[Concurrent simultaneous integrated boost radiotherapy and cetuximab in head and neck squamous cell cancer patients: is it feasible in daily clinical practice?] / Radioterapia a intensità modulata con boost simultaneo più cetuximab in pazienti con carcinoma a cellule squamose in stadio localmente avanzato del distretto testa collo: è fattibile nella pratica clinica quotidiana?

INTRODUCTION AND AIM: Locally advanced head and neck squamous cell carcinoma (LA-Hnscc) is a true therapeutical challenge in the modern era and the scientific community is trying to face this challenge with new therapeutical strategies, including combinations of monoclonal antibodies and radiation therapy. The aim of this study is to evaluate clinical outcomes in LA-Hnscc patients unfit to receive platinum-based chemotherapy, treated with concurrent simultaneous integrated boost-intensity modulated radiotherapy (Sib-Imrt) + cetuximab (Ctx) in daily clinical practice. METHODS: LA-Hnscc patients not included in other prospective studies treated in 4 Italian radiotherapy units (2 Messina, 1 Rome, and 1 Lecce) using Sib-Imrt and Ctx were included in this study. Acute and late toxicities and overall survival (OS) have been evaluated. RESULTS: Data regarding 27 patients with squamous tumour were collected and reviewed. The primary tumour sites were oropharynx in 14 patients (51.9%), oral cavity in 7 (25.9%), larynx in 3 (11%) and other sites in 3(11%). There were 20 (74%) patients had stage IV (16 IVa and 4 IVb). Complete remission was observed in 18 patients (66.7%), a partial remission in 4 (14.8%) whilst 4 had a progression disease (14.8%). After 3 year of follow-up 7/27 patients were deaths. The OS was 95.5%, 62.5% and 52.9% respectively at 1,2 and 3 years. Acute toxicities were observed in all treated patients (mucositis, dermatitis and dysphagia) while 66.7% of patients developed late toxicities. All observed toxicities were grade 1 to 3 and just 1 patient developed a G4 toxicity. CONCLUSION: The concurrent bio-radiotherapy of Sib-Imrt and cetuximab is feasible in real-life daily clinical practice for LA-Hnscc patients unfit for platinum-based chemoradiotherapy.

Modulation of Radiation Doses and Chimeric Antigen Receptor T Cells: A Promising New Weapon in Solid Tumors-A Narrative Review.

Tumor behavior is determined by its interaction with the tumor microenvironment (TME). Chimeric antigen receptor (CART) cell therapy represents a new form of cellular immunotherapy (IT). Immune cells present a different sensitivity to radiation therapy (RT). RT can affect tumor cells both modifying the TME and inducing DNA damage, with different effects depending on the low and high doses delivered, and can favor the expression of CART cells. CART cells are patients' T cells genetically engineered to recognize surface structure and to eradicate cancer cells. High-dose radiation therapy (HDRT, >10-20 Gy/fractions) converts immunologically "cold" tumors into "hot" ones by inducing necrosis and massive inflammation and death. LDRT (low-dose radiation therapy, >5-10 Gy/fractions) increases the expansion of CART cells and leads to non-immunogenetic death. An innovative approach, defined as the LATTICE technique, combines a high dose in higher FDG- uptake areas and a low dose to the tumor periphery. The association of RT and immune checkpoint inhibitors increases tumor immunogenicity and immune response both in irradiated and non-irradiated sites. The aim of this narrative review is to clarify the knowledge, to date, on CART cell therapy and its possible association with radiation therapy in solid tumors.

Stereotactic boost on residual disease after external-beam irradiation in clinical stage III non-small cell lung cancer: mature results of stereotactic body radiation therapy post radiation therapy (SBRTpostRT) study.

PURPOSE: To evaluate the role of stereotactic body radiation therapy (SBRT) delivered after external-beam fractionated irradiation in non-small-cell lung cancer (NSCLC) patients with clinical stage III A, B. MATERIALS AND METHODS: All patients received three-dimensional conformal radiotherapy (3D-CRT) or intensity modulated radiation therapy (IMRT) (60-66 Gy/30-33 fractions of 2 Gy/5 days a week) with or without concomitant chemotherapy. Within 60 days from the end of irradiation, a SBRT boost (12-22 Gy in 1-3 fractions) was delivered on the residual disease. RESULTS: Here we report the mature results of 23 patients homogeneously treated and followed up for a median time of 5.35 years (range 4.16-10.16). The rate of overall clinical response after external beam and stereotactic boost was 100%. No treatment-related mortality was recorded. Radiation-related acute toxicities with a grade ≥ 2 were observed in 6/23 patients (26.1%): 4/23 (17.4%) had esophagitis with mild esophageal pain (G2); in 2/23 (8.7%) clinical radiation pneumonitis G2 was observed. Lung fibrosis (20/23 patients, 86.95%) represented a typical late tissue damage, which was symptomatic in one patient. Median disease-free survival (DFS) and overall survival (OS) were 27.8 (95% CI, 4.2-51.3) and 56.7 months (95% CI, 34.9-78.5), respectively. Median local progression-free survival (PFS) was 17 months (range 11.6-22.4), with a median distant PFS of 18 months (range 9.6-26.4). The 5-year actuarial DFS and OS rates were 28.7% and 35.2%, respectively. CONCLUSIONS: We confirm that a stereotactic boost after radical irradiation is feasible in stage III NSCLC patients. All fit patients who have no indication to adjuvant immunotherapy and presenting residual disease after curative irradiation could benefit from stereotactic boost because outcomes seem to be better than might be historically assumed.

The "Combo" radiotherapy treatment for high-risk grade 2 meningiomas: dose escalation and initial safety and efficacy analysis.

PURPOSE: The subgroup "high-risk" WHO grade 2 (hRG2) meningiomas may benefit from adjuvant radiation therapy (RT), but results are still suboptimal with high rates of local progression. A dose escalation using high-conformal RT techniques needs to be evaluated in terms of efficacy and safety. We report the results of a dose-escalation study, named "Combo-RT", combining Intensity Modulated Radiotherapy (IMRT) or Volumetric Arc Therapy (VMAT) with Hypofractionated Stereotactic Radiotherapy (hSRT) boost. PATIENTS AND METHODS: From November 2015 to January 2019, we prospectively enrolled 16 patients with hRG2. Seven patients had subtotal resection (STR) and 9 patients had a recurrent tumor. All patients received Combo-RT: LINAC-IMRT/ VMAT on the surgical bed and CyberKnife-hSRT boost on residual/recurrent meningioma Toxicity and initial efficacy were evaluated. RESULTS: The median age was 62 years (range, 31-80 years). The median cumulative dose delivered was 46 Gy For IMRT or VMAT and 15 Gy in 3 fractions at a median isodose line of 77% for hSRT. The median cumulative BED and EQD2 were 108.75 Gy and 72.5 Gy respectively. 3-year-PFS was 75% for the whole cohort,100% for patients with STR, and 55.5% for recurrent patients. Negligible toxicities, and stable or improved symptoms during long-term follow-up were observed. Salvage treatment for recurrence was an independent predictor of treatment failure (P = 0.025). CONCLUSIONS: With the limitation of a small series of patients, our results suggest that a dose escalation for hRG2 meningiomas, using a Combo-RT approach, is safe and particularly effective in the subgroup of patients with STR. Further studies are warranted.

Impressive Results after "Metabolism-Guided" Lattice Irradiation in Patients Submitted to Palliative Radiation Therapy: Preliminary Results of LATTICE_01 Multicenter Study.

Purpose: To evaluate feasibility, toxicities, and clinical response in Stage IV patients treated with palliative "metabolism-guided" lattice technique. Patients and Methods: From June 2020 to December 2021, 30 consecutive clinical stage IV patients with 31 bulky lesions were included in this study. All patients received palliative irradiation consisting of a spatially fractionated high radiation dose delivered in spherical deposits (vertices, Vs) within the bulky disease. The Vs were placed at the edges of tumor areas with different metabolisms at the PET exam following a non-geometric arrangement. Precisely, the Vs overlapped the interfaces between the tumor areas of higher 18F-FDG uptake (>75% SUV max) and areas with lower 18F-FDG uptake. A median dose of 15 Gy/1 fraction (range 10−27 Gy in 1/3 fractions) was delivered to the Vs. Within 7 days after the Vs boost, all the gross tumor volume (GTV) was homogeneously treated with hypo-fractionated radiation therapy (RT). Results: The rate of symptomatic response was 100%, and it was observed immediately after lattice RT delivery in 3/30 patients, while 27/30 patients had a symptomatic response within 8 days from the end of GTV irradiation. Radiation-related acute grade ≥1 toxicities were observed in 6/30 (20%) patients. The rate of overall clinical response was 89%, including 23% of complete remission. The 1-year overall survival rate was 86.4%. Conclusions: "Metabolism-guided" lattice radiotherapy is feasible and well-tolerated, being able to yield very impressive results both in terms of symptom relief and overall clinical response rate in stage IV bulky disease patients. These preliminary results seem to indicate that this kind of therapy could emerge as the best therapeutic option for this patient setting.

Intensity-modulated radiotherapy does not induce volumetric changes of the Bichat fat pad in nasopharyngeal cancer.

PURPOSE: To evaluate morphological and functional changes in the Bichat fat pad (BFP) after curative concurrent chemoradiotherapy in nasopharyngeal cancer (NPC) patients. METHODS: We retrospectively analyzed the volumetric, metabolic, and dosimetry parameters of BFPs in 7 NPC patients who underwent intensity-modulated radiotherapy (IMRT) between 2015 and 2020. Inclusion criteria were i) histologically confirmed diagnosis of NPC, ii) follow-up period of at least 12 months, iii) no history of previous irradiation or surgery in the maxillofacial area, and ìv) availability of pre- and posttreatment MRI and 18F­FDG PET-CT performed in our Institution. All patients had stage III-IVA disease (n = 7) and received platinum-based chemotherapy. Planned doses in 30 daily fractions/5 days per week were 66 Gy (2.2 Gy/die 5 days/week) to the gross tumor volume, 66 Gy (2.1-2.2 Gy/die 5 days/week) to the gross nodal volume, 60 Gy (2 Gy/die 5 days week) to clinical target volume (CTV)1, and 54 Gy (1.8 Gy/die 5 days/week) to CTV2. All patients completed the planned radiotherapy course in a median time of 42 days (range 42-43). Relationships between BFP volumes and the following DVH parameters were evaluated: mean dose, maximum dose (Dmax), and percentage of BFP volume receiving more than 5 to 65 Gy (V5 to V65). RESULTS: The pre-RT volumes of the left and right BFPs were 12.24 cc (range 6.51-20.01 cc) and 11.55 cc (range 5.78-17.53 cc), respectively. The mean volumes of left BFPPRE and BFPPOST were 12.24 cc (range 6.51-20.01cc) and 13.85 cc (range 7.54-20.21 cc), respectively, with no significant statistical differences (P > 0.05). No statistically significant correlations were found between dosimetry features and BFP volumetric changes (all P > 0.05). CONCLUSION: Our original results showed that chemoradiotherapy does not induce significant volumetric changes of the BFP. Further investigations are needed to evaluate the effects of higher radiation doses on BFP. This is the first real-world study on this issue.

Non-stereotactic radiotherapy in older cancer patients.

Old or very old oncological patients represent a heterogeneous and frail population due to concomitant comorbidities. Whether radiotherapy alone or in combination with novel cancer drugs may provide a clear benefit in this setting of patients is still a matter of debate. The aim of our review is to analyze the evaluation process and the different therapeutic possibilities in older cancer patients, focusing on the different and most disparate applications of radiotherapy. We reviewed the most recent literature on radiotherapy in older patients providing clinical evidence of treatment related toxicity, tolerance and outcomes using standard fractionated and/or hypofractionated irradiation alone or in combination with chemotherapy, targeted and immunotherapy. In older cancer patients unfit for systemic therapy or surgery, radiotherapy represents a valid therapeutic approach, both with curative and palliative intents, ensuring excellent patient compliance in terms of local toxicity and adherence to therapy.

A non-surgical COMBO-therapy approach for locally advanced unresectable pancreatic adenocarcinoma: preliminary results of a prospective study.

In this short report we present a series of thirteen patients with locally advanced, unresectable, pancreatic cancer treated with a COMBO-Therapy consisting of: STEP-1: induction chemotherapy; STEP-2: concomitant chemoradiotherapy; STEP-3: stereotactic body radiotherapy boost. After four weeks from the end of each step all patients had a re-staging and a surgical re-evaluation. All patients completed STEP-1 and STEP-2. STEP-3 has been successfully delivered to 8/13 patients with a median dose of 12 Gy (range 10-21 Gy) in 1-3 fractions. The median LC was 20 months (range 10-32) with a 2-year LC of 72.9%, and none of the patients developed G3 acute or late toxicities. The median OS was 21.5 months (range 12-34), and the 2-year OS was 53.9%; the median PFS was 17.5 months (range 10-27). Our non-surgical COMBO-Therapy has demonstrated a feasible profile with good tolerance. Further prospective protocols are needed to confirm our preliminary results.

Image-Guided Multisession Radiosurgery of Skull Base Meningiomas.

BACKGROUND: The efficacy of single-session stereotactic radiosurgery (sSRS) for the treatment of intracranial meningioma is widely recognized. However, sSRS is not always feasible in cases of large tumors and those lying close to critically radiation-sensitive structures. When surgery is not recommended, multi-session stereotactic radiosurgery (mSRS) can be applied. Even so, the efficacy and best treatment schedule of mSRS are not yet established. The aim of this study is to validate the role of mSRS in the treatment of skull base meningiomas. METHODS: A retrospective analysis of patients with skull base meningiomas treated with mSRS (two to five fractions) at the University of Messina, Italy, from 2008 to 2018, was conducted. RESULTS: 156 patients met the inclusion criteria. The median follow-up period was 36.2 ± 29.3 months. Progression-free survival at 2-, 5-, and 10- years was 95%, 90%, and 80.8%, respectively. There were no new visual or motor deficits, nor cranial nerves impairments, excluding trigeminal neuralgia, which was reported by 5.7% of patients. One patient reported carotid occlusion and one developed brain edema. CONCLUSION: Multisession radiosurgery is an effective approach for skull base meningiomas. The long-term control is comparable to that obtained with conventionally-fractionated radiotherapy, while the toxicity rate is very limited.

Simultaneous Integrated Boost Radiotherapy in Unresectable Stage IV (M0) Head and Neck Squamous Cell Cancer Patients: Daily Clinical Practice.

AIM: To evaluate clinical outcome in locally-advanced stage IV (M0) head and neck cancer patients treated using intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) in daily clinical practice. BACKGROUND: Despite SIB-IMRT has been reported as a feasible and effective advanced head and neck cancer treatment, there are few data about its concurrent use with systemic therapies. MATERIAL AND METHODS: We reviewed 41 staged IV (M0) head and neck cancer patients treated in two radiotherapy units in the city of Messina (Italy) during the last six years, using intensity modulated techniques-SIB. 22/41 patients had concomitant chemotherapy or cetuximab. Acute and late toxicities, objective response (OR) rate, local control (LC) and overall survival (OS) have been evaluated. RESULTS: 37/41 patients received the planned doses of radiotherapy, 2 patients died during the therapy. The major acute regional toxicities were skin reaction and mucositis. A case of mandibular osteoradionecrosis was recorded. At completion of treatment, OR was evaluated in 38 patients: 32/38 patients (84.2%) had complete (55.3%) and partial (28.9%) response. The 1- and 5-year LC rates were 73.4% and 69.73%, respectively. The 1-, 3-, and 5-year OS rates were 85.93%, 51.49% and 44.14%, respectively. No statistically significant differences in outcomes have been observed in patients treated with radiotherapy alone vs. irradiation concomitant to chemo/biotherapy. The median OS was 45 months. CONCLUSION: SIB-IMRT is safeand can be used with concomitant chemotherapy/biotherapy in real-life daily clinical practice. SIB-IMRT alone is a valid alternative in patients unfit for systemic therapies.

Stereotactic Body Radiation Therapy With Simultaneous Integrated Boost in Patients With Spinal Metastases.

Stereotactic body radiation therapy in patients with spine metastases maximizes local tumor control and preserves neurologic function. A novel approach could be the use of stereotactic body radiation therapy with simultaneous integrated boost delivering modality. The aim of the present study is to report our experience in the treatment of spine metastases using a frameless radiosurgery system delivering stereotactic body radiation therapy-simultaneous integrated boost technique. The primary endpoints were the pain control and the time to local progression; the secondary ones were the overall survival and toxicity. A total of 20 patients with spine metastases and 22 metastatic sites were treated in our center with stereotactic body radiation therapy-simultaneous integrated boost between December 2007 and July 2018. Stereotactic body radiation therapy-simultaneous integrated boost treatments were delivered doses of 8 to 10 Gy in 1 fraction to isodose line of 50%. The median follow-up was 35 months (range: 12-110). The median time to local progression for all patients was not reached and the actuarial 1-, 2-, and 3-years local free progression rate was 86.36%. In 17 of 20 patients, a complete pain remission was observed and 3 of 20 patients had a partial pain remission (complete pain remission + partial pain remission: 100%). The median overall survival was 38 months (range 12-83). None of the patients experienced neither radiation adverse events (grade 1-4) nor reported pain flair reaction. None of the patients included in our series experienced vertebral compression fracture. Spine radiosurgery with stereotactic body radiation therapy-simultaneous integrated boost is safe. The use of this modality in spine metastases patients provides an excellent local control.

Silencing of telomere-binding protein adrenocortical dysplasia (ACD) homolog enhances radiosensitivity in glioblastoma cells.

Adrenocortical dysplasia (ACD) is a shelterin protein involved in the maintenance of telomere length and in cancer radioresistance. This study investigated the expression profile of ACD in human gliomas and its role in radioresistance of glioma cells. The expression of ACD was analyzed in 62 different grades of glioma tissues and correlated with prognosis. A radioresistant cell line was generated from U87MG cells. For mechanistic studies, ACD was inhibited by small interfering RNA-targeting ACD and the effect on cell radioresistance, telomerase activity, cyclinD1, caspase-3, hTERT, and BIRC1 was evaluated. Clonogenic assay was performed after irradiation, to investigate the effect of ACD silencing on radiation sensitivity. ACD expression appeared strongly upregulated in higher grade gliomas, and its expression was significantly correlated to grading and poor prognosis. In glioma cell lines, ACD expression pattern was similar to those observed in glioma tissues. In irradiated cells, ACD expression was increased in an ionizing radiation dose-dependent manner. A higher expression of ACD was observed in the radioresistant clones than parental cells. Silencing of ACD led to the enhanced radiation sensitivity, decreased telomerase activity and cyclin D1 expression, reduced expression of BIRC1, and finally to the upregulation of caspase-3. This study represents the first report, which demonstrated the expression pattern of ACD in gliomas and its prognostic value. Our results suggested that ACD is involved in glioblastoma radioresistance, likely through the modulation of telomerase activity, proliferation, and apoptosis. ACD might represent a potential molecular biomarker and a novel therapeutic target in glioblastoma.

Frameless Stereotactic Radiosurgery for Treatment of Multiple Sclerosis-Related Trigeminal Neuralgia.

BACKGROUND: Trigeminal neuralgia (TN) affects 7% of patients with multiple sclerosis (MS). In such patients, TN is difficult to manage either pharmacologically and surgically. Radiosurgical rhizotomy is an effective treatment option. The nonisocentric geometry of radiation beams of CyberKnife introduces new concepts in the treatment of TN. Its efficacy for MS-related TN has not yet been demonstrated. METHODS: Twenty-seven patients with refractory TN and MS were treated. A nonisocentric beams distribution was chosen; the maximal target dose was 72.5 Gy. The maximal dose to the brainstem was <12 Gy. Effects on pain, medications, sensory disturbance, rate, and time of pain recurrence were analyzed. RESULTS: Median follow-up was 37 (18-72) months. Barrow Neurological Institute pain scale score I-III was achieved in 23/27 patients (85%) within 45 days. Prescription isodose line (80%) accounting for a dose of 58 Gy incorporated an average of 4.85 mm (4-6 mm) of the nerve and mean nerve volume of 26.4 mm3 (range 20-38 mm3). Seven out of 27 patients (26%) had mild, not bothersome, facial numbness (Barrow Neurological Institute numbness score II). The rate of pain control decreased progressively after the first year, and only 44% of patients retained pain control 4 years later. CONCLUSIONS: Frameless radiosurgery can be effectively used to perform retrogasserian rhizotomy. Pain relief was satisfactory and, with our dose/volume constraints, no sensory complications were recorded. Nonetheless, long-term pain control was possible in less than half of the patients. This is a limitation that CyberKnife radiosurgery shares with other techniques in MS patients.

Three-dimensional treatment planning for vaginal cuff brachytherapy: dosimetric effects on organs at risk according to patients position.

PURPOSE: Aim of this study was to evaluate dose distribution within organs at risk (OARs) and planning target volume (PTV) based on three-dimensional treatment planning according to two different setup positions in endometrial carcinoma patients submitted to postoperative brachy-radiotherapy on vaginal vault. METHODS AND MATERIALS: Patients with endometrial cancer necessitating of adjuvant brachytherapy on vaginal vault were enrolled. Pelvic computed tomography studies were prospectively obtained in two different setup positions: extend legs (A position) and gynecological (B position). Contoured OARs were bladder, rectum, and small bowel. The PTV was identified as applicator's surface with an isotropic 5-mm margin expansion. Radiation dose delivered in 1 cc (D1cc) and 2 cc (D2cc) of OAR were calculated. RESULTS: Coverage of PTV and values of D1cc and D2cc obtained for bladder and small bowel were similar in the two positions. For rectum, both D1cc and D2cc had statistically significant lower values in A with respect to B position. CONCLUSIONS: Both in A and B positions, radiation doses delivered do not exceed the dose constraints. However, A setup seems to significantly reduce doses to rectum while obtaining the same PTV coverage. The findings from our study provide evidence supporting the use of A position setup for delivering vaginal vault brachytherapy.