A feasibility dosimetric study on prostate cancer : are we ready for a multicenter clinical trial on SBRT?

PURPOSE: The Italian Association of Medical Physics (AIFM) started a working group dedicated to stereotactic body radiotherapy (SBRT) treatment. In this work, we performed a multicenter planning study on patients who were candidates for SBRT in the treatment of prostate cancer with the aim of evaluating the dosimetric consistency among the different hospitals. METHODS AND MATERIALS: Fourteen centers were provided the contours of 5 patients. Plans were performed following the dose prescription and constraints for organs at risk (OARs) of a reference paper. The dose prescription was 35 Gy in five fractions for the planning target volume (PTV). Different techniques were used (3D-CRT, fixed-Field IMRT, VMAT, CyberKnife). Plans were compared in terms of dose-volume histogram (DVH) parameters. Furthermore, the median DVH was calculated and one patient was re-planned. RESULTS: A total of 70 plans were compared. The maximum dose to the body was 107.9 ± 4.5 % (range 101.5-116.3 %). Dose at 98 % (D98 %) and mean dose to the clinical target volume (CTV) were 102.0 ± 0.9 % (global range 101.1-102.9 %) and 105.1 ± 0.6 % (range 98.6-124.6 %). Similar trends were found for D95 % and mean dose to the PTV. Important differences were found in terms of the homogeneity index. Doses to OARs were heterogeneous. The subgroups with the same treatment planning system showed differences comparable to the differences of the whole group. In the re-optimized plans, DVH differences among institutes were reduced and OAR sparing improved. CONCLUSION: Important dosimetric differences with possible clinical implications, in particular related to OARs, were found. Replanning allowed a reduction in the OAR dose and decreased standard deviations. Multicenter clinical trials on SBRT should require a preplanning study to standardize the optimization procedure.

Head and neck intensity modulated radiotherapy parotid glands: time of re-planning.

PURPOSE: To investigate the correct time point for re-planning by evaluating dosimetric changes in the parotid glands (PGs) during intensity-modulated radiotherapy (IMRT) in head and neck cancer patients. MATERIALS AND METHODS: Patients with head and neck cancer treated with IMRT were enrolled. During treatment all patients underwent cone-beam computed tomography (CBCT) scans to verify the set-up. CBCT scans at treatment days 10, 15, 20 and 25 were used to transfer the original plan (CBCTplan I, II, III, IV, respectively) using rigid registration between the two. The PGs were retrospectively contoured and evaluated with the dose-volume histogram. The mean dose, the dose to 50 % of volume, and the percentage of volume receiving 30 and 50 Gy were evaluated for each PG. The Wilcoxon sign ranked test was used to evaluate the effects of dosimetric variations and values <0.05 were taken to be significant. RESULTS: From February to June 2011, ten patients were enrolled and five IMRT plans were evaluated for each patient. All the dosimetric parameters increased throughout the treatment course. However, this increase was statistically significant at treatment days 10 and 15 (CBCTplan I, II; p = 0.02, p = 0.03, respectively). CONCLUSION: CBCT is a feasible method to assess the dosimetric changes in the PGs. Our data showed that checking the PG volume and dose could be indicated during the third week of treatment.

Neoadjuvant Versus Adjuvant Systemic Therapy in Breast Cancer: A Matched Case-control Study.

BACKGROUND/AIM: Neoadjuvant systemic therapy (NAT) in breast cancer can make tumors resectable or reduce the extent of surgery needed for locally advanced cancers. It can also better prevent distant relapse and possibly modulate drug therapy by adjusting adjuvant therapy (AD) based on the response to NAT, either by escalating or de-escalating the treatment. However, clear evidence of improved outcomes is currently missing. Here, we report on breast cancer patients treated with NAT at our institution. PATIENTS AND METHODS: One hundred twenty-seven patients treated at our Radiation Oncology department between 2004 and 2021 were retrospectively analyzed. All patients had localized or locally advanced breast cancer, were treated with NAT, and received postoperative radiotherapy. The outcomes considered were overall survival (OS), loco-regional recurrence-free survival (LRRFS), and distant metastases-free survival (DMFS). A matched patient population treated with AD during the same period and at the same center was used for comparison. RESULTS: The 5-year predicted OS was 87% in the NAT group and 81.5% in the AD group (p-value=0.179), while LRRFS was 93.2% in the NAT group and 100% in the AD group (p=0.005). The 5-year predicted DMFS was 84.6% in the NAT group and 82.1% in AD patients (p=0.367). In the NAT group, the only prognostic factor significantly related to improved outcomes was the pathological node response, with an OS of 95.6% in patients without residual node disease compared to 75.1% in patients with evidence of residual node disease. CONCLUSION: Our study, despite the limitations of a small number of patients and its retrospective nature, confirms the data of previous larger studies. In terms of DMFS and OS, NAT is at least as effective as AD. NAT represents a great opportunity for personalized modulation of treatment in node-positive breast cancer patients.

Inter-institutional variability of knowledge-based plan prediction of left whole breast irradiation.

PURPOSE: Within a multi-institutional project, we aimed to assess the transferability of knowledge-based (KB) plan prediction models in the case of whole breast irradiation (WBI) for left-side breast irradiation with tangential fields (TF). METHODS: Eight institutions set KB models, following previously shared common criteria. Plan prediction performance was tested on 16 new patients (2 pts per centre) extracting dose-volume-histogram (DVH) prediction bands of heart, ipsilateral lung, contralateral lung and breast. The inter-institutional variability was quantified by the standard deviations (SDint) of predicted DVHs and mean-dose (Dmean). The transferability of models, for the heart and the ipsilateral lung, was evaluated by the range of geometric Principal Component (PC1) applicability of a model to test patients of the other 7 institutions. RESULTS: SDint of the DVH was 1.8 % and 1.6 % for the ipsilateral lung and the heart, respectively (20 %-80 % dose range); concerning Dmean, SDint was 0.9 Gy and 0.6 Gy for the ipsilateral lung and the heart, respectively (<0.2 Gy for contralateral organs). Mean predicted doses ranged between 4.3 and 5.9 Gy for the ipsilateral lung and 1.1-2.3 Gy for the heart. PC1 analysis suggested no relevant differences among models, except for one centre showing a systematic larger sparing of the heart, concomitant to a worse PTV coverage, due to high priority in sparing the left anterior descending coronary artery. CONCLUSIONS: Results showed high transferability among models and low inter-institutional variability of 2% for plan prediction. These findings encourage the building of benchmark models in the case of TF-WBI.

Patient-specific Monte Carlo-based organ dose estimates in spiral CT via optical 3D body scanning and adaptation of a voxelized phantom dataset: proof-of-principle.

Objective. We present a method for personalized organ dose estimates obtained before the computed tomography (CT) exam, via 3D optical body scanning and Monte Carlo (MC) simulations.Approach. A voxelized phantom is derived by adapting a reference phantom to the body size and shape measured with a portable 3D optical scanner, which returns the 3D silhouette of the patient. This was used as an external rigid envelope for incorporating a tailored version of the internal body anatomy derived from a phantom dataset (National Cancer Institute, NIH, USA) matched for gender, age, weight, and height. The proof-of-principle was conducted on adult head phantoms. The Geant4 MC code provided estimates of the organ doses from 3D absorbed dose maps in the voxelized body phantom.Main results. We applied this approach for head CT scanning using an anthropomorphic voxelized head phantom derived from 3D optical scans of manikins. We compared the estimates of head organ doses with those provided by the NCICT 3.0 software (NCI, NIH, USA). Head organ doses differed up to 38% using the proposed personalized estimate and MC code, with respect to corresponding estimates calculated for the standard (non-personalized) reference head phantom. Preliminary application of the MC code to chest CT scans is shown. Real-time pre-exam personalized CT dosimetry is envisaged with adoption of a Graphics Processing Unit-based fast MC code.Significance. The developed procedure for personalized organ dose estimates before the CT exam, introduces a new approach for realistic description of size and shape of patients via voxelized phantoms specific for each patient.

Stereotactic Radiation Therapy for Brain Metastases: Factors Affecting Outcomes and Radiation Necrosis.

Stereotactic radiation therapy (SRT) is a proven effective treatment for brain metastases (BM); however, symptomatic radiation necrosis (RN) is a late effect that may impact on patient's quality of life. The aim of our study was to retrospectively evaluate survival outcomes and characterize the occurrence of RN in a cohort of BM patients treated with ablative SRT at Federico II University Hospital. Clinical and dosimetric factors of 87 patients bearing a total of 220 BMs treated with SRT from 2016 to 2022 were analyzed. Among them, 46 patients with 127 BMs having clinical and MRI follow-up (FUP) ≥ 6 months were selected for RN evaluation. Dosimetric parameters of the uninvolved brain (brain without GTV) were extracted. The crude local control was 91% with neither clinical factors nor prescription dose correlating with local failure (LF). At a median FUP of 9 (1-68) months, the estimated median overall survival (OS), progression-free survival (PFS), and brain progression-free survival (bPFS) were 16, 6, and 9 months, respectively. The estimated OS rates at 1 and 3 years were 59.8% and 18.3%, respectively; bPFS at 1 and 3 years was 29.9% and 13.5%, respectively; PFS at 1 and 3 years was 15.7% and 0%, respectively; and local failure-free survival (LFFS) at 1 and 3 years was 87.2% and 83.8%, respectively. Extracranial disease status was an independent factor related to OS. Fourteen (30%) patients manifested RN. At multivariate analysis, adenocarcinoma histology, left location, and absence of chemotherapy were confirmed as independent risk factors for any-grade RN. Nine (20%) patients developed symptomatic (G2) RN, which improved or stabilized after 1-16 months of steroid therapy. With prompt recognition and, when necessary, medical therapy, RN radiological and clinical amelioration can be obtained.

Local tumor control and treatment related toxicity after plaque brachytherapy for uveal melanoma: A systematic review and a data pooled analysis.

Uveal melanoma (UM) represents the most common primary intraocular tumor, and nowadays eye plaque brachytherapy (EPB) is the most frequently used visual acuity preservation treatment option for small to medium sized UMs. The excellent local tumor control (LTC) rate achieved by EPB may be associated with severe complications and adverse events. Several dosimetric and clinical risk factors for the development of EPB-related ocular morbidity can be identified. However, morbidity predictive models specifically developed for EPB are still scarce. PRISMA methodology was used for the present systematic review of articles indexed in PubMed in the last sixteen years on EPB treatment of UM which aims at determining the major factors affecting local tumor control and ocular morbidities. To our knowledge, for the first time in EPB field, local tumor control probability (TCP) and normal tissue complication probability (NTCP) modelling on pooled clinical outcomes were performed. The analyzed literature (103 studies including 21,263 UM patients) pointed out that Ru-106 EPB provided high local control outcomes while minimizing radiation induced complications. The use of treatment planning systems (TPS) was the most influencing factor for EPB outcomes such as metastasis occurrence, enucleation, and disease specific survival, irrespective of radioactive implant type. TCP and NTCP parameters were successfully extracted for 5-year LTC, cataract and optic neuropathy. In future studies, more consistent recordings of ocular morbidities along with accurate estimation of doses through routine use of TPS are needed to expand and improve the robustness of toxicity risk prediction in EPB.

Potential benefits of using radioactive ion beams for range margin reduction in carbon ion therapy.

Sharp dose gradients and high biological effectiveness make ions such as 12C an ideal tool to treat deep-seated tumors, however, at the same time, sensitive to errors in the range prediction. Tumor safety margins mitigate these uncertainties, but during the irradiation they lead to unavoidable damage to the surrounding healthy tissue. To fully exploit the Bragg peak benefits, a large effort is put into establishing precise range verification methods. Despite positron emission tomography being widely in use for this purpose in 12C therapy, the low count rates, biological washout, and broad activity distribution still limit its precision. Instead, radioactive beams used directly for treatment would yield an improved signal and a closer match with the dose fall-off, potentially enabling precise in vivo beam range monitoring. We have performed a treatment planning study to estimate the possible impact of the reduced range uncertainties, enabled by radioactive 11C ions treatments, on sparing critical organs in tumor proximity. Compared to 12C treatments, (i) annihilation maps for 11C ions can reflect sub- millimeter shifts in dose distributions in the patient, (ii) outcomes of treatment planning with 11C significantly improve and (iii) less severe toxicities for serial and parallel critical organs can be expected.

Knowledge-based multi-institution plan prediction of whole breast irradiation with tangential fields.

PURPOSE: To quantify inter-institute variability of Knowledge-Based (KB) models for right breast cancer patients treated with tangential fields whole breast irradiation (WBI). MATERIALS AND METHODS: Ten institutions set KB models by using RapidPlan (Varian Inc.), following previously shared methodologies. Models were tested on 20 new patients from the same institutes, exporting DVH predictions of heart, ipsilateral lung, contralateral lung, and contralateral breast. Inter-institute variability was quantified by the inter-institute SDint of predicted DVHs/Dmean. Association between lung sparing vs PTV coverage strategy was also investigated. The transferability of models was evaluated by the overlap of each model's geometric Principal Component (PC1) when applied to the test patients of the other 9 institutes. RESULTS: The overall inter-institute variability of DVH/Dmean ipsilateral lung dose prediction, was less than 2% (20%-80% dose range) and 0.55 Gy respectively (1SD) for a 40 Gy in 15 fraction schedule; it was < 0.2 Gy for other OARs. Institute 6 showed the lowest mean dose prediction value and no overlap between PTV and ipsilateral lung. Once excluded, the predicted ipsilateral lung Dmean was correlated with median PTV D99% (R2 = 0.78). PC1 values were always within the range of applicability (90th percentile) for 7 models: for 2 models they were outside in 1/18 cases. For the model of institute 6, it failed in 7/18 cases. The impact of inter-institute variability of dose calculation was tested and found to be almost negligible. CONCLUSIONS: Results show limited inter-institute variability of plan prediction models translating in high inter-institute interchangeability, except for one of ten institutes. These results encourage future investigations in generating benchmarks for plan prediction incorporating inter-institute variability.

Dose-Response of TLD-100 in the Dose Range Useful for Hypofractionated Radiotherapy.

PURPOSE: The aim of the study was to exploit the feasibility of thermoluminescent dosimeters (TLDs) in radiation therapy techniques in which high dose per fraction is involved. METHODS: Dose-response of TLD-100 (LiF: Mg, Ti) was investigated in both 6-MV photon and 6-MeV electron beams. The element correction factor (ECF) generation method was applied to check the variability of the TLDs response. Two batches of 50 TLDs were divided into groups and exposed in the dose range 0 to 30 Gy. Regression analysis was performed with both linear and quadratic models. For each irradiation beam, the calibration curves were obtained in 3 dose range 0 to 8 Gy, 0 to 10 Gy, and 0 to 30 Gy. The best-fitting model was assessed by the Akaike Information Criterion test. RESULTS: The ECF process resulted a useful tool to reduce the coefficients of variation from original values higher than 5% to about 3.5%, for all the batches exposed. The results confirm the linearity of dose-response curve below the dose level of 10 Gy for photon and electron beam and the supralinear trend above. CONCLUSION: The TLDs are suitable dosimeters for dose monitoring and verification in radiation treatment involving dose up to 30 Gy in a single fraction.

Technological evolution of radiation treatment: Implications for clinical applications.

The contemporary approach to the management of a cancer patient requires an "ab initio" involvement of different medical domains in order to correctly design an individual patient's pathway toward cure. With new therapeutic tools in every medical field developing faster than ever before the patient care outcomes can be achieved if all surgical, drug, and radiation options are considered in the design of the appropriate therapeutic strategy for a given patient. Radiation therapy (RT) is a clinical discipline in which experts from different fields continuously interact in order to manage the multistep process of the radiation treatment. RT is found to be an appropriate intervention for diverse indications in about 50% of cancer patients during the course of their disease. Technologies are essential in dealing with the complexity of RT treatments and for driving the increasingly sophisticated RT approaches becoming available for the treatment of Cancer. High conformal techniques, namely intensity modulated or volumetric modulated arc techniques, ablative techniques (Stereotactic Radiotherapy and Stereotactic Radiosurgery), particle therapy (proton or carbon ion therapy) allow for success in treating irregularly shaped or critically located targets and for the sharpness of the dose fall-off outside the target. The advanced on-board imaging, including real-time position management systems, makes possible image-guided radiation treatment that results in substantial margin reduction and, in select cases, implementation of an adaptive approach. The therapeutic gains of modern RT are also due in part to the enhanced anticancer activity obtained by coadministering RT with chemotherapy, targeted molecules, and currently immune checkpoints inhibitors. These main clinically relevant steps forward in Radiation Oncology represent a change of gear in the field that may have a profound impact on the management of cancer patients.

Auto- versus human-driven plan in mediastinal Hodgkin lymphoma radiation treatment.

BACKGROUND: Technological advances in Hodgkin lymphoma (HL) radiation therapy (RT) by high conformal treatments potentially increase control over organs-at-risk (OARs) dose distribution. However, plan optimization remains a time-consuming task with great operator dependent variability. Purpose of the present study was to devise a fully automated pipeline based on the Pinnacle3 Auto-Planning (AP) algorithm for treating female supradiaphragmatic HL (SHL) patients. METHODS: CT-scans of 10 female patients with SHL were considered. A "butterfly" (BF) volumetric modulated arc therapy was optimized using SmartArc module integrated in Pinnacle3 v. 9.10 using Collapsed Cone Convolution Superposition algorithm (30 Gy in 20 fractions). Human-driven (Manual-BF) and AP-BF optimization plans were generated. For AP, an optimization objective list of Planning Target Volume (PTV)/OAR clinical goals was first implemented, starting from a subset of 5 patients used for algorithm training. This list was then tested on the remaining 5 patients (validation set). In addition to the BF technique, the AP engine was applied to a 2 coplanar disjointed arc (AP-ARC) technique using the same objective list. For plan evaluation, dose-volume-histograms of PTVs and OARs were extracted; homogeneity and conformity indices (HI and CI), OARs dose-volume metrics and odds for different toxicity endpoints were computed. Non-parametric Friedman and Dunn tests were used to identify significant differences between groups. RESULTS: A single AP objective list for SHL was obtained. Compared to the manual plan, both AP-plans offer comparable CIs while AP-ARC also achieved comparable HIs. All plans fulfilled the clinical dose criteria set for OARs: both AP solutions performed at least as good as Manual-BF plan. In particular, AP-ARC outperformed AP-BF in terms of heart sparing involving a lower risk of coronary events and radiation-induced lung fibrosis. Hands-on planning time decreased by a factor of 10 using AP on average. CONCLUSIONS: Despite the high interpatient PTV (size and position) variability, it was possible to set a standard SHL AP optimization list with a high level of generalizability. Using the implemented list, the AP module was able to limit OAR doses, producing clinically acceptable plans with stable quality without additional user input. Overall, the AP engine associated to the arc technique represents the best option for SHL.

The Role of Adjuvant Radiotherapy for a Case of Primary Breast Sarcoma: A Plan Comparison between Three Modern Techniques and a Review of the Literature.

A 65-year-old woman, affected by a malignant fibrous histiocytoma (undifferentiated pleomorphic sarcoma) of the left breast, presented to our department to receive the postoperative radiotherapy. In the absence of prospective and randomized trials and investigations on breast sarcoma irradiation in literature, due to the rarity of this pathology, the role of adjuvant radiotherapy remains unclear. To identify the best radiotherapy technique for this patient, three methods were compared: 3D conformal radiotherapy (3D-CRT), intensity-modulated radiation therapy (IMRT), and volumetric arc therapy (VMAT) or RapidArc® (RA). 50 Gy was prescribed to the chest wall and 66 Gy to the tumor bed. Three plans were designed, and target coverage, organs-at-risk sparing, and treatment efficiency were compared. IMRT and RA improved both target coverage and dose uniformity/homogeneity. Planning objective for the lung is always satisfied comparing the different techniques, but the volume receiving 20 Gy drops to 17% by RA compared to 3D-CRT. The heart volume receiving 30 Gy was 10% by IMRT, against 13% and 16% by RA and 3D-CRT. The monitor unit (MU) required by 3D-CRT was 527 MU, followed by RA and IMRT. Treatment time was similar with 3D-CRT and RA but doubled using IMRT. Although all three radiotherapy techniques offered a satisfactory solution, RA and IMRT offer some improvement on target coverage, dose homogeneity, and conformity for this particular case of breast sarcoma.

Lung stereotactic ablative body radiotherapy: A large scale multi-institutional planning comparison for interpreting results of multi-institutional studies.

PURPOSE: A large-scale multi-institutional planning comparison on lung cancer SABR is presented with the aim of investigating possible criticism in carrying out retrospective multicentre data analysis from a dosimetric perspective. METHODS: Five CT series were sent to the participants. The dose prescription to PTV was 54Gy in 3 fractions of 18Gy. The plans were compared in terms of PTV-gEUD2 (generalized Equivalent Uniform Dose equivalent to 2Gy), mean dose to PTV, Homogeneity Index (PTV-HI), Conformity Index (PTV-CI) and Gradient Index (PTV-GI). We calculated the maximum dose for each OAR (organ at risk) considered as well as the MLD2 (mean lung dose equivalent to 2Gy). The data were stratified according to expertise and technology. RESULTS: Twenty-six centers equipped with Linacs, 3DCRT (4% - 1 center), static IMRT (8% - 2 centers), VMAT (76% - 20 centers), CyberKnife (4% - 1 center), and Tomotherapy (8% - 2 centers) collaborated. Significant PTV-gEUD2 differences were observed (range: 105-161Gy); mean-PTV dose, PTV-HI, PTV-CI, and PTV-GI were, respectively, 56.8±3.4Gy, 14.2±10.1%, 0.70±0.15, and 4.9±1.9. Significant correlations for PTV-gEUD2 versus PTV-HI, and MLD2 versus PTV-GI, were observed. CONCLUSIONS: The differences in terms of PTV-gEUD2 may suggest the inclusion of PTV-gEUD2 calculation for retrospective data inter-comparison.

Role of the technical aspects of hypofractionated radiation therapy treatment of prostate cancer: a review.

The increasing use of moderate (<35 fractions) and extreme (<5 fractions) hypofractionated radiation therapy in prostate cancer is yielding favorable results, both in terms of maintained biochemical response and toxicity. Several hypofractionation (HF) schemes for the treatment of prostate cancer are available, although there is considerable variability in the techniques used to manage intra-/interfraction motion and deliver radiation doses. We performed a review of the published studies on HF regimens as a topic of interest for the Stereotactic Ablative Radiotherapy working group, which is part of the Italian Association of Medical Physics. Aspects of organ motion management (imaging for contouring, target volume definition, and rectum/bladder preparation) and treatment delivery (prostate localization, image guided radiation therapy strategy and frequency) were evaluated and categorized to assess outcome relative to disease control and toxicity. Despite the heterogeneity of the data, some interesting trends that emerged from the review might be useful in identifying an optimum HF strategy.

Is ExacTrac x-ray system an alternative to CBCT for positioning patients with head and neck cancers?

PURPOSE: To evaluate the usefulness of a six-degrees-of freedom (6D) correction using ExacTrac robotics system in patients with head-and-neck (HN) cancer receiving radiation therapy. METHODS: Local setup accuracy was analyzed for 12 patients undergoing intensity-modulated radiation therapy (IMRT). Patient position was imaged daily upon two different protocols, cone-beam computed tomography (CBCT), and ExacTrac (ET) images correction. Setup data from either approach were compared in terms of both residual errors after correction and punctual displacement of selected regions of interest (Mandible, C2, and C6 vertebral bodies). RESULTS: On average, both protocols achieved reasonably low residual errors after initial correction. The observed differences in shift vectors between the two protocols showed that CBCT tends to weight more C2 and C6 at the expense of the mandible, while ET tends to average more differences among the different ROIs. CONCLUSIONS: CBCT, even without 6D correction capabilities, seems preferable to ET for better consistent alignment and the capability to see soft tissues. Therefore, in our experience, CBCT represents a benchmark for positioning head and neck cancer patients.