Alessia Guarneri

Stereotactic body radiation therapy for early stage non-small cell lung cancer: Results of a prospective trial

Patients affected with early stage (IA-IB) non-small cell lung cancer (NSCLC), deemed medically inoperable, are usually treated by conventional 3D-CRT, with poor results in terms of local tumour control and survival. Hypofractionated stereotactic body radiation therapy (SBRT) appears to be a valid alternative option, with high rates of local control and promising survival rates according to recent reported series. We herein report the final results of a prospective phase II trial of SBRT in 62 stage I NSCLC patients, homogeneously treated with three fractions of 15Gy each, given every other day during a 1 week time, up to a total dose of 45Gy; dose was prescribed to the 80%-isodose encompassing planning target volume. Patients were immobilized in a dedicated stereotactic body frame; margins around gross tumour volume were 5mm in the axial plane and 10mm in the longitudinal direction. Median age was 73.7 years. A pathologic confirmation of NSCLC was obtained in 64.5% of patients. Forty-three patients had stage IA and 19 stage IB disease. The majority of patients did not experience any toxicity; mild skin reactions, fatigue, dyspnea/cough or transient thoracic pain were recorded in approximately 10% of patients. With a median follow-up time of 28 months, 2 patients experienced an isolated local relapse, 4 an isolated nodal relapse and 15 a systemic failure. At 3 years, local control rate was 87.8%, cancer-specific survival 72.5%, overall survival 57.1%, with 8 out of 20 non-cancer related deaths. In multivariate analysis, tumour volume was associated with a better outcome. In our series, SBRT was well tolerated and confirmed its efficacy, with local control and survival rates globally superior to those reported using conventional radiotherapy. A longer follow-up is needed in order to establish a correct comparison with surgical series, and to fully ascertain a potential negative impact of SBRT on comorbidities of such a fragile patients population.

Stereotactic body radiation therapy for lung metastases

INTRODUCTION Stereotactic body radiation therapy (SBRT) has an emerging role in patients affected with pulmonary metastases. Purpose of this study was to evaluate efficacy and tolerability of SBRT in a cohort of patients treated between 2003 and 2009 at our institution. METHODS A total of 61 patients with oligometastatic lung tumors (single pulmonary nodules in 73.7%) were included in the study. SBRT was performed with a stereotactic body frame and a 3D-conformal technique. Fifty-one patients received 26 Gy in 1 fraction, 22 a dose of 45 Gy in 3 fractions and 3 a dose of 36 Gy in 4 fractions. Primary tumor was lung cancer in 45.7% of patients, colorectal cancer in 21.3% and a variety of other origins in 33%. The primary endpoint was local control, secondary endpoints were survival and toxicity. RESULTS After a median follow-up interval of 20.4 months, local control rates at 2 and 3 years were 89% and 83.5%, overall survival 66.5% and 52.5%, cancer-specific survival 75.4% and 67%, progression-free survival 32.4% and 22.3%. Tumor volume was significantly associated to survival, with highest rates in patients with single small tumors. Median survival time was 42.8 months, while median progression-free survival time was 11.9 months. Toxicity profiles were good, with just one case of grade III toxicity (pneumonitis). CONCLUSION This study shows that SBRT is an effective and safe local treatment option for patients with lung metastases. Definitive results are strictly correlated to clinical selection of patients.

Stereotactic Ablative Radiotherapy for stage I histologically proven non-small cell lung cancer: An Italian multicenter observational study

OBJECTIVES Aim of this retrospective multicenter observational study was to provide data on outcomes and prognostic factors in patients affected with stage I histologically confirmed NSCLC treated with Stereotactic Ablative Radiotherapy (SABR, or Stereotactic Body Radiotherapy, SBRT) outside clinical trials. MATERIALS AND METHODS We analyzed a cohort of 196 patients with histological/cytological diagnosis of NSCLC. Median age at treatment was 75 years old; median tumor diameter was 2.48 cm, and median GTV 13.3 cc. One hundred fifty-five patients had stage IA disease (79.1%) and 41 patients stage IB disease (20.9%). Total doses ranged from 48 to 60 Gy in 3-8 fractions. Primary endpoints of the study were safety (acute and late toxicity) and efficacy (Local Control, Disease-Free Survival, Overall and Cancer-Specific Survival). RESULTS Median follow-up time was 30 months. The percentage of grade ≥2 pulmonary toxicity was 3%, and the 30 and 60 days mortality rate was 0%. Local Recurrence-Free Survival was 89.7% at 3 years. Fifty-nine patients (30.1%) had at least one failure (local and/or nodal and/or distant), with a Disease-Free Survival (DFS) rate at 3 years of 65.5%. Overall Survival (OS) and Cancer-Specific Survival (CSS) rates were 68% and 82.1% at 3 years, respectively. Median time to any recurrence was 15 months, while median overall survival time was 54 months. At multivariate analysis, stage IB was the only variable associated to a decrease in DFS, OS and CSS (HR 2.77, p = 0.006; HR 2.38, p = 0.009; HR 4.06, p ≤ 0.001, respectively). A difference in survival according to stage was also evident at the log-rank test (p ≤ 0.0001 for CSS and OS). CONCLUSION The results of the present study support the routine use of SABR for stage I NSCLC in a daily practice environment. The only prognostic factor that has been confirmed by our analysis was tumor stage (IA vs. IB).

Dosimetric predictors of radiation-induced lung injury in stereotactic body radiation therapy

Materials and methods. The aim was to retrospectively investigate correlations between potential predictive parameters and the occurrence of radiation-induced lung injury in patients with primary or secondary lung tumours treated with stereotactic body radiation therapy (SBRT). Sixty patients (63 tumours) underwent SBRT, with a dose of 45 Gy in 3 fractions over 5 days or 26 Gy in single fraction. The following parameters were tested for correlation with Radiation Therapy Oncology Group (RTOG) lung toxicity score: planning target volume (PTV), tumour location, primary vs. metastatic tumour, and Mean Lung Dose (in 2 Gy fractions, MLD2). Normal Tissue Complication Probability (NTCP) values were then estimated. Results. The median follow-up time was 30.9 months (range 6.7–56.7). RTOG grade 0–1 toxicity was observed in 54/63 (85.7%) and grade 2–3 in 9/63 (14.3%) cases. Mean values of MLD2 for RTOG grade 0–1 and 2–3 were respectively 11.2 Gy (95% Confidence Interval (CI) 10.1–12.3 Gy) and 20.3 Gy (95% CI 16.6–23.9 Gy). NTCP mean values for RTOG grade 0–1 and 2–3 were respectively 4% (95% CI 2–5.9%) and 37% (95% CI 11.6–62.3%). Univariate analysis, performed with t-Student test, showed a statistically significant difference between MLD2 values in the two groups (t = 5.93 and p ≤ 0.001). Logistic regression analysis showed a good correlation between MLD2 and toxicity scores 2–3 (p = 0.008, odds ratio 1.5). From logistic regression relationship between the observed rates of grade 2–3 and MLD2, a D50=19.8 Gy and a γ50=2.2 were obtained. From the sigmoid-shaped dose-response relationship between NTCP and MLD2, a D50=22.4 Gy and γ50=2.2 were derived. Discussion. MLD2 is strongly associated to the risk of lung injury. Higher NTCP values are associated with a higher risk, but when comparing the expected to the observed toxicity rate, NTCP seems to underestimate the risk.

Stereotactic ablative radiation therapy as first local therapy for lung oligometastases from colorectal cancer: a single-institution cohort study.

PURPOSE To estimate stereotactic ablative radiation therapy (SABR) efficacy and its potential role as an alternative to surgery for the treatment of lung metastases from colorectal cancer. METHODS AND MATERIALS Forty consecutive patients who received SABR as first local therapy at the time of lung progression were included, from 2004 to 2014. The primary study endpoint was overall survival. Secondary endpoints were progression-free survival and safety. RESULTS A single nodule was treated in 26 patients (65%), 2 nodules in 10 patients (25%), 3 in 3 patients (7.5%), and 4 in 1 patient (2.5%), for a total of 59 lesions. The median delivered biological effective dose was 96 Gy, in 1 to 8 daily fractions. Median follow-up time was 20 months (range, 3-72 months). Overall survival rates at 1, 2, and 5 years were, respectively, 84%, 73%, and 39%, with 14 patients (35%) dead. Median overall survival was 46 months. Progression occurred in 25 patients (62.5%), at a median interval of 8 months; failure at SABR site was observed in 3 patients (7.5%). Progression-free survival rates were 49% and 27% at 1 and 2 years, respectively. DISCUSSION The results of this retrospective exploratory analysis suggest safety and efficacy of SABR in patients affected with colorectal cancer lung oligometastases and urge inclusion of SABR in prospective clinical trials.

Efficacy and Safety of Tadalafil 20 mg on Demand vs. Tadalafil 5 mg Once-a-Day in the Treatment of Post-Radiotherapy Erectile Dysfunction in Prostate Cancer Men: A Randomized Phase II Trial

INTRODUCTION The role of phosphodiesterase type 5 inhibitors in the treatment of post-radiotherapy erectile dysfunction (ED) has not been extensively investigated. AIM To compare the efficacy and safety of on-demand 20-mg tadalafil (arm A) with the newly released tadalafil 5-mg once-a-day dosing (arm B) in patients with ED following radiotherapy for prostate cancer (PC). METHODS Randomized study to receive on-demand 20-mg or once-a-day 5-mg tadalafil for 12 weeks. Main Outcome Measures.  Changes in the International Index of Erectile Function (IIEF) domain scores and Sexual Encounter Profile (SEP) question 2 and 3 positive response rates. RESULTS Fifty-two out of 86 screened patients were randomized. Forty-four patients were evaluable for efficacy. A significant improvement in all domains of the IIEF was observed in both arms (P = 0.0001) with mean erectile function domain scores values of 25 and 27.1 for the 20-mg and 5-mg tadalafil, respectively (P = 0.19). SEP 2 and 3 positive response rates increased from 0% in both arms at baseline to 81% and 70% in the 20-mg arm and 90% and 73% in the 5-mg arm, respectively, at the end of treatment (P = 0.27). End of treatment global efficacy question positive answers were 86% in the 20-mg arm and 95% in the 5-mg arm (P = 0.27). Higher treatment compliance was shown in arm B (100%) as compared with arm A (86%). There was a nonstatistically significant trend toward fewer side effects in favor of the 5-mg daily dose arm. CONCLUSIONS In the study population, both tadalafil formulations generated significantly high response rates according to the outcome measures and were well tolerated. The once-a-day 5-mg dosing showed higher compliance and marginally reduced side effects, thus making it an attractive alternative to on-demand therapy for ED in post-radiotherapy PC patients.

Tracking target position variability using intraprostatic fiducial markers and electronic portal imaging in prostate cancer radiotherapy

PurposeModern radiotherapy has achieved substantial improvement in tumour control and toxicity rates by escalating the total dose to the target volume while sparing surrounding normal tissues. It has therefore become necessary to precisely track tumour position in order to minimise geometrical uncertainties due to setup errors and organ motion. We conducted this prospective evaluation of prostate cancer patients treated with image-guided conformal radiation therapy at our institution. We implanted three fiducial markers (gold seeds) within the prostatic gland in order to quantify daily target displacements and to generate specific margins around the clinical target volume (CTV) to create an appropriate planned target volume (PTV).Materials and methodsBetween April and December 2009, ten patients affected with localised prostate cancer were transrectally implanted with three radio-opaque markers. Each patient underwent a computed tomography (CT) scan for planning purposes following proper bladder and rectum preparation. During treatment two orthogonal images were acquired daily and compared with previously generated digitally reconstructed radiographs. After manual localisation, comparison between the position of the gold seeds on the portal and reference images was carried out, and a set of extrapolated lateral-lateral (LL), anterior-posterior (AP) and cranial-caudal (CC) shift corrections was calculated and recorded. Couch corrections were applied with a threshold of 3 mm displacement.ResultsSystematic and random errors for each direction were calculated either as measured according to displacement of the gold seeds prior to any couch movement and after couch position correction according to the radio-opaque markers. For skin marks, mean systematic and random errors were 0.12+2.94 mm for LL, 1.04+3.37 mm for AP, −1.14+2.71 mm for CC, whereas for seed markers, mean and systematic errors were 0.6+1.5 mm for LL, 0.51+2.45 mm for AP and −0.25+2.51 mm for CC. A scatter plot generated on all measurements after couch repositioning according to gold-seed displacement suggested a confidence range of shift distributions within 5 mm for LL, 8 mm for CC, and 7 mm for AP. The total systematic and random components were then used to calculate proper PTV in patients receiving conventional treatment (7 mm for LL and 9 mm for both AP and CC).ConclusionsProstate positional variability during a course of radiation treatment is strongly influenced by setup and organ motion. Organ tracking through fiducial markers and electronic portal imaging is able to reduce the spread of displacements, significantly contributing to improve the ballistic precision of radiation delivery.RiassuntoObiettivoLa moderna radioterapia ha raggiunto traguardi considerevoli in termini di controllo tumorale e riduzione dei tassi di tossicità associati al trattamento, con la possibilità di erogare dosi importanti al volume bersaglio, risparmiando contemporaneamente i tessuti sani. Risulta, pertanto, focale la caratterizzazione precisa della posizione della lesione neoplastica per minimizzare le incertezze geometriche dovute agli errori di posizionamento ed al movimento d’organo. Abbiamo intrapreso una valutazione prospettica dei pazienti trattati mediante radioterapia conformazionale guidata dalle immagini per carcinoma prostatico, utilizzando tre reperi fiduciali (semi d’oro) impiantati all’interno della prostata per quantificare gli scostamenti giornalieri del volume bersaglio e generare margini specifici attorno al volume bersaglio clinico (CTV) creando un appropriato volume bersaglio di pianificazione (PTV).Materiali e metodiTra aprile e dicembre 2009, 10 pazienti affetti da adenocarcinoma prostatico organo-confinato sono stati sottoposti ad impianto trans-rettale sotto guida ecografica di 3 reperi fiduciali radio-opachi. Ogni paziente è stato sottoposto a tomografia computerizzata (CT) di pianificazione con una adeguata preparazione vescicale e rettale; ad ogni seduta di trattamento, sono state acquisite 2 immagini ortogonali e poi confrontate con immagini radiografiche a ricostruzione digitale. è stata effettuata una localizzazione manuale confrontando la posizione dei reperi fiduciali nelle immagini portali con quella nelle immagini di riferimento. Sono stati estrapolati e registrati gli scostamenti nelle direzioni latero-laterale (LL), anteroposteriore (AP) e cranio-caudale (CC). La correzione della posizione del lettino di trattamento è stata effettuata con una soglia di 3 mm.RisultatiSono stati calcolati l’errore standard e sistematico per ogni direzione, misurando gli scostamenti dei semi d’oro prima del movimento del lettino di trattamento e dopo aver applicato gli spostamenti secondo i reperi fiduciali. Per i reperi cutanei, l’errore sistematico e casuale medio sono stati 0,12±2,94 mm per la direzione LL, 1,04±3,37 mm per la direzione AP e −1,14±2,71 mm per la direzione CC; per i reperi fiduciali, l’errore sistematico e casuale medio sono stati 0,6±1,5 mm per la direzione LL, 0,51±2,45 mm per la direzione AP e −0,25±2,51 mm per la direzione CC. è stato creato un diagramma di distribuzione di tutte le misure ottenute dopo il riposizionamento del lettino in funzione degli scostamenti registrati mediante i reperi fiduciali; l’ambito di confidenza della distribuzione degli spostamenti si trova entro i 5 mm per la direzione LL, entro i 6 mm per la direzione CC ed entro i 7 mm per la direzione AP. L’errore sistematico e l’errore casuale totale sono stati utilizzati per generare margini per ottenere il PTV nei pazienti trattati convenzionalmente (7 mm per la direzione LL; 9 mm sia per la direzione AP che per la direzione CC).ConclusioniLa variabilità della posizione della ghiandola prostatica durante un trattamento radiante è influenzata in modo importante dal posizionamento e dal movimento d’organo. Il monitoraggio della posizione della prostata mediante reperi fiduciali ed immagini portali è in grado di ridurre la dispersione degli scostamenti rispetto all’atteso, contribuendo in maniera significativa al miglioramento della precisione balistica della radioterapia.

Three-Dimensional Ultrasound-Based Image-Guided Hypofractionated Radiotherapy for Intermediate-Risk Prostate Cancer: Results of a Consecutive Case Series

External beam radiotherapy (EBRT) is a standard of care in the treatment of prostate cancer. Hypofractionation is a valid option either radiobiologically and logistically in this context. Image-guidance procedures are strongly needed to provide ballistic precision to radiation delivery. The Clarity platform allows for the acquisition of three-dimensional ultrasound scans (3D-US) to perform image-guided radiotherapy. We treated a consecutive series of intermediate-risk prostate cancer patients (according to NCCN stratification) with a hypofractionated schedule (70.2 Gy/26 fractions at 2.7 Gy/daily to the prostate gland excluding the seminal vesicles at 62.1 Gy) under 3D-US guidance with the Clarity platform. The 3-year biochemical-relapse-free survival, distant-metastases-free, cancer-specific and overall survival were 98.6% (CI: 91.1–99.6%), 98.6% (CI: 91.1–99.6%), 97.5% (CI: 94.5–99.1%), and 94.3% (CI: 90.4–96.7%), respectively. Maximum detected acute GU toxicity was G0 in 22 patients (29.7%), G1 in 30 (22.7%), G2 in 19 (25.6%), G3 in 3 (4%). Maximum detected acute GI toxicity at the end of EBRT was G0 in 42 patients (56.8%), G1 in 22 (29.7%), G2 in 9 (12.1%), G3 in 1 (1.4%). The 3-year actuarial rates of ≥ G2 late toxicities were 6.1% for genito-urinary and 8.9% for gastrointestinal. The whole image-guidance workflow resulted in being robust and reliable. EBRT delivered employing a hypofractionated schedule under 3D-US-based image guidance proved to be a safe and effective treatment approach with consistent biochemical control and a mild toxicity profile. Hence, it has been transferred into daily clinical practice in our Department.

125I brachytherapy for localized prostate cancer: a single institution experience.

AIMS AND BACKGROUND To evaluate the clinical outcome of a cohort of localized prostate cancer patients treated with 125I permanent brachytherapy at the University of Turin. METHODS AND STUDY DESIGN A retrospective analysis was carried out on 167 consecutive patients with early stage prostate adenocarcinoma who underwent 125I brachytherapy between January 2003 and December 2010. A minimum follow-up of ≥ 12 months was mandatory for inclusion. Biochemical disease-free survival (defined on the basis of the ASTRO definition and the ASTRO-Phoenix definition) was chosen as the primary end point. Secondary end points were gastrointestinal and genitourinary toxicity (acute and late, defined according to the RTOG scale). RESULTS With a median follow-up of 42 months (range, 13.5-90.7), biochemical disease-free survival at 3 and 5 years was respectively 91.1% and 85.7%, according to the ASTRO definition and 94.5% and 85.1% according to ASTRO-Phoenix definition (for statistical purposes, only the ASTRO definition was used). Hormone treatment and nadir PSA (cutoff of 0.35 ng/ml) were the only factors affecting biochemical disease-free survival both on univariate (P = 0.02 and P = 0.001, respectively) and multivariate analysis (HR 0.024; P = 0.021 and HR 21.6; P = 0.006, respectively). Only 3.6% of patients experienced ≥ grade 3 acute urinary toxicity and 5% ≥ grade 3 late urinary toxicity. Prior transurethral prostate resection was the only independent predictor of grade 3 late urinary toxicity on multivariate analysis (HR 0.13; P = 0.009). CONCLUSIONS This mono-institutional series confirmed that brachytherapy is an effective and safe treatment modality for localized prostate cancer, with acceptable short- and long-term morbidity rates.

Efficacy and safety of stereotactic ablative radiotherapy in patients with previous pneumonectomy.

Background Thoracic surgery for a newly diagnosed primary lung tumor following a previous pneumonectomy is rarely indicated. Stereotactic ablative radiotherapy (SABR) might represent a curative option. This report focuses on outcomes, toxicity and quality of life (QoL) after SABR. Methods Nine patients were treated with SABR between 2004 and 2011; median time since surgery was 8.4 years. In 4 cases, a histological confirmation was possible with bronchoscopy. In 5 cases, the clinical proof of malignancy was based on radiological criteria. Forced expiratory volume in 1 second (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) were tested in all patients. A SABR biologically equivalent dose of >100 Gy was prescribed in all cases. QoL questionnaire forms were administered before SABR and during follow-up. Results Median follow-up was 41.8 months. We did not observe grade >3 acute toxicity, and concerning late toxicity, we registered 2 cases. QoL was decreased during the first 12 months of follow-up, followed by a progressive improvement after this time. One patient had a local relapse at 7.4 years; 1 developed a new nodule at 5.5 years, associated with metastases; and 1 developed a new nodule without any systemic disease at 3 years. There were 2 cancer-related deaths (18.2%) at 3 and 12 months after progression. Conclusions Data support efficacy and safety of SABR in patients with a new primary lung cancer following previous pneumonectomy, with acceptable acute, late toxicity profile and without significant impairment of QoL. Our results were comparable to those in the literature.