[Brain metastases]. / Hirnmetastasen.

Cerebral metastases in patients with metastatic lung cancer are found in more than 30% of patients at baseline and manifest themselves in two out of three patients during disease evolution. For a long time, the cerebral manifestation of the disease was classified as prognostically unfavorable and hence such patients were regularly excluded from therapy studies. In the context of targeted molecular therapy strategies and established immuno-oncological systemic therapies, the blood-brain barrier no longer represents an insurmountable barrier. However, the treatment of brain metastases requires decision making in a multidisciplinary team within dedicated lung cancer and/or oncology centers. The differentiated treatment decision is based on the number, size and location of the brain metastases, neurology and general condition, comorbidities, potential life expectancy and the patient's wishes, but also tumor biology including molecular targets, extra-cranial tumor burden and availability of a CNS-effective therapy. Systemic therapies as well as neurosurgical and radiotherapeutic concepts are now often combined for optimized and prognosis-improving therapeutic strategies.

Critical evaluation of molecular tumour board outcomes following 2 years of clinical practice in a Comprehensive Cancer Centre.

BACKGROUND: Recently, molecular tumour boards (MTBs) have been integrated into the clinical routine. Since their benefit remains debated, we assessed MTB outcomes in the Comprehensive Cancer Center Ostbayern (CCCO) from 2019 to 2021. METHODS AND RESULTS: In total, 251 patients were included. Targeted sequencing was performed with PCR MSI-evaluation and immunohistochemistry for PD-L1, Her2, and mismatch repair enzymes. 125 treatment recommendations were given (49.8%). High-recommendation rates were achieved for intrahepatic cholangiocarcinoma (20/30, 66.7%) and gastric adenocarcinoma (10/16, 62.5%) as opposed to colorectal cancer (9/36, 25.0%) and pancreatic cancer (3/18, 16.7%). MTB therapies were administered in 47 (18.7%) patients, while 53 (21.1%) received alternative treatment regimens. Thus 37.6% of recommended MTB therapies were implemented (47/125 recommendations). The clinical benefit rate (complete + partial + mixed response + stable disease) was 50.0% for MTB and 63.8% for alternative treatments. PFS2/1 ratios were 34.6% and 16.1%, respectively. Significantly improved PFS could be achieved for m1A-tier-evidence-based MTB therapies (median 6.30 months) compared to alternative treatments (median 2.83 months; P = 0.0278). CONCLUSION: The CCCO MTB yielded a considerable recommendation rate, particularly in cholangiocarcinoma patients. The discrepancy between the low-recommendation rates in colorectal and pancreatic cancer suggests the necessity of a weighted prioritisation of entities. High-tier recommendations should be implemented predominantly.

Re-irradiation for humeral epicondylitis : Retrospective analysis of 99 elbows.

BACKGROUND: Humeral epicondylitis is a common elbow disease. The prevalence is about 1.7%. One of the most effective treatment options is radiotherapy. Some authors mention that they apply a second or third course of radiation for recurrent pain or partial or no response to the initial course. As the results of a re-irradiation have not been systematically analyzed, the aim of this study was to document the results of repeated radiation treatment and to identify those patients who will benefit. MATERIAL AND METHODS: The analysis was performed on patients from three German radiotherapy institutions and included 99 re-irradiated elbows. Pain was documented with the numeric rating scale (NRS). Evaluation of the NRS was done before and directly after each radiation therapy as well as for the follow-up of 24 months. The median age of the patients was 51 years with 48.8% male and 51.2% female patients. Repeated radiation was indicated because the initial radiotherapy resulted in 39.7% of no response, in 41.0% of partial response and in 19.3% of recurrent pain. RESULTS: A significant response to re-irradiation was found. For the whole sample the median pain score was 6 before re-irradiation, 3 after 6 weeks, 2 after 12 months and 1 after 24 months. The percentage of patients being free of pain or with very little pain was 50.9% 24 months after re-irradiation. All subgroups, notably those with no response, partial response and recurrent pain had a significant reduction of pain. CONCLUSION: Re-irradiation of humeral epicondylitis is an effective and safe treatment. All subgroups showed a good response to re-irradiation for at least 24 months.

Radiotherapy for osteoarthritis-an analysis of 295 joints treated with a linear accelerator.

PURPOSE: Osteoarthritis is a common disease, with a prevalence of symptomatic disease of 8.9%. One treatment option is radiotherapy. Most published samples were treated with an orthovoltage technique or with a telecobalt device. A lot of radiotherapy institutions are nowadays using linear accelerators for treatment of osteoarthritis. There is a discussion on whether the treatment results achieved with a linear accelerator are comparable to those with the orthovoltage technique. The aim of this study is to analyze the results of radiotherapy for osteoarthritis with a linear accelerator and compare the results with reference to different joints. MATERIALS AND METHODS: The analysis was performed in patients of two German radiotherapy institutions and included 295 irradiated joints. Pain was documented with the numeric rating scale (NRS). Evaluation of the NRS was done before and directly after each radiation therapy course as well as for the follow-up of 24 months. The median age of the patients was 65 years, with 39.0% male and 61.0% female patients. Most frequently, osteoarthritis of the knee (34.6%) or the finger (15.9%) was treated. RESULTS: We could find a significant response to radiotherapy. Median pain for the whole sample was 7 on the NRS before radiotherapy, 4 after 6 weeks, and 3 after 12 and 24 months. The percentage of patients with 0 or 1 on the NRS was 33.8% 12 months after radiotherapy. All investigated subgroups had a significant reduction of pain. CONCLUSION: Radiotherapy of osteoarthritis with a linear accelerator is an effective treatment which is very well tolerated. All analyzed subgroups show a good response to radiotherapy for at least 24 months. Orthovoltage therapy seems to be superior to treatment with a linear accelerator in a case-related analysis of the published samples. Further investigations should be performed for a definitive answer to this question.

Radiotherapy for osteoarthritis of the ankle and tarsal joints-analysis of 66 joints.

PURPOSE: Osteoarthritis of the ankle and tarsal joints is less common than osteoarthritis of the knee or hip, but the associated disability is at least as severe as that of the other major joints of the lower limb. The results for total arthroplasty are still not satisfactory. For this reason, arthrodesis is still the gold standard of non-joint-conserving surgery. For the reason of functionality, joint-conserving therapies play a major role in treatment of ankle and tarsal osteoarthritis. Low-dose radiotherapy has a long history of treatment of osteoarthritis. The aim of this survey was to examine the results of low-dose radiotherapy for osteoarthritis of the ankle and tarsal joints. MATERIALS AND METHODS: The analysis was performed on patients of three German radiotherapy institutions and included 66 irradiated joints. Pain was documented with the numeric rating scale (NRS). Evaluation of the NRS was done before and directly after each radiation therapy course as well as for the follow-up of 24 months. The median age of the patients was 68 years, with 24.5% male and 75.5% female patients. The upper ankle was treated in 37.9%, the lower ankle in 27.3% and the tarsal joints in 34.8%. RESULTS: We could find a significant response to radiotherapy. For the whole sample, the median pain was 7 on the NRS before radiotherapy, 5 after 6 and 12 weeks, and 4 after 12 months. The percentage of patients with 0 or 1 on the NRS was 19.6% 12 months after radiotherapy. An improvement of joint mobility could be detected in 56.7% of the cases. All investigated subgroups had a significant reduction in pain. CONCLUSION: Radiotherapy of ankle and tarsal osteoarthritis is an effective treatment without showing side effects. All analysed subgroups show a good response to radiotherapy for at least 24 months.

The influence of radiotherapy techniques on the plan quality and on the risk of secondary tumors in patients with pituitary adenoma.

BACKGROUND: This planning study compares different radiotherapy techniques for patients with pituitary adenoma, including flatness filter free mode (FFF), concerning plan quality and secondary malignancies for potentially young patients. The flatness filter has been described as main source of photon scatter. MATERIAL AND METHODS: Eleven patients with pituitary adenoma were included. An Elekta Synergy™ linac was used in the treatment planning system Oncentra® and for the measurements. 3D plans, IMRT, and VMAT plans and non-coplanar varieties were considered. The plan quality was evaluated regarding homogeneity, conformity, delivery time and dose to the organs at risk. The secondary malignancy risk was calculated from dose volume data and from measured dose to the periphery using different models for carcinoma and sarcoma risk. RESULTS: The homogeneity and conformity were nearly unchanged with and without flattening filter, neither was the delivery time found substantively different. VMAT plans were more homogenous, conformal and faster in delivery than IMRT plans. The secondary cancer risk was reduced with FFF both in the treated region and in the periphery. VMAT plans resulted in a higher secondary brain cancer risk than IMRT plans, but the risk for secondary peripheral cancer was reduced. Secondary sarcoma risk plays a minor role. No advantage was found for non-coplanar techniques. The FFF delivery times were not shortened due to additional monitor units needed and technical limitations. The risk for secondary brain cancer seems to depend on the irradiated volume. Secondary sarcoma risk is much smaller than carcinoma risk in accordance to the results of the atomic bomb survivors. The reduction of the peripheral dose and resulting secondary malignancy risk for FFF is statistically significant. However, it is negligible in comparison to the risk in the treated region. CONCLUSION: Treatments with FFF can reduce secondary malignancy risk while retaining similar quality as with flattening filter and should be preferred. VMAT plans show the best plan quality combined with lowest peripheral secondary malignancy risk, but highest level of second brain cancer risk. Taking this into account VMAT FFF seems the most advantageous technique for the treatment of pituitary adenomas with the given equipment.

Radiotherapy of patients with cardiac implantable electronic devices according to the DEGRO/DGK guideline-is the risk of relevant errors overestimated?

PURPOSE: Ionizing radiation is able to cause severe damage to cardiac implantable electronic devices (CIED). In Germany, the DEGRO/DGK guideline recommends close monitoring of patients with CIEDs undergoing radiotherapy (RT). Nevertheless, especially in the era of intensity-modulated techniques and predominant use of 6 MV photons, errors of CIEDs are rare events. Therefore, we performed daily CIED controls and hypothesized that no relevant device interaction would occur in our cohort. METHODS: From 2014 to 2018, we collected data of 51 patients (62 courses) with daily interrogation (n = 1046) of CIED. The dose to the skin above the CIED was measured by semiconductor or ion chamber dosimetry at least once per RT course. In many cases the dose was also calculated. RESULTS: The prescribed dose to the planning target volume (PTV) ranged from 7.5 to 78.0 Gy (IQR 27.8-61.0 Gy). The median measured cumulative dose to the skin above the CIED was 0.17 Gy, whereas the median calculated dose was 1.03 Gy. No error occurred in the group with maximum beam energy >10 MeV. Three events without clinical relevance could be recognized in the group with an intensity-modulated technique at 6 MV. None of the three concerned devices were located directly within the PTV. CONCLUSION: Errors of CIEDs during RT are rare events. The approach according to the DEGRO/DGK guideline is safe, but also consumes resources. In our cohort it was not compulsory to relocate any CIED. Clinically relevant events are uncommon, so it remains debatable which procedure is necessary. Daily controls could be avoided in some selected cases without compromising patient safety.

Radiotherapy of epicondylitis humeri : Analysis of 138 elbows treated with a linear accelerator.

BACKGROUND: Epicondylitis humeri is a common disease with a prevalence of 1.7%. One of the treatment options is radiotherapy. Most published cases were treated with the orthovoltage technique or with a telecobalt device. Many radiotherapy institutions are nowadays using linear accelerators for treatment of epicondylitis humeri. There is a discussion whether the treatment results with linear accelerators are comparable to the orthovoltage technique. The aim of this study was to analyze the results of radiotherapy with a linear accelerator for epicondylitis humeri. MATERIAL AND METHODS: The analysis was performed on patients of 2 German radiotherapy institutions and included 138 irradiated elbows. Pain was documented with the numeric rating scale (NRS). Evaluation of the NRS was done before and directly after each radiation therapy course as well as for the follow-up of 24 months. The median age of the patients was 49 years with 48.4% male and 51.6% female. In all, 81.0% were suffering from from epicondylitis humeri radialis while 16.7% were treated because of epicondylitis humeri ulnaris. In 65.4% the dominant arm was treated. RESULTS: A significant response to radiotherapy could be found. For the whole sample the median pain was 7 on the NRS before radiotherapy, 4 after 6 weeks and 0 after 12 and 24 months. The percentage of patients with 0 or 1 on the NRS was 64.6% 12 months after radiotherapy. All subgroups, notably those with epicondylitis humeri radialis and epicondylitis humeri ulnaris had a significant reduction of pain. CONCLUSION: Radiotherapy of epicondylitis humeri with a linear accelerator is an effective treatment without showing side effects. All analyzed subgroups showed a good response to radiotherapy for at least 24 months.

Re-irradiation for osteoarthritis-retrospective analysis of 217 joints.

PURPOSE: Osteoarthritis is a common disease with a prevalence of approximately 8.9% among the average population. One treatment option is low-dose radiotherapy. Some authors mention that they apply a second or third course of radiation for recurrent pain or partial or no response to the initial course. As the results of re-irradiation have not been analysed systematically, the aim of this study was to document the results of repeated radiation treatment and to identify those patients who will benefit. METHODS AND MATERIALS: The analysis was performed on patients of three German radiotherapy institutions and included 217 re-irradiated joints. Pain was documented with the numeric rating scale (NRS). Evaluation of the NRS was done before and directly after each radiation therapy as well as at the follow-up of 24 months. The median age of the patients was 67 years, with 40% male and 60% female patients. Re-irradiation was indicated because the initial radiotherapy resulted in no response in 21.2%, in partial response in 41.5%, and in recurrent pain in 37.3%. RESULTS: We found a significant response to re-irradiation. For the whole sample, the median pain was 6 before re-irradiation, 4 after 6 weeks, and 3 after 12 weeks, 6 months, 12 months, and 24 months. The percentage of patients being free of pain or with very little pain was approximately 25% 12 months after re-irradiation. All subgroups, notably those with no response to the first course versus partial response to the first course versus recurrent pain, had significant reduction of pain. CONCLUSION: Re-irradiation of osteoarthritis is an effective and safe treatment. All subgroups showed a good response to re-irradiation for at least 24 months.

Is low dose radiotherapy an effective treatment for Baker's cyst?

PURPOSE: Osteoarthritis of the knee is a common disease, often associated with a Baker's cyst. Besides osteoarthritis, also other joint pathologies of the knee can be causative for a Baker's cyst. Radiotherapy is known to be an effective treatment for osteoarthritis, with an anti-inflammatory effect. As the excessive production of synovia usually is associated with intraarticular inflammation, our hypothesis was that radiotherapy might positively influence the synovial production and reduce the volume of a Baker's cyst. MATERIALS AND METHODS: We performed a prospective trial, including 20 knees receiving radiotherapy for knee arthritis. Besides documentation of NRS (numeric rating scale), WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) score and Knee Society Score, the volume of the Baker's cyst was calculated for a short- (6 to 12 weeks) and long-term (9 to 12 months) follow-up. Ultrasonic volumetry was performed using an ultrasound device with a high-resolution multifrequency linear probe (6-9 MHz). RESULTS: Low-dose radiotherapy improved NRS, WOMAC score and Knee Society Score significantly. The mean volume of Baker's cyst decreased from 22.3 ml to 10.7 respectively 3.1 ml during follow-up. A decrease in volume of more than 25% compared to the baseline could be achieved for 75% of the patients in the short-term and 79% of the patients in the long-term follow up. CONCLUSION: Radiotherapy of knee osteoarthritis is an effective treatment that decreases the volume of a Baker's cyst. Most patients respond to the treatment. Whether radiotherapy is an effective treatment for Baker's cyst without associated osteoarthritis has to be further examined.

Postoperative adjuvant radiochemotherapy with cisplatin versus adjuvant radiochemotherapy with cisplatin and pembrolizumab in locally advanced head and neck squamous cell carcinoma- the study protocol of the Adrisk trial.

Most of the patients with head and neck squamous cell carcinoma (HNSCC) are diagnosed with locally advanced disease. Standards of care for curative-intent treatment of this patient group are either surgery and adjuvant radio(chemo)therapy (aRCT) or definitive chemoradiation. Despite these treatments, especially pathologically intermediate and high-risk HNSCC often recur. The ADRISK trial investigates in locally advanced HNSCC and intermediate and high risk after up-front surgery if the addition of pembrolizumab to aRCT with cisplatin improves event-free sur-vival compared to aRCT alone. ADRISK is a prospective, randomized controlled investiga-tor-initiated (IIT)-phase II multicenter trial within the German Interdisciplinary Study Group of German Cancer Society (IAG-KHT). Patients with primary resectable stage III and IV HNSCC of the oral cavity, oropharynx, hypopharynx and larynx with pathologic high (R1, extracapsular nodal extension) or intermediate risk (R0 <5 mm; N≥2) after surgery will be eligible. Two hun-dred forty patients will be randomly assigned (1:1) to either standard aRCT with cisplatin (standard arm) or aRCT with cisplatin + pembrolizumab (200 mg iv, in 3-week cycle, max. 12 months) (interventional arm). Endpoints are event-free and overall survival. Recruitment started in August 2018 and is ongoing.

A 3D In Vivo Model for Studying Human Renal Cystic Tissue and Mouse Kidney Slices.

(1) Background: Autosomal dominant polycystic kidney disease (ADPKD) is a frequent monogenic disorder that leads to progressive renal cyst growth and renal failure. Strategies to inhibit cyst growth in non-human cyst models have often failed in clinical trials. There is a significant need for models that enable studies of human cyst growth and drug trials. (2) Methods: Renal tissue from ADPKD patients who received a nephrectomy as well as adult mouse kidney slices were cultured on a chorioallantoic membrane (CAM) for one week. The cyst volume was monitored by microscopic and CT-based applications. The weight and angiogenesis were quantified. Morphometric and histological analyses were performed after the removal of the tissues from the CAM. (3) Results: The mouse and human renal tissue mostly remained vital for about one week on the CAM. The growth of cystic tissue was evaluated using microscopic and CT-based volume measurements, which correlated with weight and an increase in angiogenesis, and was accompanied by cyst cell proliferation. (4) Conclusions: The CAM model might bridge the gap between animal studies and clinical trials of human cyst growth, and provide a drug-testing platform for the inhibition of cyst enlargement. Real-time analyses of mouse kidney tissue may provide insights into renal physiology and reduce the need for animal experiments.

Durvalumab after definitive chemoradiotherapy in locally advanced NSCLC: Data of the German EAP.

Following the PACIFIC trial, durvalumab has been approved by the European Medicines Agency (EMA) for consolidation of locally advanced PD-L1-positive NSCLC after chemoradiotherapy (CRT). Patients were treated with durvalumab in the EAP from 22.11.2017 to 15.10.2018 allowing analysis of its efficacy and safety. 211 patients were registered by 90 German centres. Data were collected retrospectively by questionnaire and queries. 56 centres reported data on 126 patients who actually received at least one cycle of durvalumab. In contrast to the PACIFIC-trial population, some patients with oligometastatic disease and a history of autoimmune disease are included in the EAP population. Information on PD-L1 status was obtained for 111 patients. Baseline data include age, gender, ECOG, stage (IASLC 8th ed.), and smoking history. Treatment data include mode of chemoradiotherapy, used chemotherapy agent, and duration of durvalumab therapy. Adverse evants were documented according to CTAEC 5.0. Data were analysed for progression-free survival (PFS), overall survival (OS), and adverse events (AE). The results were published in Lung Cancer [1].

Durvalumab after definitive chemoradiotherapy in locally advanced unresectable non-small cell lung cancer (NSCLC): Real-world data on survival and safety from the German expanded-access program (EAP).

BACKGROUND: Following the PACIFIC trial, durvalumab has been approved by the European Medicines Agency (EMA) for consolidation of locally advanced PD-L1-positive NSCLC after chemoradiotherapy (CRT). Patients were treated with durvalumab in the EAP from 22.11.2017 to 15.10.2018 allowing analysis of its efficacy and safety. METHODS: Data from 56 centres were analysed for adverse events (AE), progression-free survival (PFS), overall survival (OS). RESULTS: 126 patients actually received at least 1 cycle durvalumab. Compared to the PACIFIC trial, the EAP population had more advanced stage and included "oligometastatic" stage IV patients and patients with autoimmune disease. PFS (20.1 months) and OS (not reached) were similar in the EAP and the PACIFIC trial. 42.9 % completed 12 months of durvalumab without deaths during FU. Stage IV patients (n = 7) had encouraging OS (not reached at 27 months). Autoimmune disease did not affect survival. PFS and OS were similar in PD-L1-negative patients (n = 32) and PD-L1-positive patients (n = 79). CONCLUSIONS: Survival in the EAP was comparable to the PACIFIC trial. Selected stage IV patients and patients with autoimmune disease may benefit from durvalumab consolidation and should be included in future immuno-oncological trials. PD-L1 did not predict survival challenging the exclusion of PD-L1-negative patients from durvalumab consolidation. In summary, durvalumab consolidation is safe and effective in a European real-world setting.

5-FU-induced cardiac toxicity--an underestimated problem in radiooncology?

BACKGROUND: 5-Fluorouracil (5-FU) is an antimetabolite, which is frequently used as chemotherapeutic agent for combined chemoradiotherapy. The purpose of this study was to present the clinical course of three patients who developed severe cardiac toxicity by 5-FU and to give a review of the literature on the cardiotoxic potential of 5-FU. RESULTS: Cardiotoxicity is a rare, but relevant side effect of fluoropyrimidines. It comprehends a wide spectrum of side effects, from electrocardiogram changes (69% of cardiac events) to myocardial infarction (22%) and cardiogenic shock (1%).In this case series three patients with cardiotoxic events during chemoradiotherapy including 5-FU, the reaction's characteristics and their influence on further therapy are described. Two of the patients could not be treated with 5-FU any more because they had developed a myocardial ischemia, which was most likely caused by fluorouracil. Another patient, who complained about typical angina pectoris during 5-FU-infusion and had a new left anterior hemiblock, was reexposed with prophylactic administration of nitrendipine. CONCLUSION: Cardiotoxicity caused by 5-FU is an underestimated problem in radiooncology. Especially patients without history of cardiac disease are often treated as out-patients and therefore without cardiac monitoring. Consequently asymptomatic and symptomatic cardiac events may be overlooked. The benefit of prophylactic agents remains unclear, so close cardiac monitoring is the most established method to prevent manifest cardiotoxic events.