Publications by authors named "Carlo Furlan"

22 Publications

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Metastatic salivary gland carcinoma: A role for stereotactic body radiation therapy? A study of AIRO-Head and Neck working group.

Oral Dis 2020 Dec 15. Epub 2020 Dec 15.

Radiation Oncology Unit 2, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

Objectives: The role of radiotherapy (RT) for oligometastases is currently established in different oncological settings but data on salivary gland cancer (SGC) are lacking. We evaluated the role of RT in oligometastatic SGC patients, focusing on stereotactic body radiation therapy (SBRT).

Materials And Methods: We performed a retrospective, multicentric study of oligometastatic SGC treated with palliative RT or SBRT. Endpoints included response evaluation and local control (LC).

Results: Between 2006 and 2016, 64 patients were collected from 9 Italian Cancer Centers, on behalf of the Italian Association of Radiotherapy and Clinical Oncology (AIRO) Head and Neck Working Group. 37 patients (57.8%) were suffering from adenoid cystic carcinoma (ACC) and 27 patients (42.2%) had non-ACC. Thirty-four patients underwent palliative RT (53,1%), and 30 received SBRT (46,9%). Most common metastatic sites were bone for palliative RT and lung for SBRT. Among patients treated with SBRT, an objective response or a stability was observed in all treated lesions. After a median follow-up of 29.2 months (range 2.3-117.1), LC at 12 months was 57.5% for patients treated with SBRT and was higher in ACC subgroup.

Conclusion: We confirmed the potential role of SBRT in the management of oligometastatic SGC patients to control limited burden of disease considering the absence of effective systemic therapies.
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http://dx.doi.org/10.1111/odi.13755DOI Listing
December 2020

Radical Hemithoracic Radiotherapy Versus Palliative Radiotherapy in Non-metastatic Malignant Pleural Mesothelioma: Results from a Phase 3 Randomized Clinical Trial.

Int J Radiat Oncol Biol Phys 2021 Apr 28;109(5):1368-1376. Epub 2020 Nov 28.

Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.

Purpose: We conducted a phase 3 randomized clinical trial to assess whether radical hemithoracic radiation therapy (RHR) compared with palliative radiation therapy (PR) can achieve overall survival (OS) advantages in patients with malignant pleural mesothelioma (MPM).

Methods And Materials: From August 2014 to May 2018, patients with histologically diagnosed nonmetastatic MPM, who underwent nonradical lung-sparing surgery and chemotherapy (CHT), were randomly assigned (1:1) to receive RHR or PR. RHR total dose to the involved pleural cavity was 50 Gy in 25 fractions, and the gross residual disease received a simultaneous integrated boost of 60 Gy. The primary endpoint was OS. Secondary endpoints were local control, distant metastasis-free survival, progression-free survival, and acute and late toxicity rates. A sample size of 108 patients considering a type I error (α) of 0.05 and a statistical power of 80% was calculated to prove that RHR could improve the 2-year OS. OS was estimated with the Kaplan-Meier method and the log-rank test (2-sided) tested differences between arms. The univariate and multivariate analyses were performed using Cox proportional hazard model. Possible prognostic factors investigated: age, sex, performance status, lung surgery, gross residual disease, and histology.

Results: One hundred eight patients were randomized: 53 to the PR arm and 55 to the RHR arm. Median follow-up was 14.6 months. The 2-year OS rate was 58% in the RHR arm versus 28% in the PR arm (hazard ratio, 0.54; 95% confidence interval, 0.31-0.95; P = .031). In the RHR arm: 11 patients experienced acute toxicity grade ≥3, 17 patients had grade 3 to 4 late toxicity. Nine patients experience a grade ≥2 pneumonitis, including 1 patient with grade 5.

Conclusions: RHR significantly improves survival in patients with MPM treated with nonradical lung-sparing surgery and CHT compared with palliative treatments, although it is associated with a nonnegligible toxicity profile.
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http://dx.doi.org/10.1016/j.ijrobp.2020.11.057DOI Listing
April 2021

Extra-pleural pneumonectomy in the era of image-guided intensity-modulated radiotherapy.

Radiol Med 2019 Sep 8;124(9):854-859. Epub 2019 Apr 8.

Department of Radiation Oncology, Azienda Ospedaliero Universitaria Careggi, University of Florence, Largo Brambilla, 3, 50134, Florence, Italy.

Purpose: To assess the outcome of malignant pleural mesothelioma patients treated with extra-pleural pneumonectomy (EPP) and adjuvant radiotherapy (RT), using the most advanced radiotherapeutic techniques, namely image-guided intensity-modulated RT (IG-IMRT).

Methods And Materials: Fifty-four patients were analyzed. Minimum radiation dose was 50 Gy (2 Gy/fr). Planning target volume encompassed the entire hemithorax, including the ipsilateral mediastinum if interested by disease, the pericardium and diaphragm, and any drain sites. The study endpoints included loco-regional control (LRC), distant metastases free survival (DMFS), and overall survival (OS), as well as radiation-related toxicity.

Results: Major patients and treatment characteristics were the following: median age 62 years, epithelioid histology in 51 (94%) cases, locally advanced disease in 41 (90%) cases, and metastatic mediastinal lymph nodes in 27 patients (50%). Only 7 patients (13%) had gross residual disease after surgery. Chemotherapy was administered in 38 patients (70%). Median follow-up was 16 months (range 0-73 months). Median and 2-year OS were 21 months and was 43.8%, respectively. The predominant pattern of failure was distant: 34 patients (62.9%) developed some component of distant failure, and only 5 patients (9.2%) developed an isolated loco-regional recurrence. The estimates of LRC and DMFS at 2 years were 63.4% and 43.4%, respectively. Three fatal pneumonitis were documented. Other major toxicities included: Grade 2 and 3 pneumonitis in 1 and 2 cases, respectively, 1 case of bronchial fistula, pleural empyema, and Grade 3 esophagitis, respectively.

Conclusions: Although executed in the era of high-technology radiotherapy (IG-IMRT), EPP should not be routinely performed.
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http://dx.doi.org/10.1007/s11547-019-01030-yDOI Listing
September 2019

Direct health-care cost of head and neck cancers: a population-based study in north-eastern Italy.

Med Oncol 2019 Feb 28;36(4):31. Epub 2019 Feb 28.

Unit of Radiatherapic Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, via Gallini 2, 33081, Aviano, PN, Italy.

Improvements in prognosis of head-and-neck squamous cell carcinoma (HNSCC) have paralleled with an increase in health-care costs, so that an economic evaluation is of growing importance. Presently, most of the evidence is from insurance-based studies in the USA. Between 2007 and 2010, 879 HNSCC patients were identified through the population-based cancer registry of the Friuli Venezia Giulia region, including 266 oral, 187 oropharyngeal, 136 hypopharyngeal, and 290 laryngeal cancers. Health-care costs from diagnosis to treatment initiation and in the following 2 years were retrieved through a record linkage with the regional health data warehouse. This database collected comprehensive health information on all resident citizens. Generalized linear models with a gamma distribution and log-link function were applied to model costs. The average health-care cost from diagnosis up to 2 years after treatment initiation was €20,184 (95% confidence interval: €19,634 - 20,733). Heterogeneity emerged according to cancer site, elective treatment, and retreatment for cancer persistence/recurrence (no: €13,896; yes: €24,599; p < 0.001). An advanced stage was associated with increased costs stage (I: €12,969; II: €18,276; III: €26,229; IV: €25,574; p < 0.001) as the result of treatment complexity and elevated frequency of patients retreatment due to recurrence. These findings further support strategies to diagnose patients at an earlier cancer stage and the accurate definition of diagnostic and treatment pathways, to start treating patients when radical unimodal approach is still feasible. Besides the advantage in prognosis due to timely curative treatments, this would reduce the economic burden of cancer treatment.
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http://dx.doi.org/10.1007/s12032-019-1256-2DOI Listing
February 2019

Ten daily fractions for partial breast irradiation. Long-term results of a prospective phase II trial.

Breast J 2019 03 3;25(2):243-249. Epub 2019 Feb 3.

Department of Radiation Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.

Partial breast irradiation (PBI) is an effective adjuvant treatment after breast conservative surgery for selected early-stage breast cancer patients. However, the best fractionation scheme is not well defined. Hereby, we report the 5-year clinical outcome and toxicity of a phase II prospective study of a novel regimen to deliver PBI, which consists in 40 Gy delivered in 10 daily fractions. Patients with early-stage (pT1-pT2, pN0-pN1a, M0) invasive breast cancer were enrolled after conservative surgery. The minimum age at diagnosis was 60 years old. PBI was delivered with 3D-conformal radiotherapy technique with a total dose of 40 Gy, fractionated in 10 daily fractions (4 Gy/fraction). Eighty patients were enrolled. The median follow-up was 67 months. Five-year local control (LC), disease-free survival (DFS), and overall survival (OS) were 95%, 91%, and 96%, respectively. Grade I and II subcutaneous fibrosis were documented in 23% and 5% of cases. No grade III late toxicity was observed. PBI delivered in 40 Gy in 10 daily fractions provided good clinical results and was a valid radiotherapy option for early-stage breast cancer patients.
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http://dx.doi.org/10.1111/tbj.13195DOI Listing
March 2019

A new standardized data collection system for interdisciplinary thyroid cancer management: Thyroid COBRA.

Eur J Intern Med 2018 07 21;53:73-78. Epub 2018 Feb 21.

Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.

The big data approach offers a powerful alternative to Evidence-based medicine. This approach could guide cancer management thanks to machine learning application to large-scale data. Aim of the Thyroid CoBRA (Consortium for Brachytherapy Data Analysis) project is to develop a standardized web data collection system, focused on thyroid cancer. The Metabolic Radiotherapy Working Group of Italian Association of Radiation Oncology (AIRO) endorsed the implementation of a consortium directed to thyroid cancer management and data collection. The agreement conditions, the ontology of the collected data and the related software services were defined by a multicentre ad hoc working-group (WG). Six Italian cancer centres were firstly started the project, defined and signed the Thyroid COBRA consortium agreement. Three data set tiers were identified: Registry, Procedures and Research. The COBRA-Storage System (C-SS) appeared to be not time-consuming and to be privacy respecting, as data can be extracted directly from the single centre's storage platforms through a secured connection that ensures reliable encryption of sensible data. Automatic data archiving could be directly performed from Image Hospital Storage System or the Radiotherapy Treatment Planning Systems. The C-SS architecture will allow "Cloud storage way" or "distributed learning" approaches for predictive model definition and further clinical decision support tools development. The development of the Thyroid COBRA data Storage System C-SS through a multicentre consortium approach appeared to be a feasible tool in the setup of complex and privacy saving data sharing system oriented to the management of thyroid cancer and in the near future every cancer type.
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http://dx.doi.org/10.1016/j.ejim.2018.02.012DOI Listing
July 2018

Re-irradiation with curative intent in patients with squamous cell carcinoma of the head and neck: a national survey of usual practice on behalf of the Italian Association of Radiation Oncology (AIRO).

Eur Arch Otorhinolaryngol 2018 Feb 26;275(2):561-567. Epub 2017 Dec 26.

Radiation Oncology Department, Azienda Ospedaliera Sant'Andrea, Roma, Italy.

Objective: To report the results of a national survey investigating the pattern of practice of curative re-irradiation (ReRT) for recurrent squamous cell carcinoma of the head and neck.

Methods: In March 2016, a 22-item, 4-section questionnaire was sent to all Italian Radiation Oncology centers. Sections were focused on assessing the expertise level of each center and collecting specific information on reRT prescription modalities in the adjuvant and definitive settings.

Results: Overall, 77 centers completed the survey. The majority (50/77, 64.9%) of participating radiation oncologists were senior consultants (> 10 years of experience). Of the responding centers, 63 (81.8%) performed curative ReRT, while 14 (18.1%) did not, mainly (5/14, 35.7%) due to the avoidance of severe toxicity. The use of adjuvant ReRT was reported by less than half of the interviewed radiation oncologists (36/77, 46.7%). In case of unresectable local recurrence, definitive ReRT was claimed to be adopted in 55/77 (71.4%) for non-nasopharyngeal and 47/77 (61%) for nasopharyngeal cancer. The preferred treatment technique was Intensity Modulated Radiation Therapy (IMRT) followed by Stereotactic Body Radiation Therapy (SBRT). When IMRT was applied, the most common (19/55 responders, 34.5%) selection of treatment volume consisted of the Gross Tumor Volume (GTV) + 0.5 cm margin to account for microscopic disease.

Conclusion: Despite the absence of definitive evidence-based recommendations, a possible consideration for ReRT in case of unresectable recurrent head and neck cancer was reported by over 80% of radiation oncologists taking part in the national survey.
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http://dx.doi.org/10.1007/s00405-017-4853-8DOI Listing
February 2018

Novel insights into epigenetic drivers of oropharyngeal squamous cell carcinoma: role of HPV and lifestyle factors.

Clin Epigenetics 2017 28;9:124. Epub 2017 Nov 28.

Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, PN Italy.

In the last years, the explosion of high throughput sequencing technologies has enabled epigenome-wide analyses, allowing a more comprehensive overview of the oropharyngeal squamous cell carcinoma (OPSCC) epigenetic landscape. In this setting, the cellular pathways contributing to the neoplastic phenotype, including cell cycle regulation, cell signaling, DNA repair, and apoptosis have been demonstrated to be potential targets of epigenetic alterations in OPSCC. Of note, it has becoming increasingly clear that HPV infection and OPSCC lifestyle risk factors differently drive the epigenetic machinery in cancer cells. Epigenetic changes, including DNA methylation, histone modifications, and non-coding RNA expression, can be used as powerful and reliable tools for early diagnosis of OPSCC patients and improve prognostication. Since epigenetic changes are dynamic and reversible, epigenetic enzymes may also represent suitable targets for the development of more effective OPSCC therapeutic strategies. Thus, this review will focus on the main known epigenetic modifications that can occur in OPSCC and their exploitation as potential biomarkers and therapeutic targets. Furthermore, we will address epigenetic alterations to OPSCC risk factors, with a particular focus on HPV infection, tobacco exposure, and heavy alcohol consumption.
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http://dx.doi.org/10.1186/s13148-017-0424-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704592PMC
July 2018

Voxel-by-voxel correlation between radiologically radiation induced lung injury and dose after image-guided, intensity modulated radiotherapy for lung tumors.

Phys Med 2017 Oct 23;42:150-156. Epub 2017 Sep 23.

Medical Physics, Centro di Riferimento Oncologico IRCCS Aviano, 33081 Aviano, Italy.

Purpose: To correlate radiation dose to the risk of severe radiologically-evident radiation-induced lung injury (RRLI) using voxel-by-voxel analysis of the follow-up computed tomography (CT) of patients treated for lung cancer with hypofractionated helical Tomotherapy.

Methods And Materials: The follow-up CT scans from 32 lung cancer patients treated with various regimens (5, 8, and 25 fractions) were registered to pre-treatment CT using deformable image registration (DIR). The change in density was calculated for each voxel within the combined lungs minus the planning target volume (PTV). Parameters of a Probit formula were derived by fitting the occurrences of changes of density in voxels greater than 0.361gcm to the radiation dose. The model's predictive capability was assessed using the area under receiver operating characteristic curve (AUC), the Kolmogorov-Smirnov test for goodness-of-fit, and the permutation test (P).

Results: The best-fit parameters for prediction of RRLI 6months post RT were D of 73.0 (95% CI 59.2.4-85.3.7)Gy, and m of 0.41 (0.39-0.46) for hypofractionated (5 and 8 fractions) and D of 96.8 (76.9-123.9)Gy, and m of 0.36 (0.34-0.39) for 25 fractions RT. According to the goodness-of-fit test the null hypothesis of modeled and observed occurrence of RRLI coming from the same distribution could not be rejected. The AUC was 0.581 (0.575-0.583) for fractionated and 0.579 (0.577-0.581) for hypofractionated patients. The predictive models had AUC>upper 95% band of the P.

Conclusions: The correlation of voxel-by-voxel density increase with dose can be used as a support tool for differential diagnosis of tumor from benign changes in the follow-up of lung IMRT patients.
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http://dx.doi.org/10.1016/j.ejmp.2017.09.127DOI Listing
October 2017

Local High-Dose Radiotherapy Induces Systemic Immunomodulating Effects of Potential Therapeutic Relevance in Oligometastatic Breast Cancer.

Front Immunol 2017 6;8:1476. Epub 2017 Nov 6.

Department of Radiation Oncology, Azienda Sanitaria Universitaria Integrata of Udine, Udine, Italy.

Local irradiation of cancer through radiotherapy can induce spontaneous regression of non-directly irradiated lesions, suggesting the involvement of systemic antitumor immune responses. In oligometastatic breast cancer (BC) patients, the use of stereotactic body radiotherapy (SBRT) favors the local control of treated lesions and may contribute to break local tolerance and release tumor-associated antigens (TAAs), improving host antitumor immunity. We performed a detailed immunomonitoring of BC patients undergoing SBRT to verify its ability to "switch on" the anti-tumor immunity both systemically, in peripheral blood, and locally, employing BC models. Twenty-one BC patients with ≤6 metastases were treated with 3 daily doses of 10 Gy with SBRT. Blood samples for immune profiling were collected before and after treatment. One month after treatment a third of patients displayed the boosting or even the appearance of polyfunctional CD4 and CD8 T cell responses against known BC TAAs (survivin, mammaglobin-A, HER2), through intracellular staining in flow cytometry. Half of patients showed increased numbers of activated natural killer (NK) cells, measured with multispectral flow cytometry, immediately after the first dose of SBRT. Interestingly, high levels of activated NK cells at diagnosis correlated with a longer progression-free survival. BC models, treated with the same SBRT modality, showed enhanced expression of MHC class-I and class-II, major histocompatibility complex class I-related chain A/B, and Fas molecules, and increased release of pro-inflammatory cytokines, such as IL-1β and TNF-α. Consistently, we noticed enhanced production of perforin by CD4 T cells when patients' lymphocytes were cultured in the presence of irradiated BC cell line, compared to untreated targets. Besides immunogenic effects, SBRT also enhanced the percentages of circulating regulatory T cells, and increased and PD-L1 expression in BC models. These results suggest that SBRT may boost host antitumor immune responses also in an advanced disease setting such as oligometastatic BC, by inducing immunomodulating effects both locally and systemically. However, the concomitant induction of immunosuppressive pathways suggests that a combination with immunotherapy could further enhance the vaccination ability of radiotherapy, possibly further improving the curative potential of SBRT in this subset of patients.
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http://dx.doi.org/10.3389/fimmu.2017.01476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681493PMC
November 2017

Radical radiation therapy for oligometastatic breast cancer: Results of a prospective phase II trial.

Radiother Oncol 2018 01 21;126(1):177-180. Epub 2017 Sep 21.

Department of Medical Oncology, Centro di Riferimento Oncologico of Aviano, Italy.

Background And Purpose: We conducted a prospective phase II multicentric trial to determine if radical radiation therapy to all metastatic sites might improve the progression-free survival (PFS) in oligometastatic breast cancer patients. Secondary endpoints were local control (LC), overall survival (OS) and toxicity.

Methods And Materials: Inclusion criteria were the following: oligometastatic breast cancer with ≤5 metastatic sites, FDG-PET/CT staging, no brain metastases, primary tumor controlled. Radiotherapy could be delivered using stereotactic body radiotherapy (SBRT) technique or fractionated intensity modulated radiotherapy (IMRT). SBRT consisted of 30-45Gy in 3 fractions, while IMRT was delivered to a total dose of 60Gy in 25 fractions. We hypothesized that radical radiation therapy could increase the PFS from 30% (according to the published literature) to 50% at two years.

Results: 54 Patients with 92 metastatic lesions were enrolled. Forty-four were treated with SBRT, and 10 with IMRT. Forty-eight (89%) patients received a form of systemic therapy concomitantly to radiation therapy. Sites of metastatic disease were the following: bones 60 lesions, lymph nodes 23 lesions, lung 4 lesions, liver 5 lesions. After a median follow-up of 30months (range, 6-55months), 1- and 2-year PFS was 75% and 53%, respectively. Two-year LC and OS were 97% and 95%, respectively. Radiation therapy was well tolerated, and no Grade ≥3 toxicity was documented. Grade 2 toxicity were pain and fatigue in 2 cases.

Conclusions: Patients with oligometastatic breast cancer treated with radical radiotherapy to all metastatic sites may achieve long-term progression-free survival, without significant treatment-related toxicity. While waiting for data from randomized trials, the use of radical radiation therapy to all metastatic sites in patients with oligometastatic breast cancer should be considered a valuable option, and its recommendation should be individualized.
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http://dx.doi.org/10.1016/j.radonc.2017.08.032DOI Listing
January 2018

Prognostic significance of LINE-1 hypomethylation in oropharyngeal squamous cell carcinoma.

Clin Epigenetics 2017 30;9:58. Epub 2017 May 30.

Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico, IRCCS-National Cancer Institute, Aviano, PN Italy.

Background: Inclusion of new biomarkers to improve a personalized treatment approach for oropharyngeal squamous cell carcinoma (OPSCC) is urgently needed. Hypomethylation of the Long interspersed nucleotide element-1 (LINE-1) repetitive elements, a widely accepted surrogate of overall genomic DNA methylation content, was found to be associated with a poor prognosis in several cancers. At present, no studies have investigated the influence of LINE-1 methylation levels on OPSCC relapse. The main goal of this study was the evaluation of the prognostic value of LINE-1 methylation status in predicting early tumor relapse in locally advanced OPSCC.

Methods: We retrospectively reviewed a cohort of 77 patients with stage III-IVB OPSCC. Methylation of LINE-1 repetitive sequences was evaluated by real-time quantitative methylation-specific PCR in formalin-fixed paraffin-embedded tissues. The prognostic relevance of LINE-1 methylation was assessed by comparing patients who relapsed within 2 years from the end of treatment (cases) with those who did not (controls). Results were validated in an independent cohort of 33 patients with OPSCC.

Results: With respect to early OPSCC relapse, the mean LINE-1 methylation level was significantly lower in relapsed cases than in control group ( < 0.01). Interestingly, LINE-1 methylation was lower in relapsed cases than in controls in both HPV16-negative and HPV16-positive OPSCC patients, even if statistical significance was reached only for the former group ( = 0.01). LINE-1 methylation levels were also significantly reduced in relapsed cases with respect to the controls in OPSCC current smokers ( = 0.02). Consistently, in HPV16-negative current smokers, OPSCC relapse was significantly associated with decreased levels of LINE-1 methylation ( = 0.02). Using logistic regression model, we found that patients with hypomethylated LINE-1 were associated with a 3.5 higher risk of early relapse than hypermethylated ones (OR = 3.51; 95% CI 1.03-12.00). Adjustment for potential confounders did not substantially change the risk magnitude. Results from the validation cohort confirmed the lower LINE-1 methylation in patients who early relapsed compared to relapse-free patients.

Conclusions: LINE-1 hypomethylation is associated with higher risk of early relapse in stage III-IVB OPSCC. Further validation in a prospective study is needed for its application in daily clinical practice.
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http://dx.doi.org/10.1186/s13148-017-0357-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450111PMC
March 2018

Seven fractions to deliver partial breast irradiation: the toxicity is Low.

Radiat Oncol 2017 May 23;12(1):86. Epub 2017 May 23.

Breast Surgery Unit, Department of Oncology and Surgery, Centro di Riferimento Oncologico IRCSS, 33081, Aviano, Italy.

Purpose: To assess toxicity and clinical outcome, in breast cancer patients treated with external beam partial breast irradiation (PBI) consisting of 35 Gy in 7 daily fractions (5 Gy/fraction).

Materials And Methods: Patients affected by early-stage breast cancer were enrolled in this phase II trial. Patients had to be 60 years old or over and treated with breast conservative surgery for early stage invasive carcinoma.

Results: Seventy-three patients were analyzed. Median follow-up was 40 months. The proposed schedule was well tolerated. No Grade 3 toxicity was documented. Late toxicity was assessable for all the treated patients. Two patients (2.7%) developed Grade 2 pain 6 months after PBI. Four patients (5%) developed asymptomatic fat necrosis. Grade 2 fibrosis was observed in 5 patients (6.7%). No correlation was found between early and late toxicity and the type of adjuvant systemic therapy (no therapy vs. hormonal therapy vs. chemotherapy). No statistical correlation between dosimetric parameters and toxicity was found. Patients who developed Grade 2 radiation fibrosis had not higher radiation volumes to the untreated normal breast than those without fibrosis. Cosmesis was judged good/excellent in the majority of the cases (93%). One patient relapsed locally, and one developed distant metastases, corresponding to a 5-year local control and distant metastases-free survival of 98% and 96.7%, respectively.

Conclusions: 35 Gy in 7 daily fractions is an effective and well-tolerated regimen to deliver PBI.
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http://dx.doi.org/10.1186/s13014-017-0825-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442680PMC
May 2017

The impact of time to treatment initiation on survival from head and neck cancer in north-eastern Italy.

Oral Oncol 2017 04 3;67:175-182. Epub 2017 Mar 3.

Unit of Radiotherapy, CRO Aviano National Cancer Institute, via Gallini 2, 33081 Aviano (PN), Italy.

Objectives: To evaluate the impact of time to treatment initiation (TTI) on overall survival in patients with head-and-neck squamous cell carcinoma (HNSCC).

Materials And Methods: In the period 2003-2009, 1616 HNSCC patients were diagnosed in Friuli Venezia Giulia Region, Northeastern Italy, including 462 oral, 346 oropharyngeal, 212 hypopharyngeal, and 596 laryngeal cancers. Clinical information, including date and type of first treatment, and follow-up were retrieved from the regional Cancer Registry and a population-based health database collecting comprehensive health information on people living in the Region. Multivariate hazard ratio (HR) and confidence intervals (CI) were calculated through Cox model.

Results: Overall, the median TTI was 28days, (Q1-Q3: 13-45days), but significant variations emerged according to anatomical site, cancer stage, treatment approach, and care transition to specialized centers. Five-year overall survival decreased with increasing treatment delay from 62% for TTI<30days to 39% for TTI≥90days (p<0.01). HR of death was 1.13 (95% CI: 0.92-1.39) for TTI between 45-89days, and 1.47 (1.05-2.05) for TTI≥90days. The association between TTI and poor prognosis was stronger for laryngeal cancers and early-stage HNSCCs. Further, care transition from community hospitals to specialized centers was associated to a better prognosis (HR=0.73; 95% CI: 0.60-0.88).

Conclusion: Our study findings suggest that HNSCC patients treated within 45days from diagnosis have increased survival probabilities and that early-stage patients suffered the most from treatment delay. Furthermore, care transition to specialized centers -though competitive to timely treatment- improves survival by providing the most innovative technologies and treatment approaches.
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http://dx.doi.org/10.1016/j.oraloncology.2017.02.009DOI Listing
April 2017

Policies for reirradiation of recurrent high-grade gliomas: a survey among Italian radiation oncologists.

Tumori 2018 Dec 8;104(6):466-470. Epub 2018 May 8.

29 Radiation Therapy, Azienda Ospedaliera Sant'Andrea, Rome - Italy.

Purpose: To assess the contribution of Italian radiation oncologists in the current management of recurrent high-grade gliomas (HGG), focusing on a reirradiation (reRT) approach.

Methods: In 2015, the Reirradiation and the Central Nervous System Study Groups on behalf of the Italian Association of Radiation Oncology (AIRO) proposed a survey. All Italian radiation oncologists were individually invited to complete an online questionnaire regarding their clinical management of recurrent HGG, focusing on a reRT approach.

Results: A total of 37 of 210 questionnaires were returned (18% of all centers): 16 (43%) from nonacademic hospitals, 14 (38%) from academic hospitals, 5 (13%) from private institutions, and 2 (6%) from hadron therapy centers. The majority of responding centers (59%) treated ≤5 cases per year. Performance status at the time of recurrence, along with a target diameter <5 cm and an interval from primary radiation ≥6 months, were the prevalent predictive factors considered for reRT. Sixty percent of reirradiated patients had already received a salvage therapy, either chemotherapy (40%) or reoperation (20%). The most common approach for reRT was fractionated stereotactic radiotherapy to a mean (photon) dose of 41.6 Gy.

Conclusions: Although there were wide variations in the clinical practice of reRT across the 37 centers, the core activities were reasonably consistent. These findings provide a basis for encouraging a national collaborative study to develop, implement, and monitor the use of reRT in this challenging clinical setting.
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http://dx.doi.org/10.5301/tj.5000615DOI Listing
December 2018

Low-dose radiotherapy in diffuse large B-cell lymphoma.

Hematol Oncol 2017 Dec 25;35(4):472-479. Epub 2016 Oct 25.

Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy.

Low-dose radiotherapy (LDRT) given in 2 × 2 Gy is a highly effective and safe treatment for palliation of indolent lymphomas. Otherwise, very little regarding the use of LDRT for diffuse large B-cell lymphoma (DLBCL) has been investigated. We designed a phase 2 trial of LDRT in patients with DLBCL with indication for palliative radiation. Low-dose radiotherapy was administered on symptomatic areas only. Clinical response was assessed 21 days after LDRT and defined as reduction >50% of maximum diameter of the radiated lesions. Quality of life was scored by the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. Tumor subtype (germinal center B-cell type versus activated B-cell type) and the presence of TP53 mutations in pathologic specimens of the target lesion were also evaluated. Twenty-three of twenty-five radiated patients were evaluable for response, and 2 died of disease before the visit at 21 days. The overall response rate was 70% (16 of 23 patients), with 7 complete responses and 9 partial responses (mean duration of response, 6 months; range, 1-39 months). Fifteen patients answered to the QLQ-C30 questionnaires, and an improved quality of life was documented in 9 cases. TP53 mutations were detected in 2 of 6 (33%) nonresponders and in none of the responders (P = .12). Germinal center B-cell type responded better than activated B-cell type (response rate was 83% and 29%, respectively, P = .01). These findings indicate that LDRT is effective for palliation in patients with DLBCL.
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http://dx.doi.org/10.1002/hon.2368DOI Listing
December 2017

External beam radiotherapy in thyroid carcinoma: clinical review and recommendations of the AIRO "Radioterapia Metabolica" Group.

Tumori 2017 Mar 1;103(2):114-123. Epub 2016 Sep 1.

 Radiation Oncology Department, Gemelli-ART, Università Cattolica del Sacro Cuore, Rome - Italy.

The therapeutic approach to thyroid carcinoma usually involves surgery as initial treatment. The use of external beam radiotherapy (EBRT) is limited to high-risk patients and depends on clinical stage and histologic type. Different behavior patterns and degrees of aggressiveness of thyroid carcinomas require different management for differentiated, medullary, and anaplastic carcinoma. However, the role of EBRT is an issue of debate. Most clinical studies are retrospective and based on single-institution experiences. In this article, we review the main literature and give recommendations for the use of EBRT in thyroid carcinoma on behalf of the "Radioterapia Metabolica" Group of the Italian Radiation Oncology Association.
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http://dx.doi.org/10.5301/tj.5000532DOI Listing
March 2017

Alternative options for elderly patients with limited stage diffuse large B-cell lymphoma: R-chemotherapy vs. R-chemotherapy plus radiotherapy.

Leuk Lymphoma 2016 11 1;57(11):2677-80. Epub 2016 Mar 1.

k Hematology Unit, Department of Oncology and Advanced Technology , Arcispedale Santa Maria Nuova- Istituto Di Ricovero E Cura a Carattere Scientifico , Reggio Emilia , Italy.

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http://dx.doi.org/10.3109/10428194.2016.1153088DOI Listing
November 2016

Cell-free DNA as a prognostic marker in stage I non-small-cell lung cancer patients undergoing stereotactic body radiotherapy.

Biomarkers 2015 2;20(6-7):422-8. Epub 2015 Nov 2.

d Scientific Directorate, Oncology Reference Center, IRCCS , Aviano (PN) , Italy.

Objective: To evaluate whether plasma cell-free DNA (cfDNA) was related to clinical outcome in inoperable stage I non-small cell lung cancer (NSCLC) patients undergoing stereotactic body radiotherapy (SBRT).

Materials And Methods: Plasma cfDNA was assessed at baseline, before the last day and 45 days after the end of SBRT, in 22 NSCLC patients. Twenty-two healthy controls were also evaluated.

Results: Plasma cfDNA was higher in patients than in controls. An association with unfavourable disease-free survival was found for continuous baseline cfDNA increments (HR = 5.9, 95%CI: 1.7-19.8, p = 0.04).

Conclusion: Plasma cfDNA may be a promising prognostic biomarker in high-risk NSCLC patients.
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http://dx.doi.org/10.3109/1354750X.2015.1094139DOI Listing
September 2016

Lower platelet counts and antiplatelet therapy independently predict better outcomes in patients with head and neck squamous cell carcinoma: a retrospective analysis.

Biomark Res 2015 6;3:25. Epub 2015 Oct 6.

Department of Radiation Oncology, Centro di Riferimento Oncologico (CRO) National Cancer Institute, Via Franco Gallini, 2, 33081 Aviano, Italy.

The paper by Rachidi et al. suggests that antiplatelet drugs may play a role in ameliorating the clinical outcome in a large series of patients with head and neck cancer managed with either surgery or radiation. Our data, as well as confirming the results observed by the authors, enhance their clinical relevance pointing out the effect of antiplatelet drugs in terms of locoregional control in the setting of patients with advanced head and neck cancer managed with definitive chemo-radiotherapy.
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http://dx.doi.org/10.1186/s40364-015-0051-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594894PMC
October 2015

Radical Radiation Therapy After Lung-Sparing Surgery for Malignant Pleural Mesothelioma: Survival, Pattern of Failure, and Prognostic Factors.

Int J Radiat Oncol Biol Phys 2015 Nov 20;93(3):606-13. Epub 2015 Jun 20.

Department of Radiation Oncology, Centro di Riferimento Oncologico of Aviano, Aviano, Italy.

Purpose: To prospectively assess the survival, patterns of failure, and prognostic factors in a large cohort of patients with malignant pleural mesothelioma who had undergone a novel trimodal therapeutic approach, including lung-sparing surgery, chemotherapy, and subsequent treatment with high doses of intensity modulated radiation therapy (IMRT) to the whole hemithorax.

Methods And Materials: The analysis was conducted on the data from 69 patients. Of the 69 patients, 35 underwent extended pleurectomy/decortication (P/D), with resection of the entire pleura, along with portions of the pericardium and diaphragm and 34, partial pleurectomy, defined as partial removal of parietal or visceral pleura for diagnostic purposes, leaving gross tumor behind in all cases. All patients received cisplatin/pemetrexed chemotherapy. Postoperative IMRT was delivered to the entire hemithorax, excluding the intact lung. The IMRT dose was 50 Gy in 25 fractions. Any fluorodeoxyglucose-avid areas or regions of particular concern for residual disease were given a simultaneous boost to 60 Gy.

Results: The median follow-up duration was 19 months. No difference was seen in overall survival and locoregional control between the extended P/D group and the partial pleurectomy group. The 2-year overall survival was 65% and 58% in the extended P/D and partial pleurectomy groups, respectively (P=.94). Locoregional control at 2 years was 65% and 64% in the extended P/D and partial pleurectomy groups, respectively (P=.75). The predominant pattern of failure was distant: 19 patients (27.5%) developed distant metastases as the first site of relapse. Gross residual disease after surgery was significantly associated with overall survival (hazard ratio 3.45). One fatal pneumonitis was reported; 14 cases (20%) of grade 2 to 3 pneumonitis were documented.

Conclusions: Radical IMRT after lung-sparing surgery and chemotherapy for malignant pleural mesothelioma leads to promising survival results and acceptable toxicity rates. The similarity of survival between patients treated with extended P/D or partial pleurectomy observed in our study is intriguing.
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http://dx.doi.org/10.1016/j.ijrobp.2015.06.029DOI Listing
November 2015

Half-body irradiation with tomotherapy for pain palliation in metastatic breast cancer.

J Pain Symptom Manage 2014 Jan 21;47(1):174-80. Epub 2013 Jun 21.

Department of Radiation Oncology, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy.

Context: Half-body irradiation (HBI) is the fastest and most effective tool against uncontrolled pain from widespread bone metastases but is somewhat toxic.

Objectives: To assess the feasibility of lower HBI with helical tomotherapy in patients with metastatic breast cancer in terms of acute toxicity and delay in chemotherapy administration.

Methods: Thirteen breast cancer patients with multiple painful bone metastases to the lower half of the body were enrolled in this prospective trial. Eight patients were receiving chemotherapy. Target volume included all bones from the L3-L4 interface to the femoral shafts. Radiation consisted of 8 Gy in one fraction, delivered with helical tomotherapy. Patients were premedicated only with oral steroids. Pain intensity was scored using the Numeric Rating Scale from 0 to 10. Toxicity was scored using the Common Terminology Criteria for Adverse Events, version 3.0. Quality of life was scored with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, before and 21 days after the radiation course. This trial was approved by the local review board.

Results: Median follow-up was at seven months (range 2-12 months). All but two patients had pain relief in the radiated field. Six patients stopped their analgesic drug consumption. Toxicity was acceptable: two Grade 3 hematologic toxicities were registered (anemia and leukopenia). Grade 1-2 toxicities were hematologic = 13, fever = 3, nausea = 2, and diarrhea = 1. Three of the eight patients had a delay in chemotherapy administration because of leukopenia or anemia. Twelve patients answered to European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, and an improved quality of life was documented in eight cases.

Conclusion: Lower HBI delivered with helical tomotherapy resulted in a well-tolerated regimen, without significant delay in chemotherapy schedule.
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http://dx.doi.org/10.1016/j.jpainsymman.2013.02.022DOI Listing
January 2014