Determination of the dose rate around a HDR 192Ir brachytherapy source with the microDiamond and the microSilicon detector.

PURPOSE: To employ the microDiamond and the microSilicon detector (mDD and mSD, both PTW-Freiburg, Germany) to determine the dose rate around a HDR 192Ir brachytherapy source (model mHDR-v2r, Elekta AB, Sweden). METHODS: The detectors were calibrated with a 60Co beam at the PTW Calibration Laboratory. Measurements around the 192Ir source were performed inside a PTW MP3 water phantom. The detectors were placed at selected points of measurement at radial distances r, ranging from 0.5 to 10 cm, keeping the polar angle θ = 90°. Additional measurements were performed with the mSD at fixed distances r = 1, 3 and 5 cm, with θ varying from 0 to 150°, 0 to 166°, and 0 to 168°, respectively. The corresponding mDD readings were already available from a previous work (Rossi et al., 2020). The beam quality correction factor of both detectors, as well as a phantom effect correction factor to account for the difference between the experimental geometry and that assumed in the TG-43 formalism, were determined using the Monte Carlo (MC) toolkit EGSnrc. The beam quality correction factor was factorized into energy dependence and volume-averaging correction factors. Using the abovementioned MC-based factors, the dose rate to water at the different points of measurement in TG-43 conditions was obtained from the measured readings, and was compared to the dose rate calculated according to the TG-43 formalism. RESULTS: The beam quality correction factor was considerably closer to unity for the mDD than for the mSD. The energy dependence of the mDD showed a very weak radial dependence, similar to the previous findings showing a weak angular dependence as well (Rossi et al., 2020). Conversely, the energy dependence of the mSD decreased significantly with increasing distances, and also showed a considerably more pronounced angular dependence, especially for the smallest angles. The volume-averaging showed a similar radial dependence for both detectors: the correction had a maximal impact at 0.5 cm and then approached unity for larger distances, as expected. Concerning the angular dependence, the correction for the mSD was also similar to the one previously determined for the mDD (Rossi et al., 2020): a maximal impact was observed at θ = 0°, with values tending to unity for larger angles. In general, the volume-averaging was less pronounced for the mSD due to the smaller sensitive volume radius. After the application of the MC-based factors, differences between mDD dose rate measurements and TG-43 dose rate calculations ranged from -2.6% to +4.3%, with an absolute average difference of 1.0%. For the mSD, the differences ranged from -3.1% to +5.2%, with an absolute average difference of 1.0%. For both detectors, all differences but one were within the combined uncertainty (k = 2). The differences of the mSD from the mDD ranged from -3.9% to +2.6%, with the vast majority of them being within the combined uncertainty (k = 2). For θ ≠ 0°, the mDD was able to provide sufficiently accurate results even without the application of the MC-based beam quality correction factor, with differences to the TG-43 dose rate calculations from -1.9% to +3.4%, always within the combined uncertainty (k = 2). CONCLUSION: The mDD and the mSD showed consistent results and appear to be well suitable for measuring the dose rate around HDR 192Ir brachytherapy sources. MC characterization of the detectors response is needed to determine the beam quality correction factor and to account for energy dependence and/or volume-averaging, especially for the mSD. Our findings support the employment of the mDD and mSD for source QA, TPS verification and TG-43 parameters determination.

Enhancement of the EGSnrc code egs_chamber for fast fluence calculations of charged particles.

PURPOSE: Simulation of absorbed dose deposition in a detector is one of the key tasks of Monte Carlo (MC) dosimetry methodology. Recent publications (Hartmann and Zink, 2018; Hartmann and Zink, 2019; Hartmann et al., 2021) have shown that knowledge of the charged particle fluence differential in energy contributing to absorbed dose is useful to provide enhanced insight on how response depends on detector properties. While some EGSnrc MC codes provide output of charged particle spectra, they are often restricted in setup options or limited in calculation efficiency. For detector simulations, a promising approach is to upgrade the EGSnrc code egs_chamber which so far does not offer charged particle calculations. METHODS: Since the user code cavity offers charged particle fluence calculation, the underlying algorithm was embedded in egs_chamber. The modified code was tested against two EGSnrc applications and DOSXYZnrc which was modified accordingly by one of the authors. Furthermore, the gain in efficiency achieved by photon cross section enhancement was determined quantitatively. RESULTS: Electron and positron fluence spectra and restricted cema calculated by egs_chamber agreed well with the compared applications thus demonstrating the feasibility of the new code. Additionally, variance reduction techniques are now applicable also for fluence calculations. Depending on the simulation setup, considerable gains in efficiency were obtained by photon cross section enhancement. CONCLUSION: The enhanced egs_chamber code represents a valuable tool to investigate the response of detectors with respect to absorbed dose and fluence distribution and the perturbation caused by the detector in a reasonable computation time. By using intermediate phase space scoring, egs_chamber offers parallel calculation of charged particle fluence spectra for different detector configurations in one single run.

ESTRO IORT Task Force/ACROP recommendations for intraoperative radiation therapy in borderline-resected pancreatic cancer.

Radiation therapy (RT) is a valuable component of multimodal treatment for localized pancreatic cancer. Intraoperative radiation therapy (IORT) is a very precise RT modality to intensify the irradiation effect for cancer involving upper abdominal structures and organs, generally delivered with electrons (IOERT). Unresectable, borderline and resectable disease categories benefit from dose-escalated chemoradiation strategies in the context of active systemic therapy and potential radical surgery. Prolonged preoperative treatment may act as a filter for selecting patients with occult resistant metastatic disease. Encouraging survival rates have been documented in patients treated with preoperative chemoradiation followed by radical surgery and IOERT (>20 months median survival, >35% survival at 3 years). Intensive preoperative treatment, including induction chemotherapy followed by chemoradiation and an IOERT boost, appears to prolong long-term survival within the subset of patients who remain relapse-free for>2 years (>30 months median survival; >40% survival at 3 years). Improvement of local control through higher RT doses has an impact on the survival of patients with a lower tendency towards disease spread. IOERT is a well-accepted approach in the clinical scenario (maturity and reproducibility of results), and extremely accurate in terms of dose-deposition characteristics and normal tissue sparing. The technique can be adapted to systemic therapy and surgical progress. International guidelines (National Comprehensive Cancer Network or NCCN guidelines) currently recommend use of IOERT in cases of close surgical margins and residual disease. We hereby report the ESTRO/ACROP recommendations for performing IOERT in borderline-resectable pancreatic cancer.

ESTRO IORT Task Force/ACROP recommendations for intraoperative radiation therapy in unresected pancreatic cancer.

Radiation therapy (RT) is a valuable component of multimodal treatment for localized pancreatic cancer. Intraoperative radiation therapy (IORT) is a very precise sub-component of RT that can intensify the irradiation effect for cancer involving an anatomically well-defined volume, generally delivered with electrons (IOERT). Unresectable disease categories benefit from dose-escalated chemoradiation strategies in the context of active systemic therapy and potential radical surgery. Prolonged preoperative treatment may act as a filter for selecting patients with occult resistant metastatic disease. Long-term survivors were observed among unresected patients treated with external beam RT and an IOERT boost (OS 6% at 3 years; 3% >5 years). Improvement of local control through higher RT doses has an impact on the survival of patients with a lower tendency towards disease spread. IOERT is a well-accepted asset in the clinical scenario (maturity and reproducibility of results, albeit of low official level of evidence) and extremely accurate in terms of dose-deposit characteristics and normal tissue sparing. It is a technique that can be integrated with systemic therapy and surgical progress. International guidelines (National Comprehensive Cancer Network or NCCN guidelines) currently recommend the use of IOERT in cases of close surgical margins and residual disease. We report the ESTRO/ACROP recommendations for performing IOERT in unresected pancreatic cancer.

[Detector Based Determination of Water Absorbed Dose According to DIN 6800 Teil 1: Suggestion for an Extension of the Fundamental Formalism]. / Ermittlung der Wasser-Energiedosis nach der Sondenmethode gemäß DIN 6800 Teil 1: Vorschlag für eine Erweiterung der Grundgleichung.

For any detector to be used for the determination of absorbed dose at the point of measurement in water a basic equation is required to convert the reading of the detector into absorbed dose in water. The German DIN 6800 part 1 provides a general formalism for that. A further differentiated formalism applicable to photon dosimetry is suggested in this work. This modified formalism presents the two following still general and at the same time fundamental properties of any dosimetry detector: a) a clear distinction of correction factors with respect to the physical processes involved during the measurement, and b) the fact that the process of energy absorption in the detector is determined by the spectral distribution of the fluence of the secondary charged particles. It is concluded that based on the modified formalism and knowing this spectral distribution within the detector a general method is available with benefits for ionization chambers as well as for any other dosimetry detector and which is applicable at reference as well as non-reference conditions without any preconditions.

Present state and issues in IORT Physics.

Literature was reviewed to assess the physical aspects governing the present and emerging technologies used in intraoperative radiation therapy (IORT). Three major technologies were identified: treatment with electrons, treatment with external generators of kV X-rays and electronic brachytherapy. Although also used in IORT, literature on brachytherapy with radioactive sources is not systematically reviewed since an extensive own body of specialized literature and reviews exists in this field. A comparison with radioactive sources is made in the use of balloon catheters for partial breast irradiation where these are applied in almost an identical applicator technique as used with kV X-ray sources. The physical constraints of adaption of the dose distribution to the extended target in breast IORT are compared. Concerning further physical issues, the literature on radiation protection, commissioning, calibration, quality assurance (QA) and in-vivo dosimetry of the three technologies was reviewed. Several issues were found in the calibration and the use of dosimetry detectors and phantoms for low energy X-rays which require further investigation. The uncertainties in the different steps of dose determination were estimated, leading to an estimated total uncertainty of around 10-15% for IORT procedures. The dose inhomogeneity caused by the prescription of electrons at 90% and by the steep dose gradient of kV X-rays causes additional deviations from prescription dose which must be considered in the assessment of dose response in IORT.

Intraoperative electron radiation therapy combined with external beam radiation therapy and limb sparing surgery in extremity soft tissue sarcoma: a retrospective single center analysis of 183 cases.

BACKGROUND AND PURPOSE: To report our experience with limb-sparing surgery, IOERT and EBRT in extremity STS. MATERIALS AND METHODS: 183 patients were retrospectively analyzed. 78% presented in primary situation, with 80% located in the lower limb. Stage at presentation was: I: 6%, IIa: 25%, IIb: 21%, III: 42%, IV: 7%. The majority showed high-grade lesions (grade 1: 5%, 2: 31%, 3: 64%). IOERT was applied to the tumor bed (median 15Gy) and preceded (9%) or followed (91%) by EBRT (median 45Gy) in all patients. RESULTS: Median follow-up was 64months (78months in survivors). Surgery was complete in 68%, while 32% had microscopic residual disease. 5- and 10-year-LC was 86% and 84%, respectively. LC was significantly higher in primary compared to recurrent disease and tended to be higher after complete resection. Estimated 5- and 10-year-DC was 68% and 66%, while corresponding OS was 77% and 66%, respectively. OS was significantly affected by grading and stage. Severe postoperative complications and late toxicities were observed in 19% and 20%, respectively. Limb-preservation rate was 95% with good function in 83%. CONCLUSIONS: Combination of limb-sparing surgery, IOERT and EBRT achieved encouraging LC and OS in this unfavorable patient group with acceptable postoperative complications and low rates of late toxicities resulting in a high limb-preservation rate and good functional outcome.

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.

BACKGROUND: To report an unplanned interim analysis of a prospective, one-armed, single center phase I/II trial (NCT01566123). METHODS: Between 2007 and 2013, 27 patients (pts) with primary/recurrent retroperitoneal sarcomas (size > 5 cm, M0, at least marginally resectable) were enrolled. The protocol attempted neoadjuvant IMRT using an integrated boost with doses of 45-50 Gy to PTV and 50-56 Gy to GTV in 25 fractions, followed by surgery and IOERT (10-12 Gy). Primary endpoint was 5-year-LC, secondary endpoints included PFS, OS, resectability, and acute/late toxicity. The majority of patients showed high grade lesions (FNCLCC G1:18%, G2:52%, G3:30%), predominantly liposarcomas (70%). Median tumor size was 15 cm (6-31). RESULTS: Median follow-up was 33 months (5-75). Neoadjuvant IMRT was performed as planned (median dose 50 Gy, 26-55) in all except 2 pts (93%). Gross total resection was feasible in all except one patient. Final margin status was R0 in 6 (22%) and R1 in 20 pts (74%). Contiguous-organ resection was needed in all grossly resected patients. IOERT was performed in 23 pts (85%) with a median dose of 12 Gy (10-20 Gy).We observed 7 local recurrences, transferring into estimated 3- and 5-year-LC rates of 72%. Two were located outside the EBRT area and two were observed after more than 5 years. Locally recurrent situation had a significantly negative impact on local control. Distant failure was found in 8 pts, resulting in 3- and 5-year-DC rates of 63%. Patients with leiomyosarcoma had a significantly increased risk of distant failure. Estimated 3- and 5-year-rates were 40% for PFS and 74% for OS. Severe acute toxicity (grade 3) was present in 4 pts (15%). Severe postoperative complications were found in 9 pts (33%), of whom 2 finally died after multiple re-interventions. Severe late toxicity (grade 3) was scored in 6% of surviving patients after 1 year and none after 2 years. CONCLUSION: Combination of neoadjuvant IMRT, surgery and IOERT is feasible with acceptable toxicity and yields good results in terms of LC and OS in patients with high-risk retroperitoneal sarcomas. Long term follow-up seems mandatory given the observation of late recurrences. Accrual of patients will be continued with extended follow-up. TRIAL REGISTRATION: NCT01566123.

Excellent local control with IOERT and postoperative EBRT in high grade extremity sarcoma: results from a subgroup analysis of a prospective trial.

BACKGROUND: To report the results of a subgroup analysis of a prospective phase II trial focussing on radiation therapy and outcome in patients with extremity soft tissue sarcomas (STS). METHODS: Between 2005 and 2010, 50 patients (pts) with high risk STS (size ≥ 5 cm, deep/extracompartimental location, grade II-III (FNCLCC)) were enrolled. The protocol comprised 4 cycles of neoadjuvant chemotherapy with EIA (etoposide, ifosfamide and doxorubicin), definitive surgery with IOERT, postoperative EBRT and 4 adjuvant cycles of EIA. 34 pts, who suffered from extremity tumors and received radiation therapy after limb-sparing surgery, formed the basis of this subgroup analysis. RESULTS: Median follow-up from inclusion was 48 months in survivors. Margin status was R0 in 30 pts (88%) and R1 in 4 pts (12%). IOERT was performed as planned in 31 pts (91%) with a median dose of 15 Gy, a median electron energy of 6 MeV and a median cone size of 9 cm. All patients received postoperative EBRT with a median dose of 46 Gy after IOERT or 60 Gy without IOERT. Median time from surgery to EBRT and median EBRT duration was 36 days, respectively. One patient developed a local recurrence while 11 patients showed nodal or distant failures. The estimated 5-year rates of local control, distant control and overall survival were 97%, 66% and 79%, respectively. Postoperative wound complications were found in 7 pts (20%), resulting in delayed EBRT (>60 day interval) in 3 pts. Acute radiation toxicity mainly consisted of radiation dermatitis (grade II: 24%, no grade III reactions). 4 pts developed grade I/II radiation recall dermatitis during adjuvant chemotherapy, which resolved during the following cycles. Severe late toxicity was observed in 6 pts (18%). Long-term limb preservation was achieved in 32 pts (94%) with good functional outcome in 81%. CONCLUSION: Multimodal therapy including IOERT and postoperative EBRT resulted in excellent local control and good overall survival in patients with high risk STS of the extremities with acceptable acute and late radiation side effects. Limb preservation with good functional outcome was achieved in the majority of patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01382030, EudraCT 2004-002501-72, 17.06.2011.

Technical and dosimetric aspects of the total skin electron beam technique implemented at Heidelberg University Hospital.

AIM: To give a technical description and present the dosimetric proporties of the total skin electron beam technique implemented at Heidelberg University Hospital. BACKGROUND: Techniques used for total skin electron beam irradiation were developed as early as in the 1960s to 1980s and have, since then, hardly changed. However, new measurements of the established methods allow deeper insight into the dose distributions and reasons for possible deviations from uniform dose. MATERIALS AND METHODS: The TSEI technique applied at Heidelberg University Hospital since 1992 consists of irradiating the patient with a superposition of two beams of low energy electrons at gantry angles of 72° and 108° while he is rotating in a standing position on a turntable at 370 cm distance from the accelerator. The energy of the electron beam is degraded to 3.9 MeV by passing through an attenuator of 6 mm of Perspex. A recent re-measurement of the dose distribution is presented using modern dosimetry tools like a linear array of ionization chambers in combination with established methods like thermoluminescent detectors and film dosimetry. RESULTS: The measurements show a strong dependence of dose uniformity on details of the setup like gantry angles. CONCLUSIONS: Dose uniformity of -4/+8% to the majority of the patient's skin can be achieved, however, for the described rotational technique overdoses up to more than 20% in small regions seem unavoidable.

Intraoperative electron radiation therapy (IOERT) in patients with locally recurrent renal cell carcinoma.

BACKGROUND: To analyze our experience with intraoperative electron radiation therapy (IOERT) followed by moderate doses of external beam radiation therapy (EBRT) in patients with locally recurrent renal cell carcinoma. METHODS: From 1992 to 2010, 17 patients with histologically proven, locally recurrent renal cell carcinoma (median tumor size 7 cm) were treated by surgery and IOERT with a median dose of 15 Gy. All patients met the premise of curative intent including 7 patients with oligometastases at the time of recurrent surgery, which were resected and/or irradiated. The median time interval from primary surgery to local recurrence was 26 months. Eleven patients received additional 3D-conformal EBRT with a median dose of 40 Gy. RESULTS: Surgery resulted in free but close margins in 6 patients (R0), while 9 patients suffered from microscopic (R1) and 2 patients from macroscopic (R2) residual disease. After a median follow-up of 18 months, two local recurrences were observed, resulting in an actuarial 2-year local control rate of 91%. Eight patients developed distant failures, predominantly to liver and bone, resulting in an actuarial 2-year progression free survival of 32%. An improved PFS rate was found in patients with a larger time interval between initial surgery and recurrence (> 26 months). The actuarial 2-year overall survival rate was 73%. Lower histological grading (G1/2) was the only factor associated with improved overall survival. Perioperative complications were found in 4 patients. No IOERT specific late toxicities were observed. CONCLUSIONS: Combination of surgery, IOERT and EBRT resulted in high local control rates with low toxicity in patients with locally recurrent renal cell cancer despite an unfavorable surgical outcome in the majority of patients. However, progression-free and overall survival were still limited due to a high distant failure rate, indicating the need for intensified systemic treatment especially in patients with high tumor grading and short interval to recurrence.

Primary radiotherapy with endobronchial high-dose-rate brachytherapy boost for inoperable lung cancer: long-term results.

BACKGROUND: To retrospectively evaluate the outcome of patients with inoperable non-small-cell lung cancer treated with primary external beam radiotherapy combined with high-dose-rate endobronchial brachytherapy boost. PATIENTS AND METHODS: Between 1988 and 2005, 35 patients with non-small-cell lung cancer (stage I-III) ineligible for surgical resection and/or chemotherapy, were primarily treated with external beam radiotherapy with a median total dose of 50 Gy (range, 46-60). A median of 3 fractions high-dose-rate endobronchial brachytherapy was applied as a boost after external beam radiotherapy, the median total dose was 15 Gy (range, 8-20). High-dose-rate endobronchial brachytherapy was carried out with iridium-192 sources (370 GBq) and prescribed to 1 cm distance from the source axis. RESULTS: With a median follow-up of 26 months from the first fraction of high-dose-rate endobronchial brachytherapy, the 1-, 2- and 5-year overall (local progression-free) survival rates were 76% (76%), 61% (57%) and 28% (42%), respectively. Complete or partial remission rates 6 to 8 weeks after treatment were 57% and 17%, respectively. Significant prognostic favorable factors were a complete remission 6-8 weeks after treatment and a negative nodal status. In patients without mediastinal node involvement, a long-term local control could be achieved with 56% 5-year local progression-free survival. Common Toxicity Criteria grade 3 toxicities were hemoptysis (n = 2) and necrosis (n = 1). One fatal hemoptysis occurred in combination with a local tumor recurrence. CONCLUSIONS: The combination of external beam radiotherapy with high-dose-rate endobronchial brachytherapy boost is an effective primary treatment with acceptable toxicity in patients with non-small-cell lung cancer ineligible for surgical resection and/or chemotherapy.

Intraoperative Electron Radiation Therapy (IOERT) in the management of locally recurrent rectal cancer.

BACKGROUND: To evaluate disease control, overall survival and prognostic factors in patients with locally recurrent rectal cancer after IOERT-containing multimodal therapy. METHODS: Between 1991 and 2006, 97 patients with locally recurrent rectal cancer have been treated with surgery and IOERT. IOERT was preceded or followed by external beam radiation therapy (EBRT) in 54 previously untreated patients (median dose 41.4 Gy) usually combined with 5-Fluouracil-based chemotherapy (89%). IOERT was delivered via cylindric cones with doses of 10-20 Gy. Adjuvant CHT was given only in a minority of patients (34%). Median follow-up was 51 months. RESULTS: Margin status was R0 in 37%, R1 in 33% and R2 in 30% of the patients. Neoadjuvant EBRT resulted in significantly increased rates of free margins (52% vs. 24%). Median overall survival was 39 months. Estimated 5-year rates for central control (inside the IOERT area), local control (inside the pelvis), distant control and overall survival were 54%, 41%, 40% and 30%. Resection margin was the strongest prognostic factor for overall survival (3-year OS of 80% (R0), 37% (R1), 35% (R2)) and LC (3-year LC 82% (R0), 41% (R1), 18% (R2)) in the multivariate model. OS was further significantly affected by clinical stage at first diagnosis and achievement of local control after treatment in the univariate model. Distant failures were found in 46 patients, predominantly in the lung. 90-day postoperative mortality was 3.1%. CONCLUSION: Long term OS and LC can be achieved in a substantial proportion of patients with recurrent rectal cancer using a multimodality IOERT-containing approach, especially in case of clear margins. LC and OS remain limited in patients with incomplete resection. Preoperative re-irradiation and adjuvant chemotherapy may be considered to improve outcome.

A 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.

BACKGROUND: Local 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/DESIGN: The 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. DISCUSSION: The 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 REGISTRATION: NCT01566123.

Total skin electron beam therapy as palliative treatment for cutaneous manifestations of advanced, therapy-refractory cutaneous lymphoma and leukemia.

BACKGROUND: To retrospectively access the outcome and toxicity of a total skin electron beam therapy (TSEBT) in patients with cutaneous lymphoma (CL) or leukemia. PATIENTS AND METHODS: Treatment results of 25 patients (median age 63 years; 5 female, 20 male) with cutaneous manifestations of advanced and therapy-refractory CL (n = 21; T-cell lymphomas n = 18, B-cell lymphomas n = 3) stage IIB-IV or leukemia (n = 4; AML n = 2, CLL n = 1, PDC n = 1) treated between 1993 and 2010 were reviewed. All patients were symptomatic. The median total dose was 29Gy, applied in 29 fractions of median 1 Gy each. RESULTS: The median follow-up was 10 months. Palliation was achieved in 23 patients (92%). A clinical complete response was documented in 13 (52%) and a partial response in 10 patients (40%). The median time to skin progression was 5 months (range 1-18 months) and the actuarial one-year progression-free survival 35%. The median overall survival (OS) after the initiation of TSEBT was 10 months (range 1-46 months) and the actuarial one-year OS 45%. TSEBT related acute adverse events (grade 1 or 2) were observed in all patients during the treatment period. An acute grade 3 epitheliolysis developed in eight patients (32%). Long-term adverse events as a hyperpigmentation of the skin (grade 1 or 2) were documented in 19 patients (76%), and a hypohidrosis in seven patients (28%). CONCLUSION: For palliation of symptomatic cutaneous manifestations of advanced cutaneous lymphoma or leukemia, total skin electron beam therapy is an efficient and well tolerated considerable treatment option.

Aggressive local treatment containing intraoperative radiation therapy (IORT) for patients with isolated local recurrences of pancreatic cancer: a retrospective analysis.

BACKGROUND: To evaluate the use of intraoperative radiation therapy (IORT) in the multimodality treatment of patients with isolated local recurrences of pancreatic cancer. METHODS: We retrospectively analyzed 36 patients with isolated local recurrences of pancreatic cancer who have been treated with a combination of surgery, IORT and EBRT. Median time from initial treatment to recurrence was 20 months. All patients were surgically explored. In 18 patients a gross total resection was achieved, whereas the other half received only debulking or no resection at all. All patients received IORT with a median dose of 15 Gy. Additional EBRT was applied to 31 patients with a median dose of 45 Gy, combined with concurrent, mainly gemcitabine-based chemotherapy. RESULTS: Median follow-up in surviving patients was 23 months. Local progression was found in 6 patients after a median time of 17 months, resulting in estimated 1- and 2-year local control rates of 91% and 67%, respectively. Distant failure was observed in 23 patients, mainly in liver or peritoneal space. The median estimated progression-free survival was 9 months with 1- and 2-year rates of 40% and 26%, respectively. We found an encouraging estimated median overall survival of 19 months, transferring into 1- and 2-year rates of 66% and 45%. Notably 6 of 36 patients (17%) lived for more than 3 years. Severe postoperative complications were found in 3 and chemoradiation-related grade III toxicity in 6 patients. No severe IORT related toxicity was observed. CONCLUSION: Combination of surgery, IORT and EBRT in patients with isolated local recurrences of pancreatic cancer resulted in encouraging local control and overall survival in our cohort with acceptable toxicity. Our approach seems to be superior to palliative chemotherapy or chemoradiation alone and should be further investigated in a prospective setting specifically addressing isolated local recurrences of pancreatic cancer.

Safety and efficacy of thoracic external beam radiotherapy after airway stenting in malignant airway obstruction.

PURPOSE: We retrospectively evaluated the outcome and toxicity of external beam radiotherapy (EBRT) after airway stents were placed in patients treated for malignant airway obstruction. METHODS AND MATERIALS: Between 2004 and 2009, we performed airway stenting followed by EBRT in 43 patients for symptomatic primary lung cancer (n = 31) or other thoracic malignancies (n = 12). The median time interval between stent placement and first irradiation was 14 days. A median total dose of 50 Gy was delivered. Sixty-seven percent of the patients had reduced performance status (Karnofsky performance score, ≤70). RESULTS: EBRT had to be stopped prematurely in 16 patients (37%), at a median total dose of 17 Gy, for various reasons. In this group of patients, the survival was poor, with a median overall survival (OS) of only 21 days. Twenty-seven patients (63%) completed radiotherapy as planned, with a median OS of 8.4 months. Fourteen of 43 patients (33%) developed at least one Common Terminology Criteria for Adverse Event of grade 3 to 5. The most common event was a malignant restenosis of the stent leading to asphyxia (n = 7), followed by fistula formation (n = 4), necrosis (n = 3), mediastinitis with abscess (n = 1), secondary nonmalignant airway stenosis (n = 1), and hemoptysis (n = 1). With the exception of one event, all events were associated with a local progression of the tumor. CONCLUSIONS: Although the long-term prognosis for patients with malignant airway obstruction is poor, airway stenting combined with EBRT offers a possible therapeutic option, achieving fast relief of acute respiratory distress with an associated antitumor effect, resulting in a potential survival benefit. However, due to local advanced tumor growth, increased rates of adverse events are to be expected, necessitating careful monitoring.

Clinical phase I/II trial to investigate neoadjuvant intensity-modulated short term radiation therapy (5 × 5 Gy) and intraoperative radiation therapy (15 Gy) in patients with primarily resectable pancreatic cancer - NEOPANC.

BACKGROUND: The current standard treatment, at least in Europe, for patients with primarily resectable tumors, consists of surgery followed by adjuvant chemotherapy. But even in this prognostic favourable group, long term survival is disappointing because of high local and distant failure rates. Postoperative chemoradiation has shown improved local control and overalls survival compared to surgery alone but the value of additional radiation has been questioned in case of adjuvant chemotherapy. However, there remains a strong rationale for the addition of radiation therapy considering the high rates of microscopically incomplete resections after surgery. As postoperative administration of radiation therapy has some general disadvantages, neoadjuvant and intraoperative approaches theoretically offer benefits in terms of dose escalation, reduction of toxicity and patients comfort especially if hypofractionated regimens with highly conformal techniques like intensity-modulated radiation therapy are considered. METHODS/DESIGN: The NEOPANC trial is a prospective, one armed, single center phase I/II study investigating a combination of neoadjuvant short course intensity-modulated radiation therapy (5 × 5 Gy) in combination with surgery and intraoperative radiation therapy (15 Gy), followed by adjuvant chemotherapy according to the german treatment guidelines, in patients with primarily resectable pancreatic cancer. The aim of accrual is 46 patients. DISCUSSION: The primary objectives of the NEOPANC trial are to evaluate the general feasibility of this approach and the local recurrence rate after one year. Secondary endpoints are progression-free survival, overall survival, acute and late toxicity, postoperative morbidity and mortality and quality of life. TRIAL REGISTRATION: NCT01372735.

Dosimetric verification of source strength for HDR afterloading units with Ir-192 and Co-60 photon sources: Comparison of three different international protocols.

Before clinical use of a brachytherapy source, regulations or recommendations by medical physics societies require an independent measurement of its air kerma strength by a qualified medical physicist. Currently, in addition to Ir-192, also HDR-Co-60 sources are increasingly coming into operation. However, the existing dosimetry protocols do not provide any guidelines for Co-60 sources. The purpose of this work was therefore to compare air kerma rate measurements as recommended by different dosimetry protocols for Ir-192 HDR sources and to test their applicability to Co-60 sources. Dosimetric verification of HDR afterloading source specification was performed according to three protocols, DIN 6809-2 (1993) in combination with DGMP-Report 13 (2006), IAEA-TECDOC-1274 (2002) and AAPM Report 41 (1993) for the nuclides Ir-192 and Co-60. Measurements of the sources reference air kerma rate were performed with 3 different methods (with a cylindrical chamber both in a solid phantom and in free air, and with a well chamber) and evaluated using all three protocols for each type of source and method of measurement. The measurements with all protocols and methods show deviations from the certified specification smaller than about 1.2% for Ir-192 and 2.5% for Co-60-Sources. The measurements with the well chamber showed the lowest deviations from the certificate value. Air kerma rate measurements for Co-60 HDR sources using the existing protocols are possible with accuracy sufficient to verify source calibration as provided by the source certificate. However, extension of the protocols by correction factors for measurement with Co-60 sources would be helpful.

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.