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Purpose: To extend the knowledge-based (KB) automatic planning approach to CyberKnife in the case of Stereotactic Body Radiation Therapy (SBRT) for prostate cancer., Methods: Seventy-two clinical plans of patients treated according to the RTOG0938 protocol (36.25 Gy/5fr) with CyberKnife were exported from the CyberKnife system to Eclipse to train a KB-model using the Rapid Plan tool. The KB approach provided dose-volume objectives for specific OARs only and not PTV. Bladder, rectum and femoral heads were considered in the model. The KB-model was successfully trained on 51 plans and then validated on 20 new patients. A KB-based template was tuned in the Precision system for both sequential optimization (SO) and VOLO optimization algorithms. Plans of the validation group were re-optimized (KB-TP) using both algorithms without any operator intervention and compared against the original plans (TP) in terms of OARs/PTV dose-volume parameters. Paired Wilcoxon signed-rank tests were performed to assess statistically significant differences (p < 0.05)., Results: Regarding SO, automatic KB-TP plans were generally better than or equivalent to TP plans. PTVs V95% was slightly worse while OARs sparing for KB-TP was significantly improved. Regarding VOLO optimization, the PTVs coverage was significantly better for KB-TP while there was a limited worsening in the rectum. A significant improvement was observed in the bladder in the range of low-intermediate doses., Conclusions: An extension of the KB optimization approach to the CyberKnife system has been successfully developed and validated in the case of SBRT prostate cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Background: After interstitial prostate iodine-125 brachytherapy (BT), prostate-specific antigen (PSA) evolution in time could predict overall biochemical relapse, but, considering the single patient, it is influenced by the presentation PSA amount and by the prostatic volume. It is also challenging to differentiate a PSA bounce from a biochemical relapse., Purpose: To determine the usefulness of PSA percentage (PP) defined as the rate between PSA presented by a patient at time "t" and the PSA that the same patient had presented at the time of diagnosis (t0) assumed as 100% in predicting biochemical relapse and in differentiating them from PSA Bounces., Methods and Materials: We included 721 patients from Milan S. Raffaele Turro (399) and Lucca Campo di Marte (then S. Luca) Hospital (322). The mean age of patients was 66.5 years (range, 50-79). Mean followup was 150 months (range, 24-180). For each patient, PSA was recorded before and after iodine-125 BT, and PPs were calculated. Cox regression model, relative operating characteristic curves, and Kaplan-Meier regression model were elaborated, and a cutoff of 20% was defined., Results: We observed that PP >20% is an independent variable highly associated with relapse risk (p < 0.0001) with a sensitivity of 79.7%, a specificity of 82%, and an hazard ratio of 12.1, since the 6 months of followup. A PSA increase above the nadir should be because of bounce (sensitivity and specificity of 81.4%, p < 0.0001) if patient had experienced at 6 months a PP <20%., Conclusions: PP might represent an early and useful tool, predictive of clinical outcome in patients after BT for prostate cancer., (Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Objective: To report the 3-year toxicity and outcomes of carbon 11 (11C)-choline-positron emission tomography (PET)/computed tomography (CT)-guided radiotherapy (RT), delivered via helical tomotherapy (HTT; Tomotherapy ® Hi-Art II ® Treatment System, Accuray Inc., Sunnyvale, CA, USA) after lymph node (LN) relapses in patients with prostate cancer., Patients and Methods: From January 2005 to March 2013, 81 patients with biochemical recurrence after surgery, with or without adjuvant/salvage RT or radical RT, and with evidence of LN 11C-choline-PET/CT pathological uptake, underwent HTT (median [range] prostate-specific antigen level 2.59 [0.61-187] ng/mL). Of the 81 patients, 72 were treated at the pelvic and/or lumbar-aortic LN chain with HTT at 51.8 Gy/28 fr and with simultaneous integrated boost to a median dose of 65.5 Gy on the pathological uptake sites detected by 11C-choline-PET/CT. Nine patients were treated without simultaneous integrated boost (50-65.5 Gy, 25-30 fr)., Results: With a median (range) follow-up of 36 (9-116) months, 91.4% of the patients had a PSA reduction 3 months after HTT. The 3-year overall, local relapse-free and clinical relapse-free survival rates were 80.0, 89.8 and 61.8%, respectively. The 3-year actuarial incidences of ≥grade 2 rectal and ≥grade 2 genitourinary toxicity were 6.6% (±2.9%) and 26.3% (±5.5%), respectively. A PSA nadir of ≥0.26 ng/mL (hazard ratio [HR] 3.6, 95% confidence interval [CI] 1.7-7.7; P = 0.001), extrapelvic 11C-choline-PET/CT-positive LN location (HR 2.4, 95% CI 0.9-6.4; P = 0.07), RT previous to HTT (HR 2.7; 95% CI 1.07-6.9, P = 0.04) and number of positive LNs (HR 1.13, 95% CI 1.04-1.22; P = 0.003) were the main predictors of clinical relapse after HTT., Conclusions: 11C-choline-PET/CT-guided HTT is safe and effective in the treatment of LN relapses of prostate cancer in previously treated patients., (© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.)

Objective: Low-dose-rate brachytherapy (LDR-BT) in localized prostate cancer is available since 15 years in Italy. We realized the first national multicentre and multidisciplinary data collection to evaluate LDR-BT practice, given as monotherapy, and outcome in terms of biochemical failure., Methods: Between May 1998 and December 2011, 2237 patients with early-stage prostate cancer from 11 Italian community and academic hospitals were treated with iodine-125 ((125)I) or palladium-103 LDR-BT as monotherapy and followed up for at least 2 years. (125)I seeds were implanted in 97.7% of the patients: the mean dose received by 90% of target volume was 145 Gy; the mean target volume receiving 100% of prescribed dose (V100) was 91.1%. Biochemical failure-free survival (BFFS), disease-specific survival (DSS) and overall survival (OS) were estimated using Kaplan-Meier method. Log-rank test and multivariable Cox regression were used to evaluate the relationship of covariates with outcomes., Results: Median follow-up time was 65 months. 5- and 7-year DSS, OS and BFFS were 99 and 98%, 94 and 89%, and 92 and 88%, respectively. At multivariate analysis, the National Comprehensive Cancer Network score (p < 0.0001) and V100 (p = 0.09) were correlated with BFFS, with V100 effect significantly different between patients at low risk and those at intermediate/high risk (p = 0.04). Short follow-up and lack of toxicity data represent the main limitations for a global evaluation of LDR-BT., Conclusion: This first multicentre Italian report confirms LDR-BT as an excellent curative modality for low-/intermediate-risk prostate cancer., Advances in Knowledge: Multidisciplinary teams may help to select adequately patients to be treated with brachytherapy, with a direct impact on the implant quality and, possibly, on outcome.

Purpose: To fit urinary toxicity data of patients treated with postprostatectomy radiation therapy with the linear quadratic (LQ) model with/without introducing a time factor., Methods and Materials: Between 1993 and 2010, 1176 patients were treated with conventional fractionation (1.8 Gy per fraction, median 70.2 Gy, n=929) or hypofractionation (2.35-2.90 Gy per fraction, n=247). Data referred to 2004-2010 (when all schemes were in use, n=563; conventional fractionation: 316; hypofractionation: 247) were fitted as a logit function of biological equivalent dose (BED), according to the LQ model with/without including a time factor γ (fixing α/β = 5 Gy). The 3-year risks of severe urethral stenosis, incontinence, and hematuria were considered as endpoints. Best-fit parameters were derived, and the resulting BEDs were taken in multivariable backward logistic models, including relevant clinical variables, considering the whole population., Results: The 3-year incidences of severe stenosis, incontinence, and hematuria were, respectively, 6.6%, 4.8%, and 3.3% in the group treated in 2004-2010. The best-fitted α/β values were 0.81 Gy and 0.74 Gy for incontinence and hematuria, respectively, with the classic LQ formula. When fixing α/β = 5 Gy, best-fit values for γ were, respectively, 0.66 Gy/d and 0.85 Gy/d. Sensitivity analyses showed reasonable values for γ (0.6-1.0 Gy/d), with comparable goodness of fit for α/β values between 3.5 and 6.5 Gy. Likelihood ratio tests showed that the fits with/without including γ were equivalent. The resulting multivariable backward logistic models in the whole population included BED, pT4, and use of antihypertensives (area under the curve [AUC] = 0.72) for incontinence and BED, pT4, and year of surgery (AUC = 0.80) for hematuria. Stenosis data could not be fitted: a 4-variable model including only clinical factors (acute urinary toxicity, pT4, year of surgery, and use of antihypertensives) was suggested (AUC = 0.73)., Conclusions: The unexpected impact of moderate hypofractionation on severe incontinence and hematuria after postprostatectomy radiation therapy may be explained by a bladder α/β value <1 Gy or, radiobiologically more plausible, by introducing a time factor likely to represent a previously hypothesized consequential component of late effect., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: to verify the possibility of using Helical Tomotherapy to safely escalate dose to single or multiple highly radioresistant dominant intra-prostatic lesions (DILs) as assessed by functional magnetic resonance imaging (MRI)., Material: in seven intermediate/high risk patients, T2WI, T1WI and DWI MRI imaging showed evidence of one DIL in four patients and two DILs in three patients in the peripheral zone of the prostate. The planning strategy was to deliver median doses of 80, 90, 100 and 120 Gy to PTVDIL while delivering 71.4 Gy/28 fractions (EQD(2)=75 Gy) to the remaining portion of PTV. A higher priority was assigned to rectal constraints relative to DIL coverage. Rectal NTCP calculations were performed using the most recently available model data., Results: the median dose to DIL could safely be escalated to at least 100 Gy (EQD(2,α/β=10)=113 Gy) without violating safe constraints for the organs at risk. Typical rectal NTCP values were around or below 1-3% for G3 toxicity and 5-7% for G2-G3 toxicity. For the 100 Gy DIL dose boost strategy, mean D95% of DIL and PTVDIL were 98.8 Gy and 86.7 Gy, respectively. The constraints for bladder, urethra and femoral heads were always respected., Conclusions: IGRT by Helical Tomotherapy may permit the safe escalation of EQD(2,α/β=10) to at least 113 Gy to DILs without significantly increasing rectal NTCP compared to plans without dose escalation. A Phase I-II clinical study is warranted.

Background and Purpose: To assess the impact of using MRI and Helical Tomotherapy (HT) compared to 3DCRT and dynamic IMRT on the dose to the penile bulb (PB)., Materials and Methods: Eight patients diagnosed with prostate cancer entered a treatment protocol including CT and MRI simulation. The prostate apex was defined on both MRI and CT. Treatment plans (HT, Linac-IMRT, 3DCRT and conventional technique), were elaborated on both MRI and CT images. A dose of 71.4Gy (2.55Gy/fraction) was prescribed; it was requested that PTVs be covered by 95% isodose line. The mean dose and V50 of PB were evaluated., Results: PTV-MRI plans reduced PB mean dose and V50 compared to PTV-CT plans. This improvement, deriving also from the treatment modality, was 89% for 3DCRT, 99% for Linac-IMRT and 97% for HT (p<0.01), considering V50. Conventional plans resulted in a significantly higher mean PB dose/V50 compared to 3DCRT-PTV-CT (+27%/+38%), Linac-IMRT-PTV-CT (+42%/+57%) and HT-PTV-CT (+32%/+48%) (p<0.01). The comparison between conventional and PTV-MRI techniques showed a still larger increase: +73%/+93% 3DCRT; +86%/+99% Linac-IMRT; +56%/+99% HT (p<0.01). The PB mean dose reduction with Linac-IMRT compared to 3DCRT was 24% (p=0.034) and 40% (p=0.027) for PTV-CT and PTV-MRI, respectively. This gain remained significant even when comparing Linac-IMRT to HT: 21% (p=0.07) PTV-CT and 68% (p=0.00002) PTV-MRI. HT was superior to 3DCRT with respect to PTV-CT (average gain 4%, p=0.044), whereas it resulted to be detrimental considering PTV-MRI (26Gy vs 16.5Gy), possibly due to the helical delivery of HT; however, in a patient where the distance bulb-PTV <1cm, HT provided better PB sparing than 3DCRT (29.5Gy vs 45.2Gy)., Conclusions: MRI allowed efficient sparing of PB irrespective of the treatment modality. Linac-IMRT was shown to further reduce the dose to the bulb compared to 3DCRT and HT.

Purpose: To report planning and acute toxicity data of the first 60 patients treated within a Phase I-II study with moderate hypofractionation by image-guided helical tomotherapy., Methods and Materials: Various clinical target volumes (CTVs) were defined: CTV1-pelvic nodes; CTV2-upper portion of seminal vesicles; CTV3-lower portion of SV; CTV4-prostate; overlap between planning target volume (PTV) 4 and rectum. Different doses to each PTV were simultaneously delivered in 28 fractions. For 31 low-risk patients: 56.0, 61.6, and 71.4 Gy for PTV2-4, respectively; for 20 intermediate-risk patients: 51.8, 61.6, 65.5, and 74.2 Gy for PTV1-4, respectively; for 9 high-risk patients: 51.8 and 65.5 Gy for PTV1-2 and 74.2 Gy for PTV3-4. For all patients, the dose to overlap was 65.5 Gy., Results: The mean fraction of rectum receiving more than 65 Gy (V65) and rectal Dmax were 10% and 70.8 Gy respectively. In cases of pelvic node irradiation, the intestinal cavity (outside PTV) receiving > 45 and 50 Gy was 86 and 12 cc, respectively. A homogeneous dose distribution within each PTV was guaranteed. Acute genitourinary toxicity according to RTOG scoring system was as follows: 21/60 (35%) Grade 1, 12/60 (20%) Grade 2, 2/60 (3%) Grade 3. Acute rectal toxicities were: 18/60 (30%) Grade 1. Twelve (20%) patients showed Grade 1 upper intestinal toxicity (uGI). No patients experienced > or = Grade 2 acute rectal or uGI side effects., Conclusions: This study shows excellent results with regard to acute toxicity. Further research is necessary to assess definitive late toxicity and tumor control outcome.

Purpose: To review planning and image-guidance aspects of more than 3 years experience in the treatment of prostate cancer with Helical Tomotherapy (HT)., Methods and Materials: Planning issues concerning two Phase I-II clinical studies were addressed: in the first one, 58 Gy in 20 fractions were delivered to the prostatic bed for post-prostatectomy patients: in the second one, a simultaneous integrated boost (SIB) approach was applied for radical treatment, delivering 71.4-74.2 Gy to the prostate in 28 fractions. On-line daily MVCT image guidance was applied: bone match was used for post-operative patients while prostate match was applied for radically treated patients. MVCT data of a large sample of both categories of patients were reviewed., Results: At now, more than 250 patients were treated. Planning data show the ability of HT in creating highly homogeneous dose distributions within PTVs. Organs at risk (OAR) sparing also showed to be excellent. HT was also found to favorably compare to inversely-optimized IMAT in terms of PTVs coverage and dose distribution homogeneity. In the case of pelvic nodes irradiation, a large sparing of bowel was evident compared to 3DCRT and conventional 5-fields IMRT. The analysis of MVCT data showed a limited motion of the prostate (about 5% of the fractions show a deviation > or =3 mm in posterior-anterior direction), due to the careful application of rectal emptying procedures. Based on phantom measurements and on the comparison with intra-prostatic calcification-based match, direct visualization prostate match seems to be sufficiently reliable in assessing shifts > or =3 mm., Conclusions: HT offers excellent planning solutions for prostate cancer, showing to be highly efficient in a SIB scenario. Daily MVCT information showed evidence of a limited motion of the prostate in the context of rectal filling control obtained by instructing patients in self-administrating a rectal enema.

The aim of this paper is to supplement the GEC/ESTRO/EAU recommendations for permanent seed implantations in prostate cancer to develop consistency in target and volume definition for permanent seed prostate brachytherapy. Recommendations on target and organ at risk (OAR) definitions and dosimetry parameters to be reported on post implant planning are given.

Objectives: To evaluate the technical feasibility, safety, and efficacy of seed implantation for local recurrence after radical prostatectomy and external beam radiotherapy., Methods: Between October 1999 and March 2002, 10 patients with targeted, histologically proven local relapse after surgery and subsequent external beam radiotherapy (only in 8 patients), underwent permanent brachytherapy with palladium-103 and iodine-125 after complete restaging. In all patients, an intraoperative morphovolumetric ultrasound study of the target was performed, with a planning target volume ranging from 5 to 26.7 cm(3). The preimplant prostate-specific antigen values ranged from 1.1 to 6.31 ng/mL., Results: Postplan dosimetry was performed to determine the percentage of the target volume that received a dose equal to, or greater than, the prescribed dose (range 84.5% to 95.9%) and the dose that was delivered to the 90% of the target volume (range 85.08% to 129.43%). The urinary scores, measured using the International Prostate Symptom Score, had normalized at 3 months. Only 1 patient had worsened incontinence during the first 2 months, with subsequent restoration of the previous situation. The other patients did not have any changes in their previous clinical condition. One patient experienced occasional gross hematuria that had been present after external beam radiotherapy. No rectal complications were reported. After a median follow-up of 20.6 months, 7 patients showed a decreasing or stable prostate-specific antigen level., Conclusions: This preliminary experience has demonstrated that seed implantation of a neoplastic local recurrence is technically feasible and safe and allows for accurate dosimetry when the area to be treated can be defined by ultrasonography. Longer follow-up, accurate patient selection, and larger series of patients could help to better define the oncologic outcome.