Magnetic hybrid Pd/Fe-oxide nanoparticles meet the demands for ablative thermo-brachytherapy.

OBJECTIVE: To investigate the potential of hybrid Pd/Fe-oxide magnetic nanoparticles designed for thermo-brachytherapy of breast cancer, considering their specific loss power (SLP) and clinical constraints in the applied magnetic field. METHODS: Hybrid nanoparticles consisting of palladium-core and iron oxide shell of increasing thickness, were suspended in water and their SLPs were measured at varying magnetic fields (12-26 mT peak) and frequencies (50-730 kHz) with a commercial alternating magnetic field generator (magneTherm™ Digital, nanoTherics Ltd.). RESULTS: Validation of the heating device used in this study with commercial HyperMag-C nanoparticles showed a small deviation (±4%) over a period of 1 year, confirming the reliability of the method. The integration of dual thermometers, one in the center and one at the bottom of the sample vial, allowed monitoring of homogeneity of the sample suspensions. SLPs measurements on a series of nanoparticles of increasing sizes showed the highest heating for the diameter of 21 nm (SLP = 225 W/g) at the applied frequencies of 346 and 730 kHz. No heating was observed for the nanoparticles with the size <14 nm, confirming the importance of the size-parameter. The heating ability of the best performing Pd/Fe-oxide-21 was calculated to be sufficient to ablate tumors with a radius ±4 and 12 mm using 10 and 1 mg/mL nanoparticle concentration, respectively. CONCLUSIONS: Nanoparticles consisting of non-magnetic palladium-core and magnetic iron oxide shell are suitable for magnetic hyperthermia/thermal ablation under clinically safe conditions of 346 kHz and 19.1 mT, with minimal eddy current effects in combination with maximum SLP.

Nine years of plan of the day for cervical cancer: Plan library remains effective compared to fully online-adaptive techniques.

BACKGROUND AND PURPOSE: Since 2011, our center has been using a library-based Plan-of-the-Day (PotD) strategy for external beam radiotherapy of cervical cancer patients to reduce normal tissue dose while maintaining adequate target coverage. With the advent of fully online-adaptive techniques such as daily online-adaptive replanning, further dose reduction may be possible. However, it is unknown how this reduction relates to plan library approaches, and how the most recent PotD strategies relate to no adaptation. In this study we compare the performance of our current PotD strategy with non-adaptive and fully online-adaptive techniques in terms of target volume size and normal tissue sparing. MATERIALS AND METHODS: Treatment data of 376 patients treated with the PotD protocol between June 2011 and April 2020 were included. The size of the Planning Target Volumes (PTVs) was reconstructed for different strategies: full online adaptation, no adaptation, and the latest clinical version of the PotD protocol. Normal tissue sparing was estimated by the difference in margin volume to construct the PTV and the volume overlap of the PTV with bladder and rectum. RESULTS: The current version of our PotD approach reduced the PTV margin volume by a median of 250 cm3 compared to no adaptation. Bladder-PTV overlap decreased from a median of 142 to 71 cm3, and from 39 to 16 cm3 for rectum-PTV. Fully online-adaptive approaches could further decrease the PTV volume by 144 cm3 using a 5 mm margin for residual errors. In this scenario, bladder-PTV overlap was reduced to 35 cm3 and rectum-PTV overlap to 11 cm3. CONCLUSION: The current version of the PotD protocol is an effective technique to improve normal tissue sparing compared to no adaptation. Further sparing can be achieved using fully online-adaptive techniques, but at the cost of a more complex workflow and with a potentially limited impact. PotD-type protocols can therefore be considered as a suitable alternative to fully online-adaptive approaches.

Predictive Factors for Toxicity After Primary Chemoradiation for Locally Advanced Cervical Cancer: A Systematic Review.

PURPOSE: Women with locally advanced cervical cancer (LACC) undergoing primary platinum-based chemoradiotherapy and brachytherapy often experience toxicities. Normal-tissue complication probability (NTCP) models quantify toxicity risk and aid in optimizing radiation therapy to minimize side effects. However, it is unclear which predictors to include in an NTCP model. The aim of this systematic review was to provide an overview of the identified predictors contributing to gastrointestinal (GI), genitourinary (GU), and vaginal toxicities and insufficiency fractures for LACC. METHODS AND MATERIALS: A systematic search was performed and articles evaluating the relationship between predictors and toxicities in women with LACC treated with primary chemoradiation were included. The Quality In Prognosis Studies tool was used to assess risk of bias, with high-risk studies being excluded from further analysis. Relationships between dose-volume parameters, patient and treatment characteristics, and toxicity endpoints were analyzed. RESULTS: Seventy-three studies were identified. Twenty-six had a low or moderate risk of bias and were therefore included. Brachytherapy-related dose-volume parameters of the GI tract, including rectum and bowel equivalent dose in 2 Gy fractions (EQD2) D2 cm3, were frequently related to toxicities, unlike GU dose-volume parameters. Furthermore, (recto)vaginal point doses predicted toxicities. Few studies evaluated external beam radiation therapy dose-volume parameters and identified rectum EQD2 V30 Gy, V40 Gy, and V55 Gy, bowel and bladder EQD2 V40 Gy as toxicity predictors. Also, total reference air kerma and vaginal reference length were associated with toxicities. Relationships between patient characteristics and GI toxicity were inconsistent. The extent of vaginal involvement at diagnosis, baseline symptoms, and obesity predicted GU or vaginal toxicities. Only 1 study evaluated insufficiency fractures and demonstrated lower pretreatment bone densities to be associated. CONCLUSIONS: This review detected multiple candidate predictors of toxicity. Larger studies should consider insufficiency fractures, assess dose levels from external beam radiation therapy, and quantify the relationship between the predictors and treatment-related toxicities in women with LACC to further facilitate NTCP model development for clinical use.

Multi-institutional consensus on machine QA for isochronous cyclotron-based systems delivering ultra-high dose rate (FLASH) pencil beam scanning proton therapy in transmission mode.

BACKGROUND: The first clinical trials to assess the feasibility of FLASH radiotherapy in humans have started (FAST-01, FAST-02) and more trials are foreseen. To increase comparability between trials it is important to assure treatment quality and therefore establish a standard for machine quality assurance (QA). Currently, the AAPM TG-224 report is considered as the standard on machine QA for proton therapy, however, it was not intended to be used for ultra-high dose rate (UHDR) proton beams, which have gained interest due to the observation of the FLASH effect. PURPOSE: The aim of this study is to find consensus on practical guidelines on machine QA for UHDR proton beams in transmission mode in terms of which QA is required, how they should be done, which detectors are suitable for UHDR machine QA, and what tolerance limits should be applied. METHODS: A risk assessment to determine the gaps in the current standard for machine QA was performed by an international group of medical physicists. Based on that, practical guidelines on how to perform machine QA for UHDR proton beams were proposed. RESULTS: The risk assessment clearly identified the need for additional guidance on temporal dosimetry, addressing dose rate (constancy), dose spillage, and scanning speed. In addition, several minor changes from AAPM TG-224 were identified; define required dose rate levels, the use of clinically relevant dose levels, and the use of adapted beam settings to minimize activation of detector and phantom materials or to avoid saturation effects of specific detectors. The final report was created based on discussions and consensus. CONCLUSIONS: Consensus was reached on what QA is required for UHDR scanning proton beams in transmission mode for isochronous cyclotron-based systems and how they should be performed. However, the group discussions also showed that there is a lack of high temporal resolution detectors and sufficient QA data to set appropriate limits for some of the proposed QA procedures.

The impact of bone marrow sparing on organs at risk dose for cervical cancer: a Pareto front analysis.

Background and purpose: To quantify the increase in bladder and rectum dose of a bone marrow sparing (BMS) VMAT strategy for primary treatment of locally advanced cervical cancer (LACC). Materials and methods: Twenty patients with stage IB-IVA cervical cancer were selected for this study. The whole Pelvic Bones (PB) was taken as substitute for bone marrow. For every patient, Pareto-optimal plans were generated to explore the trade-off between rectum, bladder, and PB mean dose. The PB mean dose was decreased in steps of 1 Gy. For each step, the increase in rectum and bladder mean dose was quantified. The increase in mean dose of other OAR compared to no BMS was constrained to 1 Gy. Results: In total, 931 plans of 19 evaluable patients were analyzed. The average [range] mean dose of PB without BMS was 22.8 [20.7-26.2] Gy. When maximum BMS was applied, the average reduction in mean PB dose was 5.4 [3.0-6.8] Gy resulting in an average mean PB dose of 17.5 [15.8-19.8] Gy. For <1 Gy increase in both the bladder and the rectum mean dose, the PB mean dose could be decreased by >2 Gy, >3 Gy, >4 Gy, and >5 Gy for 19/19, 13/19, 5/19, and 1/19 patients, respectively. Conclusion: Based on the comprehensive three-dimensional Pareto front analysis, we conclude that 2-5 Gy BMS can be implemented without a clinically relevant increase in mean dose to other OAR. If BMS is too dominant, it results in a large increase in mean dose to other OAR. Therefore, we recommend implementing moderate BMS for the treatment of LACC patients with VMAT.

Multi-center dosimetric predictions to improve plan quality for brachytherapy for cervical cancer treatment.

BACKGROUND AND PURPOSE: Image-guided adaptive brachytherapy (IGABT) is an important modality in the cervical cancer treatment, and plan quality is sensitive to time pressure in the workflow. Patient anatomy-based quality-assurance (QA) with overlap volume histograms (OVHs) has been demonstrated to detect suboptimal plans (outliers). This analysis quantifies the possible improvement of plans detected as outliers, and investigates its suitability as a clinical QA tool in a multi-center setting. MATERIALS AND METHODS: In previous work OVH-based models were investigated for the use of QA. In this work a total of 160 plans of 68 patients treated in accordance with the current state-of-the-art IGABT protocol from Erasmus MC (EMC) were analyzed, with a model based on 120 plans (60 patients) from UMC Utrecht (UMCU). Machine-learning models were trained to define QA thresholds, and to predict dose D2cm3 to bladder, rectum, sigmoid and small bowel with the help of OVHs of the EMC cohort. Plans out of set thresholds (outliers) were investigated and retrospectively replanned based on predicted D2cm3 values. RESULTS: Analysis of replanned plans demonstrated a median improvement of 0.62 Gy for all Organs At Risk (OARs) combined and an improvement for 96 % of all replanned plans. Outlier status was resolved for 36 % of the replanned plans. The majority of the plans that could not be replanned were reported having implantation complications or insufficient coverage due to tumor geometry. CONCLUSION: OVH-based QA models can detect suboptimal plans, including both unproblematic BT applications and suboptimal planning circumstances in general. OVH-based QA models demonstrate potential for clinical use in terms of performance and user-friendliness, and could be used for knowledge transfer between institutes. Further research is necessary to differentiate between (sub)optimal planning circumstances.

Feasibility Study on the Radiation Dose by Radioactive Magnetic Core-Shell Nanoparticles for Open-Source Brachytherapy.

BACKGROUND: Treatment of early-stage breast cancer currently includes surgical removal of the tumor and (partial) breast irradiation of the tumor site performed at fractionated dose. Although highly effective, this treatment is exhaustive for both patient and clinic. In this study, the theoretical potential of an alternative treatment combining thermal ablation with low dose rate (LDR) brachytherapy using radioactive magnetic nanoparticles (RMNPs) containing 103-palladium was researched. METHODS: The radiation dose characteristics and emission spectra of a single RMNP were calculated, and dose distributions of a commercial brachytherapy seed and an RMNP brachytherapy seed were simulated using Geant4 Monte Carlo toolkit. RESULTS: It was found that the RMNP seeds deliver a therapeutic dose similar to currently used commercial seed, while the dose distribution shows a spherical fall off compared to the more inhomogeneous dose distribution of the commercial seed. Changes in shell thickness only changed the dose profile between 2 × 10-4 mm and 3 × 10-4 mm radial distance to the RMNP, not effecting long-range dose. CONCLUSION: The dose distribution of the RMNP seed is comparable with current commercial brachytherapy seeds, while anisotropy of the dose distribution is reduced. Because this reduces the dependency of the dose distribution on the orientation of the seed, their surgical placement is easier. This supports the feasibility of the clinical application of the proposed novel treatment modality.

Multi-center analysis of machine-learning predicted dose parameters in brachytherapy for cervical cancer.

BACKGROUND AND PURPOSE: Image-guided adaptive brachytherapy (IGABT) is a key component in the treatment of cervical cancer, but the nature of the clinical workflow makes it vulnerable to suboptimal plans, as the theoretical optimal plan depends heavily on organ configuration. Patient anatomy-based quality-assurance (QA) with overlap volume histograms (OVHs) is a promising tool to detect such suboptimal plans, and in this analysis its suitability as a multi-institutional clinical QA tool is investigated. MATERIALS AND METHODS: A total of 223 plans of 145 patients treated in accordance with the current state-of-the-art IGABT protocols from UMC Utrecht (UMCU) and Erasmus MC (EMC) were included. Machine-learning models were trained to predict dose D2cm3 to bladder, rectum, sigmoid and small bowel with the help of OVHs. For this strategy, points are sampled on the organs-at-risk (OARs), and the distances of the sampled points to the target are computed and combined in a histogram. Machine-learning models can then be trained to predict dose-volume histograms (DVHs) for unseen data. Single-center model robustness to needle use and applicator type and multi-center model translatability were investigated. Performance of models was assessed by the difference between planned (clinical) and predicted D2cm3 values. RESULTS: Intra-validation of UMCU data demonstrated OVH model robustness to needle use and applicator type. The model trained on UMCU data was found to be robust within the same protocol on EMC data, for all investigated OARs. Mean squared error between planned and predicted D2cm3 values of OARs ranged between 0.13 and 0.40 Gy within the same protocol, indicating model translatability. For the former protocol cohort of Erasmus MC large deviations were found between the planned and predicted D2cm3 values, indicating plan deviation from protocol. Mean squared error for this cohort ranged from 0.84 to 4.71 Gy. CONCLUSION: OVH-based models can provide a solid basis for multi-institutional QA when trained on a sufficiently strict protocol. Further research will quantify the model's impact as a QA tool.

PROTECT: Prospective Phase-II-Trial Evaluating Adaptive Proton Therapy for Cervical Cancer to Reduce the Impact on Morbidity and the Immune System.

External beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy is a very effective treatment for locally advanced cervical cancer (LACC). However, treatment-related toxicity is common and reduces the patient's quality of life (QoL) and ability to complete treatment or undergo adjuvant therapies. Intensity modulated proton therapy (IMPT) enables a significant dose reduction in organs at risk (OAR), when compared to that of standard intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). However, clinical studies evaluating whether IMPT consequently reduces side effects for LACC are lacking. The PROTECT trial is a nonrandomized prospective multicenter phase-II-trial comparing clinical outcomes after IMPT or IMRT/VMAT in LACC. Thirty women aged >18 years with a histological diagnosis of LACC will be included in either the IMPT or IMRT/VMAT group. Treatment includes EBRT (45 Gy in 25 fractions of 1.8 Gy), concurrent five weekly cisplatin (40 mg/m2), and 3D image (MRI)-guided adaptive brachytherapy. The primary endpoint is pelvic bones Dmean and mean bowel V15Gy. Secondary endpoints include dosimetric parameters, oncological outcomes, health-related QoL, immune response, safety, and tolerability. This study provides the first data on the potential of IMPT to reduce OAR dose in clinical practice and improve toxicity and QoL for patients with LACC.

Correlations between bone marrow radiation dose and hematologic toxicity in locally advanced cervical cancer patients receiving chemoradiation with cisplatin: a systematic review.

Patients with locally advanced cervical cancer (LACC) treated with chemoradiation often experience hematologic toxicity (HT), as chemoradiation can induce bone marrow (BM) suppression. Studies on the relationship between BM dosimetric parameters and clinically significant HT might provide relevant indices for developing BM sparing (BMS) radiotherapy techniques. This systematic review studied the relationship between BM dose and HT in patients with LACC treated with primary cisplatin-based chemoradiation. A systematic search was conducted in Embase, Medline, and Web of Science. Eligibility criteria were treatment of LACC-patients with cisplatin-based chemoradiation and report of HT or complete blood cell count (CBC). The search identified 1346 papers, which were screened on title and abstract before two reviewers independently evaluated the full-text. 17 articles were included and scored according to a selection of the TRIPOD criteria. The mean TRIPOD score was 12.1 out of 29. Fourteen studies defining BM as the whole pelvic bone contour (PB) detected significant associations with V10 (3/14), V20 (6/14), and V40 (4/11). Recommended cut-off values were V10 > 95-75%, V20 > 80-65%, and V40 > 37-28%. The studies using lower density marrow spaces (PBM) or active bone marrow (ABM) as a proxy for BM only found limited associations with HT. Our study was the first literature review providing an overview of articles evaluating the correlation between BM and HT for patients with LACC undergoing cisplatin-based chemoradiation. There is a scarcity of studies independently validating developed prediction models between BM dose and HT. Future studies may use PB contouring to develop normal tissue complication probability models.

Effect of a Radiotherapeutic Megavoltage Beam on Ultrasound Contrast Agents.

Collateral damage to healthy surrounding tissue during conventional radiotherapy increases when deviations from the treatment plan occur. Ultrasound contrast agents (UCAs) are a possible candidate for radiation dose monitoring. This study investigated the size distribution and acoustic response of two commercial formulations, SonoVue/Lumason and Definity/Luminity, as a function of dose on clinical megavoltage photon beam exposure (24 Gy). SonoVue samples exhibited a decrease in concentration of bubbles smaller than 7 µm, together with an increase in acoustic attenuation and a decrease in acoustic scattering. Definity samples did not exhibit a significant response to radiation, suggesting that the effect of megavoltage photons depends on the UCA formulation. For SonoVue, the influence of the megavoltage photon beam was especially apparent at the second harmonic frequency, and can be captured using pulse inversion and amplitude modulation (3.5-dB decrease for the maximum dose), which could eventually be used for dosimetry in a well-controlled environment.

Dosimetric Impact of Intrafraction Motion in Online-Adaptive Intensity Modulated Proton Therapy for Cervical Cancer.

PURPOSE: A method was recently developed for online-adaptive intensity modulated proton therapy (IMPT) in patients with cervical cancer. The advantage of this approach, relying on the use of tight margins, is challenged by the intrafraction target motion. The purpose of this study was to evaluate the dosimetric effect of intrafraction motion on the target owing to changes in bladder filling in patients with cervical cancer treated with online-adaptive IMPT. METHODS AND MATERIALS: In 10 patients selected to have large uterus motion induced by bladder filling, the intrafraction anatomic changes were simulated for several prefraction durations for online (automated) contouring and planning. For each scenario, the coverage of the primary target was evaluated with margins of 2.5 and 5 mm. RESULTS: Using a 5- mm planning target volume margin, median accumulated D98% was greater than 42.75 GyRBE1.1 (95% of the prescribed dose) in the case of a prefraction duration of 5 and 10 minutes. For a prefraction duration of 15 minutes, this parameter deteriorated to 42.6 GyRBE1.1. When margins were reduced to 2.5 mm, only a 5-minute duration resulted in median target D98% above 42.75 GyRBE1.1. In addition, smaller bladders were found to be associated with larger dose degradations compared with larger bladders. CONCLUSIONS: This study indicates that intrafraction anatomic changes can have a substantial dosimetric effect on target coverage in an online-adaptive IMPT scenario for patients subject to large uterus motion. A margin of 5 mm was sufficient to compensate for the intrafraction motion due to bladder filling for up to 10 minutes of prefraction time. However, compensation for the uncertainties that were disregarded in this study, by using margins or robust optimization, is also required. Furthermore, a large bladder volume restrains intrafraction target motion and is recommended for treating patients in this scenario. Assuming that online-adaptive IMPT remains beneficial as long as narrow margins are used (5 mm or below), this study demonstrates its feasibility with regard to intrafraction motion.

Accuracy of dwell position detection with a combined electromagnetic tracking brachytherapy system for treatment verification in pelvic brachytherapy.

BACKGROUND AND PURPOSE: To investigate the accuracy of dwell position detection with a combined electromagnetic tracking (EMT) brachytherapy (BT) system for treatment verification, by quantifying positional errors due to EM field interference in typical pelvic BT clinical settings. MATERIALS AND METHODS: Dedicated prostate and cervix BT phantoms were imaged with CT. For the cervix phantom, the Utrecht applicator + interstitial catheters were used. The implants were reconstructed and treatment plans were created with 270/65 dwell positions for the prostate/cervix phantom. Next, EMT experiments were performed in clinical BT settings using a prototype of a combined EMT/BT system. We quantified positional errors due to EM field interference from surrounding equipment by comparing planned and EMT-measured dwell positions. The mean residual error between planned and EMT-measured dwell positions was calculated in the prostate interstitial catheters and in the whole cervix implant including the applicator. For the cervix phantom, the analysis was repeated for only the interstitial catheters. RESULTS: Mean residual errors of less than 0.5/0.4 mm in the prostate/cervix catheters were found. For the whole cervix implant including the applicator, large deviations up to 2.4 mm were found. Compared to the interference free set-up, the CT and patient bed environments showed larger residual errors in the interstitial catheters, but residual errors remained <1 mm in all cases. CONCLUSION: Dwell position detection with the combined system in interstitial catheters is sufficiently accurate to perform EMT-based treatment verification. The effect of EM interference from the surrounding equipment was limited.

Patient-reported acute GI symptoms in locally advanced cervical cancer patients correlate with rectal dose.

BACKGROUND AND PURPOSE: To investigate relationships between patient-reported acute gastro-intestinal symptoms in a locally advanced cervical cancer (LACC) prospective cohort and clinical and dosimetric parameters, while also taking spatial dose into account. MATERIAL AND METHODS: A total of 103 patients was included, receiving radiotherapy based on a plan-library-based plan-of-the-day protocol, combined either with concurrent chemotherapy or with neo-adjuvant chemotherapy and concomitant hyperthermia. Toxicity endpoints were extracted from questionnaires sent out weekly during treatment and regularly in the acute phase after treatment. Endpoints were defined for symptoms concerning obstipation, diarrhea, fecal leakage, bowel cramps and rectal bleeding. Dose surface maps were constructed for the rectum. Clinical parameters and dosimetric parameters of the bowel bag and rectum were collected for all patients. RESULTS: The use of concomitant chemotherapy and an increase in Planning Target Volume (PTV) resulted in a significant increase in reported diarrhea. The dose-volume parameters V5Gy-V25Gy of the rectum were found to be significant, unlike dose-volume parameters of the bowel bag. Additionally, a significantly higher dose to the inferior part of the rectum was found for patients reporting diarrhea. No significance was reached for fecal leakage and bowel cramps. CONCLUSION: The significance of results for patients reporting diarrhea symptoms found for PTV volume indicates a potential benefit for a plan-of-the-day protocol. Additionally, the results suggest that a reduction of inferior rectum dose could decrease patient-reported diarrhea symptoms, while the administration of concomitant chemotherapy appears to lead to radiosensitizing effects that increase these symptoms.

Radiochromic film in vivo dosimetry predicts early the risk of acute skin toxicity for brachytherapy partial breast irradiation.

Brachytherapy accelerated partial breast irradiation (APBI) is well tolerated, but reported acute toxicities including moist desquamation rates range from 7% to 39%. Moist desquamation is correlated to long-term skin toxicity and high skin dose is the main risk factor. This study uses radiochromic films for in vivo skin dosimetry of low dose rate (LDR) APBI brachytherapy and prediction of skin toxicity. Patients participating in a clinical trial assessing skin toxicity of LDR seed brachytherapy were included in this study. Following the seed implantation procedure, patients were asked to wear a customized oval shaped radiochromic film on the skin projection of the planned target volume (PTV) for 24 h. Exposed films were collected, and maximum point doses were measured. In addition, maximum doses to a small skin volume (D0.2cc) were calculated on the pre- and post-implant CT-scan. Acute skin toxicities (redness, pigmentation, induration and dermatitis) were scored by the treating physician for 2 months during follow-up visits. Skin dose measurements and acute toxicity were available for 18 consecutive patients. The post-implant calculated maximum skin doses (D0.2cc), 60.8 Gy (SD ± 41.0), were on average 30% higher than those measured in vivo (Dmax-film), 46.6 Gy (SD ± 19.3), but those values were highly significantly correlated (Spearman's rho 0.827, p < 0.001). Also, dermatitis and induration were significantly correlated with higher in vivo measured and post-implant calculated skin dose. Pre-implant dosimetry was not correlated with measured or post-implant skin dose or side effects. Radiochromic films can reliably diagnose excess dose to the skin during the first 24 h and predict skin toxicity, which enables preventative measures. Trial registration: Nederlands Trial Register (www.trialregister.nl), NTR6549, the trial was registered prospectively on 27 June 2017. ABR number: NL56210.078.16.

Subcutaneous spacer injection to reduce skin toxicity in breast brachytherapy: A pilot study on mastectomy specimens.

PURPOSE: Accelerated partial breast irradiation is a treatment option for selected patients with early-stage breast cancer. Some accelerated partial breast irradiation techniques lead to skin toxicity with the skin dose as a main risk factor. Biodegradable spacers are effective and safe in prostate brachytherapy to protect the rectum. We hypothesize that a subcutaneous spacer injection reduces the skin dose in breast brachytherapy. METHODS AND MATERIALS: Ultrasound-guided spacer injections, either hyaluronic acid (HA) or iodined polyethylene glycol (PEG), were performed on fresh mastectomy specimens. Success was defined as a spacer thickness of ≥5 mm in the high-dose skin area. Usability was scored using the system usability scale. Pre and postinjection CT scans were used to generate low-dose-rate seed brachytherapy treatment plans after defining a clinical target volume. Maximum dose to small skin volumes (D0.2cc) and existence of hotspots (isodose ≥90% on 1 cm2 of skin) were calculated as skin toxicity indicators. RESULTS: We collected 22 mastectomy specimens; half had HA and half had PEG injection. Intervention success was 100% for HA and 90.9% for PEG (p = NS). Hydrodissection was feasible in 81.8% with HA and 63.6% with PEG. Median system usability scale score was 97.5 for HA and 82.5 for PEG (p < 0.001). Mean D0.2cc was 80.8 Gy without spacer and 53.7 Gy with spacer (p < 0.001). Skin hotspots were present in 40.9% without spacer but none with spacer (p < 0.001). CONCLUSIONS: A spacer injection in mastectomy specimens is feasible. An extra 5 mm space is always achieved, thereby potentially reducing the skin dose dramatically in low-dose-rate seed breast brachytherapy.

A randomized controlled trial testing a hyaluronic acid spacer injection for skin toxicity reduction of brachytherapy accelerated partial breast irradiation (APBI): a study protocol.

BACKGROUND: Accelerated partial breast irradiation (APBI) is a treatment option for selected early stage breast cancer patients. Some APBI techniques lead to skin toxicity with the skin dose as main risk factor. We hypothesize that a spacer injected between the skin and target volume reduces the skin dose and subsequent toxicity in permanent breast seed implant (PBSI) patients. METHODS: In this parallel-group, single-center, randomized controlled trial, the effect of a subcutaneous spacer injection on skin toxicity among patients treated with PBSI is tested. Eligibility for participation is derived from international guidelines for suitable patients for partial breast radiotherapy, e.g. women aged ≥ 50 years with a histologically proven non-lobular breast carcinoma and/or ductal carcinoma in situ (DCIS), tumor size ≤ 3 cm, node-negative, and PBSI technically feasible. Among exclusion criteria are neoadjuvant chemotherapy, lymphovascular invasion, and allergy for hyaluronic acid. For the patients allocated to receive spacer, after the PBSI procedure, 4-10 cc of biodegradable hyaluronic acid (Barrigel™, Palette Life Sciences, Santa Barbara, CA, USA or Restylane SubQ®, Galderma Benelux, Breda, the Netherlands) is injected directly under the skin using ultrasound guidance to create an extra 0.5-1 cm space between the treatment volume and the skin. The primary outcome is the rate of telangiectasia at two years, blindly assessed using Bentzen's 4-point scale. Secondary outcomes include: local recurrence; disease-free and overall survival rates; adverse events (pain, redness, skin/subcutaneous induration, radiation dermatitis, pigmentation, surgical site infection); skin dose; cosmetic and functional results; and health-related quality of life. A Fisher's exact test will be used to test differences between groups on the primary outcome. Previous studies found 22.4% telangiectasia at two years. We expect the use of a spacer could reduce the occurrence of telangiectasia to 7.7%. A sample size of 230 patients will allow for a 10% lost to follow-up rate. DISCUSSION: In this study, the effect of a subcutaneous spacer injection on the skin dose, late skin toxicity, and cosmetic outcome is tested in patients treated with PBSI in the setting of breast-conserving therapy. Our results will be relevant for most forms of breast brachytherapy as well as robotic radiosurgery, as skin spacers could protect the skin with these other techniques. TRIAL REGISTRATION: Netherlands Trial Register, NTR6549 . Registered on 27 June 2017.

Evaluation of DVH-based treatment plan verification in addition to gamma passing rates for head and neck IMRT.

BACKGROUND AND PURPOSE: Treatment plan verification of intensity modulated radiotherapy (IMRT) is generally performed with the gamma index (GI) evaluation method, which is difficult to extrapolate to clinical implications. Incorporating Dose Volume Histogram (DVH) information can compensate for this. The aim of this study was to evaluate DVH-based treatment plan verification in addition to the GI evaluation method for head and neck IMRT. MATERIALS AND METHODS: Dose verifications of 700 subsequent head and neck cancer IMRT treatment plans were categorised according to gamma and DVH-based action levels. Fractionation dependent absolute dose limits were chosen. The results of the gamma- and DVH-based evaluations were compared to the decision of the medical physicist and/or radiation oncologist for plan acceptance. RESULTS: Nearly all treatment plans (99.7%) were accepted for treatment according to the GI evaluation combined with DVH-based verification. Two treatment plans were re-planned according to DVH-based verification, which would have been accepted using the evaluation alone. DVH-based verification increased insight into dose delivery to patient specific structures increasing confidence that the treatment plans were clinically acceptable. Moreover, DVH-based action levels clearly distinguished the role of the medical physicist and radiation oncologist within the Quality Assurance (QA) procedure. CONCLUSIONS: DVH-based treatment plan verification complements the GI evaluation method improving head and neck IMRT-QA.

The potential of a radiosensitive intracerebral probe to monitor 18F-MPPF binding in mouse hippocampus in vivo.

UNLABELLED: As mouse imaging has become more challenging in preclinical research, efforts have been made to develop dedicated PET systems. Although these systems are currently used for the study of physiopathologic murine models, they present some drawbacks for brain studies, including a low temporal resolution that limits the pharmacokinetic study of radiotracers. The aim of this study was to demonstrate the ability of a radiosensitive intracerebral probe to measure the binding of a radiotracer in the mouse brain in vivo. METHODS: The potential of a probe 0.25 mm in diameter for pharmacokinetic studies was assessed. First, Monte Carlo simulations followed by experimental studies were used to evaluate the detection volume and sensitivity of the probe and its adequacy for the size of loci in the mouse brain. Second, ex vivo autoradiography of 5-hydroxytryptamine receptor 1A (5-HT(1A)) receptors in the mouse brain was performed with the PET radiotracer 2'-methoxyphenyl-(N-2'-pyridinyl)-p-(18)F-fluorobenzamidoethylpiperazine ((18)F-MPPF). Finally, the binding kinetics of (18)F-MPPF were measured in vivo in both the hippocampus and the cerebellum of mice. RESULTS: Both the simulations and the experimental studies demonstrated the feasibility of using small probes to measure radioactive concentrations in specific regions of the mouse brain. Ex vivo autoradiography showed a heterogeneous distribution of (18)F-MPPF consistent with the known distribution of 5-HT(1A) in the mouse brain. Finally, the time-activity curves obtained in vivo were reproducible and validated the capacity of the new probe to accurately measure (18)F-MPPF kinetics in the mouse hippocampus. CONCLUSION: Our results demonstrate the ability of the tested radiosensitive intracerebral probe to monitor binding of PET radiotracers in anesthetized mice in vivo, with high temporal resolution suited for compartmental modeling.