Using embedded alginate microparticles to tune the properties of in situ forming poly(N-isopropylacrylamide)-graft-chondroitin sulfate bioadhesive hydrogels for replacement and repair of the nucleus pulposus of the intervertebral disc.

Low back pain is a major public health issue associated with degeneration of the intervertebral disc (IVD). The early stages of degeneration are characterized by the dehydration of the central, gelatinous portion of the IVD, the nucleus pulposus (NP). One possible treatment approach is to replace the NP in the early stages of IVD degeneration with a hydrogel that restores healthy biomechanics while supporting tissue regeneration. The present study evaluates a novel thermosensitive hydrogel based on poly(N-isopropylacrylamide-graft-chondroitin sulfate) (PNIPAAM-g-CS) for NP replacement. The hypothesis was tested that the addition of freeze-dried, calcium crosslinked alginate microparticles (MPs) to aqueous solutions of PNIPAAm-g-CS would enable tuning of the rheological properties of the injectable solution, as well as the bioadhesive and mechanical properties of the thermally precipitated composite gel. Further, we hypothesized that the composite would support encapsulated cell viability and differentiation. Structure-material property relationships were evaluated by varying MP concentration and diameter. The addition of high concentrations (50 mg/mL) of small MPs (20 ± 6 µm) resulted in the greatest improvement in injectability, compressive mechanical properties, and bioadhesive strength of PNIPAAm-g-CS. This combination of PNIPAAM-g-CS and alginate MPs supported the survival, proliferation, and differentiation of adipose derived mesenchymal stem cells toward an NP-like phenotype in the presence of soluble GDF-6. When implanted ex vivo into the intradiscal cavity of degenerated porcine IVDs, the formulation restored the compressive and neutral zone stiffnesses to intact values and resisted expulsion under lateral bending. Overall, results indicate the potential of the hydrogel composite to serve as a scaffold for supporting NP regeneration. This work uniquely demonstrates that encapsulation of re-hydrating polysaccharide-based MPs may be an effective method for improving key functional properties of in situ forming hydrogels for orthopedic tissue engineering applications.

Stereotactic Body Radiation Therapy for Intermediate-risk Prostate Cancer With VMAT and Real-time Electromagnetic Tracking: A Phase II Study.

OBJECTIVES: Stereotactic body radiation treatment represents an intriguing therapeutic option for patients with early-stage prostate cancer. In this phase II study, stereotactic body radiation treatment was delivered by volumetric modulated arc therapy with flattening filter free beams and was gated using real-time electromagnetic transponder system to maximize precision of radiotherapy and, potentially, to reduce toxicities. MATERIALS AND METHODS: Patients affected by histologically proven prostate adenocarcinoma and National Comprehensive Cancer Network (NCCN) intermediate class of risk were enrolled in this phase II study. Beacon transponders were positioned transrectally within the prostate parenchyma 7 to 10 days before simulation computed tomography scan. The radiotherapy schedule was 38 Gy in 4 fractions delivered every other day. Toxicity assessment was performed according to Common Terminology Criteria for Adverse Events (CTCAE), v4.0. RESULTS: Thirty-six patients were enrolled in this study. Median initial prostate-specific antigen was 7.0 ng/mL (range: 2.3 to 14.0 ng/mL). Median nadir-prostate-specific antigen after treatment was 0.2 ng/mL (range: 0.006 to 4.8 ng/mL). A genitourinary acute toxicity was observed in 21 patients (dysuria grade [G] 1: 41.7%, G2: 16.7%). Gastrointestinal acute toxicity was found in 9 patients (proctitis G1: 19.4%, G2: 5.6%). Late toxicity was mild (genitourinary toxicity G1: 30.6%; G2: 8.3%; gastrointestinal toxicity G1: 13.9%; G2: 19.4%). At a median follow-up time of 41 months, 3 biochemical recurrences were observed (2 local recurrences, 1 distant metastasis). Three-year biochemical recurrence-free survival was 89.8% (International Society of Urologic Pathology Grade Group 2: 100%, Grade Group 3: 77.1%, P=0.042). CONCLUSION: Ultrahypofractionated radiotherapy, delivered with flattening filter free-volumetric modulated arc therapy and gated by electromagnetic transponders, is a valid option for intermediate-risk prostate cancer.

Hypofractionated Whole Breast Irradiation and Simultaneous Integrated Boost in Large-breasted Patients: Long-term Toxicity and Cosmesis.

INTRODUCTION: The purpose of this study was to evaluate the impact of breast size on long-term toxicity and cosmesis in patients with breast cancer treated with hypofractionated simultaneous integrated boost (SIB) using volumetric modulated arc therapy (VMAT). PATIENTS AND METHODS: Patients with early stage breast cancer were treated with 3-week hypofractionated SIB-VMAT to the whole breast (40.5 Gy) and tumor bed (48 Gy). Two cohorts were identified: small/medium- (< 1000 cm3) and large- (> 1000 cm3) breasted patients. Acute and late (at 2 and 5 years) skin toxicity and cosmetic data were analyzed. Univariate and multivariate analysis evaluated associations between toxicity and dosimetric/anatomical variables. RESULTS: From August 2010 to March 2017, a total of 1160 patients were treated; 831 had at least 2 years of follow-up and were analyzed. Treated skin area (TSA) receiving at least 20 Gy > 400 cm2 and V105% of Boost > 5 cm3 were significant predictors for acute skin toxicity. Multivariate analysis at 2 years was significant for boost volume > 70 cm3, TSA > 400 cm2, and breast size > 1500 cm3. At 5 year analysis (352 patients), none of the analyzed variables was significant. For cosmetic outcome, only the breast size (> 1000 cm3) and the boost size > 70 cm3 at 2 and 5 years, respectively, confirmed significance. CONCLUSIONS: The TSA > 400 cm2 resulted as a significant predictor of both acute and late skin toxicity at 2 years; however, at 5 years, no breast size or dosimetric parameter suggested indications for increased toxicity. A worse cosmetic outcome was recorded at the 2-year follow up for large breasts, but was not confirmed at the 5-year follow-up. These long-term data suggest that hypofractionated SIB-VMAT is a viable modality also in large-breasted patients.

Role of stereotactic body radiation therapy in the treatment of liver metastases: clinical results and prognostic factors.

PURPOSE: To evaluate feasibility and efficacy of Stereotactic Body Radiation Therapy (SBRT) for unresectable liver metastasis in oligometastatic patients. METHODS: Oligometastatic patients with up to three liver metastases of a maximum diameter of 6 cm were treated with SBRT. Total dose was 75 Gy in three consecutive fractions. Study endpoints were efficacy of this fractionation in terms of local control (LC), overall survival (OS), toxicity, and prognostic factors affecting OS and LC. RESULTS: Between February 2010 and December 2016, we enrolled 202 patients, with a total of 268 unresectable liver metastases. Median follow-up time from SBRT was 33 months (5-87 months). One-, 3­, and 5­year LC rates were 92%, 84%, and 84%, respectively. In univariate analysis, the primary histology and previous local ablative therapies were significant. Median OS was 21 months and the survival rates were 79%, 27%, and 15% at 1, 3, and 5 years after SBRT, respectively. At univariate analysis, sex, primary disease histology, intra-, and extra-hepatic progression were significant prognostic factors. This analysis confirmed the absence of late toxicity >G3. CONCLUSION: This study confirms the efficacy and safety of SBRT for unresectable liver metastases. Selection of cases may improve survival and LC.

Postmastectomy radiation therapy using VMAT technique for breast cancer patients with expander reconstruction.

Postmastectomy radiotherapy (PMRT) following immediate breast reconstruction is increasingly adopted in the management of breast cancer patients. We retrospectively evaluate the complication rates of PMRT using VMAT technique to immediate tissue expander-based reconstructions and the possible impact of tissue expander volume on radiotherapy planning. We reviewed the data of patients who underwent immediate expander breast reconstruction and received PMRT with VMAT (50 Gy in 25 fractions) on the reconstructed breast and axillary levels III-IV. Neoadjuvant or adjuvant systemic therapy was administered in most of the patients. Autologous fat grafting was routinely performed at the time of second-stage reconstruction. Between 2015 and 2017, PMRT was delivered to 46 consecutive patients (median age 50 years) with expander reconstruction. Median follow-up was 27 months (range 10-41). Two patients (4.3%) had a reconstruction failure, as expander rupture and infection, following the first- and the second-stage reconstruction, respectively. In most cases expanders were completely inflated before PMRT (65.2%). Median expander volume before PMRT was 425 cm3 (range 150-700 cm3). The amount of expander inflation did not significantly affect dosimetry, except for skin dose, with a surface receiving more than 30 Gy of 36.6 ± 0.9 cm2 and 47.0 ± 2.5 cm2 for a volume expander below or above the median, respectively. However, this variable was not predictor for complications. Disease progression was recorded in 15.2% of patients. PMRT using VMAT technique for breast cancer patients with expander reconstruction is associated with a very low complication rate. The expander volume before PMRT does not significantly compromise radiotherapy dose distribution.

Reirradiation of Locally Recurrent Prostate Cancer With Volumetric Modulated Arc Therapy.

PURPOSE: This study explores the efficacy and safety of reirradiation with modern radiation therapy techniques in patients previously irradiated for prostate cancer and affected by local relapse of disease. METHODS AND MATERIALS: Patients affected by previously irradiated prostate cancer were enrolled in this reirradiation study if they had a biochemical relapse and a 11C-choline positron emission tomography scan revealing the presence of a local recurrence of disease. Reirradiation consisted of a stereotactic treatment delivered by image guided radiation therapy-volumetric modulated arc therapy with flattening filter-free technology in 5 daily fractions. RESULTS: Twenty-three patients underwent reirradiation to the prostate, prostatic bed, or prostate and local recurrence. Re-treatment consisted of a median total dose of 25 Gy in 5 fractions. A biochemical response was observed in all cases. Acute toxicity was mainly genitourinary (GU) grade 1 to 2 (n = 13; 56.5%). One patient (4.3%) had grade 3 hematuria. A grade 1 GU late toxicity was registered in 4 patients (17.4%) and grade 3 in 1 patient (4.3%, urethral obstruction). Gastrointestinal toxicity was negligible. Regression analysis showed that only a short elapsed time in months from primary radiation therapy was significantly correlated with acute GU toxicity. After a median follow-up of 33 months (range, 5-58 months), the median biochemical recurrence-free survival was 19 months, and the 2-year biochemical recurrence-free survival (BRFS) was 41.7%. Median local control was 30 months; the 2-year local control rate was 58.1%. CONCLUSIONS: Reirradiation of patients with prostate cancer who underwent previous radiation therapy is a valuable option that can be safely considered to delay the beginning of hormonal treatment.

Phase II trial on SBRT for unresectable liver metastases: long-term outcome and prognostic factors of survival after 5 years of follow-up.

BACKGROUND: The aim of this study was to evaluate long-term efficacy and survival prognostic factors of stereotactic body radiation therapy (SBRT) for un-resectable liver metastases in patients enrolled in a prospective phase II trial. METHODS AND MATERIALS: 5-year local control (LC), overall survival (OS), progression free survival (PFS) and toxicity rates were analyzed in patients with un-resectable liver metastases enrolled in a Phase II Trial on liver SBRT, with a prescription dose of 75Gy in 3 consecutive fractions. RESULTS: A total of 61 patients with 76 lesions were enrolled, with a median follow-up time of 6.1 years. One, three and 5 year LC rates were 94 ± 3.1%, 78.0 ± 5.9% and 78.0 ± 5.9%, without reaching the median LC time. Median OS was 27.6 months and the survival rates were 85.2 ± 4.5%, 31.1 ± 5.9% and 18.0 ± 4.9% at 1, 3 and 5-year after SBRT, respectively. Univariate analysis showed that favorable primary site (colorectal, breast and gynecological) of metastases (p = 0.001) improved survival. Toxicity was moderate. One patient experienced G3 late chest wall pain, which resolved within 1 year from SBRT. No cases of Radiation Induced Liver Disease (RILD) were detected. CONCLUSIONS: Long-term results of this Phase II study suggest the efficacy and safety of SBRT for un-resectable liver metastases after 5-year of follow up. Selection of cases with positive prognostic factors may improve long-term survival of these oligo-metastastic patients and may confirm the role of SBRT as an effective alternative local therapy for liver metastases.

Hypofractionation with simultaneous boost in breast cancer patients receiving adjuvant chemotherapy: A prospective evaluation of a case series and review of the literature.

INTRODUCTION: To evaluate acute toxicity and cosmetic outcomes of hypofractionated simultaneous integrated boost (SIB) as adjuvant treatment after breast-conserving surgery and adjuvant chemotherapy and to review the association of chemotherapy and short fractionation with boost. MATERIALS AND METHODS: Patients presenting early-stage breast cancer were enrolled in a phase II trial. All patients received VMAT-SIB technique to the whole breast and tumor bed in 15 fractions, for a total dose of 40.5 and 48 Gy. Acute and late skin toxicities and breast pain were recorded. Cosmetic outcomes were also assessed as excellent/good or fair/poor. RESULTS: Between August 2010 and December 2015, 787 consecutive patients were treated and had at least 2 year follow-up. A subset of 175 patients underwent adjuvant chemotherapy (median age of 55 years) and was analysed. The median follow up was 39 months (range 24-80). At the end of RT treatment, skin toxicity was G1 in 51.1% of patients, G2 in 9.7%. At 2 years of follow up, it was G1 in 13.5% of patients, no cases ≥ G2; cosmetic outcome was excellent in 63.5% and good in 36.5% of the patients. No significant difference compared to the patients without systemic therapy was observed. CONCLUSION: Hypofractionated VMAT-SIB in patients who had undergone adjuvant systemic therapy was safe and well tolerated in terms of acute and early late settings and cosmesis. Our data confirmed the results of other studies published on the association of hypofractionation and chemotherapy or concomitant boost.

Stereotactic Body Radiation Therapy in Oligometastatic Ovarian Cancer: A Promising Therapeutic Approach.

OBJECTIVE: Stereotactic body radiation therapy (SBRT) has been successfully used to treat oligometastases of several primary tumors, but few experiences have been described in patients with gynecological oligometastatic cancer, particularly in ovarian neoplasm. The aim of this study was to evaluate the role of this new radiotherapy modality in a series of oligometastatic ovarian cancer patients. MATERIALS AND METHODS: Clinical records of patients affected by oligometastatic ovarian carcinoma treated with SBRT were reviewed. RESULTS: Twenty-six patients with 44 metastatic lesions (lymph nodes, 63.6%; liver, 31.8%; and lung, 4.5%) treated with SBRT between January 2011 and May 2017 were analyzed. After a median follow-up period of 28.5 months (range, 6-86 months), 17 patients (65.4%) were still alive at time of analysis: 6 are without evidence of disease, 11 experienced a disease progression. Eight patients died of disease, 1 died because of an heart attack while being disease free. The median local control (LC) was not reached. One-, 2-, and 5-year LCs were 92.9%. Median progression-free survival was 19 months, with 1-year progression-free survival of 69.3% and 38% at 2 years, 19% at 5 years. Median overall survival was 64.5 months, with all patients alive after 1 year, 92.7% at 2 years, and 61.7% at 5 years. Five (11.3%) cases experienced G2 toxicity; most common adverse effect was nausea and vomiting (3 cases [6.8%]) followed by abdominal pain (2 cases [4.5%]). None of the patients had grade 3 or grade 4 acute or late toxicity. CONCLUSIONS: In conclusion, SBRT is a feasible and safe approach for selected cases of oligometastatic ovarian cancer, with satisfactory results in terms of LC and disease free survival.

Hypofractionated volumetric modulated arc therapy in ductal carcinoma in situ: toxicity and cosmetic outcome from a prospective series.

OBJECTIVE: Hypofractionated radiotherapy in early stage breast cancer is an effective adjuvant treatment, but there is a lack of randomized data for patients with ductal carcinoma in situ (DCIS). The aim of this study is the evaluation of skin toxicity and cosmesis, and early clinical outcome of DCIS patients enrolled in an institutional Phase II trial of hypofractionated breast irradiation. METHODS: 137 DCIS patients were enrolled in the trial. All patients underwent volumetric modulated arc therapy (VMAT) to the whole breast with a total dose of 40.5 Gy in 15 fractions over 3 weeks, without tumour bed boost. Acute and late skin toxicities were recorded. Cosmetic outcomes were assessed as excellent/good or fair/poor. Early clinical outcome was reported. RESULTS: Median age was 58 y.o. (range 30-86). The median follow-up time was 22 months (range 6-45). At the end of the radiotherapy, skin toxicity was grade G1 in 56% of the patients, G2 in 15%, no patients presented G3 toxicity. In the range of 3-9 months of follow-up, the skin toxicity was G1 in 28% of patients, no G2-G3 cases; cosmetic outcome was good/excellent in 95% of patients. In the follow-up interval of 9-24 months, the skin toxicity was G1 in 12% of patients, no G2-G3 toxicity; cosmetic outcome was good/excellent in 96% of patients. After an early evaluation of clinical outcomes, 5 patients (3.6%) presented an in-breast recurrence. CONCLUSION: Hypofractionated radiotherapy using VMAT is a viable option for DCIS. A longer follow-up is needed to assess clinical outcomes and late toxicity. Advances in knowledge: The use of hypofractionated VMAT is dosimetrically feasible for treating breast DCIS.

Stereotactic/hypofractionated body radiation therapy as an effective treatment for lymph node metastases from colorectal cancer: an institutional retrospective analysis.

OBJECTIVE: The colorectal cancer (CRC) might present loco-regional recurrence, including lymph-node metastasis. Stereotactic body radiotherapy (SBRT) is a non-invasive and well-tolerated ablative treatment. Aim of the present study is to evaluate efficacy and toxicity of SBRT with volumetric modulated arc therapy (VMAT) in this setting. METHODS: 35 patients presenting a total of 47 nodal recurrences from CRC, treated with VMAT-SBRT from 2008 to 2015, were selected. About three fourth of the treatments delivered 45 Gy in 6 daily fractions. End-points were the detection of toxicities, overall survival (OS), local control (LC), disease progression free incidence (DPFI) and disease free survival (DFS). Tumour response was assessed according to the RECIST criteria. RESULTS: Only Grade 1 and 2 toxicities were recorded. Median follow-up was 15 months (range 2-68). Local relapse was reported in 6 patients, regional relapse in 10 patients. Complete remission was reported in 20 cases (53%), partial remission in 14 (37%). Rates of LC at 1, 2 and 3 years were 85.3, 75.0 and 75.0%, respectively. At 1 year the actuarial OS was 100%, at 2 and 3 years was 81.4%. Median DFS was estimated in 16 months, with an incidence of 69.4, 33.3 and 19.4% at 1, 2 and 3 years, respectively. CONCLUSION: The use of the VMAT-SBRT in lymph-node recurrence of CRC could prevent severe complications and achieve satisfying rates of disease control. Advances in knowledge: The use of VMAT-SBRT is a viable approach for lymph-node recurrence of CRC.

Role of stereotactic body radiation therapy for lung metastases from radio-resistant primary tumours.

OBJECTIVES: A retrospective analysis was performed on patients treated for lung oligo-metastatic disease from radio-resistant histology groups. METHODS: The primary end point was local control (LC), secondary end points were overall survival (OS) and progression free survival (PFS). Toxicity was scored according to CTCAE 4.03. RESULTS: 200 patients were analyzed: 49.5% of the cases derived from colorectal primary tumors, 20.5% from sarcomas, 12.0% from renal cell carcinoma and the rest from other mixed origin. The mean follow-up was 24.2 months. LC at 1 and 2 years was 91, 84.9%. Primary histology and the presence of extra-pulmonary disease had a significant impact on LC. OS at 1 and 2 years was 88.7, 65.4%. Primary histology, disease free interval, presence of extra-pulmonary disease, number of irradiated lung lesions and age showed a correlation with prognosis at univariate analysis. PFS at 1 and 2 years was 84, 57.7%. The presence of extra-pulmonary disease and the number of irradiated lung lesions correlated with prognosis. Treatment was well tolerated with no G3-4 acute or late toxicity recorded. CONCLUSION: Colorectal metastases showed a higher rate of local relapse. However, the factors mostly influencing prognosis were the presence of extra-pulmonary disease and the number of lung lesions.

Synthesis of Thermogelling Poly(N-isopropylacrylamide)-graft-chondroitin Sulfate Composites with Alginate Microparticles for Tissue Engineering.

Injectable biomaterials are defined as implantable materials that can be introduced into the body as a liquid and solidify in situ. Such materials offer the clinical advantages of being implanted minimally invasively and easily forming space-filling solids in irregularly shaped defects. Injectable biomaterials have been widely investigated as scaffolds for tissue engineering. However, for the repair of certain load-bearing areas in the body, such as the intervertebral disc, scaffolds should possess adhesive properties. This will minimize the risk of dislocation during motion and ensure intimate contact with the surrounding tissue, providing adequate transmission of forces. Here, we describe the preparation and characterization of a scaffold composed of thermally sensitive poly(N-isopropylacrylamide)-graft-chondroitin sulfate (PNIPAAM-g-CS) and alginate microparticles. The PNIPAAm-g-CS copolymer forms a viscous solution in water at RT, into which alginate particles are suspended to enhance adhesion. Above the lower critical solution temperature (LCST), around 30 °C, the copolymer forms a solid gel around the microparticles. We have adapted standard biomaterials characterization procedures to take into account the reversible phase transition of PNIPAAm-g-CS. Results indicate that the incorporation of 50 or 75 mg/ml alginate particles into 5% (w/v) PNIPAAm-g-CS solutions quadruple the adhesive tensile strength of PNIPAAm-gCS alone (p<0.05). The incorporation of alginate microparticles also significantly increases swelling capacity of PNIPAAm-g-CS (p<0.05), helping to maintain a space-filling gel within tissue defects. Finally, results of the in vitro toxicology assay kit, 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) and Live/Dead viability assay indicate that the adhesive is capable of supporting the survival and proliferation of encapsulated Human Embryonic Kidney (HEK) 293 cells over 5 days.

Phase II trial of hypofractionated VMAT-based treatment for early stage breast cancer: 2-year toxicity and clinical results.

BACKGROUND: To report toxicity and early clinical outcomes of hypofractionated simultaneous integrated boost (SIB) approach with Volumetric Modulated Arc Therapy (VMAT) as adjuvant treatment after breast-conserving surgery. METHODS: Patients presenting early-stage breast cancer were enrolled in a phase II trial. ELIGIBILITY CRITERIA: age > 18 years old, invasive cancer or ductal carcinoma in situ (DCIS), Stage I-II (T < 3 cm and N ≤ 3), breast-conserving surgery without oncoplastic reconstruction. Any systemic therapy was allowed in neoadjuvant or adjuvant setting. All patients underwent VMAT-SIB technique to irradiate the whole breast and the tumor bed. Doses to whole breast and surgical bed were 40.5 Gy and 48 Gy, respectively, delivered in 15 fractions over 3 weeks. Acute and late skin toxicities were recorded. Cosmetic outcome was assessed as excellent/good or fair/poor. RESULTS: The present study focused on results of a cohort of 144 patients with a minimum follow-up of 24 months (median 37, range 24-55 months). Median age was 62 years old (range 30-88). All patients had an invasive carcinoma (no patients with DCIS were present in this subset). At one year, the highest reported skin toxicity was G1, in 14 % of the patients; this data dropped to 4 % at the last follow-up, after more than 2 years. Breast pain was recorded in 21.6 % of the patients 6 months after treatment, while it was present in 3.5 % of the patients at the last follow-up, showing a significant improvement with time. Correlation between liponecrosis and boost target volume was found not significant. Breast pain was correlated with breast volume. No pulmonary or cardiological toxicities were recorded. After an early evaluation of clinical outcomes, only one case presented disease relapse, as liver metastases. CONCLUSIONS: The 3-week VMAT-SIB course as adjuvant treatment after breast-conserving surgery showed to be well tolerated and was associated with optimal local control. Long-term follow-up data are needed to assess late toxicity and clinical outcomes.

Volumetric modulated arc therapy for thoracic node metastases: a safe and effective treatment for a neglected disease.

PURPOSE: To evaluate the outcome of Stereotactic Body Radiation Therapy (SBRT) with Volumetric Modulated Arc Therapy (VMAT) for thoracic node metastases. RESULTS: 18 out of 29 patients presented with isolated thoracic node metastases with no other sites of disease. Median prescribed dose was 45Gy (range 30-60Gy).Acute toxicity was recorded as G0 in 28 patients, while one patient was scored as G1. Late toxicity was G0 in 26 patients, one patient was scored G1, one as G2, and one as G4 presented acute myocardial infarction.During follow up, the best local response was complete remission in 14 patients and partial remission in 11 patients. With a median follow up of 12 months (range 2-35) 9 patients died from disease progression, 10 were still alive with distant metastases, 5 had a locally controlled disease and 5 patients were disease free.The median OS estimated was 18 months (76%, 49% at one, two years). The median PFS was 9 months (28%, 17% at one, two years). MATERIALS AND METHODS: Twenty-nine patients with 32 thoracic nodes metastases were treated with SBRT in our institution. Toxicities and response were assessed. Overall Survival (OS) and Progression Free Survival (PFS) were evaluated. CONCLUSIONS: SBRT is an efficient treatment for thoracic node metastases.

Hypo-fractionated stereotactic radiotherapy alone using volumetric modulated arc therapy for patients with single, large brain metastases unsuitable for surgical resection.

BACKGROUND: Hypo-fractionated stereotactic radiotherapy (HSRT) is emerging as a valid treatment option for patients with single, large brain metastases (BMs). We analyzed a set of our patients treated with HSRT. The aim of this study was to evaluate local control (LC), brain distant progression (BDP), toxicity and overall survival (OS). METHODS: From July 2011 to May 2015, 102 patients underwent HSRT consisting of 27Gy/3fractions for lesions 2.1-3 cm and 32Gy/4 fractions for lesions 3.1-5 cm. Local progression was defined as increase of the enhancing abnormality on MRI, and distant progression as new brain metastases outside the irradiated volume. Toxicity in terms of radio-necrosis was assessed using contrast enhanced T1MRI, T2 weighted-MRI and perfusion- MRI. RESULT: The median maximum diameter of BM was 2.9 cm (range 2.1-5 cm), the median gross target volume (GTV) was 16.3 cm(3) and the median planning target volume (PTV) was 33.7 cm(3) The median,1,2-year local control rate was 30 months, 96, 96 %; the median, 1-2-year rate of BDP was 24 months, 12, 24 %; the median,1,2-year OS was 14 months, 69, 33 %. KPS and controlled extracranial disease were associated with significant survival benefit (p <0.01). Brain radio-necrosis occurred in six patients (5.8 %). CONCLUSION: In patients with single, large BMs unsuitable for surgical resection, HSRT is a safe and feasible treatment, with good brain local control and limited toxicity.

Stereotactic body radiation therapy: A promising chance for oligometastatic breast cancer.

BACKGROUND: Multidisciplinary management of oligometastatic breast cancer with local therapy could improve disease control. The aim of our study is the assessment of safety and efficacy of Stereotactic Body Radiation Therapy (SBRT) in selected subset of patients. PATIENTS AND METHODS: Oligometastastic patients from breast cancer were treated with SBRT for 1-3 lung and liver lesions, in an observational study. Inclusion criteria were: age >18 years, ECOG 0-2, diagnosis of breast cancer, no extrapulmonary and/or extrahepatic disease, other metastatic sites stable or responding after chemotherapy were allowed, no life threatening conditions, less than 5 lung and liver lesions (with maximum diameter <5 cm), chemotherapy completed at least 3 weeks before treatment, written informed consent. Prescription dose ranged between 48 and 75 Gy in 3 or 4 consecutive fractions. Primary end-point was local control (LC). Secondary end-points were toxicity, overall survival (OS) and progression-free survival (PFS). RESULTS: From April 2010 to June 2014, 33 patients for a total number of 43 lesions were irradiated. Median follow up was 24 months (range 3-59). Actuarial LC rates were 98% at 1 year and 90% at 2 and 3 years. Complete response, partial response and progressive disease were detected in 25 (53.2%), 16 (34%), and 6 (12.8%) lesions, respectively. Median OS was 48 months. Actuarial OS rates at 1 and 2 years were 93% and 66% respectively. Median PFS was 11 months, with a PFS rate at 1 and 2 years of 48% and 27%, respectively. At univariate analysis DFI >12 months, hormonal receptor positivity, medical therapies after SBRT showed a significant impact on OS. Treatment was well tolerated, with no G3-4 toxicities. CONCLUSIONS: SBRT is a safe and feasible alternative treatment of liver and lung oligometastases from breast cancer, in selected patients not amenable to surgery, with good local control and survival rate.

Neoadjuvant Chemoradiotherapy with Volumetric-modulated Arc Therapy for Medium-distal Oesophageal and Gastro-oesophageal Junction Carcinoma.

AIM: to appraise the role of volumetric-modulated arc therapy (VMAT) in the neoadjuvant chemoradiotherapy management of advanced medium and distal oesophageal cancer in terms of toxicity and response to treatment. PATIENTS AND METHODS: Thirty patients were treated according to the neoadjuvant chemoradiation followed by surgery versus surgery-alone trial scheme with VMAT radiation therapy. Patients presented mainly T3-T4 stage (80%) and N1-2 (96.6%) disease. The chemotherapy scheme consisted of 3-5 cycles, while a radiotherapy course of 41.4 Gy in 23 fractions was administered to all patients. RESULTS: The median age of patients was 65 years, and there was a predominance of males (80%), smokers or ex-smokers (90%) and modest alcohol habit (80% negative). Primary tumor localisation was in the medium and distal third of the oesophagus in 57% of the cases, the rest being in the gastro-oesophageal junction. Modest toxicity profiles were observed, with limited incidence of grade 2-3 events. Partial or complete response was observed in more than 90% of the cases (radiological/metabolic) and was confirmed after surgical intervention (67% partial or complete and 27% stable response). Tumor down-staging was recorded in 67% of patients and nodal down-staging in 50%. CONCLUSION: VMAT was applied in the context of neoadjuvant chemoradiotherapy for the treatment of medium and distal oesophageal carcinoma with satisfactory results in terms of tolerance and toxicity.

The role of stereotactic body radiation therapy (SBRT) in the treatment of oligometastatic disease in the elderly.

OBJECTIVE: To report about clinical outcome of stereotactic body radiation therapy (SBRT) in the treatment of oligometastatic disease in elderly patients. METHODS: Patients with 1-4 inoperable metastases were treated with SBRT. Dose prescription ranged from 40 to 75 Gy in 3-8 fractions. SBRT was delivered using the volumetric modulated arc therapy technique with flattening filter-free photon beams. The primary end points were in-field local control (LC) and toxicity. Secondary end points were overall survival (OS) and disease-specific survival (DSS). RESULTS: 82 patients with 111 total metastases were treated. Median age was 79 years. 64 patients (78%) had a single lesion; the remaining patients had 2-4 lesions. 16 (14.4%) lesions were localized in the abdomen, 50 (45.0%) in the liver and 45 (40.5%) in the lungs. Local response was observed for 87 lesions (78.4%) while local progression was observed in 24 lesions (21.6%). Actuarial 1-year LC was 86.8% ± 3.3%. Actuarial 1-year OS was 93.6% ± 2.7%. 2-year findings were 76.3% ± 4.4% and 72.0% ± 5.6%, respectively. Actuarial 1- and 2-year DSS results were 97.5% ± 2.0% and 81.6% ± 4.9%, respectively. Treatment-related Grade 2-3 toxicity was observed in five patients (4.2%); Grade 1 toxicity in seven patients (5.9%) and no toxicity was observed in 85.4% of the cases. CONCLUSION: SBRT is a safe and effective therapeutic option for the treatment of oligometastatic disease in the elderly with acceptable rates of LC and low treatment-related toxicity. ADVANCES IN KNOWLEDGE: The use of SBRT for oligometastatic disease in the elderly can be considered as a valuable approach, particularly for patients with fragile status or refusing other approaches.

The challenge of inoperable hepatocellular carcinoma (HCC): results of a single-institutional experience on stereotactic body radiation therapy (SBRT).

OBJECTIVES: To evaluate the feasibility and efficacy of stereotactic body radiation therapy (SBRT) in the treatment of hepatocellular carcinoma (HCC) unsuitable for standard loco-regional therapies. MATERIALS AND METHODS: Patients with 1-3 inoperable HCC lesions with diameter ≤6 cm were treated by SBRT. According to lesions size and liver function, two prescription regimens were adopted: 48-75 Gy in three fractions or 36-60 Gy in six fractions. SBRT was delivered using the volumetric modulated arc therapy technique with flattening filter-free photon beams. The primary end points of this study were in-field local control (LC) and toxicity. Secondary end points were overall survival (OS) and progression-free survival (PFS). RESULTS: Forty-three patients with 63 HCC lesions were irradiated. All patients had Child-Turcotte-Pugh class A or B disease. Thirty lesions (48%) were treated with 48-75 Gy in three consecutive fractions, and 33 (52%) received 36-60 Gy in six fractions. Median follow-up was 8 months (range 3-43 months). Actuarial LC at 6, 12 and 24 months was 94.2 ± 3.3, 85.8 ± 5.5 and 64.4 ± 11.5%, respectively. A biological equivalent dose (BED) >100 Gy and GTV size were significant prognostic factors for LC in univariate analysis (p < 0.001 and p < 0.02). Median OS was 18.0 ± 5.8 months. Actuarial OS at 6, 12 and 24 months was 91.1 ± 4.9, 77.9 ± 8.2 and 45.3 ± 14.0%, respectively. Univariate analysis showed that OS is correlated with LC (p < 0.04), BED >100 (p < 0.05) and cumulative gross tumor volume GTV <5 cm (p < 0.04). Median PFS was 8 months, with a 1-year PFS rate of 41%. A significant (≥ grade 3) toxicity was observed in seven patients (16%) 2-6 months after the completion of the treatment. No classic radiation-induced liver disease was observed. CONCLUSION: Stereotactic body radiation therapy is a safe and effective therapeutic option for HCC lesions unsuitable to standard loco-regional therapies, with acceptable local control rates and low treatment-related toxicity. The significant correlation between LC and higher doses and between LC and OS supports the clinical value of SBRT in these patients.