Stereotactic radiosurgery and radiotherapy for resected brain metastases: current pattern of care in the Radiosurgery and Stereotactic Radiotherapy Working Group of the German Association for Radiation Oncology (DEGRO).

PURPOSE: Preoperative stereotactic radiosurgery (SRS) of brain metastases may achieve similar local control and better leptomeningeal control rates than postoperative fractionated stereotactic radiotherapy (FSRT) in patients treated with elective metastasectomy. To plan a multicentre trial of preoperative SRS compared with postoperative FSRT, a survey of experts was conducted to determine current practice. METHODS: A survey with 15 questions was distributed to the DEGRO Radiosurgery and Stereotactic Radiotherapy Working Group. Participants were asked under what circumstances they offered SRS, FSRT, partial and/or whole brain radiotherapy before or after resection of a brain metastasis, as well as the feasibility of preoperative stereotactic radiosurgery and neurosurgical resection within 6 days. RESULTS: Of 25 participants from 24 centres, 22 completed 100% of the questions. 24 respondents were radiation oncologists and 1 was a neurosurgeon. All 24 centres have one or more dedicated radiosurgery platform and all offer postoperative FSRT. Preoperative SRS is offered by 4/24 (16.7%) centres, and 9/24 (37.5%) sometimes recommend single-fraction postoperative SRS. Partial brain irradiation is offered by 8/24 (33.3%) centres and 12/24 (50%) occasionally recommend whole-brain irradiation. Two centres are participating in clinical trials of preoperative SRS. SRS techniques and fractionation varied between centres. CONCLUSION: All responding centres currently offer postoperative FSRT after brain metastasectomy. Approximately one third offer single-fraction postoperative SRS and four already perform preoperative SRS. With regard to potential co-investigators, 18 were identified for the PREOP­2 multicentre trial, which will randomise between preoperative SRS and postoperative FSRT.

Hypo- vs. normofractionated radiation therapy in breast cancer: A patterns of care analysis in German speaking countries.

AIM AND BACKGROUND: To assess the use of hypofractionated (HG-RT) versus normofractionated radiation therapy (NF-RT) in Breast Cancer in German speaking countries. MATERIALS AND METHODS: Between July 2017 and August 2017, an email-based survey was sent to all 1408 physicians that are members of the German Society of Radiation Oncology (DEGRO). The survey was completed by 180 physicians including 10 private practice owners and 52 heads of departments. The majority (82.1%) of the participants had >15 years of experience in radiation therapy (RT). RESULTS: The majority (83.9%) of the heads of the departments agreed on using the normofractionated regimen of RT as standard treatment for breast cancer. Several physicians were skeptical about HF-RT with 6.5% of the heads refusing to use HF-RT. 40.3% of the departments had not seen the new German guidelines suggesting HF-RT as the standard treatment for all patients as positive or merely adopted a neutral position toward the guidelines (33.9%). The main points of criticism were increased side effects, an impaired toxicity profile and insufficient data. Most departments (46.8%) that perform HF-RT do so in an individual based manner. CONCLUSIONS: HF-RT remains controversial in German speaking countries. Our data shows that NF-RT remains the predominant method of treatment. HF-RT is only used in a defined group of patients as most German physicians agree that particular patients, especially those at higher risk of RT late effects, may benefit from a less intense, extended fractionation schedule.

The impact of local control on overall survival after stereotactic body radiotherapy for liver and lung metastases from colorectal cancer: a combined analysis of 388 patients with 500 metastases.

BACKGROUND: The aim of this analysis was to model the effect of local control (LC) on overall survival (OS) in patients treated with stereotactic body radiotherapy (SBRT) for liver or lung metastases from colorectal cancer. METHODS: The analysis is based on pooled data from two retrospective SBRT databases for pulmonary and hepatic metastases from 27 centers from Germany and Switzerland. Only patients with metastases from colorectal cancer were considered to avoid histology as a confounding factor. An illness-death model was employed to model the relationship between LC and OS. RESULTS: Three hundred eighty-eight patients with 500 metastatic lesions (lung n = 209, liver n = 291) were included and analyzed. Median follow-up time for local recurrence assessment was 12.1 months. Ninety-nine patients with 112 lesions experienced local failure. Seventy-one of these patients died after local failure. Median survival time was 27.9 months in all patients and 25.4 months versus 30.6 months in patients with and without local failure after SBRT. The baseline risk of death after local failure exceeds the baseline risk of death without local failure at 10 months indicating better survival with LC. CONCLUSION: In CRC patients with lung or liver metastases, our findings suggest improved long-term OS by achieving metastatic disease control using SBRT in patients with a projected OS estimate of > 12 months.

MRI-based high-precision irradiation in an orthotopic pancreatic tumor mouse model : A treatment planning study.

BACKGROUND AND PURPOSE: Recently, imaging and high-precision irradiation devices for preclinical tumor models have been developed. Image-guided radiation therapy (IGRT) including innovative treatment planning techniques comparable to patient treatment can be achieved in a translational context. The study aims to evaluate magnetic resonance imaging/computed tomography (MRI/CT)-based treatment planning with different treatment techniques for high-precision radiation therapy (RT). MATERIALS AND METHODS: In an orthotopic pancreatic cancer model, MRI/CT-based radiation treatment planning was established. Three irradiation techniques (rotational, 3D multifield, stereotactic) were performed with the SARRP system (Small Animal Radiation Research Platform, Xstrahl Ltd., Camberley, UK). Dose distributions in gross tumor volume (GTV) and organs at risk (OAR) were analyzed for each treatment setting. RESULTS: MRI with high soft tissue contrast improved imaging of GTV and OARs. Therefore MRI-based treatment planning enables precise contouring of GTV and OARs, thus, providing a perfect basis for an improved dose distribution and coverage of the GTV for all advanced radiation techniques. CONCLUSION: An MRI/CT-based treatment planning for high-precision IGRT using different techniques was established in an orthotopic pancreatic tumor model. Advanced radiation techniques allow considering perfect coverage of GTV and sparing of OARs in the preclinical setting and reflect clinical treatment plans of pancreatic cancer patients.

The SBRT database initiative of the German Society for Radiation Oncology (DEGRO): patterns of care and outcome analysis of stereotactic body radiotherapy (SBRT) for liver oligometastases in 474 patients with 623 metastases.

BACKGROUND: The intent of this pooled analysis as part of the German society for radiation oncology (DEGRO) stereotactic body radiotherapy (SBRT) initiative was to analyze the patterns of care of SBRT for liver oligometastases and to derive factors influencing treated metastases control and overall survival in a large patient cohort. METHODS: From 17 German and Swiss centers, data on all patients treated for liver oligometastases with SBRT since its introduction in 1997 has been collected and entered into a centralized database. In addition to patient and tumor characteristics, data on immobilization, image guidance and motion management as well as dose prescription and fractionation has been gathered. Besides dose response and survival statistics, time trends of the aforementioned variables have been investigated. RESULTS: In total, 474 patients with 623 liver oligometastases (median 1 lesion/patient; range 1­4) have been collected from 1997 until 2015. Predominant histologies were colorectal cancer (n = 213 pts.; 300 lesions) and breast cancer (n = 57; 81 lesions). All centers employed an SBRT specific setup. Initially, stereotactic coordinates and CT simulation were used for treatment set-up (55%), but eventually were replaced by CBCT guidance (28%) or more recently robotic tracking (17%). High variance in fraction (fx) number (median 1 fx; range 1­13) and dose per fraction (median: 18.5 Gy; range 3­37.5 Gy) was observed, although median BED remained consistently high after an initial learning curve. Median follow-up time was 15 months; median overall survival after SBRT was 24 months. One- and 2-year treated metastases control rate of treated lesions was 77% and 64%; if maximum isocenter biological equivalent dose (BED) was greater than 150 Gy EQD2Gy, it increased to 83% and 70%, respectively. Besides radiation dose colorectal and breast histology and motion management methods were associated with improved treated metastases control. CONCLUSION: After an initial learning curve with regards to total cumulative doses, consistently high biologically effective doses have been employed translating into high local tumor control at 1 and 2 years. The true impact of histology and motion management method on treated metastases control deserve deeper analysis. Overall survival is mainly influenced by histology and metastatic tumor burden.

DVH- and NTCP-based dosimetric comparison of different longitudinal margins for VMAT-IMRT of esophageal cancer.

PURPOSE: To cover the microscopic tumor spread in squamous cell carcinoma of the esophagus (SCC), longitudinal margins of 3-4 cm are used for radiotherapy (RT) protocols. However, smaller margins of 2-3 cm might be reasonable when advanced diagnostic imaging is integrated into target volume delineation. Purpose of this study was to compare the dose distribution and deposition to the organs at risk (OAR) for different longitudinal margins using a DVH- and NTCP-based approach. METHODS: Ten patients with SCC of the middle or lower third were retrospectively selected. Three planning target volumes (PTV) with longitudinal margins of 4 cm, 3 cm and 2 cm and an axial margin of 1.5 cm to the gross target volume (GTV) were defined for each patient. For each PTV two treatment plans with total doses of 41.4 Gy (neoadjuvant treatment) and 50.4 Gy (definite treatment) were calculated. Dose to the lungs, heart, myelon and liver were then evaluated and compared between different PTVs. RESULTS: When using a longitudinal margin of 3 cm instead of 4 cm, all dose parameters (Dmin, Dmean, Dmedian and V5-V35), except Dmax could be significantly reduced for the lungs. Regarding the heart, a significant reduction was seen for Dmean and V5, but not for Dmin, Dmax, Dmedian and V10-V35. When comparing a longitudinal margin of 4 cm to a longitudinal margin of 2 cm, a significant difference was calculated for Dmin, Dmean, Dmedian and V5-V35 of the lungs and for Dmax, Dmean and V5-V35 of the heart. Nevertheless, no difference was seen for median heart dose. An additional dose reduction for V10 of the heart was achieved for definite treatment plans when using a longitudinal margin of 3 cm. The NTCP-based risk of pneumonitis was significantly reduced by a margin reduction to 2 cm for neoadjuvant and definite treatment plans. CONCLUSION: Reduction of longitudinal margins from 4 cm to 3 cm can significantly reduce the dose to lungs and Dmean of the heart. Despite clinical benefit and oncologic outcome remain unclear, reduction of the longitudinal margins might provide the opportunity to reduce side effects of chemoradiation (CRT) for SCC in upcoming studies.

Stereotactic body radiotherapy for oligo-metastatic liver disease - Influence of pre-treatment chemotherapy and histology on local tumor control.

INTRODUCTION: Stereotactic body radiation therapy (SBRT) is applied in the oligometastatic setting to treat liver metastases. However, factors influencing tumor control probability (TCP) other than radiation dose have not been thoroughly investigated. Here we set out to investigate such factors with a focus on the influence of histology and chemotherapy prior to SBRT using a large multi-center database from the German Society of Radiation Oncology. METHODS: 452 SBRT treatments in 363 patients were analyzed after collection of patient, tumor and treatment data in a multi-center database. Histology was considered through random effects in semi-parametric and parametric frailty models. Dose prescriptions were parametrized by conversion to the maximum biologically effective dose using alpha/beta of 10Gy (BEDmax). RESULTS: After adjusting for histology, BEDmax was the strongest predictor of TCP. Larger PTV volumes, chemotherapy prior to SBRT and simple motion management techniques predicted significantly lower TCP. The model predicted a BED of 209±67Gy10 necessary for 90% TCP at 2years with no prior chemotherapy, but 286±78Gy10 when chemotherapy had been given. Breast cancer metastases were significantly more responsive to SBRT compared to other histologies with 90% TCP at 2years achievable with BEDmax of 157±80Gy10 or 80±62Gy10 with and without prior chemotherapy, respectively. CONCLUSIONS: Besides dose, histology and pretreatment chemotherapy were important factors influencing local TCP in this large cohort of liver metastases. After adjusting for prior chemotherapy, our data add to the emerging evidence that breast cancer metastases do respond better to hypofractionated SBRT compared to other histologies.

[Radiotherapeutic management of lymphatic fistulas : An effective but disregarded therapy option]. / Strahlentherapeutisches Management von Lymphfisteln : Eine effektive, aber wenig beachtete Therapieoption.

BACKGROUND: Lymphatic fistulas and lymphoceles are known complications after vascular surgery of the groin and after extended surgical interventions in the pelvic region. Unfortunately, conservative standard therapies are not always successful. OBJECTIVES: Evaluation of the therapeutic efficacy and related side effects of percutaneous low-dose irradiation in patients with lymphorrhea and definition of its importance. MATERIAL AND METHODS: Current presentation of previously published case series, reviews and guidelines. RESULTS: The use of low-dose irradiation therapy with single doses of 0.3-0.5 Gy leads to a cessation of the lymphatic flow in a high percentage of patients when standard therapies do not show a sufficient effect. With cessation of lymphorrhea irradiation should be terminated. Acute side effects have not been reported and the risk of tumor induction is almost negligible. CONCLUSION: Low-dose irradiation is an effective and very well-tolerated therapeutic alternative in the treatment of lymphatic fistulas and lymphorrhea when conservative therapies are unsuccessful.

Time evaluation of image-guided radiotherapy in patients with spinal bone metastases. A single-center study.

PURPOSE: Time is an important factor during immobilization for radiotherapy (RT) of painful spinal bone metastases. The different RT techniques currently in use have differing impacts on medical staff requirements, treatment planning and radiation delivery. This prospective analysis aimed to evaluate time management during RT of patients with spine metastases, focusing particularly on the impact of image-guided RT (IGRT). MATERIALS AND METHODS: Between 21 March 2013 and 17 June 2013, we prospectively documented the time associated with the core work procedures involving the patient during the first day of RT at three different linear accelerators (LINACs). The study included 30 patients; 10 in each of three groups. Groups 1 and 2 were treated with a single photon field in the posterior-anterior direction; group 3 received a three-dimensional conformal treatment plan. RESULTS: The median overall durations of one treatment session were 24 and 25.5 min for the conventional RT groups and 15 min for IGRT group. The longest single procedure was patient immobilization in group 1 (median 9.5 min), whereas this was image registration and matching in groups 2 and 3 (median duration 9.5 and 5 min, respectively). Duration of irradiation (beam-on time) was similar for all groups at 4 or 5 min. The shortest immobilization procedure was observed in group 3 with a median of 3 min, compared to 4 min in group 2 and 9.5 min in group 1. CONCLUSION: With this analysis, we have shown for the first time that addition of modern IGRT does not extend the overall treatment time for patients with painful bone metastases and can be applied as part of clinical routine in a palliative setting. The choice of treatment technique should be based upon the patient's performance status, as well as the size of the target volume and location of the metastasis.

[Diagnosis of and therapy for hepatocellular carcinoma]. / Diagnostik und Therapie des hepatozellulären Karzinoms.

The interdisciplinary guidelines at the S3 level on the diagnosis of and therapy for hepatocellular carcinoma (HCC) constitute an evidence- and consensus-based instrument that is aimed at improving the diagnosis of and therapy for HCC since these are very challenging tasks. The purpose of the guidelines is to offer the patient (with suspected or confirmed HCC) adequate, scientifically based and up-to-date procedures in diagnosis, therapy and rehabilitation. This holds not only for locally limited or focally advanced disease but also for the existence of recurrences or distant metastases. Besides making a contribution to an appropriate health-care service, the guidelines should also provide the foundation for an individually adapted, high-quality therapy. The explanatory background texts should also enable non-specialist but responsible colleagues to give sound advice to their patients concerning specialist procedures, side effects and results. In the medium and long-term this should reduce the morbidity and mortality of patients with HCC and improve their quality of life.

Intensity modulated radiotherapy as neoadjuvant chemoradiation for the treatment of patients with locally advanced pancreatic cancer. Outcome analysis and comparison with a 3D-treated patient cohort.

BACKGROUND: To evaluate outcome after intensity modulated radiotherapy (IMRT) compared to 3D conformal radiotherapy (3D-RT) as neoadjuvant treatment in patients with locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: In total, 57 patients with LAPC were treated with IMRT and chemotherapy. A median total dose of 45 Gy to the PTV_baseplan and 54 Gy to the PTV_boost in single doses of 1.8 Gy for the PTV_baseplan and median single doses of 2.2 Gy in the PTV_boost were applied. Outcomes were evaluated and compared to a large cohort of patients treated with 3D-RT. RESULTS: Overall treatment was well tolerated in all patients and IMRT could be completed without interruptions. Median overall survival was 11 months (range 5-37.5 months). Actuarial overall survival at 12 and 24 months was 36 % and 8 %, respectively. A significant impact on overall survival could only be observed for a decrease in CA 19-9 during treatment, patients with less pre-treatment CA 19-9 than the median, as well as weight loss during treatment. Local progression-free survival was 79 % after 6 months, 39 % after 12 months, and 13 % after 24 months. No factors significantly influencing local progression-free survival could be identified. There was no difference in overall and progression-free survival between 3D-RT and IMRT. Secondary resectability was similar in both groups (26 % vs. 28 %). Toxicity was comparable and consisted mainly of hematological toxicity due to chemotherapy. CONCLUSION: IMRT leads to a comparable outcome compared to 3D-RT in patients with LAPC. In the future, the improved dose distribution, as well as advances in image-guided radiotherapy (IGRT) techniques, may improve the use of IMRT in local dose escalation strategies to potentially improve outcome.

Outcome after neoadjuvant chemoradiation and correlation with nutritional status in patients with locally advanced pancreatic cancer.

BACKGROUND: Cancer patients commonly suffer from weight loss since rapid tumor growth can cause catabolic metabolism and depletion of energy stores such as abdominal fat. In locally advanced pancreatic cancer this is even more pronounced due to abdominal pain, fatigue, nausea or malnutrition. In the present article, we quantify this frequently observed weight loss and assess its impact on outcome and survival. METHODS: Data on demographics, biometrics, toxicity and survival were collected for the last 100 patients treated with neoadjuvant chemoradiation for locally advanced pancreatic cancer at our department (45.0 Gy and boost up to 54.0 Gy plus concurrent and subsequent gemcitabine), and the subcutaneous fat area at the umbilicus level was measured by computer tomography before and after chemoradiation. RESULTS: After chemoradiation, patients showed a highly statistically significant weight loss and reduction of the subcutaneous fat area. We could determine a very strong correlation of subcutaneous fat area to patient BMI. By categorizing patients according to their BMI based on the WHO classification as slender, normal, overweight and obese, we found improved but not statistically significant survival among obese patients. Accordingly, patients who showed less weight loss tended to survive longer. CONCLUSIONS: In this study, patients with pancreatic cancer lost weight during chemoradiation and their subcutaneous fat diminished. Changes in subcutaneous fat area were highly correlated with patients' BMI. Moreover, obese patients and patients who lost less weight had an improved outcome after treatment. Although the extent of weight loss was not significantly correlated with survival, the observed trend warrants greater attention to nutritional status in the future.

[Database supported electronic retrospective analyses in radiation oncology: establishing a workflow using the example of pancreatic cancer]. / Datenbankbasierte digitale retrospektive Auswertung von Patientenkollektiven in der Radioonkologie: Etablierung eines Workflows am Beispiel des Pankreaskarzinoms.

PURPOSE: Especially in the field of radiation oncology, handling a large variety of voluminous datasets from various information systems in different documentation styles efficiently is crucial for patient care and research. To date, conducting retrospective clinical analyses is rather difficult and time consuming. With the example of patients with pancreatic cancer treated with radio-chemotherapy, we performed a therapy evaluation by using an analysis system connected with a documentation system. MATERIALS AND METHODS: A total number of 783 patients have been documented into a professional, database-based documentation system. Information about radiation therapy, diagnostic images and dose distributions have been imported into the web-based system. RESULTS: For 36 patients with disease progression after neoadjuvant chemoradiation, we designed and established an analysis workflow. After an automatic registration of the radiation plans with the follow-up images, the recurrence volumes are segmented manually. Based on these volumes the DVH (dose volume histogram) statistic is calculated, followed by the determination of the dose applied to the region of recurrence. All results are saved in the database and included in statistical calculations. CONCLUSION: The main goal of using an automatic analysis tool is to reduce time and effort conducting clinical analyses, especially with large patient groups. We showed a first approach and use of some existing tools, however manual interaction is still necessary. Further steps need to be taken to enhance automation. Already, it has become apparent that the benefits of digital data management and analysis lie in the central storage of data and reusability of the results. Therefore, we intend to adapt the analysis system to other types of tumors in radiation oncology.

Chemoradiation in patients with unresectable extrahepatic and hilar cholangiocarcinoma or at high risk for disease recurrence after resection : Analysis of treatment efficacy and failure in patients receiving postoperative or primary chemoradiation.

BACKGROUND: The purpose of this work was to determine efficacy, toxicity, and patterns of recurrence after concurrent chemoradiation (CRT) in patients with extrahepatic bile duct cancer (EHBDC) and hilar cholangiocarcinoma (Klatskin tumours) in case of incomplete resection or unresectable disease. PATIENTS AND METHODS: From 2003-2010, 25 patients with nonmetastasized EHBDC and hilar cholangiocarcinoma were treated with radiotherapy and CRT at our institution in an postoperative setting (10 patients, 9 patients with R1 resections) or in case of unresectable disease (15 patients). Median age was 63 years (range 38-80 years) and there were 20 men and 5 women. Median applied dose was 45 Gy in both patient groups. RESULTS: Patients at high risk (9 times R1 resection, 1 pathologically confirmed lymphangiosis) for tumour recurrence after curative surgery had a median time to disease progression of 8.7 months and an estimated mean overall survival of 23.2 months (6 of 10 patients are still under observation). Patients undergoing combined chemoradiation in case of unresectable primary tumours are still having a poor prognosis with a progression-free survival of 7.1 months and a median overall survival of 12.0 months. The main site of progression was systemic (liver, peritoneum) in both patient groups. CONCLUSION: Chemoradiation with gemcitabine is safe and can be applied safely in either patients with EHBDC or Klatskin tumours at high risk for tumour recurrence after resection and patients with unresectable tumours. Escalation of systemic and local treatment should be investigated in future clinical trials.

[Strategies for preoperative downsizing in patients with local nonresectable pancreatic cancer]. / Strategien für präoperatives Downsizing bei inoperablem Pankreaskarzinom.

In about 30-40% of all patients with pancreatic cancer a locally advanced lesion without distant metastases is found at primary diagnosis and the tumor is mostly nonresectable due to the close vicinity to blood vessels. Neoadjuvant treatment strategies, such as neoadjuvant radiochemotherapy offer the possibility to achieve substantial tumor reduction so that secondary resectability can be achieved. Therefore, treatment decisions should be made in an interdisciplinary context. In the future, innovative study protocols as well as novel radiation modalities, such as carbon ions can open new horizons in the treatment of this patient population. Additionally, molecular markers may help to stratify patients for different treatment schedules.

Dendritic cell generation and CD4+ CD25high FOXP3+ regulatory t cells in human head and neck carcinoma during radio-chemotherapy.

BACKGROUND: Regulatory T cells (Treg) and dendritic cells (DC) play an important role in tumor immunity and immune escape. However, their interplay and the effects of anti-cancer therapy on the human immune system are largely unknown. METHODS: For DC generation, CD14⊃+ monocytes were enriched by immunomagnetic selection from peripheral blood of advanced head and neck squamous cell carcinoma (HNSCC) patients and differentiated into immature DC using GM-SCF and IL-4. DC maturation was induced by addition of TNFα. The frequency of CD4⊃+CD25⊃highFOXP3⊃+ Treg in HNSCC patients was analyzed before and after radio-chemotherapy (RCT) by four-color flow cytometry. RESULTS: In HNSCC patients, the frequency of Treg (0.33 ± 0.06%) was significantly (p = 0.001) increased compared to healthy controls (0.11 ± 0.02%), whereas RCT had variable effects on the Treg frequency inducing its increase in some patients and decrease in others. After six days in culture, monocytes of all patients had differentiated into immature DC. However, DC maturation indicated by CD83 up-regulation (70.7 ± 5.5%) was successful only in a subgroup of patients and correlated well with lower frequencies of peripheral blood Treg in those patients. CONCLUSION: The frequency of regulatory T cells is elevated in HNSCC patients and may be modulated by RCT. Monocyte-derived DC in HNSCC patients show a maturation deficiency ex vivo. Those preliminary data may have an impact on multimodality clinical trials integrating cellular immune modulation in patients with advanced HNSCC.

[Radiotherapy of hepatic metastases]. / Strahlentherapie von Lebermetastasen.

Non-invasive treatment of hepatic metastases has become a focal point of interdisciplinary oncology especially since the advent of stereotactic radiation techniques. Worldwide several centers have shown that this treatment is a curative and well tolerated regimen with excellent rates of local control. Modern devices which combine radiation therapy with imaging techniques (image-guided radiotherapy) in particular allow precise dose application, especially for hypofractionated treatment concepts requiring daily repositioning.