Dario Zerini

Robotic Image-Guided Stereotactic Radiotherapy, for Isolated Recurrent Primary, Lymph Node or Metastatic Prostate Cancer

PURPOSE To evaluate the outcome of robotic CyberKnife (Accuray, Sunnyvale, CA)-based stereotactic radiotherapy (CBK-SRT) for isolated recurrent primary, lymph node, or metastatic prostate cancer. METHODS AND MATERIALS Between May 2007 and December 2009, 34 consecutive patients/38 lesions were treated (15 patients reirradiated for local recurrence [P], 4 patients reirradiated for anastomosis recurrence [A], 16 patients treated for single lymph node recurrence [LN], and 3 patients treated for single metastasis [M]). In all but 4 patients, [(11)C]choline positron emission tomography/computed tomography was performed. CBK-SRT consisted of reirradiation and first radiotherapy in 27 and 11 lesions, respectively. The median CBK-SRT dose was 30 Gy in 4.5 fractions (P, 30 Gy in 5 fractions; A, 30 Gy in 5 fractions; LN, 33 Gy in 3 fractions; and M, 36 Gy in 3 fractions). In 18 patients (21 lesions) androgen deprivation was added to CBK-SRT (median duration, 16.6 months). RESULTS The median follow-up was 16.9 months. Acute toxicity included urinary events (3 Grade 1, 2 Grade 2, and 2 Grade 3 events) and rectal events (1 Grade 1 event). Late toxicity included urinary events (3 Grade 1, 2 Grade 2, and 2 Grade 3 events) and rectal events (1 Grade 1 event and 1 Grade 2 event). Biochemical response was observed in 32 of 38 evaluable lesions. Prostate-specific antigen stabilization was seen for 4 lesions, and in 2 cases prostate-specific antigen progression was reported. The 30-month progression-free survival rate was 42.6%. Disease progression was observed for 14 lesions (5, 2, 5, and 2 in Groups P, A, LN, and M respectively). In only 3 cases, in-field progression was seen. At the time of analysis (May 2010), 19 patients are alive with no evidence of disease and 15 are alive with disease. CONCLUSIONS CyberKnife-based stereotactic radiotherapy is a feasible approach for isolated recurrent primary, lymph node, or metastatic prostate cancer, offering excellent in-field tumor control and a low toxicity profile. Further investigation is warranted to identify the patients who benefit most from this treatment modality. The optimal combination with androgen deprivation should also be defined.

PRELIMINARY RESULTS OF ELECTRON INTRAOPERATIVE THERAPY BOOST AND HYPOFRACTIONATED EXTERNAL BEAM RADIOTHERAPY AFTER BREAST-CONSERVING SURGERY IN PREMENOPAUSAL WOMEN

PURPOSE To report the acute and preliminary data on late toxicity of a pilot study of boost with electron intraoperative therapy followed by hypofractionated external beam radiotherapy (HEBRT) of the whole breast. METHODS AND MATERIALS Between June 2004 and March 2007, 211 women with a diagnosis of early-stage breast cancer were treated with breast-conserving surgery. During surgery, an electron intraoperative therapy boost of 12 Gy was administered to the tumor bed. Adjuvant local treatment was completed with HEBRT, consisting of a course of 13 daily fractions of 2.85 Gy to the whole breast to a total dose of 37.05 Gy. Acute toxicity of the breast was evaluated at the end of HEBRT and at 1 month of follow-up. Late toxicity was recorded at 6 and 12 months of follow-up. RESULTS We report the data from 204 patients. The maximal acute skin toxicity was observed at the end of HEBRT (182 patients evaluable) with 7 (3.8%) Grade 3, 52 (28.6%) Grade 2, 123 (67.6%) Grade 1, and no Grade 0 or Grade 4 cases. A total of 108 patients were evaluated for late toxicity. The recorded late skin toxicity was Grade 4 in 1 patient (0.9%), Grade 3 in 1 patient, and Grade 2 or less in 106 patients (98.2%). CONCLUSIONS The results of this study have shown that electron intraoperative therapy followed by HEBRT allows for the delivery of a high dose to the tumor bed and an adequate dose to the whole breast. This treatment is feasible, compliance is high, and the rate of acute toxicity and the preliminary data on chronic toxicity seem acceptable.

Transabdominal Ultrasonography, Computed Tomography and Electronic Portal Imaging for 3-Dimensional Conformal Radiotherapy for Prostate Cancer

Purpose:To evaluate the feasibility and accuracy of daily B-mode acquisition and targeting ultrasound-based prostate localization (BAT™) and to compare it with computed tomography (CT) and electronic portal imaging (EPI) in 3-dimensional conformal radiotherapy (3-D CRT) for prostate cancer.Patients and Methods:Ten patients were treated with 3-D CRT (72 Gy/30 fractions, 2.4 Gy/fraction, equivalent to 80 Gy/40 fractions, for α/β ratio of 1.5 Gy) and daily BAT-based prostate localization. For the first 5 fractions, CT and EPI were also performed in order to compare organ-motion and set-up error, respectively.Results:287 BAT-, 50 CT- and 46 EPI-alignments were performed. The average BAT-determined misalignments in latero-lateral, antero-posterior and cranio-caudal directions were –0.9 mm ± 3.3 mm, 1.0 mm ± 4.0 mm and –0.9 mm ± 3.8 mm, respectively. The differences between BAT- and CT-determined organ-motion in latero-lateral, antero-posterior and cranio-caudal directions were 2.7 mm ± 1.9 mm, 3.9 ± 2.8 mm and 3.4 ± 3.0 mm, respectively. Weak correlation was found between BAT- and CT-determined misalignments in antero-posterior direction, while no correlation was observed in latero-lateral and cranio-caudal directions. The correlation was more significant when only data of good image-quality patients were analyzed (8 patients).Conclusion:BAT ensures the relative positions of target are the same during treatment and in treatment plan, however, the reliability of alignment is patient-dependent. The average BAT-determined misalignments were small, confirming the prevalence of random errors in 3-D CRT. Further study is warranted in order to establish the clinical value of BAT.Ziel:Ziel dieser Studie ist es, die Möglichkeit und Genauigkeit der täglichen B-mode-Akquisition und zielgerichteten ultraschallbasierten Prostatapositionierung (BAT™) einzuschätzen und sie mit der Computertomographie (CT) und dem elektronischen Portal-Imaging (EPI) bei der 3D-konformalen Strahlentherapie (3D-CRT) des Prostatakrebses zu vergleichen.Patienten und Methodik:10 Patienten wurden mit 3D-CRT (72 Gy/30 Fraktionen, 2,4 Gy/Fraktion, äquivalent zu 80 Gy/40 Fraktionen, α/β-Verhältnis von 1,5 Gy ) und täglicher BAT behandelt. Für die ersten 5 Fraktionen wurden auch CT und EPI durchgeführt, um jeweils die Bewegung der Organe und die Set-up-Fehler zu vergleichen.Ergebnisse:287 BAT-, 50 CT- und 46 EPI-Positionierungen wurden durchgeführt. Der durchschnittliche BAT-Positionierungsfehler war jeweils –0,9 mm ± 3,3 mm, 1,0 mm ± 4,0 mm und –0,9 mm ± 3,8 mm in den latero-lateralen, anterior-posterioren und kraniokaudalen Richtungen. Die Unterschiede zwischen der BAT- und CT-Technik bei der Bestimmung der Organbewegung in den latero-lateralen, anterior-posterioren und kraniokaudalen Richtungen waren jeweils 2,7 mm ± 1,9 mm, 3,9 ± 2,8 mm und 3,4 ± 3,0 mm. Eine sehr geringe Korrelation zwischen BAT- und CT-Positionierungsungenauigkeit wurde nur für die anterior-posteriore Richtung gefunden (R = 0,29, p = 0,04). Die Korrelation war leicht besser, wenn nur die Patienten mit guter Bildqualität analysiert wurden (8 Patienten).Schlussfolgerung:BAT garantiert, dass die relative Position des Ziels dieselbe während der Behandlung und in dem Behandlungsplan ist, obwohl die Genauigkeit der Positionierung patientenabhängig ist. Die durchschnittlichen, mit BAT bestimmten, Positionierungsfehler waren klein und bestätigen, dass der statistische Fehler in 3D-CRT vorwiegend ist. Weitere Studien sind erforderlich, um den klinischen Wert von BAT festzustellen.

Sooner or Later? Outcome Analysis of 431 Prostate Cancer Patients Treated With Postoperative or Salvage Radiotherapy

PURPOSE To evaluate the outcome of postoperative radiotherapy (PORT) and salvage RT (SART) using a three-dimensional conformal two-dynamic arc (3D-ART) or 3D six-field technique in 431 prostate cancer patients. METHODS AND MATERIALS Of the 431 patients, 258 underwent PORT (started <6 months after radical prostatectomy) and 173 underwent SART because of biochemical failure after radical prostatectomy. The median patient age, preoperative prostate-specific antigen level, and Gleason score was 66 years, 9.4 ng/mL, and 7, respectively. The median radiation dose was 70 Gy in 35 fractions for both PORT and SART. The 3D six-field and 3D-ART techniques were used in 25.1% and 74.9% of patients, respectively. Biochemical failure was defined as a post-RT prostate-specific antigen nadir plus 0.1 ng/mL. RESULTS Acute toxicity included rectal events (PORT, 44.2% and 0.8% Grade 1-2 and Grade 3, respectively; SART, 42.2% and 1.2% Grade 1-2 and Grade 3, respectively) and urinary events (PORT, 51.2% and 2.3% Grade 1-2 and Grade 3-4, respectively; SART, 37.6% and 0% Grade 1-2 and Grade 3, respectively). Late toxicity also included rectal events (PORT, 14.7% and 0.8% Grade 1-2 and Grade 3-4, respectively; SART, 15.0% and 0.6% Grade 1-2 and Grade 3, respectively) and urinary events (PORT, 28.3% and 3.7% Grade 1-2 and Grade 3-4, respectively; SART, 19.3% and 0.6% Grade 1-2 and Grade 3, respectively). After a median follow-up of 48 months, failure-free survival, including biochemical and clinical failure, was significantly longer in the PORT patients (79.8% vs. 60.5%, p < 0.0001). Multivariate analysis showed that a prostate-specific antigen level postoperatively but before RT of >/=0.2 ng/mL (p < 0.001), Gleason score >6 (p = 0.025) and use of preoperative androgen deprivation (p = 0.002) correlated significantly with shorter failure-free survival. Multivariate analysis showed that PORT and the 3D-ART technique correlated with greater late urinary toxicity. CONCLUSION PORT and early referral for SART offer better disease control after radical prostatectomy. The greater urinary toxicity occurring after PORT and 3D-ART requires further investigation to improve the therapeutic index.

CORRELATION BETWEEN ACUTE AND LATE TOXICITY IN 973 PROSTATE CANCER PATIENTS TREATED WITH THREE-DIMENSIONAL CONFORMAL EXTERNAL BEAM RADIOTHERAPY

PURPOSE To analyze the correlation between acute and late injury in 973 prostate cancer patients treated with radiotherapy and to evaluate the effect of patient-, tumor-, and treatment-related variables on toxicity. METHODS AND MATERIALS Of the 973 patients, 542 and 431 received definitive or postprostatectomy radiotherapy, respectively. Three-dimensional conformal radiotherapy included a six-field technique and two-dynamic arc therapy. Toxicity was classified according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. The correlation between acute and late toxicity (incidence and severity) was assessed. RESULTS Multivariate analysis showed that age </=65 years (p = .06) and use of the three-dimensional, six-field technique (p <.0001) correlated significantly with greater acute rectal toxicity. The three-dimensional, six-field technique (p = .0002), dose >70 Gy (p = .014), and radiotherapy duration (p = .05) correlated with greater acute urinary toxicity. Acute rectal toxicity (p <.0001) was the only factor that correlated with late rectal injury on multivariate analysis. Late urinary toxicity correlated with acute urinary events (p <.0001) and was inversely related to the use of salvage radiotherapy (p = .018). A highly significant correlation was found between the incidence of acute and late events for both rectal (p <.001) and urinary (p <.001) reactions. The severity of acute toxicity (Grade 2 or greater) was predictive for the severity of late toxicity for both rectal and urinary events (p <.001). CONCLUSION The results of our study have shown that the risk of acute reactions depends on both patient-related (age) and treatment-related (dose, technique) factors. Acute toxicity was an independent significant predictor of late toxicity. These findings might help to predict and prevent late radiotherapy-induced complications.

Dose Escalation for Prostate Cancer Using the Three-Dimensional Conformal Dynamic Arc Technique: Analysis of 542 Consecutive Patients

PURPOSE To present the results of dose escalation using three-dimensional conformal dynamic arc radiotherapy (3D-ART) for prostate cancer. METHODS AND MATERIALS Five hundred and forty two T1-T3N0M0 prostate cancer patients were treated with 3D-ART. Dose escalation (from 76 Gy/38 fractions to 80 Gy/40 fractions) was introduced in September 2003; 32% of patients received 80 Gy. In 366 patients, androgen deprivation was added to 3D-ART. Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria and Houston definition (nadir + 2) were used for toxicity and biochemical failure evaluation, respectively. Median follow-up was 25 months. RESULTS Acute toxicity included rectal (G1-2 28.9%; G3 0.5%) and urinary events (G1-2 57.9%; G3-4 2.4%). Late toxicity included rectal (G1-2 15.8%; G3-4 3.1%) and urinary events (G1-2 26.9%; G3-4 1.6%). Two-year failure-free survival and overall survival rates were 94.1% and 97.9%, respectively. Poor prognostic group (GS, iPSA, T), transurethral prostate resection, and dose >76 Gy showed significant association to high risk of progression in multivariate analysis (p = 0.014, p = 0.045, and p = 0.04, respectively). The negative effect of dose >76 Gy was not observed (p = 0.10), when the analysis was limited to 353 patients treated after September 2003 (when dose escalation was introduced). Higher dose was not associated with higher late toxicity. CONCLUSIONS Three-dimensional-ART is a feasible modality allowing for dose escalation (no increase in toxicity has been observed with higher doses). However, the dose increase from 76 to 80 Gy was not associated with better tumor outcome. Further investigation is warranted for better understanding of the dose effect for prostate cancer.

Linac-based stereotactic body radiotherapy for oligometastatic patients with single abdominal lymph node recurrent cancer

Objectives:To evaluate stereotactic body radiotherapy (SBRT) for single abdominal lymph node cancer recurrence. Methods:Inclusion criteria for this retrospective study were as follows: adult oligometastatic cancer patients with single abdominal lymph node recurrence that underwent SBRT but not other local therapy, written informed consent for treatment. Previous radiotherapy or concomitant systemic therapy were allowed. Toxicity and tumor response were evaluated using Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Scale and Response Evaluation Criteria in Solid Tumors. Results:Sixty-nine patients (94 lesions) underwent SBRT (median 24 Gy/3 fractions). Primary diagnosis included urological, gastrointestinal, gynecologic, and other malignancies. Concomitant systemic therapy was performed in 35 cases. Median follow-up was 20 months. Two grade 3 acute and 1 grade 4 late toxicity events were registered. Complete radiologic response, partial response, stabilization, and progressive disease were observed in 36 (44%), 21 (26%), 20 (25%), and 4 (5%) lesions, respectively, out of 81 evaluable lesions. Response rates were similar when analysis was restricted to lesions treated with exclusive SBRT (no concomitant therapy). Actuarial 3-year in-field progression-free interval, progression-free survival and overall-survival rates were 64.3%, 11.7%, and 49.9%, respectively. Overall-survival rates were significantly higher in favorable histology cases (prostate and kidney tumors). Pattern of failure was predominantly out-field. Conclusions:SBRT is a feasible approach for single abdominal lymph node recurrence, offering excellent in-field tumor control with low-toxicity profile. Future studies are warranted to identify the patients that benefit most from this treatment. The optimal combination with systemic treatment should also be defined.

Acute toxicity of image-guided hypofractionated radiotherapy for prostate cancer: nonrandomized comparison with conventional fractionation

OBJECTIVES To compare acute toxicity of prostate cancer image-guided hypofractionated radiotherapy (hypo-IGRT) with conventional fractionation without image-guidance (non-IGRT). To test the hypothesis that the potentially injurious effect of hypofractionation can be counterbalanced by the reduced irradiated normal tissue volume using IGRT approach. MATERIALS AND METHODS One hundred seventy-nine cT1-T2N0M0 prostate cancer patients were treated within the prospective study with 70.2 Gy/26 fractions (equivalent to 84 Gy/42 fractions, α/β 1.5 Gy) using IGRT (transabdominal ultrasound, ExacTrac X-Ray system, or cone-beam computer tomography). Their prospectively collected data were compared with data of 174 patients treated to 80 Gy/40 fractions with non-IGRT. The difference between hypo-IGRT and non-IGRT cohorts included fractionation (hypofractionation vs. conventional fractionation), margins (hypo-IGRT margins: 7 mm and 3 mm, for all but posterior margins; respectively; non-IGRT margins: 10 and 5 mm, for all but posterior margins, respectively), and use of image-guidance or not. Multivariate analysis was performed to define the tumor-, patient-, and treatment-related predictors for acute toxicity. RESULTS All patients completed the prescribed radiotherapy course. Acute toxicity in the hypo-IGRT cohort included rectal (G1: 29.1%; G2: 11.2%; G3: 1.1%) and urinary events (G1: 33.5%; G2: 39.1%; G3: 5%). Acute toxicity in the non-IGRT patients included rectal (G1: 16.1%; G2: 6.3%) and urinary events (G1: 36.2%; G2: 20.7%; G3: 0.6%). In 1 hypo-IGRT and 2 non-IGRT patients, radiotherapy was temporarily interrupted due to acute toxicity. The incidence of mild (G1-2) rectal and bladder complications was significantly higher for hypo-IGRT (P = 0.0014 and P < 0.0001, respectively). Multivariate analysis showed that hypo-IGRT (P = 0.001) and higher PSA (P = 0.046) are correlated with higher acute urinary toxicity. No independent factor was identified for acute rectal toxicity. No significant impact of IGRT system on acute toxicity was observed. CONCLUSIONS The acute toxicity rates were low and similar in both study groups with some increase in mild acute urinary injury in the hypo-IGRT patients (most probably due to the under-reporting in the retrospectively analyzed non-IGRT cohort). The higher incidence of acute bowel reactions observed in hypo-IGRT group was not significant in the multivariate analysis. Further investigation is warranted in order to exclude the bias due to the nonrandomized character of the study.

Use of machine learning methods for prediction of acute toxicity in organs at risk following prostate radiotherapy

PURPOSE The goal of this study is to investigate the advantages of large scale optimization methods vs conventional classification techniques in predicting acute toxicity for urinary bladder and rectum due to prostate irradiation. METHODS Clinical and dosimetric data of 321 patients undergoing prostate conformal radiotherapy were recorded. Gastro-intestinal and genito-urinary acute toxicities were scored according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scale. Patients were classified in two categories to separate mild (Grade < 2) from severe toxicity levels (Grade > 2). Machine learning methods at different complexity were implemented to predict toxicity as a function of multiple variables. The first approach consisted of a large scale optimization method, based on genetic algorithms (GAs) and artificial neural networks (ANN). The second approach was a binary classifier based on support vector machines (SVM). RESULTS The ANN and SVM-based solutions showed comparable prediction accuracy, exhibiting an area under the receiver operating characteristic (ROC) curve of 0.7. Different sensitivity and specificity features were measured for the two approaches. The ANN algorithm showed enhanced sensitivity if combined with appropriate classification criteria. CONCLUSIONS The results demonstrate that high sensitivity in toxicity prediction can be achieved with optimized ANNs, that are put forward to represent a valuable support in medical decisions. Future studies will be focused on enlarging the available patient database to increase the reliability of toxicity prediction algorithms and to define optimal classification criteria.

Image Guided Hypofractionated Radiotherapy and Quality of Life for Localized Prostate Cancer: Prospective Longitudinal Study in 337 Patients

PURPOSE We prospectively analyzed quality of life in a cohort of patients with prostate cancer undergoing a course of hypofractionated image guided radiotherapy. MATERIALS AND METHODS Between August 2006 and January 2011, 337 patients with a median age of 73 years who had cT1-T2N0M0 prostate cancer were eligible for this prospective, longitudinal study of hypofractionated image guided radiotherapy (70.2 Gy/26 fractions) using 1 of 3 image guided radiotherapy modalities (transabdominal ultrasound, x-ray or cone beam computerized tomography) available in our radiation oncology department. Patients completed 4 questionnaires before treatment, and 6, 12 and 24 months later, including the International Index of Erectile Function-5, International Prostate Symptom Score, and EORTC (European Organization for Research and Treatment of Cancer) prostate cancer specific QLQ-PR25 and QLQ-C30. RESULTS Patient followup was updated to at least the last questionnaire time point. Median followup was 19 months. Significant deterioration in erectile function on the International Index of Erectile Function-5 was documented with time only in patients without androgen deprivation (p = 0.0002). No change with time was observed in urinary symptom related quality of life on the QLQ-PR25 or International Prostate Symptom Score. Slight deterioration in QLQ-PR25 bowel symptom related quality of life was observed (p = 0.02). Overall QLQ-C30 Global Health Status improved with time (p = 0.03). On univariate analysis it significantly correlated with the maximum RTOG (Radiation Therapy Oncology Group)/EORTC urinary and bowel late toxicity scores after radiotherapy. CONCLUSIONS The regimen of hypofractionated image guided radiotherapy with multiple imaging modalities adopted in our radiation oncology department for localized prostate cancer might be a successful strategy for dose escalation with a limited impact on different aspects of quality of life with time.