counts in whole-body planar imaging. Dosimetry of the kidneys, liver, spleen, bone marrow, and tumor lesions (≤4 per patient) was based on the activity in volumes drawn on SPECT/CT images. Doses were calculated using OLINDA/EXM version 1.0. The therapeutic index (TI), or ratio between mean dose of the metastases and mean dose of the kidneys, was calculated for each patient. Results: We found the dose to the kidneys to be higher with 177Lu-rhPSMA-10.1 than with 177Lu-PSMA-I&T (0.68 ± 0.30 vs. 0.46 ± 0.10 mGy/MBq); however, 177Lu-rhPSMA-10.1 delivered an average of a 3.3 times (range, 1.2-8.3 times) higher absorbed radiation dose to individual tumor lesions. Consequently, intraindividual comparison revealed a 1.1-3.1 times higher TI for 177Lu-rhPSMA-10.1 than for 177Lu-PSMA-I&T in all evaluated patients. The effective whole-body dose was 0.038 ± 0.008 mSv/MBq for 177Lu-rhPSMA-10.1 and 0.022 ± 0.005 mSv/MBq for 177Lu-PSMA-I&T. Conclusion: Using 177Lu-rhPSMA-10.1 can significantly increase the tumor-absorbed dose and improve the TI compared with 177Lu-PSMA-I&T. An improved TI gives the flexibility to maximize tumor-absorbed doses up to a predefined renal dose limit or, in earlier disease, to reduce the radiation exposure to the kidney while still achieving an effective tumor dose. The function of at-risk organs such as the kidneys is being assessed in a prospective clinical trial.

Trial Design for Cancer Immunotherapy: A Methodological Toolkit.

Immunotherapy with checkpoint inhibitors (CPIs) and cell-based products has revolutionized the treatment of various solid tumors and hematologic malignancies. These agents have shown unprecedented response rates and long-term benefits in various settings. These clinical advances have also pointed to the need for new or adapted approaches to trial design and assessment of efficacy and safety, both in the early and late phases of drug development. Some of the conventional statistical methods and endpoints used in other areas of oncology appear to be less appropriate in immuno-oncology. Conversely, other methods and endpoints have emerged as alternatives. In this article, we discuss issues related to trial design in the early and late phases of drug development in immuno-oncology, with a focus on CPIs. For early trials, we review the most salient issues related to dose escalation, use and limitations of tumor response and progression criteria for immunotherapy, the role of duration of response as an endpoint in and of itself, and the need to conduct randomized trials as early as possible in the development of new therapies. For late phases, we discuss the choice of primary endpoints for randomized trials, review the current status of surrogate endpoints, and discuss specific statistical issues related to immunotherapy, including non-proportional hazards in the assessment of time-to-event endpoints, alternatives to the Cox model in these settings, and the method of generalized pairwise comparisons, which can provide a patient-centric assessment of clinical benefit and be used to design randomized trials.

Assessing the health risks of coal-burning arsenic-induced skin damage: A 22-year follow-up study in Guizhou, China

Risk assessment of arsenic-induced skin damage has always received significant global attention. Theories derived from arsenic exposure in drinking water may not be applicable to the coal-burning type to arsenic-exposed area. Furthermore, very few studies have successfully determined the reference value of cumulative arsenic (CA) exposure that leads to specific skin lesions. In this study, we conducted a 22-year follow-up investigation to assess the risk of skin lesions and cancer resulting from long-term, multi-channel arsenic exposure from hazard identification, dose-response assessment, exposure assessment, and risk characterization. The results show that the arsenic exposure can significantly increase the prevalence of skin lesions. For each interquartile range increase of hair arsenic (HA) and CA, the risk of skin damage increased by 1.91 and 3.90 times, respectively. The lower confidence limit of the benchmark dose of HA of arsenic-induced various skin lesions ranged from 0.07 to 0.12 μg·g−1, and 932.57 to 1368.92 mg for CA. The chronic daily intake, lifetime average daily dose in the arsenic-exposed area after the comprehensive prevention and control measures have decreased significantly, but remained higher than the daily baseline level of 3.0 μg·kg−1·d−1. Even as recently as 2020, the hazard quotients and hazard index still exceeded 1, measuring 155.33 and 55.20, and the lifetime excess risk of skin cancer (2.80 × 10−3) remains significantly higher than the acceptable level of 10−6. Our study underscores the effectiveness of comprehensive prevention and control measures in managing high arsenic exposure in coal-burning arsenic poisoning areas. However, it is crucial to acknowledge that the risk of both non-carcinogenic and carcinogenic effects on the skin remains substantially higher than the acceptable level. We recommend setting reference limits for monitoring skin damage among individuals exposed to arsenic, with a recommended upper limit of 0.07 μg·g−1 for HA and a maximum acceptable level of 935.57 mg for CA.

A Simple Strategy to Reduce Contrast Media Use and Risk of Contrast-Induced Renal Injury during PCI: Introduction of an "Optimal Contrast Volume Protocol" to Daily Clinical Practice.

Contrast-induced acute kidney injury is the leading cause of iatrogenic acute nephropathy. Development of contrast-induced nephropathy (CIN) increases the risk of adverse long- and short-term patients outcomes, the hospital costs, and length of hospitalization. There are a couple of methods described for CIN prevention (statin prescription, prehydration, contrast media (CM) clearance from the blood system, and decrease amounts of contrast volume). The CM volume to patient's creatinine clearance ratio is the main factor to predict the risk of CIN development. The safe CM to creatinine clearance ratio limits have been established. The usage of CM amount depends on personal operators habits and inside center regulations. There is no standardized contrast usage protocol worldwide. The aim of this study was to establish an easy to use, cheap, and efficient protocol to estimate a personalized safe CM dose limit for every patient based on their kidney function. These limits are announced during the "Time Out" before the procedure. Our study included 519 patients undergoing interventional coronary procedures: 207 patients into the "Optimal Contrast Volume" arm and 312 into the control group. Applying the protocol into a daily clinical practice leads to a significant reduction in CM volume used for all type of procedures and the development of CIN in comparison with a control group.

Are 7.5 Gy×2 fractions more efficient than 6 Gy×3 in exclusive postoperative endometrial cancer brachytherapy? A clinical and dosimetrical analysis

PurposeTo compare two vaginal brachytherapy (VBT) schedules in postoperative endometrial carcinoma (PEC) patients considering vaginal-cuff relapses (VCR), late toxicities, dosimetry analysis and vaginal dilator use. Material and methods110 PEC patients were treated with exclusive high-dose-rate VBT using two schedules. Group-1:44-patients received 6 Gy×3fractions (September-2011-April-2014); Group-2:66-patients were treated with 7.5 Gy×2fractions with a dose limit of equivalent total doses in 2-Gy fr (EQD2(α/β=3)) of 68 Gy in the most exposed 2 cm3 of clinical target volume (CTV) (July-2015-November-2021). The dose was prescribed at 5 mm from the applicator surface. Were evaluated the overall radiation dose delivered to 90% of the CTV (D90), the CTV receiving 100% of the prescription dose (V100) and the EQD2(α/β=3) received in the most exposed 2 cm3 to dose in CTV. Late toxicity was prospectively assessed using RTOG scores for bladder and rectum and objective LENT-SOMA criteria for late vaginal toxicity (LVT). Statistics: Descriptive analysis, Chi-square, Student’s t-tests and Kaplan and Meier method. ResultsThe median follow-up was 60 months (15.9–60). There were no VCR or late toxicities in bladder or rectum. LVT ≥ G1 appeared in 26/44 (59.1%) in Group-1 and 25/66 (37.9%) in Group-2. The mean EQD2(α/β=3) received by the most exposed 2 cm3 of CTV was 63.7 Gy ± 10.0 in Group-1 and 60.5 Gy ± 3.8 in Group-2 (p = 0.063). There were no differences in adherence to vaginal dilator use ≥9 months, overall D90 and V100. ConclusionConsidering the lack of vaginal relapses and similar LVT over time, 7.5 Gy×2fractions seem more efficient in terms of patient comfort, workload, and cost. This is the first study using dosimetry parameters to compare effectivity of schedules. Larger series are needed to confirm the present results.

Dose analysis of nearby residents and workers due to the emission accident of gaseous radioactive material at the spent resin mixture treatment facility

The dose from a possible accident at a microwave-based spent resin mixture treatment facility that was to be installed and operated at the Wolsong nuclear power plant was analyzed to evaluate the radiological safety prior to its installation and operation. The dose to which workers and nearby residents are likely to be exposed was calculated based on the atmospheric dispersion and deposition factors using the XOQDOQ code. The highest atmospheric dispersion factors were 1.349E-05 s/m3 (workers) and 1.534E-06 s/m3 (residents). The highest doses due to emissions from the mock-up tank before operation were 1.91E-06 mSv (workers) and 1.78E-07 mSv (residents). Even after 3 h of operation, emissions from the mock-up tank had the greatest impact ranging from 4.63E-08 to 1.24E-06 mSv (workers) and 2.74E-10 to 1.16E-07 mSv (residents), respectively. The doses were 7.09E-09–4.55E-07 mSv and 4.18E-11–4.25E-08 mSv at 4–5 h of operation, and the maximum doses after operation reached 5.69E-07 mSv and 5.31E-08 mSv for the workers and residents, respectively.Even at the exclusion area boundary (EAB), 4.76E-08–9.51E-07 mSv (annual dose:9.52E-05–1.90E-03 mSv/y) was below the dose limit of the EAB, and the safety of the facility installation inside the NPP was confirmed.

P18.03.A HYPOFRACTIONATION WITH OPTIMIZED STEREOTACTIC RADIOSURGERY PLANNING FOR SKULL BASE PERIOPTIC MENINGIOMAS

Abstract BACKGROUND Skull base perioptic meningiomas are challenging for stereotactic radiosurgery (SRS). The therapeutic window between tumor control and normal tissue complication is extremely narrow in these tumors, especially of large volume and/or in close proximity to the optic apparatus (OA). To minimize the risk of radiation toxicity, we optimized our SRS plans in terms of both steeper dose fall-off and dose-volume constraints for OA and delivered hypofractionation treatment. MATERIAL AND METHODS Thirty-one patients had been treated with hypofractionated SRS using the CyberKnife for perioptic meningiomas &amp;gt; 10 cm3 in volume (median 18.9 cm3). Tumor locations were cavernous sinus (n=7), petroclival (n=6), and tentorial edge (n=6). Optimization in SRS planning was carried in two aspects: 1) for steeper dose fall-off, multiple virtual shells outside the target were introduced and appropriate dose limits (formulated from our own Gamma Knife data) were applied; and 2) to minimize the risk of optic neuropathy, dose-volume constraints for OA (from AAPM TG101) were applied. SRS was delivered in five daily fractions with a median cumulative dose 27.8 Gy. RESULTS With a median follow-up of 33 months, tumor control was achieved in 28 of 31 patients (90.3%). Treatment response on MRI included partial response (volume decrease &amp;gt; 20%) in 17 patients, stable in 11, and progression (volume increase &amp;gt; 20%) in 3. Neurological symptoms improved in 10 patients, unchanged in 20, and worsened in 1. CONCLUSION Our current results show a promising role of hypofractionated SRS with optimization in steeper dose fall-off and dose-volume constraints for OA for large-sized skull base perioptic megningiomas in terms of both tumor control and neurological outcomes.

Biological evaluation of a phosphate ester prodrug of 10-methyl-aplog-1, a simplified analog of aplysiatoxin, as a possible latency-reversing agent for HIV reactivation.

10-Methyl-aplog-1 (10MA-1), a simplified analog of aplysiatoxin, exhibits a high binding affinity for protein kinase C (PKC) isozymes with minimal tumor-promoting and pro-inflammatory activities. A recent study suggests that 10MA-1 could reactivate latent human immunodeficiency virus (HIV) in vitro for HIV eradication strategy. However, further in vivo studies were abandoned by a dose limit caused by the minimal water solubility of 10MA-1. To overcome this problem, we synthesized a phosphate ester of 10MA-1, 18-O-phospho-10-methyl-aplog-1 (phos-10MA-1), to improve water solubility for in vivo studies. The solubility, PKC binding affinity, and biological activity of phos-10MA-1 were examined in vitro, and the biological activity was comparable with 10MA-1. The pharmacokinetic studies in vivo were also examined, which suggest that further optimization for improving metabolic stability is required in the future.