Long term update on toxicity and survival of a phase II trial of linac-based stereotactic body radiation therapy for low-intermediate risk prostate cancer.

BACKGROUND: In 2016 we published a phase II study exploring safety and efficacy of Stereotactic Body Radiation Therapy (SBRT) delivered with Volumetric Modulated Arc Therapy (VMAT) and Flattening Filter Free (FFF) beams techniques in prostate cancer (PC) patients. We present herein the updated results on late toxicity and long-term survival. METHODS: Patients enrolled in the study had a biopsy-confirmed localized PC and the features of a low- or intermediate-risk disease (National Comprehensive Network Criteria). The radiotherapy (RT) schedule consisted of 35 Gy delivered in five fractions every other day. Toxicities were registered according to the common toxicity adverse events v4.0. Biochemical recurrence was defined as an increase of prostate specific antigen after nadir, confirmed at least once. Local recurrence (LR) and distant metastases were detected either with Choline- or PSMA-PET/CT scans. Kaplan-Meier curves for Biochemical Recurrence-Free Survival (BFS), Local Control (LC), Distant Metastasis Free Survival (DMFS) and Cancer Specific Survival, were calculated by using MedCalc. RESULTS: Ninety patients were submitted to SBRT between February 2012 and March 2015. Fifty-eight patients (64.5%) had a Gleason Score of 6, while 32 (35.5%) had a Gleason Score of 7. A late grade 1 Genito-Urinary toxicity was observed in 54.5% of patients while a grade 2 in 3.3%. A late Gastro-intestinal grade 1 toxicity was reported in 18.9% of patients, while a grade 2 in 2.2%. Erectile dysfunction was reported by 13% of patients No heavier toxicities were observed. At a median follow-up of 102 months, 5- and 8-year BFS were 93.0% and 84.4% respectively, 5- and 8-year LC were 95.2% and 87.0% respectively, 5- and 8-year DMFS were 95.3% and 88.4%, respectively. CONCLUSIONS: This long-term update confirms that SBRT is a valid therapeutic strategy for low-intermediate risk PC. RT with VMAT and FFF warrants optimal results in terms of toxicity and disease control.

Radiation Therapy in the Management of Adrenal Metastases.

Adrenal glands represent a common site of metastases from several primary tumors, including lung cancer, breast cancer and melanoma. Surgical resection is considered the standard of care, but surgery is not always feasible given the challenges related to anatomical site and/or due to patient and/or disease characteristics. Stereotactic body radiation therapy (SBRT) represents a promising treatment for oligometastases, though the literature on its role for adrenal metastases is still heterogeneous. Herein are summarized the most relevant published studies on the efficacy and safety of SBRT for adrenal gland metastases. The preliminary data suggests that SBRT yields high local control rates and symptom relief with a mild pattern of toxicity. Advanced radiotherapy techniques including IMRT and VMAT, a BED10 > 72 Gy and the use of 4DCT for motion control should be considered for a high quality ablative treatment of adrenal gland metastases.

Internal Guidelines for Reducing Lymph Node Contour Variability in Total Marrow and Lymph Node Irradiation.

BACKGROUND: The total marrow and lymph node irradiation (TMLI) target includes the bones, spleen, and lymph node chains, with the latter being the most challenging structures to contour. We evaluated the impact of introducing internal contour guidelines to reduce the inter- and intraobserver lymph node delineation variability in TMLI treatments. METHODS: A total of 10 patients were randomly selected from our database of 104 TMLI patients so as to evaluate the guidelines' efficacy. The lymph node clinical target volume (CTV_LN) was recontoured according to the guidelines (CTV_LN_GL_RO1) and compared to the historical guidelines (CTV_LN_Old). Both topological (i.e., Dice similarity coefficient (DSC)) and dosimetric (i.e., V95 (the volume receiving 95% of the prescription dose) metrics were calculated for all paired contours. RESULTS: The mean DSCs were 0.82 ± 0.09, 0.97 ± 0.01, and 0.98 ± 0.02, respectively, for CTV_LN_Old vs. CTV_LN_GL_RO1, and between the inter- and intraobserver contours following the guidelines. Correspondingly, the mean CTV_LN-V95 dose differences were 4.8 ± 4.7%, 0.03 ± 0.5%, and 0.1 ± 0.1%. CONCLUSIONS: The guidelines reduced the CTV_LN contour variability. The high target coverage agreement revealed that historical CTV-to-planning-target-volume margins were safe, even if a relatively low DSC was observed.

Predictive value of clinical and radiomic features for radiation therapy response in patients with lymph node-positive head and neck cancer.

BACKGROUND: Prediction of survival and radiation therapy response is challenging in head and neck cancer with metastatic lymph nodes (LNs). Here we developed novel radiomics- and clinical-based predictive models. METHODS: Volumes of interest of LNs were employed for radiomic features extraction. Radiomic and clinical features were investigated for their predictive value relatively to locoregional failure (LRF), progression-free survival (PFS), and overall survival (OS) and used to build multivariate models. RESULTS: Hundred and six subjects were suitable for final analysis. Univariate analysis identified two radiomic features significantly predictive for LRF, and five radiomic features plus two clinical features significantly predictive for both PFS and OS. The area under the curve of receiver operating characteristic curve combining clinical and radiomic predictors for PFS and OS resulted 0.71 (95%CI: 0.60-0.83) and 0.77 (95%CI: 0.64-0.89). CONCLUSIONS: Radiomic and clinical features resulted to be independent predictive factors, but external independent validation is mandatory to support these findings.

Stereotactic Body Radiation Therapy for Lung and Liver Oligometastases from Breast Cancer: Toxicity Data of a Prospective Non-Randomized Phase II Trial.

AIMS: We report the mature toxicity data of a phase II non-randomized trial on the use of SBRT for lung and liver oligometastases. METHODS: Oligometastatic patients from breast cancer were treated with SBRT for up to five lung and/or liver lesions. Inclusion criteria were: age > 18 years, ECOG 0-2, diagnosis of breast cancer, less than five lung/liver lesions (with a maximum diameter <5 cm), metastatic disease confined to the lungs and liver or extrapulmonary or extrahepatic disease stable or responding to systemic therapy. Various dose-fractionation schedules were used. Then, a 4D-CT scan and FDG-CTPET were acquired for simulation and fused for target definition. RESULTS: From 2015 to 2021, 64 patients and a total of 90 lesions were irradiated. Treatment was well tolerated, with no G 3-4 toxicities. No grade ≥3 toxicities were registered and the coprimary endpoint of the study was met. Median follow-up was 19.4 months (range 2.6-73.1). CONCLUSIONS: The co-primary endpoint of this phase II trial was met, showing excellent tolerability of SBRT for lung and liver oligometastatic in breast cancer patients. Until efficacy data will mature with longer follow-up, SBRT should be regarded as an opportunity for oligometastatic breast cancer patients.

Phase II trial of stereotactic body radiation therapy on adrenal gland metastases: evaluation of efficacy and impact on hormonal production.

PURPOSE: The purpose of this study was to assess prospectively the efficacy and safety of stereotactic body radiation therapy (SBRT) for adrenal gland metastasis, with a focus on the assessment of the irradiated subjects' endocrinological function. MATERIALS AND METHODS: A total of 36 patients were enrolled from 2017 to 2020 in this prospective phase II trial. Patients were treated with Linac-based SBRT, with a dose of 45 Gy in 3 consecutive fractions. Primary end-point was local control (LC) of the treated lesions and secondary end-points included evaluation of acute and late toxicity, progression free survival (PFS), overall survival (OS) and the impact on the hormonal production of adrenal glands. RESULTS: With a median follow-up of 9.5 months, LC rates at 1 and 2 years were 94.7% and 88.4%, respectively. Rates of PFS at 1 and 2 years were 50.5% and 29.8%, with a median PFS of 14.7 months. Rates of OS at 1 and 2 years were 62.9% and 44.1%. At univariate analysis, oligorecurrence was associated with better OS compared to oligoprogressive or synchronous metastatic disease. No grade 3 or greater toxicities were registered and only a minority of patients (22.2%) reported mild treatment-related side effects. Hormonal and electrolytes production was assessed before and after treatment, showing only a slight and transient variation within the reference ranges. CONCLUSION: SBRT on adrenal metastases has been confirmed to be a feasible and effective treatment. With an excellent disease control and the preservation of the endocrine function, SBRT with ablative dose can be considered a viable alternative to more invasive approaches.

Seedling Establishment of Tall Fescue Exposed to Long-Term Starvation Stress.

In germinating seeds under unfavorable environmental conditions, the mobilization of stores in the cotyledons is delayed, which may result in a different modulation of carbohydrates balance and a decrease in seedling vigor. Tall fescue (Festuca arundinacea Schreb.) caryopses grown at 4°C in the dark for an extended period in complete absence of nutrients, showed an unexpected ability to survive. Seedlings grown at 4°C for 210 days were morphologically identical to seedlings grown at 23°C for 21 days. After 400 days, seedlings grown at 4°C were able to differentiate plastids to chloroplast in just few days once transferred to the light and 23°C. Tall fescue exposed to prolonged period at 4°C showed marked anatomical changes: cell wall thickening, undifferentiated plastids, more root hairs and less xylem lignification. Physiological modifications were also observed, in particular related to sugar content, GA and ABA levels and amylolytic enzymes pattern. The phytohormones profiles exhibited at 4 and 23°C were comparable when normalized to the respective physiological states. Both the onset and the completion of germination were linked to GA and ABA levels, as well as to the ratio between these two hormones. All plants showed a sharp decline in carbohydrate content, with a consequent onset of gradual sugar starvation. This explained the slowed then full arrest in growth under both treatment regimes. The analysis of amylolytic activity showed that Ca2+ played a central role in the stabilization of several isoforms. Overall, convergence of starvation and hormone signals meet in crosstalk to regulate germination, growth and development in tall fescue.

Physiological and morphological factors influencing wear resistance and recovery in C3 and C4 turfgrass species.

High turfgrass wear resistance and recovery are the most sought after characteristics in turfgrass species when used for sports turf, but they are also very important in home gardens and public parks. Several wear resistance investigations have been conducted in field conditions in recent years, but these investigations involved the use of machinery and techniques that are not able to segregate the plant wounding and death effects from soil compaction effects that are generally associated with turfgrass wear. The same can be said of wear recovery investigations, with an extensive use of agronomical machinery for field trials. This study focussed on the wear resistance and recovery of mature swards of Cynodon dactylon (L.) Pers. var. dactylon×C. transvaalensis Burt-Davy cv. Tifway 419, Zoysia matrella (L.) Merr. cv. Zeon and Paspalum vaginatum Swartz. cv. Salam and a typical sports-type mix of Lolium perenne L. (cvv. Speedster 35% and Greenway 35%)+Poa pratensis L. (cvv. SR2100 15% and Greenknight 15%). The goal of this trial was to evaluate turfgrass wear resistance and recovery devoid of climatic and soil effects and thus, sward growing, wear simulation and recovery were conducted in controlled environment. Furthermore, wear simulation was conducted with FIFA-approved, numerical control machinery (Lisport). Wear resistance and recovery data was plotted against results from laboratory investigations on key tissue constituents. Zoysia matrella proved to be the most wear resistant, but the slowest in recovery, whereas the bermudagrass hybrid showed the exact opposite behaviour. Lignin and carbohydrate concentrations proved to be the two factors most closely correlated with wear resistance and recovery respectively. These two classes of compounds were present in an equilibrium that was species specific, with a frequent mutual exclusion between lignin and starch concentrations that deserves further investigation at the intra-specific level.

Physiological and morphological factors influencing leaf, rhizome and stolon tensile strength in C4 turfgrass species.

The intrinsic resistance of plant tissue to several biomechanical stresses, including tensile stress, is a decisive factor in determining the wear resistance of a turfgrass species. Lignin, dry matter, starch, sugars and silica are some of the tissue constituents that have been associated with leaf and stem mechanical resistance, whereas little information is available concerning stolons and rhizomes. These organs not only enable C4 turfgrass species lateral growth, soil colonisation and injury recovery, but are also key constituents of mature swards. This study consisted in an extensive investigation on the effective leaf, stolon and rhizome tensile strength of Cynodon dactylon (L.) Pers. var. dactylon×C. transvaalensis Burt-Davy cv. Tifway 419, Zoysia matrella (L.) Merr. cv. Zeon and Paspalum vaginatum Swartz. cv. Salam, as measured with a Fédération Internationale de Football Association (FIFA)-approved dynamometer and correlating the results with laboratory investigations on key tissue constituents. Tensile strength per unit area was influenced by both tissue constituents and tissue dimension. In rhizomes and stolons, tissue breakage usually occurred in the area at the intercalary meristem at the apical zone in the immediate proximity of a node. Older tissues had higher tensile strength owing to their higher levels of lignification. Lignin was the principal constituent determining tissue tensile strength and as such it could be used as a turfgrass wear resistance predictor in the cultivar breeding stages. Stolon total soluble sugars were generally inversely proportional to lignin content and, therefore, can also be considered clear markers of tissue mechanical strength. Silica was found to have no influence on the mechanical properties tissues.