Oligoprogression : Eine innovative Indikation für die Körperstereotaxie bei metastasierten Tumorsituationen

Hintergrund: Erlotinib ist beim nichtkleinzelligen Lungenkarzinom (NSCLC) in der metastasierten Situation zugelassen nach dem Versagen der Erstlinien-Chemotherapie, unabhängig vom EGFR-Mutationsstatus. Die vorliegende Phase-II-Studie untersuchte den Stellenwert einer lokalen körperstereotaktischen Bestrahlung simultan zur Erlotinib-Therapie nach Progress in der Erstlinien-Chemotherapie beim NSCLC im Stadium IV [1]. Methode: In dieser prospektiven Phase-II-Studie wurden 24 Patienten mit NSCLC im Stadium IV nach Progress der Erstlinien- (n = 15), Zweitlinien- (n = 7) und Drittlinien-Chemotherapie (n = 2) (Cisplatin-basiert 21/24) mit Körperstereotaxie (SBRT) behandelt, wenn sie an bis zu 6 Läsionen im FDG-PET progredient waren und nicht bereits mit einem EGFR-Inhibitor behandelt worden waren. Die SBRT konnte in einer Fraktion (Gesamtdosis: 19–24 Gy), 3 (27–33 Gy) oder 5 (35–40 Gy) Fraktionen appliziert werden; mit Erlotinib wurde in einer Dosierung von 150 mg/Tag eine Woche vor der SBRT begonnen und bis zur Progression weitergeführt. Primärer Endpunkt war das progressionsfreie Überleben nach 6 Monaten. Ergebnisse: Die 24 Patienten wurden zwischen 2007 und 2013 rekrutiert, und die Auswertung erfolgte nach einer medianen Nachbeobachtungszeit von 16,3 Monaten. Die bestrahlten Läsionen, insgesamt 52, waren am häufigsten in der Lunge (n = 18), im Mediastinum (n = 13) und den Nebennieren (n = 7) lokalisiert. 48/52 Läsionen konnten ohne relevante Dosisabweichung bestrahlt werden. Erlotinib wurde für eine mediane Dauer von 273 Tagen eingenommen. Ein Patient erlitt eine Grad-IV- und anschließend eine Grad-V-Toxizität (pulmonal), die möglicherweise auf die SBRT zurückzuführen ist. Das mediane Gesamtüberleben betrug 20,4 Monate und das mediane progressionsfreie Überleben 14,7 Monate. Eine Progression wurde nur selten in den bestrahlten Lokalisationen beobachtet (n = 3/21 Patienten), häufiger an neuen Lokalisationen (n = 10/21). Bei 10/21 Patienten kam es während der gesamten Nachbeobachtungzeit aber zu keiner Krankheitsprogression. Schlussfolgerung der Autoren: Mit der Kombination aus systemischer Erlotinib-Therapie und lokaler SBRT kann man eine lange Progressionsfreiheit und ein vielversprechendes Gesamtüberleben erzielen

Evolution of surface-based deformable image registration for adaptive radiotherapy of non-small cell lung cancer (NSCLC)

<p>Abstract</p> <p>Background</p> <p>To evaluate the performance of surface-based deformable image registration (DR) for adaptive radiotherapy of non-small cell lung cancer (NSCLC).</p> <p>Methods</p> <p>Based on 13 patients with locally advanced NSCLC, CT images acquired at treatment planning, midway and the end of the radio- (n = 1) or radiochemotherapy (n = 12) course were used for evaluation of DR. All CT images were manually [gross tumor volume (GTV)] and automatically [organs-at-risk (OAR) lung, spinal cord, vertebral spine, trachea, aorta, outline] segmented. Contours were transformed into 3D meshes using the Pinnacle treatment planning system and corresponding mesh points defined control points for DR with interpolation within the structures. Using these deformation maps, follow-up CT images were transformed into the planning images and compared with the original planning CT images.</p> <p>Results</p> <p>A progressive tumor shrinkage was observed with median GTV volumes of 170 cm³(range 42 cm³- 353 cm³), 124 cm³(19 cm³- 325 cm³) and 100 cm³(10 cm³- 270 cm³) at treatment planning, mid-way and at the end of treatment. Without DR, correlation coefficients (CC) were 0.76 ± 0.11 and 0.74 ± 0.10 for comparison of the planning CT and the CT images acquired mid-way and at the end of treatment, respectively; DR significantly improved the CC to 0.88 ± 0.03 and 0.86 ± 0.05 (p = 0.001), respectively. With manual landmark registration as reference, DR reduced uncertainties on the GTV surface from 11.8 mm ± 5.1 mm to 2.9 mm ± 1.2 mm. Regarding the carina and intrapulmonary vessel bifurcations, DR reduced uncertainties by about 40% with residual errors of 4 mm to 6 mm on average. Severe deformation artefacts were observed in patients with resolving atelectasis and pleural effusion, in one patient, where the tumor was located around large bronchi and separate segmentation of the GTV and OARs was not possible, and in one patient, where no clear shrinkage but more a decay of the tumor was observed.</p> <p>Discussion</p> <p>The surface-based DR performed accurately for the majority of the patients with locally advanced NSCLC. However, morphological response patterns were identified, where results of the surface-based DR are uncertain.</p

A comprehensive and longitudinal evaluation of the different populations of lymphoid and myeloid cells in the peripheral blood of patients treated with chemoradiotherapy for head and neck cancer

BACKGROUND Immunotherapy provided significant survival benefits for recurrent and metastatic patients with head and neck cancer. These improvements could not be reproduced in patients treated with curative-intent chemoradiotherapy (CRT) and the optimal radio-immunotherapy (RIT) concepts have yet to be designed. Exploration and analysis of the pre-therapeutic immune status of these patients and the changes occurring during the treatment course could be crucial in rationally designing future combined treatments. METHODS Blood samples were collected from a cohort of 25 head and neck cancer patients treated with curative-intended (C)-RT prior to therapy, after the first week of treatment, and three months after treatment completion. Peripheral blood mononuclear cells (PBMCs) or all nucleated blood cells were isolated and analyzed via flow cytometry. RESULTS At baseline, patients showed reduced monocyte and lymphocyte counts compared to healthy individuals. Although overall CD8$^{+}$ T-cell frequencies were reduced, the proportion of memory subsets were increased in patients. Radiotherapy (RT) treatment led to a further increase in CD8$^{+}$ effector memory T-cells. Among myeloid populations, tumor-promoting subsets became less abundant after RT, in favor of pro-inflammatory cells. CONCLUSION The present study prospectively demonstrated a complex interplay and distinct longitudinal changes in the composition of lymphocytic and myeloid populations during curative (C)-RT of head and neck cancer. Further validation of this method in a larger cohort could allow for better treatment guidance and tailored incorporation of immunotherapies (IT) in the future

Recommendations for radiation therapy in oligometastatic prostate cancer: An ESTRO-ACROP Delphi consensus

BACKGROUND AND PURPOSE Oligometastatic prostate cancer is a new and emerging treatment field with only few prospective randomized studies published so far. Despite the lack of strong level I evidence, metastasis-directed therapies (MDT) are widely used in clinical practice, mainly based on retrospective and small phase 2 studies and with a large difference across centers. Pending results of ongoing prospective randomized trials, there is a clear need for more consistent treatment indications and radiotherapy practices. MATERIAL AND METHODS A European Society for Radiotherapy and Oncology (ESTRO) Guidelines Committee consisting of radiation oncologists' experts in prostate cancer was asked to answer a dedicated questionnaire, including 41 questions on the main controversial issues with regard to oligometastatic prostate cancer. RESULTS The panel achieved consensus on patient selection and routine use of prostate-specific membrane antigen positron emission tomography (PSMA PET) imaging as preferred staging and restaging imaging. MDT strategies are recommended in the de novo oligometastatic, oligorecurrent and oligoprogressive disease setting for nodal, bone and visceral metastases. Radiation therapy doses, volumes and techniques were discussed and commented. CONCLUSION These recommendations have the purpose of providing standardization and consensus to optimize the radiotherapy treatment of oligometastatic prostate cancer until mature results of randomized trials are available

Definitions and treatment of oligometastatic oesophagogastric cancer according to multidisciplinary tumour boards in Europe

BACKGROUND Consensus about the definition and treatment of oligometastatic oesophagogastric cancer is lacking. OBJECTIVE To assess the definition and treatment of oligometastatic oesophagogastric cancer across multidisciplinary tumour boards (MDTs) in Europe. MATERIAL AND METHODS European expert centers (n = 49) were requested to discuss 15 real-life cases in their MDT with at least a medical, surgical, and radiation oncologist present. The cases varied in terms of location and number of metastases, histology, timing of detection (i.e. synchronous versus metachronous), primary tumour treatment status, and response to systemic therapy. The primary outcome was the agreement in the definition of oligometastatic disease at diagnosis and after systemic therapy. The secondary outcome was the agreement in treatment strategies. Treatment strategies for oligometastatic disease were categorised into upfront local treatment (i.e. metastasectomy or stereotactic radiotherapy), systemic therapy followed by restaging to consider local treatment or systemic therapy alone. The agreement across MDTs was scored to be either absent/poor (<50%), fair (50%-75%), or consensus (≥75%). RESULTS A total of 47 MDTs across 16 countries fully discussed the cases (96%). Oligometastatic disease was considered in patients with 1-2 metastases in either the liver, lung, retroperitoneal lymph nodes, adrenal gland, soft tissue or bone (consensus). At follow-up, oligometastatic disease was considered after a median of 18 weeks of systemic therapy when no progression or progression in size only of the oligometastatic lesion(s) was seen (consensus). If at restaging after a median of 18 weeks of systemic therapy the number of lesions progressed, this was not considered as oligometastatic disease (fair agreement). There was no consensus on treatment strategies for oligometastatic disease. CONCLUSION A broad consensus on definitions of oligometastatic oesophagogastric cancer was found among MDTs of oesophagogastric cancer expert centres in Europe. However, high practice variability in treatment strategies exists

Stereotactic body radiotherapy of adrenal metastases-A dose-finding study

Optimal doses for the treatment of adrenal metastases with stereotactic radiotherapy (SBRT) are unknown. We aimed to identify dose-volume cut-points associated with decreased local recurrence rates (LRR). A multicenter database of patients with adrenal metastases of any histology treated with SBRT (biologically effective dose, BED10 ≥50 Gy, ≤12 fractions) was analyzed. Details on dose-volume parameters were required (planning target volume: PTV-D98%, PTV-D50%, PTV-D2%; gross tumor volume: GTV-D50%, GTV-mean). Cut-points for LRR were optimized using the R maxstat package. One hundred and ninety-six patients with 218 lesions were included, the largest histopathological subgroup was adenocarcinoma (n = 101). Cut-point optimization resulted in significant cut-points for PTV-D50% (BED10: 73.2 Gy; P = .003), GTV-D50% (BED10: 74.2 Gy; P = .006), GTV-mean (BED10: 73.0 Gy; P = .007), and PTV-D2% (BED10: 78.0 Gy; P = .02) but not for the PTV-D98% (P = .06). Differences in LRR were clinically relevant (LRR ≥ doubled for cut-points that were not achieved). Further dose-escalation was not associated with further improved LRR. PTV-D50%, GTV-D50%, and GTV-mean cut-points were also associated with significantly improved LRR in the adenocarcinoma subgroup. Separate dose optimizations indicated a lower cut-point for the PTV-D50% (BED10: 69.1 Gy) in adenocarcinoma lesions, other values were similar (73.2 Gy (adenocarcinoma: 69.1 Gy) should be considered

Radiation-induced lymphopenia does not impact treatment efficacy in a mouse tumor model

Radiation-induced lymphopenia is a common occurrence in radiation oncology and an established negative prognostic factor, however the mechanisms underlying the relationship between lymphopenia and inferior survival remain elusive. The relevance of lymphocyte co-irradiation as critical normal tissue component at risk is an emerging topic of high clinical relevance, even more so in the context of potentially synergistic radiotherapy-immunotherapy combinations. The impact of the radiotherapy treatment volume on the lymphocytes of healthy and tumor-bearing mice was investigated in a novel mouse model of radiation-induced lymphopenia. Using an image-guided small-animal radiotherapy treatment platform, translationally relevant tumor-oriented volumes of irradiation with an anatomically defined increasing amount of normal tissue were irradiated, with a focus on the circulating blood and lymph nodes. In healthy mice, the influence of irradiation with increasing radiotherapy treatment volumes was quantified on the level of circulating blood cells and in the spleen. A significant decrease in the lymphocytes was observed in response to irradiation, including the minimally irradiated putative tumor area. The extent of lymphopenia correlated with the increasing volumes of irradiation. In tumor-bearing mice, differential radiotherapy treatment volumes did not influence the overall therapeutic response to radiotherapy alone. Intriguingly, an improved treatment efficacy in mice treated with draining-lymph node co-irradiation was observed in combination with an immune checkpoint inhibitor. Taken together, our study reveals compelling data on the importance of radiotherapy treatment volume in the context of lymphocytes as critical components of normal tissue co-irradiation and highlights emerging challenges at the interface of radiotherapy and immunotherapy. Keywords: Image-guided small animal radiotherapy platform; Lymphopenia; Normal tissue injury; Radioimmunotherapy; Radiotherap

Feasibility and Usability Aspects of Continuous Remote Monitoring of Health Status in Palliative Cancer Patients Using Wearables

Background: Mobile health is a promising strategy aiming to anticipate and prevent the deterioration of health status in palliative cancer patients. A prerequisite for successful implementation of this technology into clinical routine is a high level of usability and acceptance of devices. Objectives: We aimed to evaluate feasibility as well as patients’ acceptance of remote monitoring using wearables in palliative cancer patients. Methods: In this prospective single-center observational feasibility study, 30 cancer patients treated with palliative intent in an inpatient setting with an estimated life expectancy of >8 weeks and <12 months were provided with a smartphone including a pre-installed “Activity Monitoring” app and a sensor-equipped bracelet and monitored over a period of 12 weeks starting at discharge from hospital. We report detailed feasibility and usability aspects and comment on patients’ acceptance of the wearables. Results: Between February 2017 and May 2018 a total of 30 patients were included in the study. From these, 25 participants (83%) completed the whole study period. On average, the bracelet was worn on 53% and smartphone used on 85% of the study days. The completion rate of daily digital questionnaires for subjective ratings (pain and distress scale) was 73%, and 28 patients were able to handle the wearables and to operate the app without major problems. Use of the bracelet was low during the night hours, with a wearing time of 1.7% of all night hours (8 p.m. to 8 a.m.). Conclusions: Remote monitoring of health care status in palliative cancer patients with a limited life expectancy is feasible and patients are able to handle the smartphone and the sensor-equipped bracelet. Feedback towards use of this monitoring system was mostly positive