A Phase 1 Study of the DNA-PK Inhibitor Peposertib in Combination With Radiation Therapy With or Without Cisplatin in Patients With Advanced Head and Neck Tumors.

PURPOSE: DNA-dependent protein kinase (DNA-PK) plays a key role in the repair of DNA double strand breaks via nonhomologous end joining. Inhibition of DNA-PK can enhance the effect of DNA double strand break inducing anticancer therapies. Peposertib (formerly "M3814") is an orally administered, potent, and selective small molecule DNA-PK inhibitor that has demonstrated radiosensitizing and antitumor activity in xenograft models and was well-tolerated in monotherapy. This phase 1 trial (National Clinical Trial 02516813) investigated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, and tolerability of peposertib in combination with palliative radiation therapy (RT) in patients with thoracic or head and neck tumors (arm A) and of peposertib in combination with cisplatin and curative-intent RT in patients with squamous cell carcinoma of the head and neck (arm B). METHODS AND MATERIALS: Patients received peposertib once daily in ascending dose cohorts as a tablet or capsule in combination with palliative RT (arm A) or in combination with intensity modulated curative-intent RT and cisplatin (arm B). RESULTS: The most frequently observed treatment-emergent adverse events were radiation skin injury, fatigue, and nausea in arm A (n = 34) and stomatitis, nausea, radiation skin injury, and dysgeusia in arm B (n = 11). Based on evaluations of dose-limiting toxicities, tolerability, and pharmacokinetic data, RP2D for arm A was declared as 200 mg peposertib tablet once daily in combination with RT. In arm B (n = 11), 50 mg peposertib was declared tolerable in combination with curative-intent RT and cisplatin. However, enrollment was discontinued because of insufficient exposure at that dose, and the RP2D was not formally declared. CONCLUSIONS: Peposertib in combination with palliative RT was well-tolerated up to doses of 200 mg once daily as tablet with each RT fraction. When combined with RT and cisplatin, a tolerable peposertib dose yielded insufficient exposure.

The tumor core boost study: A feasibility study of radical dose escalation to the central part of large tumors with an integrated boost in the palliative treatment setting.

PURPOSE: For patients with large tumors palliative radiotherapy often is the only local treatment option. To prevent toxicity the administered doses are low. Dose escalation to the tumor could be an option to better smyptom control and prolong local control rates. In this prospective study we used a very pragmatic approach with a simultaneously integrated boost (SIB) to an almost geometrically defined tumor core to achieve this. The primary endpoint was to demonstrate feasibility. METHOD: Patients with solid tumors > 4 cm in diameter of different histologies were eligible in this single arm, prospective, multi-institutional clinical feasibility trial with two treatment concepts: 5â€¯× 5 Gy with an integrated boost to the tumor core of 5â€¯× 10 Gy or 10â€¯× 3 Gy with a boost of 10â€¯× 6 Gy. The objective of dose escalation in this study was to deliver a minimum dose of 150% of the prescribed dose to the gross tumor volume (GTV) tumor core and to reach a maximum of at least 200% in the tumor core. RESULTS: In all, 21 patients at three study sites were recruited between January 2019 and November 2020 and were almost evenly spread (9 to 12) between the two concepts. The treated planning target volumes (PTV) averaged 389.42 cm3 (range 49.4-1179.6 cm3). The corresponding core volumes were 72.85 cm3 on average (range 4.21-338.3 cm3). Dose escalation to the tumor core with mean doses of 167.7-207.7% related to the nonboost prescribed isodose led to PTV mean doses of 120.5-163.3%. Treatment delivery and short-term follow-up was successful in all patients. CONCLUSIONS: Palliative radiotherapy with SIB to the tumor core seems to be a feasible and well-tolerated treatment concept for large tumors. The applied high doses of up to 50 Gy in 5 fractions (or 60 Gy in 10 fractions) did not cause unexpected side effects in the 42 day follow-up period. Further research is needed for more information on efficacy and long-term toxicity.

Use and Reporting of Patient-Reported Outcomes in Trials of Palliative Radiotherapy: A Systematic Review.

Importance: Approximately 50% of all patients with cancer have an indication for radiotherapy, and approximately 50% of radiotherapy is delivered with palliative intent, with the aim of alleviating symptoms. Symptoms are best assessed by patient-reported outcomes (PROs), yet their reliable interpretation requires adequate reporting in publications. Objective: To investigate the use and reporting of PROs in clinical trials of palliative radiotherapy. Evidence Review: This preregistered systematic review searched PubMed/Medline, EMBASE, and the Cochrane Center Register of Controlled Trials for clinical trials of palliative radiotherapy published from 1990 to 2020. Key eligibility criteria were palliative setting, palliative radiotherapy as treatment modality, and clinical trial design (per National Institutes of Health definition). Two authors independently assessed eligibility. Trial characteristics were extracted and standard of PRO reporting was assessed in adherence to the Consolidated Standards of Reporting Trials (CONSORT) PRO extension. The association of the year of publication with the use of PROs was assessed by logistic regression. Factors associated with higher CONSORT-PRO adherence were analyzed by multiple regression. This study is reported following the PRISMA guidelines. Findings: Among 7377 records screened, 225 published clinical trials representing 24 281 patients were eligible. Of these, 45 trials (20%) used a PRO as a primary end point and 71 trials (31%) used a PRO as a secondary end point. The most prevalent PRO measures were the Numeric Rating Scale/Visual Analogue Scale (38 trials), European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (32 trials), and trial-specific unvalidated measures (25 trials). A more recent year of publication was significantly associated with a higher chance of PROs as a secondary end point (odds ratio [OR], 1.04 [95% CI, 1.00-1.07]; P = .03) but not as primary end point. Adherence to CONSORT-PRO was poor or moderate for most items. Mean (SD) adherence to the extension adherence score was 46.2% (19.6%) for trials with PROs as primary end point and 31.8% (19.8%) for trials with PROs as a secondary end point. PROs as a primary end point (regression coefficient, 9.755 [95% CI, 2.270-17.240]; P = .01), brachytherapy as radiotherapy modality (regression coefficient, 16.795 [95% CI, 5.840-27.751]; P = .003), and larger sample size (regression coefficient, 0.028 [95% CI, 0.006-0.049]; P = .01) were significantly associated with better PRO reporting per extension adherence score. Conclusions and Relevance: In this systematic review of palliative radiotherapy trials, the use and reporting of PROs had room for improvement for future trials, preferably with PROs as a primary end point.

Evaluation of Prognostic Factors and Role of Participation in a Randomized Trial or a Prospective Registry in Pediatric and Adolescent Nonmetastatic Medulloblastoma - A Report From the HIT 2000 Trial.

PURPOSE: We aimed to compare treatment results in and outside of a randomized trial and to confirm factors influencing outcome in a large retrospective cohort of nonmetastatic medulloblastoma treated in Austria, Switzerland and Germany. METHODS AND MATERIALS: Patients with nonmetastatic medulloblastoma (n = 382) aged 4 to 21 years and primary neurosurgical resection between 2001 and 2011 were assessed. Between 2001 and 2006, 176 of these patients (46.1%) were included in the randomized HIT SIOP PNET 4 trial. From 2001 to 2011 an additional 206 patients were registered to the HIT 2000 study center and underwent the identical central review program. Three different radiation therapy protocols were applied. Genetically defined tumor entity (former molecular subgroup) was available for 157 patients. RESULTS: Median follow-up time was 7.3 (range, 0.09-13.86) years. There was no difference between HIT SIOP PNET 4 trial patients and observational patients outside the randomized trial, with 7 years progression-free survival rates (PFS) of 79.5% ± 3.1% versus 78.7% ± 3.1% (P = .62). On univariate analysis, the time interval between surgery and irradiation (≤ 48 days vs ≥ 49 days) showed a strong trend to affect PFS (80.4% ± 2.2% vs 64.6% ± 9.1%; P = .052). Furthermore, histologically and genetically defined tumor entities and the extent of postoperative residual tumor influenced PFS. On multivariate analyses, a genetically defined tumor entity wingless-related integration site-activated vs non-wingless-related integration site/non-SHH, group 3 hazard ratio, 5.49; P = .014) and time interval between surgery and irradiation (hazard ratio, 2.2; P = .018) were confirmed as independent risk factors. CONCLUSIONS: Using a centralized review program and risk-stratified therapy for all patients registered to the study center, outcome was identical for patients with nonmetastatic medulloblastoma treated on and off the randomized HIT SIOP PNET 4 trial. The prognostic values of prolonged time to RT and genetically defined tumor entity were confirmed.

106Ruthenium eye plaque brachytherapy in the management of medium sized uveal melanoma.

BACKGROUND: To evaluate 106Ruthenium Brachytherapy in management of medium sized uveal melanoma, with emphasis on 5-year outcome and toxicity. METHODS: From April 2007 to October 2015, 39 patients with medium sized uveal melanoma were treated with 106 Ru eye plaques brachytherapy. At the time of diagnosis, the mean tumor depth was 3.7 mm (±SD:1.6 mm). The mean dose at the tumor apex was 141.4 Gy (± SD: 12.1 Gy) and 557.7 Gy (± SD: 257.3 Gy) to the sclera. RESULTS: Mean follow-up was 69.5 months (± SD: 53.8 months). Thirty-four patients (87.1%) remained free of recurrence. Twenty-six patients (66.7%) demonstrated a complete tumor regression after a median period of 12 months (3-60 mon.). By the final examination, the visual acuity of 26 patients (66.7%) was better than 20/200, and 12 patients (30.7%) had a visual acuity better than 20/40. Retinopathy was detected in 11 patients (28.2%). After treatments only one patient (5.1%) had active vascular changes by the last examination. Moderate optic neuropathy was observed in 4 patients (10.3%). Cataract development was diagnosed in 21 patients (53.8%), and 16 patients (41%) had bilateral cataract development. Special emphasis was made on patients with larger tumors. Twelve out of the 39 patients had a tumor with a depth of 5 mm or more. There was no significant difference in local control or in side effects between both groups observed. CONCLUSIONS: Our study proved 106Ru -brachytherapy to be an excellent treatment option with regard to tumor control and preservation of the visual acuity in well-selected patients. Our data suggested that this treatment is also suitable for tumors with a depth of more than 5 mm.

Automatic image segmentation based on synthetic tissue model for delineating organs at risk in spinal metastasis treatment planning.

PURPOSE: One of the main goals in software solutions for treatment planning is to automatize delineation of organs at risk (OARs). In this pilot feasibility study a clinical validation was made of computed tomography (CT)-based extracranial auto-segmentation (AS) using the Brainlab Anatomical Mapping tool (AM). METHODS: The delineation of nine extracranial OARs (lungs, kidneys, trachea, heart, liver, spinal cord, esophagus) from clinical datasets of 24 treated patients was retrospectively evaluated. Manual delineation of OARs was conducted in clinical routine and compared with AS datasets using AM. The Dice similarity coefficient (DSC) and maximum Hausdorff distance (HD) were used as statistical and geometrical measurements, respectively. Additionally, all AS structures were validated using a subjective qualitative scoring system. RESULTS: All patient datasets investigated were successfully processed with the evaluated AS software. For the left lung (0.97 ± 0.03), right lung (0.97 ± 0.05), left kidney (0.91 ± 0.07), and trachea (0.93 ± 0.04), the DSC was high with low variability. The DSC scores of other organs (right kidney, heart, liver, spinal cord), except the esophagus, ranged between 0.7 and 0.9. The calculated HD values yielded comparable results. Qualitative assessment showed a general acceptance in more than 85% of AS OARs-except for the esophagus. CONCLUSIONS: The Brainlab AM software is ready for clinical use in most of the OARs evaluated in the thoracic and abdominal region. The software generates highly conformal structure sets compared to manual contouring. The current study design needs revision for further research.

Outcomes After Radiotherapy Alone for Metastatic Spinal Cord Compression in Patients with Oligo-metastatic Breast Cancer.

BACKGROUND/AIM: Patients with oligo-metastatic breast cancer are a unique patient subgroup with more favourable outlook than most patients with metastatic disease. Prognostic factors in these patients with metastatic spinal cord compression (MSCC) were evaluated. PATIENTS AND METHODS: In 159 patients irradiated for MSCC from oligo-metastatic breast cancer, seven characteristics were retrospectively analyzed including age, interval between breast cancer diagnosis and irradiation of MSCC, time developing motor deficits, ambulatory status, involved vertebrae, performance score (ECOG-PS) and radiotherapy regimen. RESULTS: Improvement of motor function was significantly associated with time developing motor deficits (p=0.017), post-radiotherapy ambulatory status with pre-radiotherapy ambulation (p=0.012) and ECOG-PS 1-2 (p=0.029). Radiation doses of 39-40 Gy (equivalent doses) resulted in 1- and 2-year local control of 100% and 95%. On multivariate analyses, higher doses were associated with local control (p=0.011). Pre-radiotherapy ambulatory status (p=0.001) and ECOG-PS 1-2 (p=0.002) were associated with survival. CONCLUSION: Significant prognostic factors were identified for patients with MSCC from oligo-metastatic breast cancer. Higher radiation doses improved local control.

Efficacy and the toxicity of the interstitial high-dose-rate brachytherapy in the management of recurrent keloids: 5-year outcomes.

PURPOSE: Recurring keloids are a clinical challenge. Interdisciplinary treatments are required in most cases. Owing to the wide variety of concepts, the optimal treatment regime remains unclear. Our clinic established a protocol of perioperative interstitial high-dose-rate brachytherapy with three fractions of 6 Gy and achieved an excellent 2-year local control rate of 94% (In search of the optimal treatment of keloids: Report of a series and a review of the literature). This report is an update on our long-term results of prospective study. Twenty-nine patients were included with a median followup of 5 years. METHODS AND MATERIALS: From 2009 to 2015, 29 patients with 37 recurrent keloids were treated with perioperative interstitial high-dose-rate brachytherapy; 3 patients had been previously treated with adjuvant external beam radiotherapy and presented with recurrences in the pretreated area. Brachytherapy was given in three fractions with a single dose of 6 Gy in 5-mm tissue depth and covered the scar in total length. Followup visits were scheduled at 6 weeks, 3 months, 6 months, 1 year, and annually thereafter. Therapeutic outcome was assessed in terms of recurrence, acute and late complications, and cosmetic results. RESULTS: No procedure-related complications occurred. Improvement of keloid-related symptoms was noticed in all patients after treatment. After a median followup of 49.7 months (range: 7.9-91.9 months), three keloid recurrences and two hypertrophied scars were observed. CONCLUSIONS: Our results suggest that brachytherapy may be advantageous in the management of high-risk keloids, even after failure of external beam radiotherapy and other treatment procedures. Our three-fraction treatment schedule reduces the treatment period to 2 days and is therefore convenient for the patients.

Oligometastases in prostate cancer : Metabolic response in follow-up PSMA-PET-CTs after hypofractionated IGRT.

BACKGROUND: Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMAPET/CT) is a new and evolving diagnostic method in prostate cancer with special impact on treatment planning in image-guided radiotherapy (IGRT). Initial results of metabolic response in repeated PSMA PET/CTs after hypofractionated IGRT for metastatic lesions are reported here. MATERIALS AND METHODS: Of 280 patients investigated with 68Ga-PSMA PET/CT in the period from 01/2014 through 12/2016 in the authors' department, patients were selected according to the following criteria: oligometastatic disease at initial PSMA PET/CT defined as not more than five metastatic lesions, hypofractionated IGRT to all lesions, no systemic therapy in the last 6 months and during follow-up, and at least one follow-up PSMA PET after radiotherapy. Radiotherapy was administered to all PSMA PET-detected lesions (CTV = PET-GTV + 1 to 2 mm), mostly with 35 Gy in five fractions (one lesion with four fractions of 7 Gy due to dose constraints, two lymph nodes with 50 Gy in 25 fractions to an extended volume plus a boost of 7 Gy × 2 to the PET-positive volume). Metabolic response of irradiated lesions was evaluated on repeated PSMA PET/CTs according to PERCIST criteria. Five patients with a total number of 12 PSMA PETs matched the criteria. Patients received radiotherapy to all PET-positive lesions and had at least one (in one case three) follow-up PSMA PET examinations after radiotherapy with an interval to the first PET of 2-15 months; the median follow-up for all patients was 11 months. RESULTS: The mean prostate-specific antigen (PSA) values at the time of examination were 8.9 ± 8.5 ng/ml (median 3.3 ng/ml, range 0.17-21.8 ng/ml). A total number of 18 metastatic deposits were detected. The PET-positive tumor volume was 5.9 ± 13.3 cm3 (median 1.25 cm3). The mean standardized uptake value (mean SUVmax) of the 18 metastatic lesions decreased from 19.9 ± 23.3 (mean ± SD) prior to RT to 5.4 ± 4.6 at post-radiotherapy PSMA PET/CT. Using PERCIST criteria, 14 lesions (78%) showed a metabolic response in PSMA PET with a reduction of SUV of at least 30%, as well as a significant decrease in lesion size; in seven of these lesions, no uptake of 68Ga-PSMA was detectable. In follow-up PET scans, only two lesions showed metabolic progression with an increase in SUVmax yielding a local progression-free survival of 88% after 1 year. There was a correlation between the time interval after radiotherapy (median 3 months, range 1-9 months) and response (p = 0.04) with better metabolic response after longer follow-up. CONCLUSIONS: Preliminary results of this study show high metabolic response rates of PSMA PET-positive metastatic lesions after hypofractionated radiotherapy in follow-up PSMA PET with promising local control rates. An interval of several months may be required to fully estimate the efficacy of radiotherapy in control PSMA PET.

Interstitial high-dose-rate brachytherapy as salvage treatment for locally recurrent prostate cancer after definitive radiation therapy: Toxicity and 5-year outcome.

PURPOSE: We report our results with interstitial high-dose-rate brachytherapy (HDR-BT) as a salvage therapy option after external beam therapy with or without BT. Emphasis was put on toxicity and 5-year outcome. METHODS AND MATERIALS: From 2003 to 2011, 29 patients with local failure after previous radiotherapy for prostate cancer were treated with salvage interstitial HDR-BT. The diagnosis of local recurrence was made on the basis of choline positron emission tomography. Salvage HDR-BT was given in three fractions with a single dose of 10 Gy per fraction and weekly. The target volume covered the peripheral zone of the prostate and the positron emission tomography-positive area. Acute and late toxicities were documented according to common terminology criteria for adverse events (CTCAE v 4.0). RESULTS: Twenty-two patients with minimum followup of 60 months were analyzed. The 5-year overall survival was 95.5% with a disease-specific survival of 100%. The 5-year biochemical control was 45%. Late grade 2 gastrointestinal toxicities were observed in two patients (9%). No grade 3 or higher gastrointestinal late toxicities were observed. Urinary incontinence found in 2 patients (9%) and grade 2 obstruction of urinary tract occurred in one patient (4%). CONCLUSIONS: Interstitial HDR-BT was feasible and effective in the treatment of locally recurrent prostate cancer after definitive radiotherapy. The long-term toxicity was low and acceptable.

Targeting hypoxia to overcome radiation resistance in head & neck cancers: real challenge or clinical fairytale?

INTRODUCTION: Tumor hypoxia is a major cause for failure of therapy in patients with inoperable head and neck cancers. AREAS COVERED: Various anti-hypoxic treatment strategies (e.g. hyperbaric oxygenation, hypoxic cell sensitizers) have been tested in clinical trials in head and neck cancer over the past 30 years and have shown modest improvements in combination with radiotherapy in meta-analyses. Anemia worsens tumor hypoxia, but anemia correction had no significant effect. New approaches (e.g. anti-HIF-directed molecular therapies) have just entered early clinical studies and data are lacking. Expert commentary: A new attractive and promising approach derives from recent advances in imaging and radiotherapy delivery. Progress in imaging of hypoxia (e.g. by positron emission tomography) can select patients for specific therapies and may, in particular, facilitate anti-hypoxia-directed radiotherapy which has become feasible with advanced radiotherapy techniques (IMRT with 'dose-painting'). The combination of both methods may offer a powerful tool for effective targeting of hypoxia in the near future.

Perioperative Interstitial High-Dose-Rate Brachytherapy for the Treatment of Recurrent Keloids: Feasibility and Early Results.

PURPOSE: To prospectively evaluate high-dose-rate brachytherapy in the treatment of therapy-resistant keloids and report first results, with emphasis on feasibility and early treatment outcome. METHODS AND MATERIALS: From 2009 to 2014, 24 patients with 32 recurrent keloids were treated with immediate perioperative high-dose-rate brachytherapy; 3 patients had been previously treated with adjuvant external beam radiation therapy and presented with recurrences in the pretreated areas. Two or more different treatment modalities had been tried in all patients and had failed to achieve remission. After (re-)excision of the keloids, a single brachytherapy tube was placed subcutaneously before closing the wound. The target volume covered the scar in total length. Brachytherapy was given in 3 fractions with a single dose of 6 Gy in 5 mm tissue depth. The first fraction was given within 6 hours after surgery, the other 2 fractions on the first postoperative day. Thus, a total dose of 18 Gy in 3 fractions was administered within 36 hours after the resection. RESULTS: The treatment was feasible in all patients. No procedure-related complications (eg, secondary infections) occurred. Nineteen patients had keloid-related symptoms before treatment like pain and pruritus; disappearance of symptoms was noticed in all patients after treatment. After a median follow-up of 29.4 months (range, 7.9-72.4 months), 2 keloid recurrences and 2 mildly hypertrophied scars were observed. The local control rate was 94%. Pigmentary abnormalities were detected in 3 patients, and an additional 6 patients had a mild delay in the wound-healing process. CONCLUSIONS: The early results of this study prove the feasibility and the efficacy of brachytherapy for the prevention of keloids. The results also suggest that brachytherapy may be advantageous in the management of high-risk keloids or as salvage treatment for failure after external beam therapy.

Emerging Role of Hypofractionated Radiotherapy with Simultaneous Integrated Boost in Modern Radiotherapy of Breast Cancer.

Hypofractionated radiotherapy for breast cancer is becoming increasingly important. The scientific background of this development as well as the introduction of the simultaneous integrated boost to the primary tumor region in this context are discussed here.

The expression level of the transcription factor Aryl hydrocarbon receptor nuclear translocator (ARNT) determines cellular survival after radiation treatment.

BACKGROUND: Tumour hypoxia promotes radioresistance and is associated with poor prognosis. The transcription factor Aryl hydrocarbon receptor nuclear translocator (ARNT), also designated as Hypoxia-inducible factor (HIF)-1ß, is part of the HIF pathway which mediates cellular adaptations to oxygen deprivation and facilitates tumour progression. The subunits HIF-1α and ARNT are key players within this pathway. HIF-1α is regulated in an oxygen-dependent manner whereas ARNT is considered to be constitutively expressed. However, there is mounting evidence that certain tumour cells are capable to elevate ARNT in hypoxia which suggests a survival benefit. Therefore the objective of this study was to elucidate effects of an altered ARNT expression level on the cellular response to radiation. METHODS: Different human cell lines (Hep3B, MCF-7, 786-Owt, 786-Ovhl, RCC4wt and RCC4vhl) originating from various tumour entities (Hepatocellular carcinoma, breast cancer and renal cell carcinoma respectively) were X-irradiated using a conventional linear accelerator. Knockdown of ARNT expression was achieved by transient siRNA transfection. Complementary experiments were performed by forced ARNT overexpression using appropriate plasmids. Presence/absence of ARNT protein was confirmed by Western blot analysis. Clonogenic survival assays were performed in order to determine cellular survival post irradiation. Statistical comparison of two groups was achieved by the unpaired t-test. RESULTS: The results of this study indicate that ARNT depletion renders tumour cells susceptible to radiation whereas overexpression of this transcription factor confers radioresistance. CONCLUSIONS: These findings provide evidence to consider ARNT as a drug target and as a predictive marker in clinical applications concerning the response to radiation.

Cardiac Toxicity after Radiotherapy for Breast Cancer: Myths and Facts.

Radiotherapy is an important component in the multidisciplinary treatment of breast cancer. In recent years, the cardiac risks of radiation have been discussed several times. This problem has long been known and resolved from the radiotherapeutic point of view. The current data is briefly described here.

Pulmonary vein isolation by radiosurgery: implications for non-invasive treatment of atrial fibrillation.

AIMS: Electrical isolation of the pulmonary veins (PVs) has been established in clinical routine as a curative treatment for atrial fibrillation (AF). While catheter ablation carries procedural risks, radiosurgery might be able to non-invasively induce lesions at the PV ostia to block veno-atrial electrical conduction. This porcine feasibility and dose escalation study determined the effect of radiosurgery on electrophysiologic properties of the left atrial-PV junction. METHODS AND RESULTS: Eight adult Goettingen mini-pigs underwent electrophysiological voltage mapping in the left atrium and the upper right PV. Radiation was delivered with a conventional linear accelerator. A single homogeneous dose ranging from 22.5 to 40 Gy was applied circumferentially to the target vein antrum. Six months after radiosurgery, electrophysiological mapping was repeated and a histological examination performed. Voltage mapping consistently showed electrical potentials in the upper right PV at baseline. Pacing the target vein prompted atrial excitation, thus proving veno-atrial electrical conduction. After 6 months, radiation had reduced PV electrogram amplitudes. This was dose dependent with a mean interaction effect of -5.8%/Gy. Complete block of atrio-venous electrical conduction occurred after 40 Gy dose application. Histology revealed transmural scarring of the targeted PV musculature with doses >30 Gy. After 40 Gy, it spanned the entire circumference in accordance with pulmonary vein isolation. CONCLUSION: Pulmonary vein isolation to treat AF can be achieved by radiosurgery with a conventional linear accelerator. Yet, it requires a high radiation dose which might limit clinical applicability.

Dose-escalation study for cardiac radiosurgery in a porcine model.

PURPOSE: To perform a proof-of-principle dose-escalation study to radiosurgically induce scarring in cardiac muscle tissue to block veno-atrial electrical connections at the pulmonary vein antrum, similar to catheter ablation. METHODS AND MATERIALS: Nine mini-pigs underwent pretreatment magnetic resonance imaging (MRI) evaluation of heart function and electrophysiology assessment by catheter measurements in the right superior pulmonary vein (RSPV). Immediately after examination, radiosurgery with randomized single-fraction doses of 0 and 17.5-35 Gy in 2.5-Gy steps were delivered to the RSPV antrum (target volume 5-8 cm(3)). MRI and electrophysiology were repeated 6 months after therapy, followed by histopathologic examination. RESULTS: Transmural scarring of cardiac muscle tissue was noted with doses ≥32.5 Gy. However, complete circumferential scarring of the RSPV was not achieved. Logistic regressions showed that extent and intensity of fibrosis significantly increased with dose. The 50% effective dose for intense fibrosis was 31.3 Gy (odds ratio 2.47/Gy, P<.01). Heart function was not affected, as verified by MRI and electrocardiogram evaluation. Adjacent critical structures were not damaged, as verified by pathology, demonstrating the short-term safety of small-volume cardiac radiosurgery with doses up to 35 Gy. CONCLUSIONS: Radiosurgery with doses >32.5 Gy in the healthy pig heart can induce circumscribed scars at the RSPV antrum noninvasively, mimicking the effect of catheter ablation. In our study we established a significant dose-response relationship for cardiac radiosurgery. The long-term effects and toxicity of such high radiation doses need further investigation in the pursuit of cardiac radiosurgery for noninvasive treatment of atrial fibrillation.

Dose escalation for metastatic spinal cord compression in patients with relatively radioresistant tumors.

PURPOSE: Radiotherapy alone is the most common treatment for metastatic spinal cord compression (MSCC) from relatively radioresistant tumors such as renal cell carcinoma, colorectal cancer, and malignant melanoma. However, the results of the "standard" regimen 30 Gy/10 fractions need to be improved with respect to functional outcome. This study investigated whether a dose escalation beyond 30 Gy can improve treatment outcomes. METHODS AND MATERIALS: A total of 91 patients receiving 30 Gy/10 fractions were retrospectively compared to 115 patients receiving higher doses (37.5 Gy/15 fractions, 40 Gy/20 fractions) for motor function and local control of MSCC. Ten further potential prognostic factors were evaluated: age, gender, tumor type, performance status, number of involved vertebrae, visceral or other bone metastases, interval from tumor diagnosis to radiotherapy, pretreatment ambulatory status, and time developing motor deficits before radiotherapy. RESULTS: Motor function improved in 18% of patients after 30 Gy and in 22% after higher doses (p = 0.81). On multivariate analysis, functional outcome was associated with visceral metastases (p = 0.030), interval from tumor diagnosis to radiotherapy (p = 0.010), and time developing motor deficits (p < 0.001). The 1-year local control rates were 76% after 30 Gy and 80% after higher doses, respectively (p = 0.64). On multivariate analysis, local control was significantly associated with visceral metastases (p = 0.029) and number of involved vertebrae (p = 0.043). CONCLUSIONS: Given the limitations of a retrospective study, escalation of the radiation dose beyond 30 Gy/10 fractions did not significantly improve motor function and local control of MSCC in patients with relatively radioresistant tumors.

Comparison of four cisplatin-based radiochemotherapy regimens for nonmetastatic stage III/IV squamous cell carcinoma of the head and neck.

PURPOSE: To compare the outcomes of four cisplatin-based radiochemotherapy regimens in 311 patients with Stage III/IV squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Concurrent chemotherapy consisted of three courses of cisplatin 100 mg/m(2) on Day 1 (Group A, n = 74), two courses of cisplatin 20 mg/m(2) on Days 1-5 plus 5-fluorouracil 1,000 mg/m(2) on Days 1-5 (Group B, n = 49), two courses of cisplatin 20 mg/m(2) on Days 1-5 plus 5-fluorouracil 600 mg/m(2) on Days 1-5 (Group C, n = 102), or two courses of cisplatin 20 mg/m(2) on Days 1-5 (Group D, n = 86). The groups were retrospectively compared for toxicity and outcomes, and 11 additional factors were evaluated for outcomes. RESULTS: No significant difference was observed among the groups regarding radiation-related acute oral mucositis and radiation-related late toxicities. Acute Grade 3 skin toxicity was significantly more frequent in Group B than in the patients of the other three groups (p = .013). The chemotherapy-related Grade 3 nausea/vomiting rate was 24% for Group A, 8% for Group B, 9% for Group C, and 6% for Group D (p = .003). The corresponding Grade 3 nephrotoxicity rates were 8%, 1%, 2%, and 1% (p = .019). The corresponding Grade 3-4 hematologic toxicity rates were 35%, 41%, 19%, and 21% (p = .027). Chemotherapy could be completed in 50%, 59%, 74%, and 83% of the Group A, B, C, and D patients, respectively (p = .002). Toxicity-related radiotherapy breaks occurred in 39%, 43%, 21%, and 15% of Groups A, B, C, and D, respectively (p = .005). The 3-year locoregional control rate was 67%, 72%, 60%, and 59% for Groups A, B, C, and D, respectively (p = .48). The corresponding 3-year metastasis-free survival rates were 67%, 74%, 63%, and 79% (p = .31), and the corresponding 3-year survival rates were 60%, 63%, 50%, and 71% (p = .056). On multivariate analysis, Karnofsky performance status, histologic grade, T/N category, preradiotherapy hemoglobin level, completion of chemotherapy, and radiotherapy breaks were associated with the outcome. CONCLUSION: The four compared radiochemotherapy regimens were not significantly different regarding treatment outcomes. Two courses of cisplatin 20 mg/m(2) on Days 1-5 were better tolerated than the other three regimens.