External Validation of the Graded Prognostic Assessment in Patients with Brain Metastases from Small Cell Lung Cancer.

BACKGROUND: Recently, graded prognostic assessment (GPA) for small cell lung cancer (SCLC) patients with brain metastases has been developed. This includes age, performance status, number of brain metastases and presence of extracranial metastases. The aim of the present study was to validate this four-tiered prognostic score in a European cohort of patients. METHODS: The retrospective validation study included 180 patients from two centers in Germany and Norway. RESULTS: Median survival from radiological diagnosis of brain metastases was 7 months. The GPA point sum as continuous variable (0-4 points) was significantly associated with survival (p < 0.001). However, no significant survival difference was observed between patients in the two strata with better survival (3.5-4 and 2.5-3 points, respectively). Long-term survival in the poor prognosis group (0-1 points) was better than expected. CONCLUSION: This study supports the prognostic impact of all four parameters contributing to the GPA. The original way of grouping the parameters and breaking the final strata did not give optimal results in this cohort. Therefore, additional validation databases from different countries should be created and evaluated.

Cost effectiveness and health-related quality of life of chemoradiotherapy versus radiation therapy alone in elderly head and neck cancer patients.

PURPOSE: Radiotherapy (RT) constitutes a mainstay in the treatment of elderly patients with head and neck cancer (HNC), but use of simultaneous chemoradiotherapy (CRT) remains controversial. We have conducted a prospective analysis based on real-world patient data to examine the health-related quality of life (HRQoL) and cost effectiveness (CE) of CRT vs. RT in elderly HNC patients. METHODS: Eligible participants ≥ 65 years treated in a large tertiary cancer center between July 2019 and February 2020 who completed the validated EQ-5D-5L questionnaire (health state index [HI] and visual analog scale [VAS]) before and after RT were included. CE referred to direct medical costs, including diagnosis-related group (DRG)-based billings for inpatients and uniform assessment standard (EBM)-based costs for outpatients. The primary endpoint was cost (euros [€]) per quality-adjusted life year (QALY). The incremental cost-effectiveness ratios (ICERs) were calculated. Costs and QALYs were not discounted for short overall survival (OS). RESULTS: Baseline HRQoL was 0.878 (±0.11) in the CRT group and 0.857 (±0.17) in the RT group. Upon completion of therapy, HRQoL amounted to 0.849 (±0.14) in the CRT and 0.850 (±0.13) in the RT group. The mean treatment-related cost in the CRT cohort was €22,180.17 (±8325.26) vs. €18,027.87 (±26,022.48) in the RT group. The corresponding QALYs amounted to 2.62 in the CRT and 1.91 in the RT groups. The ICER was €5848.31. CONCLUSION: This is the first analysis from the German health care system demonstrating that the addition of chemotherapy to RT for selected elderly HNC patients is cost effective and not associated with a significant HRQoL decline.

Financial toxicity in cancer patients treated with radiotherapy in Germany-a cross-sectional study.

PURPOSE: Financial toxicity arises in cancer patients from subjective financial distress due to objective financial burden from the disease or treatment. Financial toxicity associates with worse outcomes. It has not been described in cancer patients undergoing radiotherapy in Germany and its publicly funded health system. In this context, we therefore investigated the prevalence of financial toxicity, associated risk factors, and patient preferences on communication of financial burden. METHODS: We conducted a preregistered ( https://doi.org/10.17605/OSF.IO/KH6VX ) cross-sectional study surveying patients at the end of their course of radiotherapy in two institutions. Objective financial burden was assessed by direct costs and loss of income. Financial toxicity was measured by subjective financial distress per EORTC QLQ-C30. We used Spearman's correlation and Fisher's exact test for univariate analysis, an ordinal regression for multivariate analysis. A p-value < 0.05 was considered statistically significant. RESULTS: Of the 100 patients participating in the study, 68% reported direct costs, 25% loss of income, and 31% subjective financial distress. Per univariate analysis, higher subjective financial distress was significantly associated with active employment, lower quality of life, lower household income, higher direct costs, and higher loss of income. The latter three factors remained statistically significant in the multivariate analysis. A relative majority of the patients welcomed communication regarding financial burden with their radiation oncologist. CONCLUSION: Financial toxicity is prevalent in cancer patients treated with radiotherapy in Germany. The reported risk factors may help to identify patients at risk. Future studies should validate these results and investigate interventions for financial toxicity to potentially improve outcomes.

Assessment of extracranial metastatic disease in patients with brain metastases: How much effort is needed in the context of evolving survival prediction models?

Survival prediction models may serve as decision-support tools for clinicians who have to assign the right treatment to each patient, in a manner whereby harmful over- or undertreatment is avoided as much as possible. Current models differ regarding their components, the overall number of components and the weighting of individual components. Some of the components are easy to assess, such as age or primary tumor type. Others carry the risk of inter-assessor inconsistency and time-dependent variation. The present publication focuses on issues related to assessment of extracranial metastases and potential surrogates, e.g. blood biomarkers. It identifies areas of controversy and provides recommendations for future research projects, which may contribute to prognostic models with improved accuracy.

Validation of the graded prognostic assessment for gastrointestinal cancers with brain metastases (GI-GPA).

PURPOSE: The purpose of this study was to validate a new prognostic model (GI-GPA) originally derived from a multi-center database (USA, Canada, Japan). PATIENTS AND METHODS: This retrospective study included 92 German and Norwegian patients treated with individualized approaches, always including brain radiotherapy. Information about age, extracranial spread, number of brain metastases, performance status and other variables was collected. The GI-GPA score was calculated as described by Sperduto et al. RESULTS: Median survival was 4 months. The corresponding figures for the 4 different prognostic strata were 2.3, 4.4, 9.4 and 12.7 months, respectively (p = 0.0001). Patients whose management included surgical resection had longer median survival than those who were treated with other approaches (median 11.9 versus 3.0 months, p = 0.002). Comparable results were seen for additional systemic therapy (median 8.5 versus 3.5 months, p = 0.01). CONCLUSION: These results confirm the validity of the GI-GPA in an independent dataset from a different geographical region, despite the fact that overall survival was shorter in all prognostic strata, compared to Sperduto et al. Potential explanations include differences in molecular tumor characteristics and treatment selection, both brain metastases-directed and extracranially. Long-term survival beyond 5 years is possible in a small minority of patients.

Validation of the Graded Prognostic Assessment for Melanoma Using Molecular Markers (Melanoma-molGPA).

BACKGROUND: It has been suggested to replace the diagnosis-specific graded prognostic assessment (DS-GPA, based on performance status and number of brain metastases) for patients with primary malignant melanoma with the new Melanoma-molGPA. The latter is a more complex assessment, which also includes BRAF mutation status, age and extracranial metastases. To test the performance of the Melanoma-molGPA, we performed a validation study of this new survival prediction tool. METHODS: A retrospective analysis of patients treated at two different academic institutions was performed. The four-tiered Melanoma-molGPA was calculated as suggested in the original study. RESULTS: Median overall survival was 5.4 months (95% confidence interval: 3.1 - 7.7 months). Median survival in the four prognostic classes was 2.1, 7.8, 11.8, and 18.0 months, respectively. The 1-year survival rates were 3%, 25%, 43%, and 80%, respectively. The difference between the Kaplan-Meier curves was significant (P = 0.0001, log-rank test). CONCLUSIONS: The present survival outcomes support the use of the Melanoma-molGPA. However, survival was better in each of the four groups in the original study. Possible reasons include lead-time bias and different treatment policies.

Validation of the graded prognostic assessment for lung cancer with brain metastases using molecular markers (lung-molGPA).

BACKGROUND: Many patients with brain metastases from non-small cell lung cancer have limited survival, while others survive for several years, depending on patterns of spread, EGFR and ALK alterations, among others. The purpose of this study was to validate a new prognostic model (Lung-molGPA) originally derived from a North American database. PATIENTS AND METHODS: This retrospective study included 269 German and Norwegian patients treated with individualized approaches, always including brain radiotherapy. Information about age, extracranial spread, number of brain metastases, performance status, histology, EGFR and ALK alterations was collected. The Lung-molGPA score was calculated as described by Sperduto et al. RESULTS: Median survival was 5.4 months. The score predicted survival in patients with adenocarcinoma histology and those with other types. For example, median survival was 3.0, 6.2, 14.7 and 25.0 months in the 4 different prognostic strata for adenocarcinoma. The corresponding figures were 2.4, 5.5 and 12.5 months in the 3 different prognostic strata for non-adenocarcinoma. CONCLUSIONS: These results confirm the validity of the Lung-molGPA in an independent dataset from a different geographical region. However, median survival was shorter in 6 of 7 prognostic strata. Potential explanations include lead time bias and differences in treatment selection, both brain metastases-directed and systemically.

Diagnosis-specific graded prognostic assessment score is valid in patients with brain metastases treated in routine clinical practice in two European countries.

BACKGROUND: Assessment of cancer- and host-related prognostic factors has a long tradition in patients with brain metastases. In continuation of large-scale studies performed by the Radiation Therapy Oncology Group (RTOG) in the United States, the 4-tiered diagnosis-specific graded prognostic assessment (DS-GPA) score has been developed. It stratifies patients with common primary tumours metastasizing to the brain (malignant melanoma, lung, breast, kidney and gastrointestinal cancers) into subgroups with different prognoses. However, many patients in the DS-GPA study were treated with surgical resection or radiosurgery (SRS). The present multi-institutional analysis examined for the first time whether DS-GPA is a valid score in European patients managed in routine clinical practice. MATERIAL/METHODS: This was a retrospective analysis of 412 patients with primary malignant melanoma, lung, breast, kidney or gastrointestinal cancers. Survival was evaluated in uni- and multivariate tests. RESULTS: DS-GPA significantly predicted survival and outperformed initial GPA, a score that is not diagnosis-specific. Median survival by DS-GPA strata (all 412 patients) was 2.7, 3.6, 7.0 and 11.3 months in the 4 groups with 0-1, 1.5-2, 2.5-3 and 3.5-4 points, respectively. The previously published survival data (median 7.2 months for all patients) could not be replicated in this cohort (median 3.6 months). CONCLUSIONS: DS-GPA is a valid prognostic score that might improve shared decision making as well as patient stratification in prospective clinical trials.

[Survey of potential improvements during the course of the radiotherapy treatment--a patient questionnaire]. / Erfassung möglicher Verbesserungen im Ablauf der Strahlentherapie--eine Patientenbefragung.

INTRODUCTION AND BACKGROUND: In the context of quality assurance, increasing demands are placed on the whole radiotherapy treatment process. The patients directly concerned generally do not realize most aspects of the quality assurance program (e.g., additional safety checks) during their daily therapy. It was the aim of this study to systematically ask patients about potential improvements during the course of radiotherapy treatment from their own perspective. PATIENTS AND METHODS: In the defined time span (1 month), 624 radiotherapy patients (600 questionnaires were returned, 96.2%) were interviewed using a questionnaire newly developed to inquire about several aspects of their treatment. Furthermore, they were asked for their specific needs and suggestions for improvements that could be made during the course of radiotherapy treatment. RESULTS: Overall, the patients were satisfied with the course of their radiotherapy treatment and with patient care. As an example, about 90% agreed with the statement: "My first contact with the radiation oncology unit proceeded with kindness and competence so that I was given the impression that I will be well cared for in this clinic." Considering the organization of the course of radiotherapy, a large majority of patients attached great value to set appointments for the therapy fractions. A main point of criticism was waiting times or delays caused by servicing or machine failures. Small, low cost improvements as music in the therapy room were considered as important as expensive measures (e.g., daylight in the therapy room). The patients emphasized the importance of staff friendliness. CONCLUSION: The situation of radiotherapy patients was, in general, satisfactory. Future improvements can be mainly expected from smooth organisation of both planning and treatment which can be achieved by electronic scheduling systems. Many results of the survey could be easily implemented in daily practice. In matters of organization radiation oncology with its complex procedures can be used as a model for other clinical departments.

Can current prognostic scores reliably guide treatment decisions in patients with brain metastases from malignant melanoma?

PURPOSE: We evaluated the performance of the new 4-tiered melanoma-specific graded prognostic assessment (GPA) score and the previously published general GPA score in patients with brain metastases from malignant melanoma managed with different approaches including best supportive care. MATERIALS AND METHODS: Retrospective analysis of 51 patients. Compared with the original analysis of the melanoma-specific GPA score, these patients were more representative of the general population of patients with brain metastases from this disease. RESULTS: The present data confirmed that both scores identify patients with favorable prognosis who might be candidates for focal treatments. However, survival in the 2 unfavorable prognostic subgroups defined by the melanoma-specific GPA was not significantly different. Median survival in the melanoma-specific GPA classes was 3.1, 3.7, 7.5, and 12.7 months. Karnofsky performance status (KPS) and serum lactatdehydrogenase (LDH) level significantly predicted survival. CONCLUSION: In order to select the right patient to the right treatment and avoid overtreatment and suboptimal resource utilization in patients with very limited survival, improved prognostic tools are needed. The melanoma-specific GPA does not include extracranial disease extent or surrogate markers such as LDH. We suggest that a combination of KPS <70 and elevated LDH might better predict short survival than any of the GPA scores. This hypothesis should be confirmed in larger studies.

[Automated delivery of codes for charge in radiotherapy]. / Automatisierte Leistungsübermittlung in der Strahlenheilkunde.

BACKGROUND AND PURPOSE: For the medical billing of Radiotherapy every fraction has to be encoded, including date and time of all administered treatments. With fractions averaging 30 per patient and about 2,500 new patients every year the number of Radiotherapy codes reaches an amount of 70,000 and more. Therefore, an automated proceeding for transferring and processing therapy codes has been developed at the Department of Radiotherapy Freiburg, Germany. This is a joint project of the Department of Radiotherapy, the Administration Department, and the Central IT Department of the University Hospital of Freiburg. MATERIAL AND METHODS: The project consists of several modules whose collaboration makes the projected automated transfer of treatment codes possible. The first step is to extract the data from the department's Clinical Information System (MOSAIQ). These data are transmitted to the Central IT Department via an HL7 interface, where a check for corresponding hospitalization data is performed. In the further processing of the data, a matching table plays an important role allowing the transformation of a treatment code into a valid medical billing code. In a last step, the data are transferred to the medical billing system. RESULTS AND CONCLUSION: After assembling and implementing the particular modules successfully, a first beta test was launched. In order to test the modules separately as well as the interaction of the components, extensive tests were performed during March 2006. Soon it became clear that the tested procedure worked efficiently and accurately. In April 2006, a pilot project with a few qualities of treatment (e.g., computed tomography, simulation) was put into practice. Since October 2006, nearly all Radiation Therapy codes (approximately 75,000) are being transferred to the comprehensive Hospital Information System (HIS) automatically in a daily routine.

[The situation of radiation oncology patients' relatives. A stocktaking]. / Die Situation der Angehörigen von Strahlentherapiepatienten. Eine Bestandsaufnahme.

BACKGROUND AND PURPOSE: Recent studies have shown a very high importance of relatives in decisions about medical interventions. Therefore, the situation of this group was investigated in the sense of a stocktaking by interviewing the closest relatives of radiotherapy patients. INTERVIEWED PERSONS AND METHODS: In a defined span of time (6 weeks), a total of 470 relatives (evaluable: n = 287, 61%) of radiotherapy patients were interviewed by a newly developed questionnaire about their contentment with their inclusion in the therapy course. Further, they gave information about specific needs of relatives as well as proposals for direct improvements in the context of a radiation therapy. RESULTS: In total, the relatives were satisfied with their inclusion in the radiotherapy course and with the patient care. As an example, more than 95% of the relatives agreed with the statement "Here in the hospital my ill relative is cared for well." Nevertheless, direct possibilities for improvements were found in the interdisciplinary information about oncologic topics and in the organization of the therapy course. CONCLUSION: In the stocktaking the situation of radiotherapy patients' relatives was generally satisfactory. Further improvements for the future can be expected mainly from interdisciplinary cancer centers having the best suppositions to care for the relatives, if necessary. Structures known from palliative care can be used as a model.

Assessment of tumor volumes in skull base glomus tumors using Gluc-Lys[(18)F]-TOCA positron emission tomography.

PURPOSE: To assess a threshold for Gluc-Lys[(18)F]-TOCA positron emission tomography (PET) in target volume delineation of glomus tumors in the skull base and to compare with MRI-based target volume delineation. METHODS AND MATERIALS: The threshold for volume segmentation in the PET images was determined by a phantom study. Nine patients with a total of 11 glomus tumors underwent PET either with Gluc-Lys[(18)F]-TOCA or with (68)Ga-DOTATOC (in 1 case). All patients were additionally scanned by MRI. Positron emission tomography and MR images were transferred to a treatment-planning system; MR images were analyzed for lesion volume by two observers, and PET images were analyzed by a semiautomated thresholding algorithm. RESULTS: Our phantom study revealed that 32% of the maximum standardized uptake value is an appropriate threshold for tumor segmentation in PET-based target volume delineation of gross tumors. Target volume delineation by MRI was characterized by high interobserver variability. In contrast, interobserver variability was minimal if fused PET/MRI images were used. The gross tumor volumes (GTVs) determined by PET (GTV-PET) showed a statistically significant correlation with the GTVs determined by MRI (GTV-MRI) in primary tumors; in recurrent tumors higher differences were found. The mean GTV-MRI was significantly higher than mean GTV-PET. The increase added by MRI to the common volume was due to scar tissue with strong signal enhancement on MRI. CONCLUSIONS: In patients with glomus tumors, Gluc-Lys[(18)F]-TOCA PET helps to reduce interobserver variability if an appropriate threshold for tumor segmentation has been determined for institutional conditions. Especially in patients with recurrent tumors after surgery, Gluc-Lys[(18)F]-TOCA PET improves the accuracy of GTV delineation.

Tirapazamine plus cisplatin and irradiation in a mouse model: improved tumor control at the cost of increased toxicity.

PURPOSE: Tirapazamine (TPZ) reportedly enhances the tumor cell killing effect of cisplatin up to fivefold and it is an attractive drug for combination with radiotherapy. We evaluated the toxicity of a fractionated combined treatment. METHODS: Murine RIF-1 fibrosarcomas growing on the right hind foot of C3-H mice were used. Within 2 weeks, animals were treated with six i.p. injections of TPZ (43.2-172.8 mg/kg total), and/or cisplatin (24 mg/kg total) and ten fractions of 2 Gy to the tumor. All treatments were carried out under anesthesia. Maximum follow-up was 35 days. The local tumor control was determined by calculating the tumor doubling time t (2vo). In addition to standard toxicity assessment, the major inner organs were examined histologically. RESULTS: The administration of low TPZ doses to the cisplatin/radiotherapy treatment caused only little changes in tumor doubling time (t (2vo)) and led to a lethality rate of 15-30%. Higher TPZ doses caused an increase in t (2vo), but also a further increase in lethality and toxicity in particular to the heart, liver, kidney and stomach. Cisplatin/radiotherapy treatment without TPZ produced no severe toxicity. CONCLUSIONS: This is a detailed study of both the acute and delayed toxicities of combined TPZ treatment in a mouse model. In our study the addition of TPZ to the cisplatin/radiotherapy treatment caused a significant increase in toxicity with only moderate effect on the tumor.