Immunogenicity after two and three doses of mRNA vaccine in patients with cancer treated with exclusive radiotherapy.

BACKGROUND AND PURPOSE: Data on immunoresponse after SARS-CoV-2 vaccines for patients treated with exclusive radiotherapy (RT) are scarce. Since RT may affect the immune system, we conducted the MORA trial (Antibody response and cell-mediated immunity of MOderna mRNA-1273 vaccine in patients treated with RAdiotherapy). MATERIALS AND METHODS: Data regarding humoral and cellular immune response of patients treated with RT were prospectively collected after the second and third dose of mRNA vaccines. RESULTS: Ninety-two patients were enrolled. With a median of 147 days after the second dose, the median SARS-CoV-2 IgG titer was 300 BAU/mL: six patients were seronegative (Spike IgG titer ≤ 40 BAU/mL), whereas 24, 46 and 16 were poor responders (Spike IgG titer:41-200 BAU/mL), responders (Spike IgG titer:201-800 BAU/mL) and ultraresponders (Spike IgG titer > 800 BAU/mL), respectively. Among seronegative patients, two patients were negative also for cell mediated response, as tested with IFN-γ release Assay (IGRA) test. With a median of 85 days after the third dose, the median SARS-CoV-2 IgG titer was 1632 BAU/mL in 81 patients: only two patients were seronegative, whereas 16 and 63 patients were responders and ultraresponders, respectively. Among the 2 persistently seronegative patients, IGRA test was negative in one who had previously received anti-CD20 therapy. Documented paucisymptomatic (n = 3) or asymptomatic (n = 4) infection occurred after the third dose, during the Omicron wave. CONCLUSION: In patients treated with exclusive RT, even during the Omicron breakthrough, robust humoral response and clinical protection from severe SARS-CoV-2 disease were achievable with three doses of mRNA vaccine.

Local treatment for relapsing glioblastoma: A decision-making tree for choosing between reirradiation and second surgery.

In case of circumscribed recurrent glioblastoma (rec-GBM), a second surgery (Re-S) and reirradiation (Re-RT) are local strategies to consider. The aim is to provide an algorithm to use in the daily clinical practice. The first step is to consider the life expectancy in order to establish whether the patient should be a candidate for active treatment. In case of a relatively good life expectancy (>3 months) and a confirmed circumscribed disease(i.e. without multiple lesions that are in different lobes/hemispheres), the next step is the assessment of the prognostic factors for local treatments. Based on the existing prognostic score systems, patients who should be excluded from local treatments may be identified; based on the validated prognostic factors, one or the other local treatment may be preferred. The last point is the estimation of expected toxicity, considering patient-related, tumor-related and treatment-related factors impacting on side effects. Lastly, patients with very good prognostic factors may be considered for receiving a combined treatment.

Dosimetric Predictors of Acute and Chronic Alopecia in Primary Brain Cancer Patients Treated With Volumetric Modulated Arc Therapy.

Purpose: To determine dose constraints that correlate with alopecia in patients treated with photon-based Volumetric Modulated Arc Therapy (VMAT) for primary brain tumors. Methods: During the treatment planning process, the scalp was drawn as a region of interest. Dose received by 0.1 cc (D0.1cc), mean dose (Dmean), absolute volumes receiving different doses (V16Gy, V20Gy, V25Gy, V30Gy, V35Gy, V40Gy, and V43Gy) were registered for the scalp. Alopecia was assessed according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Receiver operating characteristics (ROC) curve analysis was used to identify parameters associated with hair-loss. Results: One-hundred and one patients were included in this observational study. At the end of radiotherapy (RT), 5 patients did not develop alopecia (Dmean scalp 3.1 Gy). The scalp of the patients with G1 (n = 11) and G2 (n = 85) alopecia received Dmean of 10.6 Gy and 11.8 Gy, respectively. At ROC analysis, V16Gy20Gy ≥ 5.2 cc were the strongest predictors of acute alopecia risk. Chronic hair-loss assessment was available for 74 patients: median time to recovery from G2 alopecia was 5, 9 months. The actuarial rate of hair regrowth was 98.1% at 18 months after the end of RT. At ROC analysis, V40Gy43Gy ≥2.2 cc were the strongest predictors of chronic G2-alopecia risk. V20Gy, V40Gy, and D0,1cc were shown to be independent variables according to correlation coefficient r. Conclusions: V20Gy and V40Gy were the strongest predictors for acute and chronic G2 hair-loss, respectively. The low-dose bath typical of VMAT corresponds to large areas of acute but transient alopecia. However, the steep dose gradient of VMAT allows to reduce the areas of the scalp that receive higher doses, minimizing the risk of permanent alopecia. The application of our dosimetric findings for the scalp may help in reducing the alopecia risk and also in estimating the probability of hair-loss during patient counseling before starting radiotherapy.

Patterns of Care and Survival in Elderly Patients With Locally Advanced Soft Tissue Sarcoma.

OBJECTIVES: The aim of this study was to analyze patterns of care in elderly soft tissue sarcoma (STS) patients and their impact on clinical outcome and treatment-related toxicity. MATERIALS AND METHODS: We retrospectively collected data of >65-year-old patients diagnosed with locally advanced STS between 1991 and 2017 in a single institution. RESULTS: The study included 111 patients: 105 (94.6%) patients underwent surgery, associated with preoperative (n=19, 17.1%) or postoperative radiotherapy (n=72, 64.8%). Anthracycline-based chemotherapy was prescribed in 41.4% of patients (n=46). Acute grade ≥3 postoperative radiotherapy-related radiation dermatitis and all grades of chemotherapy-induced neutropenia were significantly correlated to age >80 years (P=0.02) and >70 years (P=0.045), respectively. The mean follow-up was 4.1 years (range, 0.1 to 17.7). Three-year and 5-year local recurrence-free survival were 80.3% and 75.7%, respectively; neither treatment-related nor patient-related characteristics affected local recurrence. Three-year and 5-year distant relapse-free survival were 59.6% and 44.6%, respectively. On multivariate Cox regression, undifferentiated pleomorphic sarcoma histology and Charlson Comorbidity Index >7 were independent factors associated with distant relapse-free survival (P=0.026 and P=0.0001). Overall survival was 62% and 46.6% at 3 and 5 years, respectively. On multivariate Cox regression, surgery and Charlson Comorbidity Index <7 were independent factors associated with overall survival (P=0.006 and P=0.0001). CONCLUSIONS: In this study, elderly STS patients receiving a tailored treatment encompassing surgery, radiotherapy, and/or chemotherapy obtained an improved outcome, although caution is advised because of increased toxicity in relation to age. Comorbidities should be considered to offer the best treatment option to this frail patient population.

High-dose intensity-modulated radiation therapy as primary treatment of prostate cancer: genitourinary/gastrointestinal toxicity and outcomes, a single-institution experience.

PURPOSE: Prostatectomy, radiotherapy and watchful waiting are the main therapeutic options available for local stage of prostate cancer (PCa). We report our experience on 394 patients affected by prostate cancer primarily treated with high-dose, image-guided, IMRT, focusing on gastrointestinal, genitourinary toxicities and biochemical control. METHODS: From July 2003 to August 2014, 394 patients were treated with radical high-dose radiotherapy (HDRT) for prostate cancer; the mean total radiation dose was 79 Gy in standard fractions. Hormonal therapy (HT) was administered to 7.6% of low-risk patients, to 20.3% of intermediate-risk patients and to 72% of high-risk patients. Patients were evaluated for biochemical failure, local recurrence (LR) and metastases. RESULTS: Ninety-seven patients (26.65%) developed acute GU toxicity at the medium dose of 25.4 Gy, grade 1 (G1) or grade 2 (G2) in 94 cases. Only 16 patients (4.06%) reported chronic GU toxicity (G1 or G2), and one case developed G3 cystitis. No G3 GI acute and late toxicity were detected. Fifty-six (14.2%) patients experienced LR, 26 (6.6%) developed metastases and 70 patients (17.8%) were deceased. Gleason sum score > 7 was predictive for worse overall survival (GS = 7 was borderline) and for metastasis. No factors resulted predictive for local relapse. HT pre-RT had been demonstrated as a negative predictor for OS and DFS-DM. CONCLUSIONS: Data confirm the safety of HDRT for PCa. Treatment was efficient with low toxicity profile. Moreover, continued technologic advancements, as image-guided radiotherapy, could lead to further reduction in toxicity, thus increasing the therapeutic index.

Phase 2 placebo-controlled, single-blind trial to evaluate the impact of oral ibandronate on bone mineral density in osteopenic breast cancer patients receiving adjuvant aromatase inhibitors: 5-year results of the single-centre BONADIUV trial.

AIM: We present the final results of the BONADIUV trial, a single-blind, randomised, placebo-controlled phase 2 study to evaluate the impact of ibandronate treatment on bone mineral density (BMD) in osteopenic women taking aromatase inhibitors (AI). PATIENTS AND METHODS: Between 2011 and 2014, 171 osteopenic patients were randomised in a 1:1 ratio to receive either placebo or oral monthly ibandronate (150 mg). Treatment duration was 2 years, with 6-month evaluation. Primary end-point was the 2-year lumbar spine (LS) and total hip (TH) T-score mean differences as measure of BMD variation. Secondary analyses of survival outcomes have been performed at a 5-year median follow-up. CLINICALTRIALS. GOV IDENTIFIER: NCT02616744. RESULTS: Median age of study population was 60.2 years (range 44-75). At the database cut-off time, the median follow-up was 63.3 months (range 2.7-87.3). No difference in terms of T-score was shown at baseline between arms both for TH (P = 0.61) and LS (P = 0.96). At 2-year follow up, the mean change was statistically significant in favour of ibandronate arm both at TH (P = 0.0002) and LS (P < 0.0001). No significant difference in terms of adverse events was observed between arms. At a median follow-up of 63.3 months (range 2.7-87.3), the overall survival (OS) rate was 97.5% in the placebo group and 93.0% in the ibandronate arm (P = 0.19). The invasive disease-free survival (iDFS) rates did not differ between groups (P = 0.42). CONCLUSIONS: Ibandronate compared to placebo improved BMD change in osteopenic women treated with adjuvant AI. Five-year survival analyses showed no difference between arms in terms of OS and iDFS rates.

Soft tissue sarcomas: new opportunity of treatment with PARP inhibitors?

BACKGROUND: Poly(ADP-ribose) polymerases (PARP) are a large family of enzymes involved in several cellular processes, including DNA single-strand break repair via the base-excision repair pathway. PARP inhibitors exert antitumor activity by both catalytic PARP inhibition and PARP-DNA trapping, moreover PARP inhibition represents a potential synthetic lethal approach against cancers with specific DNA-repair defects. Soft tissue sarcoma (STSs) are a heterogeneous group of mesenchymal tumors with locally destructive growth, high risk of recurrence and distant metastasis. OBJECTIVES: The purpuse of this review is to provide an overview of the main preclinical and clinical data on use of PARPi in STSs and of effect and safety of combination of PARPi with irradiation. RESULTS: Due to numerous genomic alterations in STSs, the DNA damage response pathway can offer an interesting target for biologic therapy. Preclinical and clinical studies showed promising results, with the most robust evidences of PARPi efficacy obtained on Ewing sarcoma bearing EWS-FLI1 or EWS-ERG genomic fusions. The activity of PARP inhibitors resulted potentiated by chemotherapy and radiation. Although mechanisms of synergisms are not completely known, combination of radiation therapy and PARP inhibitors exerts antitumor effect by accumulation of unrepaired DNA damage, arrest in G2/M, activity both on oxic and hypoxic cells, reoxygenation by effect on vessels and promotion of senescence. Early trials have shown a good tolerance profile. CONCLUSIONS: The use of PARP inhibitors in advanced stage STSs, alone or combined in multimodal treatments, is of great interest and warrants further investigations.

A national multicenter study on 1072 DCIS patients treated with breast-conserving surgery and whole breast radiotherapy (COBCG-01 study).

BACKGROUND AND PURPOSE: Breast-conserving surgery (BCS) and whole breast radiation (RT) with or without endocrine therapy (ET) represent the standard of care for ductal carcinoma in situ (DCIS). The use of adjuvant treatments after surgery is still controversial in this setting. We performed a retrospective multicenter analysis on a series of DCIS patients treated with BCS and adjuvant RT. MATERIALS AND METHODS: We collected clinical data from nine Italian centers on 1072 women having a diagnosis of DCIS and treated between 1997 and 2012. We reported on the 5- and 10-year local recurrence (LR) rates, overall survival, and breast cancer specific survival (BCSS) employing the Kaplan-Meier method. RESULTS: At a median follow-up of 8.4 years, 67 LR (6.3%) and 47 deaths (4.4%) were observed. LR rates at 5 and 10 years were 3.4% and 7.6%, respectively. BCSS rates at 5 and 10 years were 99.7% and 99.1%, respectively. At univariate regression analysis, postmenopausal state (p = 0.009), estrogen receptor (ER) (p = 0.0001) and progesterone receptor (p = 0.018) positivity and ET (p = 0.006) were inversely correlated with LR. Final surgical margins (FSM) status <1 mm was significantly correlated with higher LR (p = 0.003). At multivariate regression analysis postmenopausal state (p = 0.03), and ER positive (p = 0.045) maintained the significant favorable feature, while FSM <1 mm (p = 0.024) confirmed its negative impact on LR. CONCLUSIONS: Our real-life study pointed out the significant favorable prognostic role of postmenopausal state and ER positive status on LR occurrence. FSM <1 mm was significantly correlated to a higher chance to experience LR.

Assessment of a guideline-based heart substructures delineation in left-sided breast cancer patients undergoing adjuvant radiotherapy : Quality assessment within a randomized phase III trial testing a cardioprotective treatment strategy (SAFE-2014).

BACKGROUND AND PURPOSE: In our institute, breast cancer patients undergoing adjuvant treatment are included in a protocol aimed to reduce cardiovascular morbidity (SAFE-2014, NCT2236806), assessing preclinical heart damage with heart speckle-tracking ultrasound. To develop a dose constraint related to subclinical heart damage, a reliable delineation of heart substructures based on a pre-existing guideline was made. PATIENTS AND METHODS: Heart substructures of 16 left-sided breast cancer patients included in the SAFE protocol were delineated by five operators. For each substructure, a multi-contour delineation based on a majority vote algorithm (MCD) was created. A consensus-based delineation (CBD) was developed by an independent team of two blinded operators. Dice similarity coefficients (DSC) between volumes delineated by different operators and the MCD were collected and reported, as well as DSC between CBD and MCD. RESULTS: Mean DSCs between heart chambers delineated by each operator and the corresponding MCDs ranged between 0.78 and 0.96. Mean DSC between substructures delineated by all single operators and the corresponding MCD ranged between 0.84 and 0.94. Mean DSC between CBD and the corresponding MCD ranged from 0.89 to 0.97. CONCLUSION: Results showed low inter-observer variability of heart substructure delineation. This constitutes an external validation of the contouring atlas used, allowing a reliable dosimetric assessment of these volumes within the SAFE-2014 trial.

A matched cohort study of radio-chemotherapy versus radiotherapy alone in soft tissue sarcoma patients.

PURPOSE: Adjuvant radiotherapy is the standard postoperative treatment after conservative surgery in high risk soft tissue sarcoma. The role of adjuvant chemotherapy is still debated. Therefore, a matched cohort analysis was performed in high risk soft tissue patients to analyse differences in terms of clinical outcome and toxicity between patients treated with concomitant radio-chemotherapy (RTCT) and radiotherapy (RT) alone. MATERIALS AND METHODS: For each patient in RT group was selected a patient in the RTCT group matching for age, T stage and grading. Acute and late toxicity were recorded, overall survival, recurrence free survival and distant metastases free survival were analysed and compared between the two groups. RESULTS: Ninety patients were selected, half of patients underwent radio-chemotherapy and half received radiotherapy alone. During the treatment Grade 3 dermatitis was recorded in 15 (16.7%) patients, 6 (6.7%) patients associated chemotherapy and during follow up 12 (13.3%) patients developed grade 2 late fibrosis, 3 (3.3%) joint stiffness and 1 (1.1%) patient experienced a bone fracture. There were no differences in the rate of acute and late toxicity between RTCT and RT alone group. Nineteen (21.1%) patients developed local recurrence, overall 5-year local relapse free survival was 83%. There were no differences between the two groups. 29 patients developed distant metastases, 14 (15.6%) patients in the RTCT group and 15 (16.7%) patients in the RT group. The 5-year distant metastases free survival was 67%. Age > 65 years was the only independent factor affecting distant recurrence (HR = 5.7, 95% CI 2.7-11.9; p = 0.001). At the time of analysis 15 (16.7%) patients were dead, 6 (6.7%) patients in the RTCT group and 9 (10%) patients in the RT group. 5-years overall survival was: 88%. At multivariate analysis age > 65 years was an independent prognostic factor of overall survival (HR = 3.7, 95% CI 1.2-12.1, p = 0.037). CONCLUSIONS: Prospective randomized studies with large size population and with subgroup analysis for histological subtypes are necessary to clarify the role of adjuvant chemotherapy in soft tissue sarcoma patients. Tailored treatment has to be considered in elderly soft tissue patients to guarantee a better outcome in this high risk and fragile population.

Enhancement of Soft Tissue Sarcoma Cell Radiosensitivity by Poly(ADP-ribose) Polymerase-1 Inhibitors.

Soft tissue sarcomas (STS) are aggressive tumors with a poor prognosis. Poly(ADP-ribose) polymerase (PARP)-1 inhibitors (PARPi) enhance the cytotoxic effects of radiation. In this study, we evaluated the effect of PARPi on survival and DNA damage of irradiated STS cells. For clonogenic assays, STS cell lines were irradiated with or without olaparib, iniparib or veliparib pretreatment. The effect of PARP inhibition on γ-H2AX and Rad51 foci formation, on PARP-1, phospho-ERK and cleaved caspase-3 protein expression and on cell cycle progression was evaluated on irradiated rhabdomyosarcoma cells pretreated with olaparib. The results from this work showed that PARPi induced significant radiosensitization in STS cells. Rhabdomyosarcoma cells showed the highest increase in radiosensitivity, with a radiosensitization enhancement ratio at 50% survival (ER50) of 3.41 with veliparib. All PARPi exerted a synergistic effect when combined with radiation. Fibrosarcoma cells showed an ER50 of 2.29 with olaparib. Leiomyosarcoma and liposarcoma cells showed their highest ER50 with veliparib (1.71 and 1.84, respectively). In rhabdomyosarcoma, olaparib enhanced the formation of radiation-induced γ-H2AX/Rad51 foci and PARP-1 cleavage, induced slightly increased expression of cleaved caspase-3 and reduced phospho-ERK expression. Moreover, the combination of olaparib and radiation resulted in a significantly enhanced cell cycle arrest in the G2/M phase compared to the two treatments alone. In conclusion, we have shown that PARPi are potent radiosensitizers of human STS cells. These results support the pursuit of further investigations into the effects of PARPi combined with radiation on STS.

The Evolving Role of Ultrasound Guided Percutaneous Laser Ablation in Elderly Unresectable Breast Cancer Patients: A Feasibility Pilot Study.

BACKGROUND AND OBJECTIVES: Breast-conserving surgery represents the standard of care for the treatment of small breast cancers. However, there is a population of patients who cannot undergo the standard surgical procedures due to several reasons such as age, performance status, or comorbidity. Our aim was to investigate the feasibility and safety of percutaneous US-guided laser ablation for unresectable unifocal breast cancer (BC). METHODS: Between December 2012 and March 2017, 12 consecutive patients underwent percutaneous US-guided laser ablation as radical treatment of primary inoperable unifocal BC. RESULTS: At median follow-up of 28.5 months (range 6-51), no residual disease or progression occurred; the overall success rate for complete tumor ablation was therefore 100%. No significant operative side effects were observed, with only 2 (13.3%) experiencing slight to mild pain during the procedure, and all patients complained of a mild dull aching pain in the first week after procedure. CONCLUSIONS: Laser ablation promises to be a safe and feasible approach in those patients who are not eligible to the standard surgical approach. However, longer follow-up results and larger studies are strongly needed.

Safety of concurrent adjuvant radiotherapy and chemotherapy for locally advanced soft tissue sarcoma.

INTRODUCTION:: This retrospective study analyzes the safety and feasibility of concurrent chemoradiotherapy (CRT) in adjuvant treatment of soft tissue sarcoma (STS). METHODS:: A total of 158 patients with STS were retrospectively analyzed. Anthracycline-based computed tomography was performed in high-risk patients. Acute radiotherapy toxicity and chemotherapy-related toxicity were assessed according to the Common Terminology Criteria for Adverse Events 4.0; late radiotherapy toxicity was recorded according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. RESULTS:: Fifty-four (34.2%) patients received CRT. Mean follow up was 5.4 years (range .2-21.1 years). Local DFS-recurrence-free survival, distant DFS-relapse-free survival, and overall survival were 79.1%, 76.4%, and 64.6%, respectively, at last follow-up. Leukopenia occurred in 11.4% of patients. Skin acute toxicity developed in 60.1% of patients and determined interruption of radiotherapy treatment in 19 (12%) patients. Nineteen patients (12%) experienced moderate fibrosis (grade 2). Mild and moderate joint stiffness was recorded in 16 (10.1%) patients. Size ≥5 cm was the only predictor of local recurrence at multivariate analysis (hazard ratio [HR] 9.65, 95% confidence interval [CI] 1.28-72.83, p = .028). Age and stage resulted as independent distant relapse predictors (HR 4.77, 95% CI 1.81-12.58, p = .002 and HR 4.83, CI 1.41-16.57, p = .012, respectively). At Cox regression univariate analysis, Karnofsky Performance Status, size, and stage were significant survival predictors (HR 2.23, 95% CI 1.02-4.87, p = .045; HR 2.88, 95% CI 1.10-7.52, p = .031; HR 2.59, 95% CI 1.11-6.04, p = .028). CONCLUSIONS:: Concurrent CRT is a well-tolerated treatment option with no additional toxicity compared to exclusive radiotherapy or sequential CRT.

Incidence of skin toxicity in squamous cell carcinoma of the head and neck treated with radiotherapy and cetuximab: A systematic review.

PURPOSE: Radiotherapy plus cetuximab is an effective combination therapy for locally advanced head and neck squamous cell carcinoma. The aim of our study was to determine the frequency of skin toxicity in patients receiving the combined treatment. RESULTS: Forty-eight studies were included in our analysis, for a total of 2152 patients. The mean rates of G3/G4 radiation dermatitis and acneiform rash were 32.5% (SD: 20.4; 95% CI: 28.5-36.5) and 13.4% (SD: 11.5; 95% CI: 11.2-15.6), respectively. The majority of studies referred to CTCAE scales for reporting both side effects (85.7% and 92.1%, respectively). Data on the management of skin toxicity were available in only 35.4% of the reviewed literature. CONCLUSIONS: severe radiation dermatitis is a frequent side effect induced by the combination of radiotherapy and cetuximab in head and neck cancer. The lack of predictive biomarkers of toxicity hampers the possibilty to design preventive measures on a personalized basis.

Elderly patients affected by head and neck squamous cell carcinoma unfit for standard curative treatment: Is de-intensified, hypofractionated radiotherapy a feasible strategy?

OBJECTIVES: The aim of our work was to report on the clinical outcome of a moderately hyprofractionated radiotherapy regimen in elderly patients affected by head and neck squamous cell carcinoma (HNSCC). MATERIAL AND METHODS: HNSCC aged ≥65 deemed unsuitable for curatively-intended concurrent chemo-radiotherapy or high-dose radiotherapy by clinical judgement were further evaluated with the Geriatric 8 (G8) questionnaire and Charlson comorbidity index (CCI). In case of a G8 score ≤14, a de-intensified radiation schedule of 40 Gy delivered in 16 fractions was prescribed. RESULTS: Thirty-six patients were treated between 2011 and 2016. The median age of the cohort was 77.5 (range: 65-91 years) with a combined ECOG PS of 2-3 in 77.8% and CCI of ≥8 in 25% patients, respectively. At a median follow-up of 13 months (range 2-62 months), the 6-month and 1-year rates of loco-regional control and progression-free survival were 42%, 28% and 36% and 20%, respectively. At univariate analysis, log-rank test showed that age >75 years (p=0.036), worse PS (ECOG≥2; p=0.027), lower G8 score (<9; p=0.027) and PTV volume greater than 200 cc (p=0.038) had a significant correlation with PFS. The negative impact of the PTV volume on PFS was the only parameter confirmed in the multivariate analysis (HR 2.68; 95% CI: 1.24-5.81, p=0.013). No grade 4-5 toxicity was observed, while 13/36 patients (36%) had G3 acute side effects. CONCLUSION: The hypofractionated radiation schedule evaluated provides clinical benefit with low toxicity in frail, elderly patients affected by locally advanced HNSCC.

Radiotherapy in the age of cancer immunology: Current concepts and future developments.

Major advances in the knowledge of cancer biology and its interactions with tumor immune environment led to the emergence, in the last five years of new immunotherapy-based treatment strategies in cancer patients. At the same time, improvement in radiation technique and progress in radiobiology allowed in the last decade to expand the applications of radiotherapy in a growing number of settings. At present, there are strong theoretical basis to propose immune-enhanced radiation therapy that may represent in the future a new paradigm of treatment, combining the intrinsic power of radiotherapy to elicit a specific, systemic, tumor-directed immune response with modern highly conformal and precise dose delivery, in order to maximize response at the major site of disease and obtain durable disease control. The aim of this review is to describe the principal mechanisms of immune modulation of response to radiation and investigational strategies to harness the potential of radiation-inducible immune response: radiation therapy is expected to be not just a local treatment but the cornerstone of a multimodal strategy that might achieve long-lasting tumor remission at the primary site and systemic efficacy metastatic lesions.

Use of an alpha lipoic, methylsulfonylmethane and bromelain dietary supplement (Opera®) for chemotherapy-induced peripheral neuropathy management, a prospective study.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major clinical problem associated with a number of cytotoxic agents. OPERA® (GAMFARMA srl, Milan, Italy) is a new dietary supplement where α-lipoic acid, Boswellia Serrata, methylsulfonylmethane and bromelain are combined in a single capsule. The aim of this prospective study was to determine the efficacy and safety of OPERA® supplementation in a series of patients affected by CIPN. We selected 25 subjects with CIPN evolving during or after chemotherapy with potentially neurotoxic agents. Patients were enrolled at the first clinical manifestation of neuropathy. CIPN was assessed at the enrollment visit and subsequently repeated every 3 weeks until 12 weeks. Primary endpoint was the evaluation of changes of measured scores after 12 weeks of therapy compared to baseline evaluation. Secondary endpoints were the evaluation of neuropathy reduction at 12 weeks after beginning of therapy with OPERA®. Analysis of VAS data showed reduction in pain perceived by patients. According to NCI-CTC sensor and motor score, mISS scale and TNSc scale, both pain and both sensor and motor neuropathic impairment decreased after 12 weeks of treatments. Treatment with OPERA supplement was well tolerated; no increase in the toxicity profile of any of the therapeutic regimen that the patients were undergoing was reported. OPERA® was able to improve CIPN symptoms in a prospective series of patients treated with neurotoxic chemotherapy, with no significant toxicity or interaction. Prospective RCT in a selected patients' population is warranted to confirm its promising activity.

A PPAR gamma agonist protects against oral mucositis induced by irradiation in a murine model.

BACKGROUND: Due to its anti-inflammatory, antifibrotic and antineoplastic properties, the PPAR gamma agonist rosiglitazone is of interest in prevention and therapy of radiation-induced toxicities. We aimed to evaluate the radioprotective effect of rosiglitazone in a mouse model of radiation-induced oral mucositis. MATERIAL AND METHODS: Oral mucositis was obtained by irradiation of the oral region of C57BL/6J mice, pretreated or not with rosiglitazone. Mucositis was assessed by macroscopic scoring, histology and molecular analysis. Tumor xenograft was obtained by s.c. injection of Hep-2 cells in CD1 mice. Tumor volume was measured twice a week to evaluate effect of rosiglitazone alone and combined with radiotherapy. RESULTS: Irradiated mice showed typical features of oral mucositis, such as oedema and reddening, reaching the peak of damage after 12-15days. Rosiglitazone markedly reduced visible signs of mucositis and significantly reduced the peak. Histological analysis showed the presence of an inflammatory cell infiltrate after irradiation; the association with rosiglitazone noticeably reduced infiltration. Rosiglitazone significantly inhibited radiation-induced tnfα, Il-6 and Il-1ß gene expression. Rosiglitazone controlled the increase of TGF-ß and NF-kB p65 subunit proteins induced by irradiation, and enhanced the expression of catalase. Irradiation and rosiglitazone significantly reduced tumor volume as compared to control. Rosiglitazone did not protect tumor from the therapeutic effect of radiation. CONCLUSION: Rosiglitazone exerted a protective action on normal tissues in radiation-induced mucositis. Moreover, it showed antineoplastic properties on head-neck carcinoma xenograft model and selective protection of normal tissues. Thus, PPAR gamma agonists should be further investigated as radioprotective agents in head and neck cancer.