Emanuela Olmetto

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-1β gene expression. Rosiglitazone controlled the increase of TGF-β 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.

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.

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.

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

AbstractBackgroundPoly(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. ObjectivesThe 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. ResultsDue 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.ConclusionsThe use of PARP inhibitors in advanced stage STSs, alone or combined in multimodal treatments, is of great interest and warrants further investigations.

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.

Analysis of dysphagia in advanced-stage head-and-neck cancer patients: impact on quality of life and development of a preventive swallowing treatment

ObjectivesSwallowing and voice dysfunctions are common side effects following head-and-neck squamous-cell carcinoma (HNSCC) treatment. Our aim was to analyze the relationships between quality of life, swallowing, and phonatory problems in patients with an advanced-stage HNSCC and to prospectively evaluate the effects of a prophylactic swallowing program.MethodsFirst, we retrospectively studied 60 advanced HNSCC patients treated with exclusive or adjuvant radiotherapy/chemoradiotherapy (RT/CRT). Subjects were classified according to general and clinical–therapeutic features. Outcome measures included EORTC QLQ-C30, EORTC QLQ-H&N35, Dysphagia Handicap Index (DHI), M.D.Anderson Dysphagia Inventory (MDADI), and Voice Handicap Index (VHI). Then, we conducted a prospective evaluation of a prophylactic swallowing counselling in 12 consecutive advanced-stage HNSCC patients by a two-arm case–control analysis. These patients were treated with exclusive or adjuvant RT/CRT.Results71% of the retrospective population studied reported swallowing dysfunction as a major side effect. No differences were detected in the severity of dysphagia or dysphonia according to type of treatment or staging of the primary tumour, while hypopharyngeal and laryngeal cancer patients showed significantly better swallowing ability and better QoL compared to oral cavity and oropharyngeal localisation (p < 0.05). In addition, a relevant correlation between swallowing and voice problems emerged (p < 0.05). In the prospective part, while no statistical correlation was evident before the start of RT/CRT in the experimental group compared to the control one, the former showed better performances at MDADI (p = 0.006) and DHI (p = 0.002) test 3 months after its end.ConclusionDysphagia is both an acute-and-long-term side effect which greatly affects QoL of HNSCC patients undergoing multimodality treatment. Our data show that a prophylactic swallowing program could actually produce a beneficial effect on patients’ outcomes.Level of evidence1b and 2b.

Stereotactic Ablative Radiotherapy as an Alternative to Lobectomy in Patients With Medically Operable Stage I NSCLC: A Retrospective, Multicenter Analysis

Background: Stereotactic ablative body radiation therapy (SBRT) has evolved as the standard treatment for patients with inoperable stage I non–small‐cell lung cancer (NSCLC). We report the results of a retrospective analysis conducted on a large, well‐controlled cohort of patients with stage I to II NSCLC who underwent lobectomy (LOB) or SBRT. Materials and Methods: One hundred eighty‐seven patients with clinical‐stage T1a‐T2bNoMO NSCLC were treated in 2 academic hospitals between August 2008 and May 2015. Patients underwent LOB or SBRT; those undergoing SBRT were sub‐classified as surgical candidates and nonsurgical candidates, according to the presence of surgical contraindications or comorbidities. Results: In univariate analysis, no significant difference was found in local control between patients who underwent SBRT and LOB, with a trend in favor of surgery (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.07‐1.01; P < .053). Univariate analysis showed that overall survival (OS) was significantly better in patients who underwent LOB (HR, 0.44; 95% CI, 0.23‐0.85) with a 3‐year OS of 73.4% versus 65.2% for surgery and radiation therapy patients, respectively (P < .01). However, no difference in OS was observed between operable patients undergoing SBRT and patients who underwent LOB (HR, 1.68; 95% CI, 0.72‐3.90). Progression‐free survival was comparable between patients who underwent LOB and SBRT (HR, 0.61; P = .09). Conclusion: SBRT is a valid therapeutic approach in early‐stage NSCLC. Furthermore, SBRT seems to be very well‐tolerated and might lead to the same optimal locoregional control provided by surgery for patients with either operable or inoperable early‐stage NSCLC.

BRCA mutation in breast cancer patients: Prognostic impact and implications on clinical management

BRCA1/2 mutations are involved in breast cancer (BC) susceptibility but their influence on outcome is unclear. We reviewed BC patients tested for BRCA to determine biological features and influence on outcome. BRCA‐1 was correlated to younger age (P = 0.035), nodal involvement (P = 0.030), higher tumor grade (P = 0.0022) and Ki‐67 (P = 0.014), ER/PgR negative status (P = 0.00042 and 0.0091, respectively), and use of adjuvant chemotherapy (P = 0.000038); BRCA was neither predictive for chemotherapy administration nor resulted in impaired outcome or occurrence of secondary BC. BRCA status did not influence outcome despite higher biological aggressiveness and younger age at presentation.

PO-0695: Lobectomy vs Stereotactic Ablative Radiotherapy in NSCLC:a multicentric series in four centers

S325 ________________________________________________________________________________ Patients were treated consecutively in the University Hospitals of Leuven between 2005 and 2014 and their data were retrospectively retrieved. PORT MPM patients were treated with RT doses up to 64 Gy in 2-Gy fractions. PORT NSCLC were treated with RT doses up to 60 Gy in 2-Gy fractions. Non-surgical patients were treated with RT doses up to 66 Gy in 2.75 Gy sequentially with chemotherapy or up to 70 Gy in 2 Gy fractions concurrently with chemotherapy. Dyspnea scores (CTCAE 4.03) before and after RT were retrieved and delta dyspnea was calculated as the difference between the dyspnea after RT (worse at any time point) and before RT. For every patient, 2 CT scans were retrieved: 1) CT0: a free breathing planning CT scan; 2) CT3M: deep inspiration breath-hold diagnostic follow up CT scan 3-6 months after the end of RT. CT0 and CT3M were non-rigidly co-registered in MIM. Differences in Hounsfield Unit (delta HU=HU3M-HU0) were represented as the slope of the dosedependent delta HU between 0 and 20 Gy (expressed in delta HU/Gy). Primary endpoint was delta dyspnea >= 2. Univariate and multivariate logistic regression analysis were performed in order to identify significant predictors of delta dyspnea >= 2. A p-value of < 0.05 was considered statistically significant.

Complete response in metastatic renal cell carcinoma after radiotherapy and everolimus: a clinical case and review of the literature

We report the case of a man affected by renal cell carcinoma with vertebral metastases, who presented a radiological complete response after systemic treatment with everolimus.