Frank W. Hensley

Estimation of pneumonitis risk in three-dimensional treatment planning using dose-volume histogram analysis

PURPOSE Investigations to study correlations between the estimations of biophysical models in three dimensional (3D) treatment planning and clinical observations are scarce. The development of clinically symptomatic pneumonitis in the radiotherapy of thoracic malignomas was chosen to test the predictive power of Lymans normal tissue complication probability (NTCP) model for the assessment of side effects for nonuniform irradiation. METHODS AND MATERIALS In a retrospective analysis individual computed-tomography-based 3D dose distributions of a random sample of 46/20 patients with lung/esophageal cancer were reconstructed. All patients received tumor doses between 50 and 60 Gy in a conventional treatment schedule. Biological isoeffective dose-volume histograms (DVHs) were used for the calculation of complication probabilities after applying Lymans and Kutchers DVH-reduction algorithm. Lung dose statistics were performed for single lung (involved ipsilateral and contralateral) and for the lung as a paired organ. RESULTS In the lung cancer group, about 20% of the patients (9 out of 46) developed pneumonitis 3-12 (median 7.5) weeks after completion of radiotherapy. For the majority of these lung cancer patients, the involved ipsilateral lung received a much higher dose than the contralateral lung, and the pneumonitis patients had on average a higher lung exposure with a doubling of the predicted complication risk (38% vs. 20%). The lower lung exposure for the esophagus patients resulted in a mean lung dose of 13.2 Gy (lung cancer: 20.5 Gy) averaged over all patients in correlation with an almost zero complication risk and only one observed case of pneumonitis (1 out of 20). To compare the pneumonitis risk estimations with observed complication rates, the patients were ranked into bins of mean ipsilateral lung dose. Particularly, in the bins with the highest patient numbers, a good correlation was achieved. Agreement was not reached for the lung functioning as a paired organ. CONCLUSIONS Realistic assessments for the prediction of radiation-induced pneumonitis seem to be possible. In this respect, the implementation of DVH-analysis in 3D planning could be a helpful tool for the evaluation of treatment plans.

Deletion of Running-Induced Hippocampal Neurogenesis by Irradiation Prevents Development of an Anxious Phenotype in Mice

Recent evidence postulates a role of hippocampal neurogenesis in anxiety behavior. Here we report that elevated levels of neurogenesis elicit increased anxiety in rodents. Mice performing voluntary wheel running displayed both highly elevated levels of neurogenesis and increased anxiety in three different anxiety-like paradigms: the open field, elevated O-maze, and dark-light box. Reducing neurogenesis by focalized irradiation of the hippocampus abolished this exercise-induced increase of anxiety, suggesting a direct implication of hippocampal neurogenesis in this phenotype. On the other hand, irradiated mice explored less frequently the lit compartment of the dark-light box test irrespective of wheel running, suggesting that irradiation per se induced anxiety as well. Thus, our data suggest that intermediate levels of neurogenesis are related to the lowest levels of anxiety. Moreover, using c-Fos immunocytochemistry as cellular activity marker, we observed significantly different induction patterns between runners and sedentary controls when exposed to a strong anxiogenic stimulus. Again, this effect was altered by irradiation. In contrast, the well-known induction of brain-derived neurotrophic factor (BDNF) by voluntary exercise was not disrupted by focal irradiation, indicating that hippocampal BDNF levels were not correlated with anxiety under our experimental conditions. In summary, our data demonstrate to our knowledge for the first time that increased neurogenesis has a causative implication in the induction of anxiety.

Intraoperative radiation therapy using mobile electron linear accelerators: Report of AAPM Radiation Therapy Committee Task Group No. 72

Intraoperative radiation therapy (IORT) has been customarily performed either in a shielded operating suite located in the operating room (OR) or in a shielded treatment room located within the Department of Radiation Oncology. In both cases, this cancer treatment modality uses stationary linear accelerators. With the development of new technology, mobile linear accelerators have recently become available for IORT. Mobility offers flexibility in treatment location and is leading to a renewed interest in IORT. These mobile accelerator units, which can be transported any day of use to almost any location within a hospital setting, are assembled in a nondedicated environment and used to deliver IORT. Numerous aspects of the design of these new units differ from that of conventional linear accelerators. The scope of this Task Group (TG-72) will focus on items that particularly apply to mobile IORT electron systems. More specifically, the charges to this Task Group are to (i) identify the key differences between stationary and mobile electron linear accelerators used for IORT, (ii) describe and recommend the implementation of an IORT program within the OR environment, (iii) present and discuss radiation protection issues and consequences of working within a nondedicated radiotherapy environment, (iv) describe and recommend the acceptance and machine commissioning of items that are specific to mobile electron linear accelerators, and (v) design and recommend an efficient quality assurance program for mobile systems.

Image fusion of CT and MRI data enables improved target volume definition in 3D-brachytherapy treatment planning

PURPOSE To integrate MRI into CT-based 3D-brachytherapy treatment planning using a software system for image registration and fusion. METHODS AND MATERIALS Sixteen patients with recurrent head-and-neck cancer, vulvar cancer, liposarcoma, and cervical cancer were treated with interstitial (n=12) and endocavitary (n=4) brachytherapy. CT and MRI scans were performed after implantation and prior to treatment planning. Image registration to integrate the CT and MR information into a single geometric framework was performed using a software algorithm based on mutual information. Conventional 3D-brachytherapy planning based on CT-information alone was compared to brachytherapy planning based on fused CT and MRI data. The accuracy of the image fusion was measured using predefined corresponding landmarks in the CT and MRI data. RESULTS The presented automated algorithm proved to be robust and reliable (mean registration error 1.8 mm, range 0.8-4.1 mm, SD 0.9 mm). Tumor visualization was difficult using CT alone in all cases. Brachytherapy treatment planning based on fused CT and MRI data enabled better definition of target volume and risk structures as compared to treatment planning based on CT alone. CONCLUSIONS Image registration and fusion is feasible for afterloading brachytherapy treatment planning. Treatment planning based on fused CT and MRI data resulted in improved target volume and risk structure definition.

Electromagnetically navigated brachytherapy as a new treatment option for peripheral pulmonary tumors.

Purpose:This technical note describes the principles of navigated brachytherapy for treatment of peripheral non-small cell lung cancer (NSCLC).Material and Methods:In a prospective feasibility trial a first patient with medically inoperable NSCLC in the right upper lobe was treated with external-beam radiotherapy (50 Gy) and navigated endoluminal brachytherapy (15 Gy). Navigated bronchoscopy was performed with an electromagnetic navigation system for localization of a microsensor mounted on the tip of a dedicated catheter placed within the working channel of a bronchoscope. The probe can be actively guided by a steering mechanism to targeted lesions in the periphery of the lung. After successful localization of the NSCLC, endobronchial ultrasound (EBUS) was performed to confirm the exact position in the center of the lesion. A 6-F brachytherapy catheter was placed within the tumor. Primary 3-D-planned brachytherapy was performed on chest CTs acquired with the inserted catheter. High-dose-rate brachytherapy (370 GBq iridium-192) was applied as a boost three times a week (single dose 5 Gy) and provided highly conformal irradiations of the NSCLC including the draining bronchovascular bundle.Results:The brachytherapy catheter was tolerated well during treatment (5 days) and alimentation was possible without any problems. Repeated CTs showed stable positioning of the catheter. During follow-up (12 months), endoluminal ultrasound and CT demonstrated a partial remission while histology showed a complete remission of the tumor.Conclusion:Navigated brachytherapy for peripheral pulmonary tumors not amenable to conventional bronchoscopy is feasible.Ziel:Diese technische Mitteilung beschreibt die Grundlagen einer navigierten Brachytherapie zur Therapie von peripheren, nichtkleinzelligen Bronchialkarzinomen (NSCLC).Material und Methodik:Im Rahmen einer prospektiven Machbarkeitsstudie wurde ein Patient mit einem aus internistischen Gründen inoperablen NSCLC im rechten Oberlappen mit einer Teletherapie (50 Gy) und einer navigierten Brachytherapie behandelt (15 Gy). Die navigierte Bronchoskopie wurde mit einem elektromagnetischen Navigationssystem durchgeführt. Dieses System erlaubte eine Echtzeitdarstellung eines Mikrosensors, der an der Spitze eines speziellen Navigationskatheters angebracht und in den Arbeitskanal des Bronchoskops eingeschoben wurde. Der Navigationskatheter kann aktiv mit Hilfe eines Lenkungssystems zu peripheren Lungentumoren geführt werden. Nach erfolgreicher Ansteuerung des NSCLC wurde ein endobronchialer Ultraschall (EBUS) zur Bestätigung einer zentralen Positionierung im Tumor durchgeführt (Abbildungen 1 und 2). Im Anschluss wurde ein konventioneller 6-F-Bronchuskatheter im Tumor platziert. Auf der Basis eines Planungs-CT, das mit liegendem Brachytherapiekatheter gefahren wurde, erfolgte eine primäre 3-D-geplante Brachytherapie. Die High-Dose-Rate-Brachytherapy (370 GBq Iridium-192) wurde als Boostbestrahlung appliziert (3 × 5 Gy/Woche) und erlaubte eine hochkonformale Bestrahlung des peripheren NSCLC und des zuführenden bronchovaskulären Bündels (Abbildungen 3 und 4).Ergebnisse:Der Brachytherapiekatheter wurde während der Behandlung gut toleriert und erlaubte eine problemlose Ernährung des Patienten. Wiederholte CT-Untersuchungen zeigten eine stabile Lage des Katheters. In der Nachsorge (12 Monate) zeigten EBUS und CT eine partielle und die histologische Untersuchung eine komplette Remission des Tumors.Schlussfolgerung:Eine navigierte Brachytherapie zur Therapie peripherer NSCLCs, die nicht mit einer konventionellen Bronchoskopie erreicht werden können, ist durchführbar.

Results of chest wall reirradiation using pulsed-dose-rate (PDR) brachytherapy molds for breast cancer local recurrences

PURPOSE We report in a retrospective study on the effect and toxicity of chest wall reirradiation using pulsed-dose-rate (PDR) afterloading molds. METHODS AND MATERIALS Between 1993 and 1999, a total of 58 patients were treated. All patients presented with locally recurrent breast cancer (31 patients had concomitant distant metastases) after mastectomy and a previously completed course of radiation therapy (median, 54 Gy; range, 36-70). Indication for reirradiation was a progressive macroscopic skin recurrence in 30 cases and an incomplete surgical resection in 28 patients. Standard treatment consisted of a split course with two fractions of 20 Gy (interval, 31 days). The reference dose was prescribed to the skin surface at 5 mm distance from the source. PDR brachytherapy (37 GBq, (192)Ir) was carried out after geometric distance optimization with 0.5-1 Gy/pulse/h. The irradiated median area was 423 cm(2) (range, 100-919). The median follow-up was 18 months (range, 7-84). RESULTS The actuarial 1-, 2- and 3-year local recurrence-free survival rates in patients treated for macroscopic disease (microscopic disease in parenthesis) were 89% (96%), 81% (85%), and 75% (71%). Local control was obtained in 24/30 (22/28) patients. Twenty-nine of the 34 patients (85%) who deceased during follow-up were locally controlled. 9/58 patients experienced Grade III acute toxicity, 35/58 patients Grade III (29/58 telangiectasia, 6/58 contracture), and 4/58 Grade IV late toxicity (RTOG/EORTC). CONCLUSION Reirradiation of the chest wall using PDR brachytherapy molds is effective and provides a high local control rate with acceptable toxicity.

Clinical Phase I/II trial to Investigate Preoperative Dose-Escalated Intensity-Modulated Radiation Therapy (IMRT) and Intraoperative Radiation Therapy (IORT) in patients with retroperitoneal soft tissue sarcoma: interim analysis

BackgroundLocal control rates in patients with retroperitoneal soft tissue sarcoma (RSTS) remain disappointing even after gross total resection, mainly because wide margins are not achievable in the majority of patients. In contrast to extremity sarcoma, postoperative radiation therapy (RT) has shown limited efficacy due to its limitations in achievable dose and coverage. Although Intraoperative Radiation Therapy (IORT) has been introduced in some centers to overcome the dose limitations and resulted in increased outcome, local failure rates are still high even if considerable treatment related toxicity is accepted. As postoperative administration of RT has some general disadvantages, neoadjuvant approaches could offer benefits in terms of dose escalation, target coverage and reduction of toxicity, especially if highly conformal techniques like intensity-modulated radiation therapy (IMRT) are considered.Methods/designThe trial is a prospective, one armed, single center phase I/II study investigating a combination of neoadjuvant dose-escalated IMRT (50–56 Gy) followed by surgery and IORT (10–12 Gy) in patients with at least marginally resectable RSTS. The primary objective is the local control rate after five years. Secondary endpoints are progression-free and overall survival, acute and late toxicity, surgical resectability and patterns of failure. The aim of accrual is 37 patients in the per-protocol population.DiscussionThe present study evaluates combined neoadjuvant dose-escalated IMRT followed by surgery and IORT concerning its value for improved local control without markedly increased toxicity.Trial registrationNCT01566123

CORRELATION OF INTRAOPERATIVELY IRRADIATED VOLUME AND FIBROSIS IN PATIENTS WITH SOFT-TISSUE SARCOMA OF THE EXTREMITIES

PURPOSE To investigate the influence of intraoperatively irradiated volume on soft-tissue fibrosis. METHODS AND MATERIALS Fifty-three patients with soft-tissue sarcoma of the extremities were treated with intraoperative radiotherapy (IORT) (median dose 15 Gy) and postoperative fractionated therapy (median dose 46 Gy). The median follow-up was 41.5 months (range 18-94). Late toxicity was classified according to the LENT-SOMA criteria. A Cox regression model was calculated to identify the parameters that could influence soft-tissue fibrosis Grade 3 or 4. Five parameters were observed: extent of surgical procedure, IORT in case of recurrence, extent of IORT volume, extent of IORT dose, and extent of postoperative volume. In addition, a logistic regression model was calculated to demonstrate the relationship between the IORT volume and fibrosis development. RESULTS The overall survival rate after 5 years was 84%. The actuarial tumor control rate was 90% after 5 years. Eleven patients developed soft-tissue fibrosis. Five patients developed Grade 3 fibrosis and 1 patient developed Grade 4 fibrosis. Only the IORT volume had a significant influence on Grade 3 or 4 fibrosis development. An IORT volume of 210 cm(3) conveyed a 5% risk (confidence interval 1-20%) of the development of severe fibrosis. The risk of severe Grade 3 or 4 fibrosis increased to 50% (confidence interval 15-80%) if a volume of 420 cm(3) was irradiated. CONCLUSION The effect of volume in patients treated with IORT was remarkable. The ratio of side effects was relatively low. The risk of soft-tissue Grade 3 or 4 fibrosis increased with the extent of the IORT volume. Compared with the literature, IORT provides excellent local control in these patients.

5-Year Results of Pulsed Dose Rate Brachytherapy Applied as a Boost after Breast-Conserving Therapy in Patients at High Risk for Local Recurrence from Breast Cancer

Purpose: The aim of this study was to evaluate effect, toxicity, and cosmesis of a prospectively applied pulsed dose rate (PDR) brachytherapy boost schedule in patients with stage I/II/IIIa invasive breast cancer. Patients and Methods: A total of 113 patients were treated after breast-conserving surgery (BCS) and external beam radiotherapy (median 50 Gy, range 46–52). The boost dose was graded in accordance to the pathologic tumor characteristics: 20–25 Gy: incomplete resection (n = 34), vascular invasion (n = 27), close margin resection (n = 41); 15 Gy: T2G3 stage (n = 11). PDR brachytherapy (37 GBq, 192Ir source) was carried out after geometric volume optimization with 1 Gy/pulse/h. The implantation and dose specification were performed similar to the rules of the Paris system. Results: The overall local failure rate after a median follow-up of 61 months was 4.4% (5/113). The actuarial 5- and 8-year local recurrence-free survival rates were 95% and 93%, respectively. Cosmesis was rated by 90% of the patients as excellent or good. 14/113 patients experienced grade III (all caused by planar telangiectasia) and none of the patients grade IV late toxicity of the skin (RTOG/EORTC). A boost dose of 25 Gy resulted in a significantly higher rate of late toxicity (Fishers exact test, p < 0.01). Conclusions: PDR brachytherapy is safe, effective, and provides good cosmesis. A CLDR breast boost can be replaced by PDR brachytherapy without significant loss of therapeutic ratio.Ziel: Diese Studie diente der Evaluierung von Effektivität, Toxizität und kosmetischen Ergebnissen eines prospektiv applizierten PDR- (pulsed dose-rate-)Brachytherapieboostkonzeptes bei Patienten mit invasivem Mammakarzinom im Stadium I/II/IIIa. Patienten und Methoden: Insgesamt wurden 113 Patienten nach brusterhaltender Therapie (BET) und externer Bestrahlung (Median 50 Gy, Range 46–52) behandelt. Die Boostdosis wurde anhand histopathologischer Tumorcharakteristika graduiert (Tabelle 1): 20–25 Gy: inkomplette Resektion (n = 34), Lymphgefäß- oder Gefäßinvasion (n = 27), “close-margin”-Resektion (n = 41); 15 Gy: T2G3 Stadium (n = 11). Die gepulste Brachytherapie (37 GBq, 192Ir-Quelle) wurde nach geometrischer Volumenoptimierung mit 1 Gy/Puls/h durchgeführt. Applikation und Dosisspezifikation erfolgten in Anlehnung an das Pariser System. Ergebnisse: Die Lokalrezidivrate betrug nach einer medianen Nachbeobachtungszeit von 61 Monaten 4,4% (5/113). Das aktuarische lokalrezidivfreie 5- und 8-Jahres-Überleben betrug 95% bzw. 93% (Abbildungen 1 und 2). 90% der Patienten beurteilten ihre kosmetischen Ergebnisse als gut oder exzellent (Tablle 3). Bedingt durch flächige Teleangiektasien im Boostareal entwickelten 14/113 Patienten eine Grad-III-Spättoxizität (0/113 Grad IV) der haut (RTOG/EORTC, Tabelle 2). Eine Boostdosis von 25 Gy resultierte in einer signifikant erhöhten Spättoxizitätsrate (Fishers Exakt-Test, p < 0,01, Abbildung 3). Schlussfolgerung: Die gepulste Brachytherapie ist sicher und effektiv. Die kosmetischen Ergebnisse sind gut. Der interstitielle CLDR-Mammaboost kann durch die PDR-Brachytherapie ohne signifikanten Verlust an therapeutischer Breite ersetzt werden.

PDR brachytherapy with flexible implants for interstitial boost after breast-conserving surgery and external beam radiation therapy

BACKGROUND AND PURPOSE For radiobiological reasons the new concept of pulsed dose rate (PDR) brachytherapy seems to be suitable to replace traditional CLDR brachytherapy with line sources. PDR brachytherapy using a stepping source seems to be particularly suitable for the interstitial boost of breast carcinoma after breast-conserving surgery and external beam irradiation since in these cases the exact adjustment of the active lengths is essential in order to prevent unwanted skin dose and consequential unfavorable cosmetic results. The purpose of this study was to assess the feasibility and morbidity of a PDR boost with flexible breast implants. MATERIALS AND METHODS Sixty-five high risk patients were treated with an interstitial PDR boost. The criteria for an interstitial boost were positive margin or close margin, extensive intraductal component (EIC), intralymphatic extension, lobular carcinoma, T2 tumors and high nuclear grade (GIII). Dose calculation and specification were performed following the rules of the Paris system. The dose per pulse was 1 Gy. The pulse pauses were kept constant at 1 h. A geometrically optimized dose distribution was used for all patients. The treatment schedule was 50 Gy external beam to the whole breast and 20 Gy boost. PDR irradiations were carried out with a nominal 37 GBq 192-Ir source. RESULTS The median follow-up was 30 months (minimum 12 months, maximum 54 months). Sixty percent of the patients judged their cosmetic result as excellent, 27% judged it as good, 11% judged it as fair and 2% judged it as poor. Eighty-six percent of the patients had no radiogenous skin changes in the boost area. In 11% of patients minimal punctiform telangiectasia appeared at single puncture sites. In 3% (2/65) of patients planar telangiectasia appeared on the medial side of the implant. The rate of isolated local recurrence was 1.5%. In most cases geometrical volume optimization (GVO) yields improved dose distributions with respect to homogeneity and compensation of underdosage at the margins of the implant. Only in 9% of patients was the dose distribution impaired by GVO. However, GVO causes a number of substantial changes of the dose distribution which have consequences for its application. CONCLUSIONS The interstitial CLDR boost of the breast can be replaced by the PDR technique without severe acute and late complications and without deterioration of the cosmetic results.