The value of brachytherapy in the age of advanced external beam radiotherapy: a review of the literature in terms of dosimetry.

Brachytherapy (BT) has long been used for successful treatment of various tumour entities, including prostate, breast and gynaecological cancer. However, particularly due to advances in modern external beam techniques such as intensity-modulated radiotherapy (IMRT), volume modulated arc therapy (VMAT) and stereotactic body radiotherapy (SBRT), there are concerns about its future. Based on a comprehensive literature review, this article aims to summarize the role of BT in cancer treatment and highlight its particular dosimetric advantages. The authors conclude that image-guided BT supported by inverse dose planning will successfully compete with high-tech EBRT in the future and continue to serve as a valuable modality for cancer treatment.

Comparative dosimetrical analysis of intensity-modulated arc therapy, CyberKnife therapy and image-guided interstitial HDR and LDR brachytherapy of low risk prostate cancer.

BACKGROUND: The objective of the study was to dosimetrically compare the intensity-modulated-arc-therapy (IMAT), Cyber-Knife therapy (CK), single fraction interstitial high-dose-rate (HDR) and low-dose-rate (LDR) brachytherapy (BT) in low-risk prostate cancer. MATERIALS AND METHODS: Treatment plans of ten patients treated with CK were selected and additional plans using IMAT, HDR and LDR BT were created on the same CT images. The prescribed dose was 2.5/70 Gy in IMAT, 8/40 Gy in CK, 21 Gy in HDR and 145 Gy in LDR BT to the prostate gland. EQD2 dose-volume parameters were calculated for each technique and compared. RESULTS: EQD2 total dose of the prostate was significantly lower with IMAT and CK than with HDR and LDR BT, D90 was 79.5 Gy, 116.4 Gy, 169.2 Gy and 157.9 Gy (p < 0.001). However, teletherapy plans were more conformal than BT, COIN was 0.84, 0.82, 0.76 and 0.76 (p < 0.001), respectively. The D2 to the rectum and bladder were lower with HDR BT than with IMAT, CK and LDR BT, it was 66.7 Gy, 68.1 Gy, 36.0 Gy and 68.0 Gy (p = 0.0427), and 68.4 Gy, 78.9 Gy, 51.4 Gy and 70.3 Gy (p = 0.0091) in IMAT, CK, HDR and LDR BT plans, while D0.1 to the urethra was lower with both IMAT and CK than with BTs: 79.9 Gy, 88.0 Gy, 132.7 Gy and 170.6 Gy (p < 0.001). D2 to the hips was higher with IMAT and CK, than with BTs: 13.4 Gy, 20.7 Gy, 0.4 Gy and 1.5 Gy (p < 0.001), while D2 to the sigmoid, bowel bag, testicles and penile bulb was higher with CK than with the other techniques. CONCLUSIONS: HDR monotherapy yields the most advantageous dosimetrical plans, except for the dose to the urethra, where IMAT seems to be the optimal modality in the radiotherapy of low-risk prostate cancer.

Normal tissue sparing using different techniques for prostate irradiation.

AIM: The aim of this study was to investigate normal tissue sparing through dosimetric parameters of normal tissue volumes using different irradiation techniques for conventional (CFRT) and simultaneously integrated boost (SIB) schedules. BACKGROUND: Several dose-escalation studies for localized prostate cancer (PCa) have shown advanced biochemical relapse-free (bRFS) rates and also better local control for higher total doses using either CFRT or SIB schedules. Besides the most important organs-at-risk, absorbed dose reduction of other surrounding normal tissues are also preferable. In order to analyse the normal tissue sparing, dosimetric parameters of different normal tissue volumes were examined. MATERIALS AND METHODS: Treatment plans for 15 high risk prostate cancer patients were created using RapidArc (RA), Sliding Window (SW) IMRT and 4-field box (3D-CRT) technique. In order to evaluate normal tissue sparing, the volume of pelvic region was divided into six normal tissue cylinders with 1 cm wall thickness, located in each other. RESULTS: All plans met the criteria of target coverage (V95%>95%). All techniques provided the same results for OARs except 3D-CRT for rectum and bilateral femoral heads. The values of V5, V10 and V15 increased in cases which included RapidArc technique and decreased for V20 and V30. CONCLUSIONS: The dosimetric parameters for the cylindrical normal tissue volumes show that using RapidArc technique gives equal or slightly better normal tissue sparing and SIB provided the same normal tissue sparing as CFRT planned with RapidArc.

NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial.

BACKGROUND: Pathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2-3 trial evaluated the safety and efficacy of the hafnium oxide (HfO2) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma. METHODS: Act.In.Sarc is a phase 2-3 randomised, multicentre, international trial. Adults (aged ≥18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0-2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53·3 g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete. FINDINGS: Between March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group. Two patients in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0·044). In both treatment groups, the most common grade 3-4 treatment-emergent adverse event was postoperative wound complication (eight [9%] of 89 patients in the NBTXR3 group and eight [9%] of 90 in the radiotherapy alone group). The most common grade 3-4 adverse events related to NBTXR3 administration were injection site pain (four [4%] of 89) and hypotension (four [4%]) and the most common grade 3-4 radiotherapy-related adverse event was radiation skin injury in both groups (five [6%] of 89 in the NBTXR3 group and four [4%] of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3-4 adverse event related to NBTXR3 was hypotension (six [7%] of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred. INTERPRETATION: This trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers. FUNDING: Nanobiotix SA.

Dosimetric comparison of inverse optimisation methods versus forward optimisation in HDR brachytherapy of breast, cervical and prostate cancer.

OBJECTIVE: Dosimetric comparison of HIPO (hybrid inverse planning optimisation) and IPSA (inverse planning simulated annealing) inverse and forward optimisation (FO) methods in brachytherapy (BT) of breast, cervical and prostate cancer. METHODS: At our institute 38 breast, 47 cervical and 50 prostate cancer patients treated with image-guided interstitial high-dose-rate BT were selected. Treatment plans were created using HIPO and IPSA inverse optimisation methods as well as FO. The dose-volume parameters of different treatment plans were compared with Friedman ANOVA and the LSD post-hoc test. RESULTS: IPSA creates less dose coverage to the target volume than HIPO or FO: V100 was 91.7%, 91% and 91.9% for HIPO, IPSA and FO plans (p = 0.1784) in breast BT; 90.4%, 89.2% and 91% (p = 0.0045) in cervical BT; and 97.1%, 96.2% and 97.7% (p = 0.0005) in prostate BT, respectively. HIPO results in more conformal plans: COIN was 0.72, 0.71 and 0.69 (p = 0.0306) in breast BT; 0.6, 0.47 and 0.58 (p < 0.001) in cervical BT; and 0.8, 0.7 and 0.7 (p < 0.001) in prostate BT, respectively. In breast BT, dose to the skin and lung was smaller with HIPO and FO than with IPSA. In cervical BT, dose to the rectum, sigmoid and bowel was larger using IPSA than with HIPO or FO. In prostate BT, dose to the urethra was higher and the rectal dose was smaller using FO than with inverse methods. CONCLUSION: In interstitial breast and prostate BT, HIPO results in comparable dose-volume parameters to FO, but HIPO plans are more conformal. In cervical BT, HIPO produces dosimetrically acceptable plans only when more needles are used. The dosimetric quality of IPSA plans is suboptimal and results in unnecessary larger active lengths.

Transperineal gold marker implantation for image-guided external beam radiotherapy of prostate cancer : A single institution, prospective study.

PURPOSE: To present the feasibility and complications of transperineal fiducial marker implantation in prostate cancer patients undergoing image-guided radiotherapy (IGRT) METHODS AND MATERIALS: Between November 2011 and April 2016, three radiopaque, gold-plated markers were transperineally implanted into the prostate of 300 patients under transrectal ultrasound guidance and with local anaesthesia. A week after the procedure patients filled in a questionnaire regarding pain, dysuria, urinary frequency, nocturia, rectal bleeding, hematuria, hematospermia or fever symptoms caused by the implantation. Pain was scored on a 1-10 scale, where score 1 meant very weak and score 10 meant unbearable pain. The implanted gold markers were used for daily verification and online correction of patients' setup during IGRT. RESULTS: Based on the questionnaires no patient experienced fever, infection, dysuria or rectal bleeding after implantation. Among the 300 patients, 12 (4%) had hematospermia, 43 (14%) hematuria, which lasted for an average of 3.4 and 1.8 days, respectively. The average pain score was 4.6 (range 0-9). Of 300 patients 87 (29%) felt any pain after the intervention, which took an average of 1.5 days. None of the patients needed analgesics after implantation. Overall, 105 patients (35%) reported less, 80 patients (27%) more, and 94 patients (31%) equal amount of pain during marker implantation compared to biopsy. The 21 patients who had a biopsy performed under general anesthesia did not answer this question. CONCLUSION: Transperineal gold marker implantation under local anesthesia was well tolerated. Complications were limited; rate and frequency of perioperative pain was comparable to the pain caused by biopsy. The method can be performed safely in clinical practice.

[Image-guided radiotherapy for muscle invasive bladder cancer with intravesical lipiodol injection. A new option for bladder sparing treatment]. / Izominvazív hólyagrák képvezérelt sugárkezelése intravesicalisan befecskendezett lipiodolos jelöléssel. A hólyagmegtartó kezelés új lehetosége.

INTRODUCTION AND AIM: To implement lipiodol as a fiducial marker of the tumor bed for image-guided radiotherapy with simultaneous integrated boost technique as part of radiochemotherapy for muscle invasive bladder tumors. METHOD: Since April 2016, radiochemotherapy was performed in 3 male patients with muscle invasive, transitional cell bladder carcinoma. Prior to radiochemotherapy, tumor bed resection was performed for each patient, at the same time 10 ml of lipiodol solution was injected submucosally into the resection site, thus marking the tumor bed for escalated dose irradiation. During radiochemotherapy 51 Gy (1.7 Gy/die) to the pelvis, 57 Gy (1.9 Gy/die) to the whole bladder, and 63 Gy (2.1 Gy/die) to the lipiodol-labeled tumor bed was delivered with simultaneous integrated boost technique. The accuracy of the irradiation was controlled by daily kilovoltage CT. Early radiogenic urogenital and gastrointestinal side effects were recorded according to Radiation Therapy Oncology Group side-effects grading recommendation. RESULTS: Substantial perioperative side effect or toxicity were not observed during and after the injection of lipiodol. The prescribed dose was successfully delivered in all patients. Radiotherapy duration was 6 weeks. The lipiodol-labeled tumor bed was clearly visible on daily kilovoltage cone beam CT. In one patient grade II cystitis and proctitis was observed, another patient experienced only grade I cystitis. These complaints improved with symptomatic medication. In the third patient no significant side effect occurred. CONCLUSIONS: The injection of lipiodol into the bladder wall is a safe technique, without any perioperative toxicity or complication. The tumor bed demarcated by lipiodol was visible both on treatment planning and kilovoltage CTs. The total treatment time was shortened by 4 days. The treatment was well tolerated, early side effects were moderate, or slight. Orv Hetil. 2017; 158(51): 2041-2047.

[Intraoperative and post-implant dosimetry in patients treated with permanent prostate implant brachytherapy]. / Intraoperatív és posztimplantációs dozimetria összehasonlítása permanens implantációs prosztata-brachyterápiával kezelt betegeknél.

The purpose of our work was to compare intraoperative and four-week post-implant dosimetry for loose and stranded seed implants for permanent prostate implant brachytherapy. In our institute low-dose-rate (LDR) prostate brachytherapy is performed with encapsulated I-125 isotopes (seeds) using transrectal ultrasound guidance and metal needles. The SPOT PRO 3.1 (Elekta, Sweden) system is used for treatment planning. In this study the first 79 patients were treated with loose seed (LS) technique, the consecutive patients were treated with stranded seed (SS) technique. During intraoperative planning the dose constraints were the same for both techniques. All LSs were placed inside the prostate capsule, while with SS a 2 mm margin around the prostate was allowed for seed positioning. The prescribed dose for the prostate was 145 Gy. This study investigated prostate dose coverage in 30-30 randomly selected patients with LS and SS. Four weeks after the implantation native CT and MRI were done and CT/MRI image fusion was performed. The target was contoured on MRI and the plan was prepared on CT data. To assess the treatment plan dose-volume histograms were used. For the target coverage V100, V90, D90, D100, for the dose inhomogeneity V150, V200, and the dose-homogeneity index (DHI), for dose conformality the conformal index (COIN) were calculated. Intraoperative and postimplant plans were compared. The mean V100 values decreased at four-week plan for SS (97% vs. 84%) and for LS (96% vs. 80%) technique, as well. Decrease was observed for all parameters except for the DHI value. The DHI increased for SS (0.38 vs. 0.41) and for LS (0.38 vs. 0.47) technique, as well. The COIN decreased for both techniques at four-week plan (SS: 0.63 vs. 0.57; LS: 0.67 vs. 0.50). All differences were significant except for the DHI value at SS technique. The percentage changes were not significant, except the COIN value. The dose coverage of the target decreased significantly at four-week plans for both techniques. The decrease was larger for LS technique, but the difference between techniques was not significant at this patient number. The dose distribution was more homogenous, but the conformality was worse at four-week plans.

[Radiotherapy of soft tissue sarcomas of the extremities and superficial trunk]. / A végtag és a törzsfelszín lágyrészszarkómáinak sugárkezelése.

Soft tissue sarcomas represent a histopathologically and clinically heterogeneous group of tumors that make up around 1% of malignancies, in which soft tissue sarcomas of the extremities and superficial trunk (STSET) are treated with more or less the same strategy. Over the past 30 years, there has been a migration away from amputation and radical ablative surgical procedures for localized STSET toward more conservative, function-preserving surgery combined with radiotherapy +/- chemotherapy. The latter complex treatment ensures equal local control to radical surgery. This multidisciplinary management includes organ sparing surgery as the main procedure but also radiotherapy of different types applied before, during or after the surgery, chemotherapy depending of the stadium of the tumor and plastic, reconstructive surgery, and last but not least rehabilitation of the patient after treatment. In this publication we overview the practical guidelines for the treatment of STSET based on the available literature from the last decades. Indication and timing of radiotherapy of STSET as well as available external beam and brachytherapy techniques are summarized. The prescribed radiation dose, the role of alternative fractionations, the combination of radiotherapy and systemic chemotherapy, hyperthermia or limb perfusion regards to STSET are also discussed. Practical considerations of radiotherapy, the target volumes and the role of newer radiotherapy technology in STSET treatment are overviewed.

[Role of radiotherapy in the treatment of retroperitoneal soft tissue sarcomas]. / A sugárterápia szerepe a retroperitoneális lágyrészszarkómák kezelésében.

Soft tissue sarcomas are rare tumors, composing 1% of all malignancies. Fifteen percent of them are situated in the retroperitoneal region. The primary curative treatment for this group of patients is complete surgical resection. In most cases, due to their large size and localization at diagnoses, complete resection (R0) is not feasible. The main cause of disease-specific death is local recurrence. Therefore, improved local control by radiotherapy (RT) may contribute to better survival results. Based on international studies, despite the frequent positive surgical margins, only 25% of the patients with retroperitoneal sarcoma (RPS) receive perioperative RT. We performed a literature review based on the available data on the role of RT in the management of RPS. The 5-year local recurrence-free survival after surgery alone, and surgery + RT has been reported in the range of 23-54% and 40-62%, respectively. The respective 5-year rate of overall survival was of 33-49% and 48-64%. There are no available results from prospective randomized studies comparing surgery to surgery + RT. The majority of studies were retrospective and the treatments were performed over a time span of several decades. The total dose, technique and timing of RT were not standardized. Gastrointestinal and genitourinary side effects of RT are common, but their incidence and severity can be significantly reduced by using modern techniques. Based on the currently available studies, RT improves local control and it may play a role in the prolongation of overall survival as well. However, prospective randomized studies are needed to clarify the role of RT in the multidisciplinary management of RPS.

[Use of gold radionuclide markers implanted into the prostate for image-guided radiotherapy in prostate cancer: side effects caused by the marker implantation]. / A prosztatába ültetett aranymarkerek alkalmazásának bevezetése prosztatarákos betegek képvezérelt sugárkezeléséhez. A beültetés okozta mellékhatások ismertetése.

The purpose of the study was to introduce the use of the gold radiopaque markers implanted into the prostate for image-guided radiotherapy of prostate cancer patients and to present the side effects caused by the marker implantation. Between November 2011 and November 2013, three radiopaque, gold-plated markers (Best Medical International, Springfield, VA, USA, 1.0 mm x 3.0 mm) were implanted transperineally into the prostate of 60 patients under transrectal ultrasound guidance. Local anaesthesia was performed in all patients. A week after the procedure the patients filled in a questionnaire regarding the pain, dysuria, urinary frequency, nycturia, rectal bleeding, haematuria, haematospermia or fever symptoms caused by the implantation. The pain caused by the intervention was scored on a 1-10 scale, where 1 was a very weak and 10 was an unbearable pain. Ten days after the implantation a treatment planning CT was performed and subsequently patients started intensity-modulated radiation therapy (IMRT) within one week. During the treatments markers were used for daily verification and correction of patient's setup. No patients experienced fever or infection. Based on the questionnaires nobody experienced dysuria or rectal bleeding after implantation. Among the 60 patients studied, five (8 %) had haematospermia, nine (15 %) haematuria, which lasted in average of 3.4 and 1.8 days, respectively. The average pain score on 1-10 scale was 4.2 (range: 0-9). After the marker implantation 18 patients (30%) reported less, 10 patients (17%) more, and 27 patients (45%) equal amount of pain compared to biopsy. Five patients, who had a biopsy performed under general anaesthesia, did not answer this question. None of the patients needed analgesics after implantation. The gold marker implantation implemented for image-guided radiotherapy was well tolerated under a local anaesthesia. The complications were limited, rate and frequency of perioperative pain was comparable to the pain caused by biopsy. After implantation, the patients did not require analgesics. The method can be performed safely in clinical practice.

[Salvage 125I brachytherapy of locally recurrent prostate cancer]. / Prosztatadaganat sugárkezelését követo helyi kiújulás "salvage" kezelése 125I brachyterápiával.

The purpose of the study is to report a case of salvage low dose rate (LDR) prostate brachytherapy in a patient with locally recurrent prostate cancer, four years after his first treatment with combined external beam radiation therapy (EBRT) and high dose rate (HDR) brachytherapy. A 61-year-old man was treated with 1x10 Gy HDR brachytherapy and a total of 60 Gy EBRT for an organ confined intermediate risk carcinoma of the prostate in 2009. The patient's tumor had been in regression with the lowest PSA level of 0.09 ng/ml, till the end of 2013. After slow but continuous elevation, his PSA level had reached 1.46 ng/ml by February 2014. Pelvis MRI and whole body acetate PET/CT showed recurrent tumor in the dorsal-right region of the prostate. Bone scan was negative. After discussing the possible salvage treatment options with the patient, he chose LDR brachytherapy. In 2014, in spinal anesthesia 21 125I "seeds" were implanted with transrectal ultrasound guidance into the prostate. The prescribed dose to the whole prostate was 100 Gy, to the volume of the recurrent tumor was 140 Gy. The patient tolerated the salvage brachytherapy well. The postimplant dosimetry was evaluated using magnetic resonance imaging-computed tomography (MR-CT) fusion and appeared satisfactory. PSA level decreased from the pre-salvage value of 1.46 ng/ml to 0.42 ng/ml by one month and 0.18 ng/ml by two months after the brachytherapy. No gastrointestinal side effects appeared, the patient's urination became slightly more frequent. In selected patients, salvage LDR brachytherapy can be a good choice for curative treatment of locally recurrent prostate cancer, after primary radiation therapy. Multiparametric MRI is fundamental, acetate PET/CT can play an important role when defining the localization of the recurrent tumor.

[Surgical treatment of retroperitoneal sarcomas]. / A retroperitoneális sarcomák sebészi kezelése.

Retroperitoneal sarcomas make up 0.15% of all solid tumors. The mainstay of their treatment is surgical resection, though the removal of the often sizable tumors may pose serious challenge to surgeons. There is no clear-cut recommendation for neoadjuvant, nor for adjuvant treatment so far. We collected the data and recommendations concerning the attributes and the treatment options for retroperitoneal sarcomas. Mainly we focused on the possibilities and the recent change in tactics of surgery. There is no prospective randomized study dealing with surgical treatment of retroperitoneal sarcomas. According to data in the literature the en-block R0 resection along with all the possibly involved neighboring organs offers the best chance for cure. The greatest problem is to define the required resection margin which is needed for R0 resection. Radio- and/or chemotherapy can be used for diminishing the possibility of tumor recurrence. The greatest risk factors for recurrence are incomplete resection, high grade tumor, and non-liposarcoma type histology. Survival depends on local recurrence rather than on distant metastases. Retroperitoneal sarcomas are ideally treated in sarcoma centers, where multidisciplinary consultation is available and complex treatment plans can be set. Complete recovery can be achieved with radical surgical excision. The chance for R0 resection is enhanced by chemo- and radiotherapy.

Alterations of Sexual and Erectile Functions after Brachytherapy for Prostate Cancer Based on Patient-Reported Questionnaires.

The aim of the study was to compare the side effects of high-dose-rate brachytherapy (HDRBT) and low-dose-rate brachytherapy (LDRBT), with a particular focus on the effects on sexual functions and sexual well-being (PROMOBRA study, NCT02258087). Localized low-risk and low-intermediate-risk prostate cancer patients were treated with mono LDR (N = 123, 145 Gy dose) or mono HDR brachytherapy (N = 117, 19/21 Gy). Prior to the treatment and during follow-up (at 3, 6, 9, 12, 18, and 24 months after treatment, and then annually after two years), patients completed patient-reported outcome measurement (PROM) questionnaires EORTC QLQ-PR-25, International Index of Erectile Function (IIEF), and IIEF-5 (SHIM). We compared the patients in different group breakdowns (HDR vs. LDR, hormone naïve and hormone-receiving HDR vs. LDR, hormone naïve and hormone-receiving patients in general, and 19 Gy HDR vs. 21 Gy HDR). In the hormone-naive LDR group, erectile function, orgasm function, sexual desire, satisfaction with intercourse, and overall satisfaction functions significantly decreased compared to baseline throughout the whole follow-up period. However, there were significant decreases in function at a maximum of three time points after HDR therapy without hormone therapy. In hormone-receiving patients, the orgasm function was significantly better in the HDR group at multiple time points compared to the baseline, and sexual desire improved at four time points. According to our results, both LDRBT and HDRBT can be safely administered to patients with localized prostate cancer. In hormone-naive patients, the HDR group showed only recovering decreases in sexual functions, while the LDR group showed a lasting decline in multiple areas. Thus, HDR appears to be more advantageous to hormone-naive patients.

Size-dependent lattice expansion in nanoparticles: reality or anomaly?

Size-dependent lattice expansion of nanoparticles is observed for many ionic compounds, including metal oxides, while lattice contraction prevails for pure metals. However, the physical origin of this effect, which is of importance for the thermodynamic, chemical and electronic properties of nanoparticles, is discussed controversially. After a survey of the experimental literature, revealing a wide variety of materials with size-dependent lattice expansion, we show that the negative surface stress is the key reason for lattice expansion, while the excess of lattice sums or point defects of various charge states can be excluded as general explanations. Ab initio calculations of surface stresses for various surface structures of metal oxides confirm the model of a surface-induced lattice expansion.

[Application of image-guided radiotherapy in external beam radiation of cancer patients]. / Képvezérelt sugárterápia klinikai alkalmazása daganatos betegek külso besugárzásánál.

The aim of the study was to present the clinical application of megavoltage cone beam CT (MV-CBCT) for image-guided radiotherapy at different tumour sites in our department. Altogether 2772 CT examinations were performed to verify the accuracy of patient setup before irradiation of 462 patients with pelvic (n=281), thoracic (n=107), head and neck (n=33) and cranial (n=41) tumours. A MV-CBCT with 6 MV photon beam integrated into a linear accelerator was used for imaging. The verification CT images were registered to planning CTs using bony structures, and in the three main directions (lateral, longitudinal, vertical) deviation between treatment and planning isocentres was determined in order to characterise the accuracy of patient setup. The verifications were performed before the first four fractions, and weekly-biweekly thereafter. From data obtained during the first three measurements systematic error of patient setup was calculated "off line", and the setup was corrected with the calculated value. At errors larger than 5 mm "on line" table correction was applied. The measured data were grouped and analysed according to location, and systematic and random errors were determined. From the data safety zone around clinical target volume (CTV) was calculated to create planning target volume (PTV). Following isocentre correction after the first three fractions the patient setup became more accurate at all site locations. At pelvic irradiation the mean error in all the three directions was below 1 mm, and the range of standard deviation was 0.32-0.38. At pelvic and thoracic irradiation the CTV-PTV safety zone calculated without any correction was 9-13 mm depending on direction, while at head and neck and cranial irradiation it was 6-9 mm. After correction of systematic error these data were 7-9 mm and 3-6 mm. After on line correction of setup errors larger than 5 mm the safety zone was 5-6 mm at pelvic and thoracic irradiation, 5 mm at head and neck, and 3-5 mm at cranial irradiation. Verification of patient setup with MV-CBCT at different locations can be easily performed. The initial systematic error can be corrected with a simple verification protocol which results in a few millimeter decrease of the CTV-PTV safety zone. Use of smaller safety zone is possible only with more frequent verifications and on line corrections.

[Patient positioning using in-room kV CT for image-guided radiotherapy (IGRT) of prostate cancer]. / Kilovoltos CT-vel végzett betegbeállítás vizsgálata prosztatarákos betegek képvezérelt külsõ besugárzásakor.

The purpose of the study was to evaluate accuracy of patients' set up verified by kV CT-on-rails system and compare automatic and manual image registration of planning and verification kVCT-s. Between January 2001 and March 2011, at ten patients with prostate cancer the clinical target volumes (CTVs) for prostate (CTV-PROS), and prostate plus caudal 1 cm of seminal vesicles (CTV-PVS) with or without pelvic lymph node region were contoured on the treatment planning CT, according to risk category of the patient. Planning target volumes (PTVs) were created with 1 cm margin extended around the CTVs in each direction. The isocentre was marked on the skin with three radiopaque markers. After the set up, treatment couch with the patient was turned by 180 degree and images were acquired of the region of the isocentre with a kV helical CT-on-rails system (treatment CT). An image registration software was used to co-register planning and treatment CT images. Automatic CT image co-registration was followed by manual co-registration taking into account the CTV-PROS contour and soft tissue informations. Deviations of the isocentres in lateral (LAT), longitudinal (LONG) and vertical (VERT) directions were recorded after each image co-registration. Corresponding data were compared using the t-probe. Systematic (S) and random (s) errors of the set up were calculated. Adequate PTV to CTV margins were calculated by van Herk's formula (2.5xS + 0,7xs). Overall 252 deviations were analysed on fourty-two CT series of 10 patients. The mean errors of the set up with automatic and manual image co-registrations were 0.19 cm and 0.07 cm (p=0.001) in LAT, 0.05 cm and 0.03 cm (p=0.07) in LONG and 0.16 cm and 0.22 cm (p=0.16) in VERT directions, respectively. The systematic errors of the set up for automatic and manual image registrations were 0.22 cm and 0.26 cm in LAT, 0.17 cm and 0.18 cm in LONG, 0.25 cm and 0.26 cm in VERT directions, respectively. The random errors of the set up for automatic and manual image registrations were 0.31 cm and 0.26 cm in LAT, 0.27 cm and 0.27 cm in LONG and 0.24 cm and 0.33 cm in VERT directions, respectively. In case of manual image co-registration, the required PTV to CTV margins to cover at least 95% of the CTVs with at least 95% percent of the prescribed dose were calculated to 0.93 cm in LAT, 0.65 cm in LONG, and 0.89 cm in VERT directions. Patients set up can be verified with manual image co-registration based on soft tissues around the prostate using a kV CT-on-rails system installed in the treatment room. The difference between automatic and manual image co-registration was significant in LAT direction. A PTV to CTV margin <1 cm seems to be appropriate to cover the CTVs in image-guided prostate radiotherapy. These findings support our recent clinical protocol.

[Comparison of CT- and MRI-based clinical target volumes for 3-dimensional conformal external-beam radiotherapy of prostate cancer]. / CT és MRI alapján meghatározott céltérfogatok összehasonlítása prosztatarákos betegek 3 dimenziós konformális külso sugárkezelésében.

The aim of the study was to compare clinical target volumes defined by CT and MRI for 3 dimensional conformal external beam radiotherapy of prostate cancer. CT and T2-weighed MRI images with 3 mm slice thickness were acquired for 13 patients with clinically organ-confined prostate cancer. Target volumes were contoured by two clinicians ("AP" and "SZ") experienced in prostate radiotherapy. Two clinical target volumes were defined: prostate (CTVpros) and prostate with a margin including the proximal 1 cm of the seminal vesicles (CTVpvs). Eight clinical target volumes were outlined for all patients: CTVprosAPCT, CTVprosAPMR, CTVpvsAPCT, CTVpvsAPMR, CTVprosSZCT, CTVprosSZMR, CTVpvsSZCT, CTVpvsSZMR. Volumes were measured in cm3. The volumes of different PTVs were compared using the Student's t-test. Mean CTVpros and CTVpvs using CT vs. MRI were 36.9 (range:13.8-121) vs. 32.0 (9.7-120.1) (p=0.0002), and 77.2 (30.5-209.5) vs. 67.6 (29.8-191.1) (p=0.0001), respectively. Mean CTVprosAPCT vs. CTVprosAPMR were 39.2 vs. 32.0 (p<0.00005), respectively. Mean CTVprosSZCT vs. CTVprosSZMR were 34.6 vs. 31.9 (p=0.15). Mean CTVpvsAPCT vs. CTVpvsAPMR were 85.8 vs. 70.9 (p<0.00006). Mean CTVpvsSZCT vs. CTVpvsSZMR were 68.6 vs. 64.4 (p=0.14). Interobserver difference for CTVpros defined by CT images was significant (39.2 vs. 34.6; p=0,0058). However, the difference was not significant using MRI images (32.0 vs. 31.9; p=0.93). Interobserver differences for CTVpvs were significant using either CT (85.8 vs. 68.6; p=0.0001) or MRI (70.9 vs. 64.4; p=0.004). Ratio of mean volumes contoured by the two observers were 1,12 (CT) vs. 1 (MRI) for CTVpros and 1,2 (CT) vs. 1,09 (MRI) for CTVpvs. Clinical target volumes defined for prostate cancer external beam radiotherapy by MRI images are significantly smaller compared to CT image based contouring. The magnitudes of differences are observer dependent. The use of MRI decreases the interobserver difference of mean volumes with 11% and 12% for CTVpvs and CTVpros.

Prostate Cancer Survivors Present Long-Term, Residual Systemic Immune Alterations.

BACKGROUND: The development of cancer and anti-tumor therapies can lead to systemic immune alterations but little is known about how long immune dysfunction persists in cancer survivors. METHODS: We followed changes in the cellular immune parameters of prostate cancer patients with good prognostic criteria treated with low dose rate brachytherapy before and up to 3 years after the initiation of therapy. RESULTS: Patients before therapy had a reduced CD4+ T cell pool and increased regulatory T cell fraction and these alterations persisted or got amplified during the 36-month follow-up. A significant decrease in the total NK cell number and a redistribution of the circulating NK cells in favor of a less functional anergic subpopulation was seen in patients before therapy but tumor regression led to the regeneration of the NK cell pool and functional integrity. The fraction of lymphoid DCs was increased in patients both before therapy and throughout the whole follow-up. Increased PDGF-AA, BB, CCL5 and CXCL5 levels were measured in patients before treatment but protein levels rapidly normalized. CONCLUSIONS: while NK cell dysfunction recovered, long-term, residual alterations persisted in the adaptive and partly in the innate immune system.

Final Safety and Health-Related Quality of LIfe Results of the Phase 2/3 Act.In.Sarc Study With Preoperative NBTXR3 Plus Radiation Therapy Versus Radiation Therapy in Locally Advanced Soft-Tissue Sarcoma.

PURPOSE: Act.In.Sarc (NCT02379845) demonstrated that the first-in-class radioenhancer NBTXR3, activated by preoperative radiation therapy (RT), doubled the rate of pathologic complete response after resection compared with preoperative RT alone in adult patients with locally advanced soft tissue sarcoma of the extremity or trunk wall (16.1% vs 7.9%, P = .045), and more patients achieved R0 resections (77.0% vs 64.0%, P = .042). These are the toxicity and health-related quality of life (HRQoL) results. METHODS AND MATERIALS: Act.In.Sarc randomized eligible patients 1:1 to either NBTXR3 (single intratumoral injection, volume equivalent to 10% of baseline tumor volume, at 53.3 g/L) activated by external-beam RT (arm A) or external-beam RT alone (arm B) (50 Gy in 25 fractions), followed by surgery in both arms. Here, we report the safety analyses in the all-treated population with a long-term follow-up of at least 2 years, and HRQoL in the intention-to-treat full analysis set. RESULTS: During the on-treatment period, serious adverse events (SAEs) of all grades related to NBTXR3 occurred in 10.1% (9/89) of patients (arm A), and SAEs related to RT occurred in 5.6% (5/89) (arm A) versus 5.6% (5/90) (arm B); postsurgery hospitalization owing to SAEs occurred in 15.7% (14/89) (arm A) versus 24.4% (22/90) (arm B). During the follow-up period, posttreatment SAEs (regardless of relationship) occurred in 13.5% (12/89) (arm A) versus 24.4% (22/90) (arm B). NBTXR3 did not negatively affect HRQoL; during the follow-up period, there was an improvement in most mean Toronto extremity salvage, EuroQoL 5-dimension (EQ-5D), EQ5D02-EQ visual analog scale, reintegration to normal living index, and musculoskeletal tumor rating scale scores. CONCLUSIONS: NBTXR3 did not negatively affect safety or HRQoL. Long-term safety results reinforce the favorable benefit-risk ratio of NBTXR3 plus RT.