Stereotactic Radiation Therapy for Brain Metastases: Factors Affecting Outcomes and Radiation Necrosis.

Stereotactic radiation therapy (SRT) is a proven effective treatment for brain metastases (BM); however, symptomatic radiation necrosis (RN) is a late effect that may impact on patient's quality of life. The aim of our study was to retrospectively evaluate survival outcomes and characterize the occurrence of RN in a cohort of BM patients treated with ablative SRT at Federico II University Hospital. Clinical and dosimetric factors of 87 patients bearing a total of 220 BMs treated with SRT from 2016 to 2022 were analyzed. Among them, 46 patients with 127 BMs having clinical and MRI follow-up (FUP) ≥ 6 months were selected for RN evaluation. Dosimetric parameters of the uninvolved brain (brain without GTV) were extracted. The crude local control was 91% with neither clinical factors nor prescription dose correlating with local failure (LF). At a median FUP of 9 (1-68) months, the estimated median overall survival (OS), progression-free survival (PFS), and brain progression-free survival (bPFS) were 16, 6, and 9 months, respectively. The estimated OS rates at 1 and 3 years were 59.8% and 18.3%, respectively; bPFS at 1 and 3 years was 29.9% and 13.5%, respectively; PFS at 1 and 3 years was 15.7% and 0%, respectively; and local failure-free survival (LFFS) at 1 and 3 years was 87.2% and 83.8%, respectively. Extracranial disease status was an independent factor related to OS. Fourteen (30%) patients manifested RN. At multivariate analysis, adenocarcinoma histology, left location, and absence of chemotherapy were confirmed as independent risk factors for any-grade RN. Nine (20%) patients developed symptomatic (G2) RN, which improved or stabilized after 1-16 months of steroid therapy. With prompt recognition and, when necessary, medical therapy, RN radiological and clinical amelioration can be obtained.

Long-Term Outcomes in Uveal Melanoma After Ruthenium-106 Brachytherapy.

Uveal melanoma is the most common primary intraocular malignancy. The aim of this retrospective study was to report the results after ruthenium-106 (Ru-106) plaque brachytherapy for uveal melanoma in terms of tumor control, visual acuity, radiation-related complications, tumor recurrence, metastases, and patients' survival rate during 4 years' follow-up. A total of 355 eyes from 355 patients have been treated with Ru-106 plaque brachytherapy for uveal melanoma between February 2011 and March 2020. Five patients were lost to follow-up, and then 350 eyes of 350 patients (mean age 58 ± 11 years) were enrolled in this retrospective study. All patients underwent a complete ophthalmic examination including echography and spectral domain-optical coherence tomography. The mean follow-up was 4 years (3 months to 9 years). After treatment, the mean tumor thickness was reduced to 1.75 ± 0.21 mm. Radiation complications were found in 63% of patients: 38% showed radiation maculopathy, 11% had optic neuropathy, and 14% developed cataracts. Cancer-free survival was 99%, 97%, and 85%, respectively, at 5, 7, and 9 years. Ru-106 plaque brachytherapy represents a reliable treatment of uveal melanoma. This technique is valid and safe with a low rate of ocular complications during a long-term follow-up.

Retinal Vascular Changes in Radiation Maculopathy after Intravitreal Ranibizumab by Optical Coherence Tomography Angiography.

In this prospective study, we investigated the structural and vascular retinal changes at baseline and after Ranibizumab injections at the last follow up to one year in patients affected by Radiation Maculopathy (RM) after plaque brachytheraphy in choroidal melanoma, using Spectral Domain Optical Coherence Tomography (SD-OCT) and OCT Angiography (OCTA). A total of 40 eyes with RM of 40 patients (18 females, 22 males, mean age 51.9 ± 11 years) that underwent ruthenium-106 plaque brachytherapy were included. All patients received one monthly intravitreal injection of Ranibizumab (Pro Re Nata regimen). We analyzed the Foveal Avascular Zone (FAZ) area, the retinal vessel density (VD) of the superficial capillary plexus (SCP) and of the deep capillary plexus (DCP), using OCTA, and we detected the Central Foveal Thickness (CFT) by SD-OCT at baseline and after treatment. At the last follow up, we found a significant improvement of the CFT (p < 0.001) while OCTA parameters revealed no change in VD of the SCP (p = 0.402), DCP (p = 0.282), and FAZ area (p = 0.255), resulting in a stabilization of the visual acuity (p = 0.210) respect to baseline. The absence of functional improvement, despite the anatomical recovery of the macula, could be due to the absence of improvement in FAZ area and in retinal VD after treatment. OCTA parameters could represent predictive biomarkers to anti-vascular endothelial growth factor (anti-VEGF) intravitreal response and to help to better understand the physiopathological mechanisms of the RM.

Evaluation of Vascular Changes with Optical Coherence Tomography Angiography after Plaque Radiotherapy of Choroidal Melanoma.

AIM: The purpose of this paper was to evaluate whether optical coherence tomography angiography (OCT-A) can be used to quantify the vascular changes in radiation maculopathy, and changes in the tumor vasculature in eyes treated with plaque radiotherapy for choroidal melanoma. METHODS: In this prospective study, we evaluated 39 Caucasian patients with choroidal melanoma (39 eyes) treated with ruthenium-106 plaque radiotherapy. The patients underwent complete ophthalmic examination, bulbar echography, and OCT-A before and 1 year after treatment. RESULTS: At baseline, the mean best-corrected visual acuity (BCVA) in the affected eyes was 0.35 ± 0.40 logMAR, and the mean tumor thickness was 2.68 ± 0.25 mm at A-scan echography. After treatment, the mean BCVA increased to 0.41 logMAR, the mean tumor thickness decreased to 1.66 ± 0.23 mm, and the tumor basal diameter was significantly reduced (U = 108, p = 0.001). Moreover, the capillary vessel density was significantly lower in all Early Treatment of Diabetic Retinopathy Study sectors, and both the vessel and flow areas were significantly reduced (p = 0.030 and p = 0.001, respectively). CONCLUSIONS: OCT-A is a noninvasive, reliable method with which to quantify the vessel changes in radiation maculopathy and, given the association between vascularization and malignancy, this procedure may be an aid in treatment decision-making and in monitoring the efficacy of treatment.

Evaluation of vascular changes with optical coherence tomography angiography after ruthenium-106 brachytherapy of circumscribed choroidal hemangioma.

PURPOSE: To describe the vascular changes of circumscribed choroidal hemangioma (CCH) after ruthenium-106 brachytherapy using optical coherence tomography angiography (angio-OCT). METHODS: Seven eyes of 7 patients diagnosed with symptomatic CCH who underwent ruthenium-106 plaque radiotherapy were included in the study. Patients underwent complete ophthalmic examination, bulbar echography and angio-OCT. The same protocol was applied 1 year after ruthenium-106 brachytherapy. RESULTS: At baseline, the mean best-corrected visual acuity (BCVA) in affected eyes was 0.67 ± 0.14 logMAR, and the mean tumor thickness was 4.46 ± 0.91 mm measured by standardized A-scan echography. After ruthenium-106 plaque treatment, the mean BCVA increased to 0.17 ± 0.10 logMAR (p = 0.001) and the mean tumor thickness to 2.29 ± 0.71 mm (p = 0.003). Moreover, there was a significant reduction of the tumor basal diameter (p= 0.009). Intra-tumor angio-OCT measurements revealed a statistically significant reduction of the vessel and flow areas (p = 0.006 and p = 0.002, respectively) 1 year after brachytherapy. CONCLUSIONS: Angio-OCT is a non-invasive reliable method with which to evaluate the vascular features of CCH and consequently to monitor changes after conservative treatment.

Dose-surface analysis for prediction of severe acute radio-induced skin toxicity in breast cancer patients.

BACKGROUND: Severe acute radiation-induced skin toxicity (RIST) after breast irradiation is a side effect impacting the quality of life in breast cancer (BC) patients. The aim of the present study was to develop normal tissue complication probability (NTCP) models of severe acute RIST in BC patients. PATIENTS AND METHODS: We evaluated 140 consecutive BC patients undergoing conventional three-dimensional conformal radiotherapy (3D-CRT) after breast conserving surgery in a prospective study assessing acute RIST. The acute RIST was classified according to the RTOG scoring system. Dose-surface histograms (DSHs) of the body structure in the breast region were extracted as representative of skin irradiation. Patient, disease, and treatment-related characteristics were analyzed along with DSHs. NTCP modeling by Lyman-Kutcher-Burman (LKB) and by multivariate logistic regression using bootstrap resampling techniques was performed. Models were evaluated by Spearman's Rs coefficient and ROC area. RESULTS: By the end of radiotherapy, 139 (99%) patients developed any degree of acute RIST. G3 RIST was found in 11 of 140 (8%) patients. Mild-moderate (G1-G2) RIST was still present at 40 days after treatment in six (4%) patients. Using DSHs for LKB modeling of acute RIST severity (RTOG G3 vs. G0-2), parameter estimates were TD50=39 Gy, n=0.38 and m=0.14 [Rs = 0.25, area under the curve (AUC) = 0.77, p = 0.003]. On multivariate analysis, the most predictive model of acute RIST severity was a two-variable model including the skin receiving ≥30 Gy (S30) and psoriasis [Rs = 0.32, AUC = 0.84, p < 0.001]. CONCLUSIONS: Using body DSH as representative of skin dose, the LKB n parameter was consistent with a surface effect for the skin. A good prediction performance was obtained using a data-driven multivariate model including S30 and a pre-existing skin disease (psoriasis) as a clinical factor.

Radiation therapy following surgery for localized breast cancer: outcome prediction by classical prognostic factors and approximated genetic subtypes.

The purpose of this study was to evaluate the outcome prediction power of classical prognostic factors along with surrogate approximation of genetic signatures (AGS) subtypes in patients affected by localized breast cancer (BC) and treated with postoperative radiotherapy. We retrospectively analyzed 468 consecutive female patients affected by localized BC with complete immunohistochemical and pathological information available. All patients underwent surgery plus radiotherapy. Median follow-up was 59 months (range, 6-132) from the diagnosis. Disease recurrences (DR), local and/or distant, and contralateral breast cancer (CBC) were registered and analyzed in relation to subtypes (luminal A, luminal B, HER-2, and basal), and classical prognostic factors (PFs), namely age, nodal status (N), tumor classification (T), grading (G), estrogen receptors (ER), progesterone receptors and erb-B2 status. Bootstrap technique for variable selection and bootstrap resampling to test selection stability were used. Regarding AGS subtypes, HER-2 and basal were more likely to recur than luminal A and B subtypes, while patients in the basal group were more likely to have CBC. However, considering PFs along with AGS subtypes, the optimal multivariable predictive model for DR consisted of age, T, N, G and ER. A single-variable model including basal subtype resulted again as the optimal predictive model for CBC. In patients bearing localized BC the combination of classical clinical variables age, T, N, G and ER was still confirmed to be the best predictor of DR, while the basal subtype was demonstrated to be significantly and exclusively correlated with CBC.

Thyroid V30 predicts radiation-induced hypothyroidism in patients treated with sequential chemo-radiotherapy for Hodgkin's lymphoma.

PURPOSE: Hypothyroidism (HT) is a frequent late side effect of Hodgkin's lymphoma (HL) therapy. The purpose of this study is to determine dose-volume constraints that correlate with functional impairment of the thyroid gland in HL patients treated with three-dimensional radiotherapy. METHODS AND MATERIALS: A total of 61 consecutive patients undergoing antiblastic chemotherapy and involved field radiation treatment (median dose, 32 Gy; range, 30-36 Gy) for HL were retrospectively considered. Their median age was 28 years (range, 14-70 years). Blood levels of thyroid-stimulating hormone (TSH), free triiodo-thyronine (FT3), free thyroxine (FT4), and thyroglobulin antibody (ATG) were recorded basally and at different times after the end of therapy. For the thyroid gland, normal tissue complication probability (NTCP), dosimetric parameters, and the percentage of thyroid volume exceeding 10, 20, and 30 Gy (V10, V20, and V30) were calculated in all patients. To evaluate clinical and dosimetric factors possibly associated with HT, univariate and multivariate logistic regression analyses were performed. RESULTS: Eight of 61 (13.1%) patients had HT before treatment and were excluded from further evaluation. At a median follow-up of 32 months (range, 6-99 months), 41.5% (22/53) of patients developed HT after treatment. Univariate analyses showed that all dosimetric factors were associated with HT (p < 0.05). On multivariate analysis, the thyroid V30 value was the single independent predictor associated with HT (p = 0.001). This parameter divided the patients into low- vs. high-risk groups: if V30 was ≤ 62.5%, the risk of developing HT was 11.5%, and if V30 was >62.5%, the risk was 70.8% (p < 0.0001). A Cox regression curve stratified by two levels of V30 value was created (odds ratio, 12.6). CONCLUSIONS: The thyroid V30 predicts the risk of developing HT after sequential chemo-radiotherapy and defines a useful constraint to consider for more accurate HL treatment planning.

Dosimetric predictors of asymptomatic heart valvular dysfunction following mediastinal irradiation for Hodgkin's lymphoma.

PURPOSE: To identify dose-heart-volume constraints that correlate with the risk of developing asymptomatic valvular defects (VD) in Hodgkin's lymphoma (HL) patients treated with three-dimensional radiotherapy (RT). PATIENTS AND METHODS: Fifty-six patients undergoing cytotoxic chemotherapy (CHT) and involved-field radiation treatment for HL were retrospectively analyzed. Electro-echocardiography was performed before CHT, after CHT, and after RT. For the entire heart, for right and left ventricle (RV, LV), right and left atrium (RA, LA) percentage of volume exceeding 5-30Gy in increment of 5Gy (V(x)), and dosimetric parameters were calculated using 1.6Gy fraction as reference. To evaluate clinical and dosimetric factors possibly associated with VD, univariate and multivariate logistic regression analyses were performed. RESULTS: At a median follow up of 70.5 months, 32.1% of patients developed VD (regurgitation and/or stenosis): 25.0% developed mitral, 5.4% developed aortic, and 14.3% tricuspid VD. In particular the percentage of LA exceeding 25Gy (LA-V(25)) and the percentage of LV exceeding 30Gy (LV-V(30)) correlated with mitral and aortic VD with an odds ratio (OR) of 5.7 (LA-V(25)>63.0% vs. LA-V(25)≤63.0%) and OR of 4.4 (LV-V(30)>25% vs. LV-V(30)≤25%), respectively. RV-V(30) correlated with tricuspid VD (OR=7.2, RV-V(30)>65% vs. RV-V(30)≤65%). CONCLUSION: LA-V(25), LV- and RV-V(30) prove to be predictors of asymptomatic alteration of valve functionality.

Fractionated stereotactic radiation therapy for orbital optic nerve sheath meningioma - a single institution experience and a short review of the literature.

Optic nerve sheath meningioma (ONSM) is a rare orbital tumor that generally induces a slow progressive visual loss in affected patients. Radiotherapy (RT) has currently become the first choice to treat ONSM. In this study our experience in ONSM treatment with fractionated stereotactic radiotherapy (FSRT) is reported. Five patients with diagnosis of orbital ONSM were treated between April 2007 and December 2009 at the Radiation Oncology department of our institution. All patients underwent history and physical, and ophthalmic examinations. Orbital MRI was performed before and 6 weeks after treatment; thereafter every 6 months for the first 2 years. By previous stereotactic localization of the target, RT was delivered with 28 daily fraction of 1.8 Gy by multiple non coplanar arcs dynamically conformed by a micro multileaf-collimator. At diagnosis, in all 5 patients, visual acuity limitations of different degrees were found, while exophthalmos was present in 2, diplopy in 2, orbital pain in 1, and proptosis in 1. In all patients pre-treatment MRI showed an orbital mass involving the optic nerve. After radiotherapy, previous symptoms improved in all patients. However, after RT the MRI consistently showed a stationary status compared to the MRI before RT. At a median follow up of 26 months (range 9-37) all patients had a subjective and/or objective better visual performance than before RT without any evidence of disease progression. No late side effects were recorded. Accordingly to the current literature, our experience confirms the efficacy and the safety of FSRT in patients with orbital ONSM.

Radiation therapy in primary orbital lymphoma: a single institution retrospective analysis.

BACKGROUND: Primary orbital lymphoma is a rare disease that accounts for 10% of all orbital tumors. Radiotherapy on the orbital cavity is the treatment of choice for this unusual presentation of localized non-Hodgkin's lymphoma (NHL). The aim of this study is to retrospectively evaluate the effectiveness and the toxicity of radiation treatment in patients with primary orbital lymphoma. METHODS: Forty-seven consecutive patients having primary orbital lymphoma treated in our department between May 1983 and September 2006 were investigated in a retrospective study. Either 60Co gamma rays or 6 MV X rays were used to deliver daily fractions of 1.8 or 2.0 Gy, 5 times/week, with total doses ranging from 34.2 to 50 Gy. Forty-three patients had stage IE, three had stage II and one stage IV disease. Thirty-eight patients had marginal zone B-cell lymphoma, 5 diffuse large B cell lymphoma, 3 mantle cell lymphoma and 1 Burkitt lymphoma. Local control (LC), disease free survival (DFS), overall survival (OS) and late side effects were evaluated in all patients. RESULTS: With a median follow up of 45 months, LC was obtained in 100% of patients. The estimated 5- and 7-year DFS rates were 75.8% and 55.3%, and the 5- and 7-year OS rates were 88.7% and 79.9% respectively. Acute toxicity was minimal. Late toxicity such as cataract, keratitis, retinopathy and xerophthalmia occurred respectively in 12 (25.5%), 5 (10.6%), 1 (2.1%), and 9 (19.1%) patients. CONCLUSION: Radiotherapy is an effective and at the same time well tolerated treatment for primary orbital lymphoma.

Preoperative radiation treatment for rectal cancer: comparison of target coverage and small bowel NTCP in conventional vs. 3D-conformal planning.

A prospective study was undertaken to evaluate the improvement in rectal cancer radiation treatment achieved with the implementation of target delineation for conformal radiotherapy, replacing conventional technique using standard radiological anatomy for target volume definition. In 10 patients receiving preoperative pelvic irradiation for rectal cancer, a 3-field technique was designed by a 3-dimensional (3D) planning system. Two plans were simulated for each patient, one with the fields designed in the conventional way based on radiological anatomy, and the other with the fields designed on the basis of a computed tomography (CT) delineated planning target volume (PTV). A total dose of 45 Gy in 25-daily fractions of 1.8 Gy in 5 weeks was planned. Dose-volume histograms (DVHs) of PTV, small bowel, anal sphincter, and urinary bladder were analyzed to compare plans. The minimum, maximum, and mean dose in the PTV and in critical organs were also evaluated. The inhomogeneity coefficient (IC) and the target coverage (TC) were calculated. The normal tissue complication probability (NTCP) for each organ at risk (OAR) was determined. NTCP for small bowel and urinary bladder was not statistically different, while the PTV coverage was significantly lower with conventional treatment relative to conformal treatment (median IC=7.2, median TC=0.91 vs. median IC=0.14 and median TC=1, p<0.005). The 3D conformal treatment plan in preoperative radiotherapy for rectal cancer improves target coverage without significantly affecting small bowel and urinary bladder NTCP.

Bladder-sparing, combined-modality approach for muscle-invasive bladder cancer: a multi-institutional, long-term experience.

BACKGROUND: The authors evaluated their long-term experience with combined-modality, conservative treatment in patients with muscle-invasive bladder cancer. METHODS: In total, 121 patients with T2, T3, or T4 bladder cancer (mean age, 63 years; ratio of men to women, 3:1) underwent induction by transurethral resection (TUR) of the tumor and received 2 cycles of neoadjuvant chemotherapy followed by radiotherapy (RT) (n = 43 patients) or radiochemotherapy (RCT) (n = 78 patients). Six weeks after RT or RCT, responses were evaluated by restaging TUR. Patients who achieved a complete response (CR) were observed at regular intervals. In patients who had persistent or recurrent invasive tumor, further treatment was recommended. RESULTS: Local response evaluation by restaging TUR was possible in 119 patients, and 102 of those patients (85.7%) achieved a CR. After a median follow-up of 66 months (range, 6-182 months), no local or distant disease recurrences were observed in 67 of 102 complete responders (65.7%), 17 of 102 complete responders (16.7%) experienced superficial local disease recurrence, and 18 of 102 complete responders (17.6%) had a muscle-invasive relapse. The 5-year tumor-specific, overall, and bladder-intact survival rates were 73.5%, 67.7%, and 51.2%, respectively. Treatment modality, tumor classification, and resection status after initial TUR had an impact on survival rates (P = .04, P = .02, and P = .02, respectively). CONCLUSIONS: The current results indicated that conservative combined treatment is a reasonable alternative to radical cystectomy in selected patients with muscle-invasive bladder cancer.