Serena Badellino

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).

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.

Stereotactic body radiotherapy for early stage lung cancer: History and updated role

Stereotactic Body Radiotherapy (SBRT) represents a consolidated treatment option for patients with medically inoperable early stage non-small cell lung cancer (NSCLC). The clinical evidence accumulated over the past decade supports its use as an alternative to surgery with comparable survival outcomes. Due to its limited toxicity, SBRT is also applicable to elderly patients with very poor baseline pulmonary function or other severe comorbidities. Recent comparative studies in operable patients raised the issue of the possible use of SBRT also for this subgroup, with quite promising results that still should be fully confirmed by prospective trials with long-term follow up. In early stage lung cancer, clinicians are now faced with a decision-making process that should take into account different factors. The need of pathological diagnosis and accurate nodal staging still represents a challenge, as well as the interpretation of radiological findings after SBRT, often confusing du to the difficulties in distinguishing between radiation-induced changes and local relapse. Aim of this review is to summarize and discuss the major studies on SBRT for early stage lung cancer, providing data on its efficacy and toxicity and discussing the still open issues on its role. Quality of life, pulmonary function and risk of secondary cancers are also discussed, as well as future perspectives and current research topics.

Stereotactic radiotherapy for early stage non-small cell lung cancer.

Stereotactic body radiotherapy (SBRT) represents a consolidated treatment option for patients with medically inoperable early stage non-small cell lung cancer (NSCLC). The clinical evidence accumulated in the past decade supports its use as an alternative to surgery with comparable survival outcomes. Due to its limited toxicity, SBRT is also applicable to elderly patients with very poor baseline pulmonary function or other severe comorbidities. Recent comparative studies in operable patients raised the issue of the possible use of SBRT also for this subgroup, with quite promising results that still should be fully confirmed by prospective trials with long-term follow-up. Aim of this review is to summarize and discuss the major studies conducted over the years on SBRT and to provide data on the efficacy and toxicity of this radiotherapy technique for stage I NSCLC. Technical aspects and quality of life related issues are also discussed, with the goal to provide information on the current role and limitations of SBRT in clinical practice.

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.

Radiotherapy and immune checkpoints inhibitors for advanced melanoma

INTRODUCTION The therapeutic landscape of metastatic melanoma drastically changed after the introduction of targeted therapies and immunotherapy, in particular immune checkpoints inhibitors (ICI). In recent years, positive effects on the immune system associated to radiotherapy (RT) were discovered, and radiation has been tested in combination with ICI in both pre-clinical and clinical studies (many of them still ongoing). We here summarize the rationale and the preliminary clinical results of this approach. MATERIALS AND METHODS In the first part of this review article, redacted with narrative non-systematic methodology, we describe the clinical results of immune checkpoints blockade in melanoma as well as the biological basis for the combination of ICI with RT; in the second part, we systematically review scientific publications reporting on the clinical results of the combination of ICI and RT for advanced melanoma. RESULTS The biological and mechanistic rationale behind the combination of ICI and radiation is well supported by several preclinical findings. Retrospective observational series and few prospective trials support the potential synergistic effect between radiation and ICI for metastatic melanoma. CONCLUSION RT may potentiate anti-melanoma activity of ICI by enhancing response on both target and non-target lesions. Several prospective trials are ongoing with the aim of further exploring this combination in the clinical setting, hopefully confirming initial observations and opening a new therapeutic window for advanced melanoma patients.

Clinical applications of stereotactic radiation therapy for oligometastatic cancer patients: a disease-oriented approach

Oligometastases from solid tumors are currently recognized as a distinct clinical entity, corresponding to an intermediate state between local and widespread disease. It has been suggested that local ablative therapies (including surgery, radiofrequency ablation and radiation therapy) play an important role in this setting, in combination or not with systemic therapies, particularly in delaying disease progression and hopefully in increasing the median survival time. Stereotactic body radiation therapy (SBRT) rapidly emerged in recent years as one of the most effective and less toxic local treatment modalities for lung, liver, adrenal, brain and bone metastases. The aim of this review was to focus on its clinical role for oligometastatic disease in four major cancer subtypes: lung, breast, colorectal and prostate. On the basis of the available evidence, SBRT is able to provide high rates of local tumor control without significant toxicity. Its global impact on survival is uncertain; however, in specific subpopulations of oligometastatic patients there is a trend towards a significant improvement in progression-free and overall survival rates; these important data might be used as a platform for clinical decision-making and establish the basis for the current and future prospective trials investigating its role with or without systemic treatments.

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.

Pulmonary function and quality of life after VMAT-based stereotactic ablative radiotherapy for early stage inoperable NSCLC: a prospective study

OBJECTIVES To analyze changes in pulmonary function and quality of life (QoL) at different time points after Stereotactic Ablative Radiotherapy (SABR) for early stage inoperable lung cancer, and potential correlations between radiation dose-volume parameters and pulmonary toxicity or changes in pulmonary function tests (PFT) and QoL. MATERIALS AND METHODS From July 2012 to October 2013, 30 patients were enrolled in this prospective observational study. Complete PFT were performed and Lung Cancer Symptoms Scale (LCSS) questionnaire administered prior to SABR; all patients then underwent Computed Tomography (CT) scan and PFT at 45, 135, 225 and 315 days after SABR, together with LCSS questionnaire. Clinical lung toxicity and radiological toxicity (acute and late) were prospectively recorded by using the Radiation Therapy Oncology Group (RTOG) scoring system. RESULTS A decline in Slow Vital Capacity (SVC), Forced Expiratory Volume in 1s (FEV1), Single-breath lung diffusing capacity (DLCO) and blood partial pressure of oxygen (PaO2) was seen at 135 days post-SABR. PaO2 values rescued to normal levels at 315 days. None of the baseline PFT parameters resulted to be associated with the occurrence of pulmonary toxicity or with late radiological changes. Mean V5, V10, and V20 and MLD2Gy were higher in patients who developed radiation pneumonitis, even if not significantly associated at Cox regression analysis. LCSS QoL showed a significant worsening of the single item fatigue at 135 days after SABR. CONCLUSIONS A small (mean 10%) but significant decline in lung volumes and DLCO was recorded after SABR, with clinical impact of such change difficult to estimate in individual patients. Global QoL was not significantly impaired. Dose-volume parameters did not emerge as significantly predictive of any clinical, radiological or functional toxicity.

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.