Radiation treatment of hemato-oncological patients in times of the COVID-19 pandemic : Expert recommendations from the radiation oncology panels of the German Hodgkin Study Group and the German Lymphoma Alliance.

PURPOSE: The coronavirus pandemic is affecting global health systems, endangering daily patient care. Hemato-oncological patients are particularly vulnerable to infection, requiring decisive recommendations on treatment and triage. The aim of this survey amongst experts on radiation therapy (RT) for lymphoma and leukemia is to delineate typical clinical scenarios and to provide counsel for high-quality care. METHODS: A multi-item questionnaire containing multiple-choice and free-text questions was developed in a peer-reviewed process and sent to members of the radiation oncology panels of the German Hodgkin Study Group and the German Lymphoma Alliance. Answers were assessed online and analyzed centrally. RESULTS: Omission of RT was only considered in a minority of cases if alternative treatment options were available. Hypofractionated regimens and reduced dosages may be used for indolent lymphoma and fractures due to multiple myeloma. Overall, there was a tendency to shorten RT rather than to postpone or omit it. Even in case of critical resource shortage, panelists agreed to start emergency RT for typical indications (intracranial pressure, spinal compression, superior vena cava syndrome) within 24 h. Possible criteria to consider for patient triage are the availability of (systemic) options, the underlying disease dynamic, and the treatment rationale (curative/palliative). CONCLUSION: RT for hemato-oncological patients receives high-priority and should be maintained even in later stages of the pandemic. Hypofractionation and shortened treatment schedules are feasible options for well-defined constellations, but have to be discussed in the clinical context.

Reimbursement of radiotherapy in Germany.

Reimbursement of radiotherapy in Germany is mainly based on a certain fixed fee for treatment planning and patient set up in addition to payment per fraction. This applies to outpatient care for patients with public health insurance or private health insurance. Payment per fraction has a considerable influence on reimbursement of inpatients as well. The advantage of payment per fraction is the simplicity and transparency. The disadvantage is an inadequate reimbursement for new treatment modalities like hypofractionation or stereotactic body radiotherapy.

Heart dose exposure as prognostic marker after radiotherapy for resectable stage IIIA/B non-small-cell lung cancer: secondary analysis of a randomized trial.

Background: Heart exposure to ionizing irradiation can cause ischaemic heart disease. The partial heart volume receiving ≥5 Gy (heartV5) was supposed to be an independent prognostic factor for survival after radiochemotherapy for locally advanced non-small-cell lung cancer (NSCLC). But validation of the latter hypothesis is needed under the concurrent risks of lung cancer patients. Patients and methods: The ESPATUE phase III trial recruited patients with potentially operable IIIA(N2)/selected IIIB NSCLC between 01/2004 and 01/2013. Cisplatin/paclitaxel induction chemotherapy was given followed by neoadjuvant radiochemotherapy (RT/CT) to 45 Gy (1.5 Gy bid/concurrent cisplatin/vinorelbine). Operable patients were randomized to definitive RT/CT(arm A) or surgery (arm B) and therefore were treated at two different total dose levels of radiotherapy. HeartV5 and mean heart dose (MHD) were obtained from the 3D radiotherapy plans, the prognostic value was analysed using multivariable proportional hazard analysis. Results: A total of 161 patients were randomized in ESPATUE, heartV5 and MHD were obtained from the 3D radiotherapy plans for 155 of these [male/female:105/50, median age 58 (33-74) years, stage IIIA/IIIB: 54/101]. Power analysis revealed a power of 80% of this dataset to detect a prognostic value of heartV5 of the size found in RTOG 0617. Multivariable analysis did not identify heartV5 as an independent prognostic factor for survival adjusting for tumour and clinical characteristics with [hazard ratio 1.005 (0.995-1.015), P = 0.30] or without lower lobe tumour location [hazard ratio 0.999 (0.986-1.012), P = 0.83]. There was no influence of heartV5 on death without tumour progression. Tumour progression, and pneumonia were the leading causes of death representing 65% and 14% of the observed deaths. Conclusions: HeartV5 could not be validated as an independent prognostic factor for survival after neoadjuvant or definitive conformal radiochemotherapy. Tumour progression was the predominant cause of death. Register No: Z5 - 22461/2 - 2002-017 (German Federal Office for Radiation Protection).

New quality assurance program integrating "modern radiotherapy" within the German Hodgkin Study Group.

INTRODUCTION: Field design changed substantially from extended-field RT (EF-RT) to involved-field RT (IF-RT) and now to involved-node RT (IN-RT) and involved-site RT (IS-RT) as well as treatment techniques in radiotherapy (RT) of Hodgkin's lymphoma (HL). The purpose of this article is to demonstrate the establishment of a quality assurance program (QAP) including modern RT techniques and field designs within the German Hodgkin Study Group (GHSG). METHODS: In the era of modern conformal RT, this QAP had to be fundamentally adapted and a new evaluation process has been intensively discussed by the radiotherapeutic expert panel of the GHSG. RESULTS: The expert panel developed guidelines and criteria to analyse "modern" field designs and treatment techniques. This work is based on a dataset of 11 patients treated within the sixth study generation (HD16-17). CONCLUSION: To develop a QAP of "modern RT", the expert panel defined criteria for analysing current RT procedures. The consensus of a modified QAP in ongoing and future trials is presented. With this schedule, the QAP of the GHSG could serve as a model for other study groups.

Quality control of involved field radiotherapy in the HD 13 and HD 14 trials : Report of the radiotherapy panel of the German Hodgkin Study Group (GHSG).

INTRODUCTION: As part of the foundation of the German Hodgkin Study Group (GHSG) in 1978, a central radiotherapy (RT) reference centre was established to evaluate and to improve the quality of treatment. During the study generations, the quality assurance programs (QAP) were continued and adapted to the demands of each study. The purpose of this article is to demonstrate the results of the fifth study generation and to compare them to the previous findings. METHODS: With the start of the fourth GHSG study generation (HD10-12), a central prospective review of all diagnostic images was established to create an individual treatment plan for each early stage study patient. The quality of involved field RT was retrospectively evaluated by an expert panel of radiation oncologists. In the fifth study generation (HD13-15), the retrospective review of radiotherapy performed was refined and the results were compared with the findings of the fourth generation. RESULTS: The expert panel analyzed the RT planning and application of 1037 (28 %) patients (HD13 n = 465, HD14 n = 572). Simulation films were available in 85 % of cases and verification films in 87 %. RT was assessed as major violation in 46 % (HD13 = 38 %, HD14 = 52 %), minor violation in 9 % (HD13 = 9 %, HD14 = 9 %) and according to the protocol in 45 % (HD13 = 52 %, HD14 = 38 %). CONCLUSION: The value for QAP of RT within the GHSG trials is well known. Still there were several protocol violations. In the future, the QAP program has to be adapted to the requirements of "modern RT" in malignant lymphoma.

[The importance of pathology in the German prostate cancer study PREFERE]. / Die Bedeutung der Pathologie in der deutschen Prostatakrebsstudie PREFERE.

Prostate cancer is the most common carcinoma of elderly males and holds the third place in the ranking of cancer-specific mortality. However, total mortality rate of 3 % is low and half of the patients die from other diseases, which is for the most part due to significantly improved diagnostic methods and the increasing use of prostate-specific antigen (PSA) screening. This has led to a stage migration towards early tumor stages that are prognostically heterogeneous and require differentiated treatment. The German and European guidelines recommend four therapy options (i.e. radical prostatectomy, percutaneous irradiation, permanent seed implantation and active surveillance) for localized prostate cancer and from contemporary study data it is unclear which therapy is most beneficial. This will be the subject of the PREFERE trial, a prospective randomized multicentre trial which plans to recruit 7,600 patients and to observe them over a period of up to 17 years. The histopathological diagnosis of the primary biopsy plays a crucial role in the inclusion criteria, as this article outlines in detail.

The German evidence-based guidelines for Hodgkin's lymphoma. Aspects for radiation oncologists.

This report reviews aspects of the German evidence-based guidelines for Hodgkin's lymphoma relevant to radiation oncologists. Stage-adapted treatment is discussed with the focus on radiotherapy. Up-to-date literature citations provide an overview of current recommendations.

[PREFERE - the German prostatic cancer study: questions and claims surrounding study initiation in January 2013]. / PREFERE - die Deutsche Prostatakrebsstudie : Fragen und Behauptungen rund um den Studienbeginn im Januar 2013.

The PREFERE study is a multicenter randomized study of patients with low or early intermediate risk for prostatic cancer. The four treatment options, radical prostatectomy, percutaneous irradiation therapy, permanent seed implantation and active surveillance recommended by the German S3 guidelines and international guidelines will be tested and compared with respect to effectiveness and potential side effects. Over a period of 4 years a total of 7,600 patients are to be recruited and assigned to 1 of these 4 therapy forms according to personal preference (by possible exclusion of 1 or 2 therapy options) in a 2-4 arm study design by randomization.

Lacking hypoxia-mediated downregulation of E-cadherin in cancers of the uterine cervix.

BACKGROUND: Experimental studies have established a causal connection between tumour hypoxia, hypoxia-associated proteome changes and downregulation of E-cadherin, the final common pathway of epithelial-to-mesenchymal transition (EMT). Our study aimed at elucidating the interrelationship of these processes in cancers of the uterine cervix in vivo. METHODS: Tumour oxygenation was assessed in 48 squamous cell carcinomas (SCC) of the uterine cervix using polarographic needle electrodes. The expression pattern of E-cadherin was investigated by immunohistochemistry and western blotting, and was compared with that of the hypoxia-inducible proteins glucose transporter (GLUT)-1 and carbonic anhydrase (CA) IX in biopsy specimens of the oxygenation measurement tracks. RESULTS: The majority of cervical cancers (52%) were E-cadherin positive, with a complete absence of the antigen in only 10% of the tumours. No correlation was found between the level of E-cadherin expression and the oxygenation status (mean pO(2), median pO(2) and hypoxic fractions). In patients showing partial expression of E-cadherin (38%), staining was not preferentially diminished in GLUT-1- or CA IX-positive areas, and loss of E-cadherin occurred independently of tumour cell scattering. CONCLUSION: Our data provide no evidence in favour of a hypoxia-induced EMT as a mechanistic basis of cervical cancer invasiveness.

Rectal cancer : when is the local recurrence risk low enough to refrain from the aim to prevent it?

Recently, preliminary results of the OCUM study (optimized surgery and MRI-based multimodal therapy of rectal cancer) were published and raised concern in the scientific community. In this observational study, the circumferential resection margin status assessed in preoperative MRI (mrCRM) was used to decide for either total mesorectal excision (TME) alone or neoadjuvant radiochemotherapy (nRCT). In contrast to current guidelines, neither T3 stage (with negative CRM) nor clinically positive lymph nodes were an indication for nRCT. Pathologically node-positive patients received chemotherapy (ChT). Overall, 230 patients were included, of whom 96 CRM-positive patients received nRCT. The CRM was accurately predicted in MRI, the rate of mesorectal plane resection was high. Recurrence rates have not yet been reported, but an impressive rate of down-staging for both T and N stage after nRCT was observed, while acute side effects were minimal. Nonetheless, the authors conclude that a substantial number of patients could be "spared severe radiation toxicity" and propagate their concept for prospectively replacing current guidelines. This is based on the hypothesis that CRM is a valid surrogate parameter for the risk of local recurrence and in case of a negative CRM, nRCT becomes dispensable. Moreover, it is assumed that lymph node status is no more relevant. Both assumptions are a contradiction to recent data from randomized studies as specified below. As 5-year locoregional recurrence rate (LRR) of only of 5-8% and < 5% in low risk rectal cancer can be achieved by the addition of RT, the noninferiority of surgery alone can not be presumed unless the expected 5-year LRR is ≤ 5-8%, whereas any excess of this range renders the study design inacceptable. Unless a publication explicitly specifies 5-year LRR, results are not exploitable for clinical decisions.

Dosimetric feasibility study for an extracorporeal BNCT application on liver metastases at the TRIGA Mainz.

This study investigates the dosimetric feasibility of Boron Neutron Capture Therapy (BNCT) of explanted livers in the thermal column of the research reactor in Mainz. The Monte Carlo code MCNP5 is used to calculate the biologically weighted dose for different ratios of the (10)B-concentration in tumour to normal liver tissue. The simulation results show that dosimetric goals are only partially met. To guarantee effective BNCT treatment the organ has to be better shielded from all gamma radiation.

Boron determination in liver tissue by combining quantitative neutron capture radiography (QNCR) and histological analysis for BNCT treatment planning at the TRIGA Mainz.

The typical primary malignancies of the liver are hepatocellular carcinoma and cholangiocarcinoma, whereas colorectal liver metastases are the most frequently occurring secondary tumors. In many cases, only palliative treatment is possible. Boron neutron capture therapy (BNCT) represents a technique that potentially destroys tumor tissue selectively by use of externally induced, locally confined secondary particle irradiation. In 2001 and 2003, BNCT was applied to two patients with colorectal liver metastases in Pavia, Italy. To scrutinize the rationale of BNCT, a clinical pilot study on patients with colorectal liver metastases was carried out at the University of Mainz. The distribution of the (10)B carrier (p-borono-phenylalanine) in the liver and its uptake in cancerous and tumor-free tissue were determined, focusing on a potential correlation between the uptake of p-borono-phenylalanine and the biological characteristics of cancerous tissue. Samples were analyzed using quantitative neutron capture radiography of cryosections combined with histological analysis. Methodological aspects of the combination of these techniques and results from four patients enrolled in the study are presented that indicate that the uptake of p-borono-phenylalanine strongly depends on the metabolic activity of cells.

[Palliative care for patients with oesophageal cancer]. / Palliativtherapie beim Ösophaguskarzinom.

BACKGROUND: Palliative therapy for patients with incurable oesophageal cancer necessitates a broad spectrum of different measures to relieve symptoms. METHODS: Surgical procedures (palliative tumour resections, bypass surgery) are rarely indicated on account of the high morbidity. Preeminent treatment options to eliminate dysphagia and to ensure food passage are endoscopic procedures, in particular, the endoscopically or radiologically guided stent implantation. In case of failure, a percutaneous feeding tube and general palliative measures are required. Furthermore tumour-specific therapies (brachytherapy, radiochemotherapy, chemotherapy) are applied. DISCUSSION: The choice of the procedure is based on the symptoms, the tumour situation, the patients' general status, and their preferences. If possible, an individual, interdisciplinary treatment concept for each patient should be designed and modified according to the course of the disease. CONCLUSIONS: It should be the aim of future studies to elucidate the optimal combination of a merely symptomatic treatment with tumour-specific measures under the aspect of the achievable quality of life.

[Therapy choices of German urologists and radio-oncologists if personally diagnosed with localized prostate cancer]. / Bevorzugte Behandlungsoptionen des lokalisierten Prostatakarzinoms von deutschen Urologen und Radioonkologen bei eigener Erkrankung.

INTRODUCTION: We evaluated the currently preferred primary treatment options among German urologists and radio-oncologists if personally diagnosed with localized prostate cancer, taking into consideration the different prognostic risk groups. MATERIALS AND METHODS: A questionnaire was mailed to 3,217 urologists and 598 radio-oncologists. They were asked to choose their preferred primary treatment option if they were personally diagnosed with prostate cancer, taking into consideration the different prognostic risk groups: low risk [Gleason score < or =6, prostate-specific antigen (PSA) < or =10 microg/l, T1c], intermediate risk (Gleason score 7, PSA 11-19 microg/l, T2), and high risk (Gleason score > or =8, PSA> or =20 microg/l, T3). Surgical options were further subdivided according to technique (retropubic, laparoscopic, perineal). RESULTS: The questionnaire return rate was 49% for urologists and 41% for radio-oncologists. The mean age was 48 years (28-86) for urologists and 47 years (29-68) for radio-oncologists. Primary surgical treatment was selected by 62% of urologists for low-risk prostate cancer, 90% for intermediate-risk prostate cancer, and 77% for high-risk prostate cancer. Radiotherapy as a primary treatment option was elected by 71% of radio-oncologists for low-risk prostate cancer, 84% for intermediate-risk prostate cancer, and 89% for high-risk prostate cancer. Retropubic, laparoscopic, and perineal prostatectomy would be chosen by 61%, 28%, and 10% of urologists, respectively, for low-risk prostate cancer; by 70%, 24%, and 6%, respectively, for intermediate-risk prostate cancer, and by 80%, 15%, and 5%, respectively for high-risk prostate cancer. CONCLUSION: Urologists prefer surgery and radio-oncologists radiotherapy for primary treatment of prostate cancer, irrespective of the prognostic risk group. Particularly for high-risk prostate cancer, the majority of radiooncologists would still choose radiotherapy as a primary treatment option. In the age of minimally invasive surgery, radical retropubic prostatectomy is still the preferred surgical treatment option among urologists for any prognostic risk group.

Determination of the irradiation field at the research reactor TRIGA Mainz for BNCT.

For the application of the BNCT for the excorporal treatment of organs at the TRIGA Mainz, the basic characteristics of the radiation field in the thermal column as beam geometry, neutron and gamma ray energies, angular distributions, neutron flux, as well as absorbed gamma and neutron doses must be determined in a reproducible way. To determine the mixed irradiation field thermoluminescence detectors (TLD) made of CaF(2):Tm with a newly developed energy-compensation filter system and LiF:Mg,Ti materials with different (6)Li concentrations and different thicknesses as well as thin gold foils were used.

Irradiation facility at the TRIGA Mainz for treatment of liver metastases.

The TRIGA Mark II reactor at the University of Mainz provides ideal conditions for duplicating BNCT treatment as performed in Pavia, Italy, in 2001 and 2003 [Pinelli, T., Zonta, A., Altieri, S., Barni, S., Braghieri, A., Pedroni, P., Bruschi, P., Chiari, P., Ferrari, C., Fossati, F., Nano, R., Ngnitejeu Tata, S., Prati, U., Ricevuti, G., Roveda, L., Zonta, C., 2002. TAOrMINA: from the first idea to the application to the human liver. In: Sauerwein et al. (Eds.), Research and Development in Neutron Capture Therapy. Proceedings of the 10th International Congress on Neutron Capture Therapy, Monduzzi editore, Bologna, pp. 1065-1072]. In order to determine the optimal parameters for the planned therapy and therefore for the design of the thermal column, calculations were conducted using the MCNP-code and the transport code ATTILA. The results of the parameter study as well as a possible configuration for the irradiation of the liver are presented.

Chemoradioimmunotherapy with 5-fluorouracil, cisplatin and interferon-alpha in pancreatic and periampullary cancer: results of a feasibility study.

BACKGROUND: Recent studies give rise to the hypothesis, that adjuvant chemoradioimmunotherapy with 5-fluorouracil (5-FU), cisplatin and interferon-alpha (IFN-alpha) might be a possible new treatment of pancreatic cancer in resected patients. We report the up-to-now experience at our institution. PATIENTS AND METHODS: Eleven patients with histological diagnosis of localized carcinoma of the pancreas (n=7) or periampullary (n=4) were prospectively analyzed. Four patients were deemed unresectable because of local invasion of adjacent organs (neoadjuvant setting) and seven patients underwent curative resection (adjuvant setting). Eight patients were classified as T3 carcinomas and three T4 carcinomas. Fifty-five per cent (6/11) of the patients presented with positive lymph node involvement. One histological Grade I, six Grade II and three Grade III were detected. External conformal irradiation to a total dose of 50.4 Gy with 1.8 Gy per day was delivered. All patients received a concomitant chemotherapy with continuous 5-FU 200 mg/m2 per day on 28 treatment days and intravenous bolus cisplatin 30 mg/m2 per week (Day 2, 9, 16, 23, 30). A recombinant r-IFN-alpha was administered on three days weekly during Week one to five of the radiotherapy course as subcutanous injections with 3*3 Mio. I.U. weekly. RESULTS: The four-year overall survival rate for all patients was 55%. In the neoadjuvant group, three of four patients died due to progressive disease; in the adjuvant group, combined chemoradioimmunotherapy lead to controlled disease in five of seven patients. The overall toxicity was well-managed. CONCLUSION: Our data strengthens the hypothesis of concomitant chemoradioimmunotherapy with 5-FU, IFN-alpha and cisplatin as a possible new treatment of pancreatic cancer in resected patients.