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Concurrent platinum-based chemoradiation (CRT) followed by consolidation PD-L1 inhibition with durvalumab is the standard of care for patients with inoperable stage III NSCLC [1]. However, in high-...

Purpose The advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced NSCLC, leading to a string of approvals in recent years. Herein, a narrative review on the role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in the ever-evolving treatment landscape of advanced NSCLC is presented. Methods This comprehensive review will begin with an introduction into current treatment paradigms incorporating ICIs; the evolution of CT-based criteria; moving onto novel phenomena observed with ICIs and the current state of hybrid imaging for diagnosis, treatment planning, evaluation of treatment efficacy and toxicity in advanced NSCLC, also taking into consideration its limitations and future directions. Conclusions The advent of ICIs marks the dawn of a new era bringing forth new challenges particularly vis-à-vis treatment response assessment and observation of novel phenomena accompanied by novel systemic side effects. While FDG PET/CT is widely adopted for tumor volume delineation in locally advanced disease, response assessment to immunotherapy based on current criteria is of high clinical value but has its inherent limitations. In recent years, modifications of established (PET)/CT criteria have been proposed to provide more refined approaches towards response evaluation. Not only a comprehensive inclusion of PET-based response criteria in prospective randomized controlled trials, but also a general harmonization within the variety of PET-based response criteria is pertinent to strengthen clinical implementation and widespread use of hybrid imaging for response assessment in NSCLC.

Background Durvalumab as maintenance treatment after platinum-based concurrent chemoradiotherapy (cCRT) has become the standard of care in inoperable stage III non-small cell lung cancer (NSCLC). In this nationwide survey, we solicited members of the German Radiation Oncology Society to review the current distribution and clinical settings of durvalumab treatment after cCRT, observed side effects and summarize follow-up management. Methods We surveyed radiation oncology institutions in Germany via an anonymous online questionnaire sent by e-mail to all members of the German Radiation Oncology Society which agreed their willingness to participate. Results We received a total of 255 responses (response rate: 18%). Of which 203 (80%) were completed and returned and thus eligible for further evaluation. The respondents work in 87 different cities and 44% in a private medical practice, 29% in university and 22% in a general hospital. Durvalumab was implemented in clinical routine by 70% of respondents. Major reasons for failed implementation in clinical practice reported by the respondents were patient's ineligibility (42%), lack of required PD-L1 status (25%), decision of medical oncologists (7%) or absence of updated German guidelines (7%). Thirty-six percent of all respondents report low (≤30%) PD-L1 testing before cCRT based on IHC assay. No respondent had applied durvalumab in less than 14 days after the completion of CRT. Severe side effects requiring hospital admission in more than 10% of all patients were reported by 12% of all respondents. Conclusions Durvalumab maintenance is already implemented in the radiation oncology community and administered by the absolute majority of respondents. Low testing rates of PD-L1 at initial diagnosis were observed and should be considered a major barrier to universal adoption and integration in the clinical work-flow in countries with durvalumab approval restricted to PD-L1 positive patients. No respondent applies durvalumab in less than 14 days after cCRT.

In order to personalize multimodal treatment regimens in limited-stage small cell lung cancer (LS-SCLC), a survival score for these patients was proposed. The aim of this study is to validate the score in an independent external patient cohort. We collected data of 78 patients treated with chemoradiotherapy for LS-SCLC between 2004 and 2015. The survival score was calculated by independent prognostic factors: gender, Karnofsky performance status, tumor substage, and hemoglobin level before treatment. Scoring points were derived from 2-year survival rates divided by 10 and the values for each prognostic factor were tallied. Three risk subgroups were defined (high, intermediate, low risk: 9–13, 14–18, 19–26 points). The 2-year survival rate of each subgroup from the original study was compared to its corresponding subgroup from the validation cohort. Median survival time in the entire validation cohort was 17 months (range: 1–123 months). The 2-year survival rates were 0% in the 9–13, 35% in the 14–18, and 43% in the 19–26 points group, respectively (p = 0.018). The difference in 2-year survival between the 9–13 points and the 14–18 points group was significant in the validation cohort (p = 0.007) as well after stratification of concurrent chemoradiotherapy (p

Background/aim Patient performance scores are used widely in clinical practice to assess a patient's general condition. The aim of this study was to evaluate the prognostic role of Eastern Cooperative Oncology Group performance score (ECOG PS) before, after and its changes during chemoradiotherapy in patients with stage III non-small cell lung cancer (NSCLC). Patients and methods Records of 99 patients with stage III NSCLC were evaluated. ECOG PS before, during and after chemoradiotherapy was analyzed for prognostic impact on overall (OS) and event-free (EFS) survival. Results Median OS considering the entire cohort was 20.8 months (range=15.3-26.2 months). Median OS, and 1- and 2-year survival rates were 26.4 months, 85% and 53% in patients with ECOG PS 0 versus 18.9 months, 69% and 37% in patients with ECOG PS 1 (p=0.1, log-rank test), respectively. After the first follow-up, 35% of patients presented worsening ECOG PS, while in 65% it was stable or improved. Median EFS according to ECOG PS 0, 1, 2 and 3 was 9.6, 9.0, 7.9 and 3.5 months, respectively, at the first follow-up (p=0.018, log-rank test). Deterioration of ECOG PS after chemoradiotherapy resulted in reduced OS in the subgroups with initial ECOG PS 0 and 1 (p=0.005 and p=0.001, log-rank test). Conclusion ECOG PS and its changes have a strong impact on patient outcome. Deterioration of performance status was a strong negative prognostic factor for EFS and OS.

Inoperable stage III non-small cell lung cancer (NSCLC) represents a highly heterogeneous patient cohort. Multimodal treatment approaches including radiotherapy have been the new standard of care, with promising outcomes. The planning target volume (PTV), including the primary tumor, involved lymph node stations and safety margins, can vary widely. In order to evaluate the impact of the PTV for overall survival (OS), progression-free survival (PFS) and loco-regional control, we analyzed retrospective and prospective data of 122 consecutive patients with inoperable stage III NSCLC treated with CRT. The majority of patients (93%) received a total dose &ge, 60 Gy and 92% of all patients were treated with concurrent or sequential chemotherapy. Median follow-up for the entire cohort was 41.2 (range: 3.7&ndash, 108.4) months, median overall survival (OS) reached 20.9 (95% CI: 14.5&ndash, 27.3) months. PTVs from 500 to 800 ccm were evaluated for their association with survival in a univariate analysis. In a multivariate analysis including age, gender, total radiation dose and histology, PTV &ge, 700 ccm remained a significant prognosticator of OS (HR: 1.705, 95% CI: 1.071&ndash, 2.714, p = 0.025). After propensity score matching (PSM) analysis with exact matching for Union internationale contre le cancer (UICC) TNM Classification (7th ed.)T- and N-stage, patients with PTV &lt, 700 ccm reached a median PFS and OS of 11.6 (95% CI: 7.3&ndash, 15.9) and 34.5 (95% CI: 25.6&ndash, 43.4) months vs. 6.2 (95% CI: 3.1&ndash, 9.3) (p = 0.057) and 12.7 (95% CI: 8.5&ndash, 16.9) (p &lt, 0.001) months in patients with PTV &ge, 700 ccm, respectively. Inoperable stage III NSCLC patients with PTV &ge, 700 ccm had significantly detrimental outcomes after conventionally fractionated CRT. PTV should be considered as a stratification factor in multimodal clinical trials for inoperable stage III NSCLC.

BACKGROUND: 18F-FDG-positron emission tomography (PET)/computed tomography (CT) is a standard for initial staging in patients with locally advanced stage III non-small cell lung cancer (NSCLC). We evaluated a PET/CT staging score to characterize disease extension and patient outcome in this disease. METHODS: Ninety-nine consecutive patients with NSCLC stage IIIA–B (UICC 7th edition), who underwent 18F-FDG-PET/CT before the start of chemoradiotherapy (CRT) were analyzed. Maximum standardized uptake value of primary tumor (SUVmax_PT) and range between two most distant PET-positive (SUV ≥2.5) lymph nodes in two directions were analyzed for their correlation with patient outcome. The vertical distance was defined as A- and the horizontal as a B-line. RESULTS: According to the results of univariate analysis, score included the SUVmax_PT and horizontal B-line, patients were divided into three risk subgroups: low, intermediate and high-risk subgroups. Subgroups were defined as SUVmax_PT 8 or B-line >3.7 cm and SUVmax_PT >8 plus B-line >3.7 cm, respectively. Twenty-eight (28%), 45 (46%) and 26 (26%) patients were assigned to the low, intermediate and high-risk subgroup, respectively. Median event-free survival (EFS) in low, intermediate and high-risk subgroups was 16 (95% CI: 7–25), 13 (95% CI: 12–15) and 10 (95% CI: 7–13) months (P=0.002, log-rank test). Median OS in the low, intermediate and high-risk subgroups was 40 (95% CI: 11–69), 23 (95% CI: 15–31) and 14 (95% CI: 13–14) months (P=0.0001, log-rank test). In the multivariate analysis, SUV, B-line and PET/CT score were significantly associated with EFS [harard ratio (HR) 2.12 (95% CI: 1.27–3.55) and intermediate risk HR 2.01 (95% CI: 1.13–3.59), P=0.003] and OS [high-risk HR 2.79 (95% CI: 1.16–4.55) and intermediate risk HR 2.30 (95% CI: 1.58–4.94), P=0.001]. CONCLUSIONS: A PET/CT score was developed for inoperable stage III NSCLC patients treated with CRT and was an independent predictor of patient outcome in the single-center cohort.

Background Loco-regional and distant failure are common in inoperable stage III non small-cell lung cancer (NSCLC) after chemoradiotherapy (CRT). However, there is limited real-world data on failure pattern, patient prognosis and salvage options. Methods We analysed 99 consecutive patients with inoperable stage III NSCLC treated with CRT between 2011 and 2016. Follow up CT scans from date of the first-site failure were matched with the delivered radiation treatment plans. Intra-thoracic loco-regional relapse was defined as in-field (IFR) vs. out-of-field recurrence (OFR) [in- vs. outside 50Gy isodose line in the involved lung], respectively. Extracranial distant (DMs) and brain metastases (BMs) as first site of recurrence were also evaluated. Using the Kaplan-Meier method, impact of salvage surgery (sS), radiotherapy (sRT), chemotherapy (sCT) and immunotherapy (sIO) on patient survival was assessed. Results Median follow-up was 60.0 months. Median PFS from the end of CRT for the entire cohort was 7.5 (95% CI: 6.0–9.0 months) months. Twenty-six (26%) and 25 (25%) patients developed IFR and OFR. Median time to diagnosis of IFR and OFR was 7.2 and 6.2 months. In the entire cohort, onset of IFR and OFR did not influence patient outcome. However, in 73 (74%) patients who survived longer than 12 months after initial diagnosis, IFR was a significant negative prognostic factor with a median survival of 19.3 vs 40.0 months (p p = 0.014). Four (16%) patients with OFR received sIO with a numerical survival benefit (64.6 vs. 26.4 months, p = 0.222). DMs and BMs were detected in 27 (27%) and 16 (16%) patients after median time of 5.8 and 5.13 months. Both had no impact on patient outcome in the entire cohort. However, patients with more than three BMs showed significantly poor OS (9.3 vs 26.0 months; p = 0.012). Conclusions After completion of CRT, IFR was a negative prognostic factor in those patients, who survived longer than 12 months after initial diagnosis. Patients with OFR benefit significantly from salvage local treatment. Patients with more than three BMs as first site of failure had a significantly inferior outcome.

Radiotherapy and radiation oncology play a key role in the clinical management of patients suffering from oncological diseases. In clinical routine, anatomic imaging such as contrast-enhanced CT and MRI are widely available and are usually used to improve the target volume delineation for subsequent radiotherapy. Moreover, these modalities are also used for treatment monitoring after radiotherapy. However, some diagnostic questions cannot be sufficiently addressed by the mere use standard morphological imaging. Therefore, positron emission tomography (PET) imaging gains increasing clinical significance in the management of oncological patients undergoing radiotherapy, as PET allows the visualization and quantification of tumoral features on a molecular level beyond the mere morphological extent shown by conventional imaging, such as tumor metabolism or receptor expression. The tumor metabolism or receptor expression information derived from PET can be used as tool for visualization of tumor extent, for assessing response during and after therapy, for prediction of patterns of failure and for definition of the volume in need of dose-escalation. This review focuses on recent and current advances of PET imaging within the field of clinical radiotherapy / radiation oncology in several oncological entities (neuro-oncology, head & neck cancer, lung cancer, gastrointestinal tumors and prostate cancer) with particular emphasis on radiotherapy planning, response assessment after radiotherapy and prognostication.

Aim We investigated blood parameters in patients with inoperable stage III non-small cell lung cancer (NSCLC) to predict individual outcomes after definitive chemoradiotherapy (CRT). Patients and methods Blood parameters of consecutive patients undergoing definitive CRT between 2010 and 2016 for inoperable stage III NSCLC before multimodal treatment and at first follow-up were measured and analyzed. Results Blood parameters from 99 patients were evaluated. Histologically, about 50% of patients had an adenocarcinoma. All patients received platinum-based sequential or concurrent CRT. The median total dose to the primary tumor was 60 (range=48-70) Gy. On multivariate analysis after adjustment for all co-founders, median overall survival for pre-treatment cutoffs were: lactate dehydrogenase (LDH) >250 U/l was 17 vs. 27 months [hazard ratio (HR)=2.05, 95% confidence intervaI (CI)=1.15-3.66; p=0.015], thrombocytosis >400×106/l: 11 vs. 23 months (HR=2.75, 95% CI=1.1-6.88; p=0.03), hypoalbuminemia 7×106/l: 12 vs. 27 months (HR=2.5, 95% CI=1.21-5.17; p=0.013). Conclusion Pre-treatment elevated LDH, thrombocytosis, hypoalbuminemia and post-treatment neutrophilia were associated with significantly worse overall survival in patients with inoperable stage III NSCLC treated with CRT. Patients with both pre-therapeutic elevated LDH and hypoalbuminemia demonstrated a dismal prognosis despite completion of multimodal treatment.

Background/aim mmune checkpoint inhibition (CPI) has an increasing impact in the multimodal treatment of locally advanced non-small cell lung cancer (LA-NSCLC). Increasing evidence suggests treatment outcome depending on tumor cell PD-L1 expression. The purpose of this retrospective study was to investigate the prognostic value of PD-L1 expression on tumor cells in combination with CD8+ tumor stroma-infiltrating lymphocyte (TIL) density in inoperable LA-NSCLC treated with concurrent chemoradiotherapy (CRT). Patients and method We retrospectively assessed clinical characteristics and initial tumor biopsy samples of 31 inoperable LA-NSCLC patients treated with concurrent CRT. Prognostic impact of tumor cell PD-L1 expression (0% versus ≥1%) and CD8+ TIL density (0–40% vs. 41–100%) for local control, progression-free (PFS) and overall survival (OS) as well as correlations with clinicopathological features were evaluated. Results Median OS was 14 months (range: 3–167 months). The OS rates at 1- and 2 years were 68 and 20%. Local control of the entire cohort at 1 and 2 years were 74 and 61%. Median PFS, 1-year and 2-year PFS were 13 ± 1.4 months, 58 and 19%. PD-L1 expression neg/CD8low) and type IV (PD-L1pos/CD8low) tumors (median OS: 57 ± 37 vs. 10 ± 5 months, p = 0.05), respectively. Conclusion Assessment of PD-L1 expression on tumor cells in combination with CD8+ TIL density can be a predictive biomarker in patients with inoperable LA-NSCLC treated with concurrent CRT.

Background/Aim: The general pattern of care regarding the application of prophylactic cranial irradiation (PCI) in small cell lung cancer (SCLC) patients in Germany has not been previously evaluated. This survey was conducted to assess patterns of care. Patients and Methods: Radiation oncology institutions in Germany were surveyed via an anonymous online questionnaire sent by e-mail to member institutions of the German Society for Radiation Oncology. Results: A total of 95 responses were received (29% response rate). Eighty-eight percent of all responders recommended a PCI total dose of 30Gy delivered in 15 daily fractions. Overall, 11 and 38% of the respondents applied PCI simultaneously with chemo- and radiotherapy, respectively. A quarter of respondents offered hippocampal-avoidance PCI and followed their patients with serial brain imaging. Conclusion: PCI with a total dose of 30 Gy in 15 daily fractions, without neuropsychological testing and hippocampus-avoidance, delivered after completion of primary multimodal treatment remains standard in Germany.

Background There is limited data on the use of targeted or immunotherapy (TT/IT) in combination with single fraction stereotactic radiosurgery (SRS) in patients with melanoma brain metastasis (MBM). Therefore, we analyzed the outcome and toxicity of SRS alone compared to SRS in combination with TT/IT. Methods Patients with MBM treated with single session SRS at our department between 2014 and 2017 with a minimum follow-up of 3 months after first SRS were included. The primary endpoint of this study was local control (LC). Secondary endpoints were distant intracranial control, radiation necrosis-free survival (RNFS), and overall survival (OS). The local/ distant intracranial control rates, RNFS and OS were analyzed using the Kaplan-Meier method. The log-rank test was used to test differences between groups. Cox proportional hazard model was performed for univariate continuous variables and multivariate analyses. Results Twenty-eight patients (17 male and 11 female) with 52 SRS-lesions were included. The median follow-up was 19 months (range 14–24 months) after first SRS. Thirty-six lesions (69.2%) were treated with TT/IT simultaneously (4 weeks before and 4 weeks after SRS), while 16 lesions (30.8%) were treated with SRS alone or with sequential TT/IT. The 1-year local control rate was 100 and 83.3% for SRS with TT/IT and SRS alone (p = 0.023), respectively. The estimated 1-year RNFS was 90.0 and 82.1% for SRS in combination with TT/IT and SRS alone (p = 0.935). The distant intracranial control rate after 1 year was 47.7 and 50% for SRS in combination with TT/IT and SRS alone (p = 0.933). On univariate analysis, the diagnosis-specific Graded Prognostic Assessment including the BRAF status (Melanoma-molGPA) was associated with a significantly improved LC. Neither gender nor SRS-PTV margin had a prognostic impact on LC. V10 and V12 were significantly associated with RNFS (p p = 0.004). Conclusion SRS with simultaneous TT/IT significantly improved LC with no significant difference in radiation necrosis rate. The therapy combination appears to be effective and safe. However, prospective studies on SRS with simultaneous TT/IT are necessary and ongoing. Trial registration The institutional review board approved this analysis on 10th of February 2015 and all patients signed informed consent (UE nr. 128–14).

We analysed a correlation between pre- to post-treatment primary tumour metabolic volume (PT-MV) reduction on 18F-FDG-PET/CT and survival in non-small cell lung cancer (NSCLC) patients treated with chemoradiotherapy (CRT). Sixty consecutive patients with NSCLC stage IIIA-B (UICC 7th edition), treated with chemoradiotherapy, who underwent 18F-FDG-PET/CT at the same institution before and 6 weeks after treatment, were analysed. Different metabolic response values were investigated on their correlation with survival parameters: complete response (100% PT-MV reduction); major response (80–99% PT-MV reduction); moderate response (50–79% PT-MV reduction); minor response (1–49% PT-MV reduction) and non-response (no change or increase in uptake). From 60 patients, 52 (87%) had repeat PET/CT scans 6 weeks after completion of CRT. Complete metabolic response (CR) was reached in ten (17%), whereas major and moderate metabolic responses occurred in 16 (27%) and 15 (25%) patients, respectively. Four patients (7%) had minor metabolic response. Non-response was documented in seven patients (12%). Median overall survival (MS) for the entire cohort was 17 months (95% CI: 11.9–22.1 months). MS according to the different metabolic response values was as follows: 34 months (95% CI: 0–84.1); 22 months (95% CI: 14.2–29.8); 12 months (95% CI: 0.4–23.6); 11 months (95% CI: 0.2–21.8) and 17 months in patients with complete, major, moderate, minor and non-response (95% CI: 6.7–27.3), respectively (p = 0.008). On multivariate analysis, significant predictors of survival included ECOG performance status (p = 0.035, HR 0.49, 95% CI: 0.25–0.95) as well as complete and major metabolic response as a continuous variable with PT-MV reduction of at least 80% (p = 0.021, HR 0.36, 95% CI: 0.15–0.86). Moderate metabolic response did not correlate with improved outcome (p = 0.522). In this homogeneous locally-advanced NSCLC single-centre patient cohort, a PT-MV reduction of at least 80% (complete and major metabolic response) following CRT was necessary to significantly improve patient outcome.

Prophylactic cranial irradiation (PCI) has proven to decrease the incidence of brain metastases (BMs), with a modest improvement in survival.The impact of PCI was evaluated in 184 patients treated with chemoradiotherapy. PCI was applied to patients with disease with partial and complete response only when cranial magnetic resonance imaging before and after primary treatment revealed no BMs. Correlation between PCI and overall survival (OS), BM-free survival (BMFS), and time to progression (TTP) was analyzed to describe survival within subgroups.Concurrent and sequential chemoradiotherapy was applied in 71 patients (39%) and 113 patients (61%), respectively. Seventy-one patients (39%) with partial and complete response were treated with PCI. Metachronous BMs were detected in 16 (23%) of 71 patients in the PCI group compared to 42 (37%) of 113 patients in the non-PCI group. Median BMFS in the PCI group was not reached; it was 23.6 months in the non-PCI group. Median OS and TTP were 26 months (range, 19.4-32.6 months) in the PCI group versus 14 months (range, 11.4-16.6 months) in patients without PCI whose disease responded to therapy versus 9 months in patients with disease that did not respond to therapy (P .0001), and 27 versus 14.5 months (range, 9.0-19.9 months) versus 8.8 months (range, 7.7-9.9 months) (P .0001) in the PCI group versus those with response without PCI versus those with nonresponse. The effect of PCI was independent of gender. On multivariate analysis, PCI was a variable correlating with OS (hazard ratio = 1.899; 95% confidence interval, 1.370-2.632; P .0001) and TTP (hazard ratio = 2.164; 95% confidence interval, 1.371-3.415; P = .001) after adjustment for other prognostic factors.In real-life patients comprehensively staged with cranial magnetic resonance imaging, treatment response and PCI strongly correlated with prolonged OS, TTP, and BMFS.

Patients with locally advanced lung cancer and very limited pulmonary function (forced expiratory volume in 1 second [FEV1] ≤ 1 L) have dismal prognosis and undergo palliative treatment or best supportive care. We describe two cases of locally advanced node-positive non-small cell lung cancer (NSCLC) patients with very limited lung function treated with induction chemotherapy and moderate hypofractionated image-guided radiotherapy (Hypo-IGRT). Hypo-IGRT was delivered to a total dose of 45 Gy to the primary tumor and involved lymph nodes. Planning was based on positron emission tomography-computed tomography (PET/ CT) and four-dimensional computed tomography (4D-CT). Internal target volume (ITV) was defined as the overlap of gross tumor volume delineated on 10 phases of 4D-CT. ITV to planning target volume margin was 5 mm in all directions. Both patients showed good clinical and radiological response. No relevant toxicity was documented. Hypo-IGRT is feasible treatment option in locally advanced node-positive NSCLC patients with very limited lung function (FEV1 ≤ 1 L).

BACKGROUND: Stage III non-small cell lung cancer (NSCLC) represents a heterogeneous disease regarding principal patient- and tumor characteristics. A simple score may aid in personalizing multimodal therapy. METHODS: The data of 99 consecutive patients with performance status ECOG 0–1 treated until the end of 2016 with multimodal approach for inoperable NSCLC (UICC 7(th) edition stage IIIA/B) were evaluated. Patient- and tumor-related factors were examined for their impact on overall survival. Factors showing a negative association with prognosis were then included in the score. Three subgroups with low, intermediate and high-risk score were defined. The results were then validated in the prospective cohort, which includes 45 patients. RESULTS: Most Patients were treated with concurrent (78%) or sequential (11%) chemoradiotherapy. 53% received induction chemotherapy. Median survival for the entire cohort was 20.8 (range: 15.3–26.3) months. Age (P=0.020), gender (P=0.007), pack years (P=0.015), tumor-associated atelectasis (P=0.004) and histology (P=0.004) had a significant impact on overall survival and were scored with one point each. Twelve, 59 and 28 patients were defined to have a low (0–1 points), intermediate (2–3 points) and high-risk (4–5 points) score. Median survival, 1-, 2- and 3-year survival rates were not reached, 100%, 83% and 67% in the low, 22.9 months, 80%, 47% and 24% intermediate and 13.7 months, 57%, 25% and 18% high-risk patients, respectively (P

Background To determine the feasibility of PET/CT-based image-guided moderate hypofractionated thoracic irradiation (Hypo-IGRT) in locally advanced node-positive non-small cell lung cancer patients with highly compromised pulmonary function. Method Eight highly-selected and closely monitored patients with highly diminished pulmonary function (FEV1 ≤ 1.0 L and/or DLCO-SB ≤ 40% and/or on long-term oxygen therapy) were treated with Hypo-IGRT. Planning was based on 18F-FDG-PET/CT and 4D-CT in the treatment position. Hypo-IGRT was delivered to a total dose of 45 Gy (ICRU) in 15 daily fractions under strict image-guidance. Vital capacity (VC), forced expiratory volume in 1 s (FEV1), and single-breath diffusing capacity of the lung for CO (DLCO-SB) were analyzed prior to, 3 and 6 months after Hypo-IGRT. Result Eight patients with stage IIIA-C NSCLC (8th TNM Ed.) completed Hypo-IGRT. The median follow-up was 29.4 months. The median age was 64 years. Four, three and one patient(s) presented with COPD GOLD IV, III and II, respectively and 5 patients (63%) were on long-term oxygen therapy. The median PTV was 226.9 cc (range: 100.17–379.80 cc). Median PFS and OS were 19 and 34.3 months. The 6 months and 1-year OS rates were 100, 87.5%, respectively. The 6- and 12- months PFS rates were 87.5 and 52.5%. Three patients developed local failure. Median initial VC, FEV1 and DLCO-SB was 1.69 L/64.8% predicted (range: 1.36–2.66 L/33–80%), 1 L/39.4% predicted (range:0.78–1.26 L/28–60% predicted) and 33.3% (range: 13.3–54%) predicted, respectively. Median values for VC, FEV1, DLCO-SB 3 and 6 months after Hypo-IGRT were 2.05 L/56.35% predicted (range: 1.34–2.33 L/47–81.5%), 1.08 L/47.5% predicted (range: 0.74–1.60 L/30.8–59.59%), 38.55% (range: 24–68%) and 1.64 L/66% predicted (range: 1.41–2.79/35.5–75.5%), 1.0 L/47% predicted (range: 0.65–1.28 L/24.5–54.10%), 31% (range: 27–43%), respectively. Mean lung dose was 9.4 Gy (range: 5.3–11.6 Gy) and V20 for both lungs was 15% (range: 6–19%). Mean esophageal dose was 12.76 Gy (range: 2.1–26.7 Gy). There was no case of grade 2 or higher radiation pneumonitis. Four patients developed grade 2 radiation esophagitis. Conclusion Hypo-IGRT can be considered for individual and closely monitored patients with locally advanced node-positive NSCLC with highly compromised pulmonary function. No severe pulmonary toxicity and significant decline of pulmonary function parameters was observed in our cohort. Currently, this protocol is being assessed in an ongoing single-centre prospective study.

e21011 Background: Lymphocytopenia is associated with deterioration of patient survival in solid cancers treated with concurrent chemo/radiotherapy (cCRT). A prospective analysis of peripheral blood mononuclear cells during cCRT in inoperable stage III NSCLC patients was performed to determine dynamic changes of individual lymphocyte subsets. Methods: Twenty-one patients were prospectively enrolled in this study. Eighteen patients received platinum-based cCRT, seven of them received, additionally, concurrent and/or sequential immune checkpoint-inhibition (ICI). Thoracic irradiation (TRT) was delivered with median total dose of 62Gy (31 daily fractions of 2Gy) in all patients. Peripheral blood was collected 5-10 days before treatment (A1), three weeks after start of cCRT (A3), on the last day of TRT (RTend) and during follow-up. Samples were analyzed using polychromatic flow cytometry. Results are reported for time-points A1, A3 and RTend. Results: Sixteen patients met final analysis criteria, 50% of them received concurrent and/or sequential ICI. All patients developed severe lymphocytopenia; in 81% of them lymphocyte nadir was documented at A3. Lymphocyte subsets, B cells, T cells (CD4, CD8), regulatory T cells, and NK cells, decreased with medians between 99.9% and 59%. Lymphocyte nadir was independent of the absolute numbers of immune cells that a patient had before start of cCRT or whether additional ICI was applied. From A3 to RTend, all lymphocyte subsets started to recover in patients treated with cCRT alone, while they remained low in patients who received additional ICI. The ratios of CD4/CD8 and CD8/Treg cells did not change during treatment (A1 to RTend) and was not different between the patients treated with or without ICI. However, the fraction of PD-1 cells among CD8 T-cells decreased in patients treated with ICI and remained low until RTend (range 0.55%-13.8%). In contrast, in 50% of patients treated with cCRT alone, PD-1 T-cell among CD8 T-cells increased and remained high (range 6.8%-46.3%) until RTend. Conclusions: Delayed recovery of lymphocyte subsets in peripheral blood was observed in patients treated with cCRT combined with concurrent or sequential ICI. A decrease of PD-1 T-cells among CD8 T-cells was described exclusively in patients treated with additional ICI.

9049 Background: The metabolic tumor volume (MTV) is a functional and volumetric PET/CT parameter that has been investigated in recent years with respect to its predictive and prognostic value in different tumor entities. In this study, we investigated the role of residual MTV after completion of thoracic irradiation in inoperable stage III non-small cell lung cancer (NSCLC). Methods: We analyzed retrospective and prospective data of 56 patients with inoperable stage III NSCLC treated with chemoradiotherapy (CRT) and chemoradioimmunotherapy (CRT-IO). All patients received an 18F-FDG-PET/CT 3 to max. 6 months after completion of thoracic irradiation. The measurement of the residual MTV of the primary tumor was performed by calculating the SUVmean of the liver + 2SD as threshold. The patients were divided into the following groups: residual-MTV < 1ml; residual-MTV 1-25ml and residual-MTV > 26ml. Survival, local recurrence, and distant metastasis rates were calculated using the Kaplan-Meier method from the last day of thoracic irradiation. Results: The median follow-up was 45 months (range 16-74) in the CRT group and 16 months in the CRT-IO group (range13-19). Twenty-two (39%) patients had a residual MTV < 1ml (1st group), 19 (34%) a residual MTV between 1-25ml (2nd group) and 15 (27%) a residual MTV > 25ml (3rd group) after completion of thoracic irradiation. Median overall survival was 61, 20 and 12 months (p = 0.006) in the 1st, 2nd and 3rd groups, respectively. 12-month survival was 86%, 50% and 33% after CRT vs. 88%, 71% and 50% after CRT-IO in the 1st, 2nd and 3rd groups, respectively. The median time to in-field recurrence in the 1st, 2nd and 3rd groups was 51, 20 and 15 months (p = 0.011). The prognostic value of the residual MTV on OS was confirmed exclusively in the CRT patient cohort (p = 0.04), but not in the CRT-IO patient cohort (p = 0.174). Residual MTV demonstrated no influence on the local recurrence rate in the CRT-IO patient cohort, but only in patients treated with CRT (p = 0.007). Conclusions: Patients with inoperable stage III NSCLC in whom the residual MTV was < 1ml after completion of thoracic irradiation showed significantly better survival than patients with a residual MTV of 1-25ml and MTV > 25ml. The subgroup analysis confirmed the prognostic value of residual MTV only in patients who received chemoradiotherapy without consolidation immunotherapy.

Combinations of immune checkpoint inhibitors (ICIs) with radiotherapy and/or chemoradiotherapy are currently under investigation in many cancer types and clinical settings. In this survey, we solicited members of the German Radiation Oncology Society and young DEGRO (working group of DEGRO e.V.) to review the current status of research in this field and underline critical issues such as oncological benefit, treatment toxicity and obstacles in clinical research. The responses represent 14 different departments of radiation oncology at German university hospitals. Respondents of the same department were analysed for congruence. Sixty-one percent of all respondents perform radiotherapy/chemoradiotherapy and ICI therapy combination studies at their institutions and participate in multicentre studies. Combinations were investigated mainly in head and neck tumours (95%), lung cancer (57%), malignant melanoma (48%) and tumours of the upper gastrointestinal tract (9%). Combination of chemoradiotherapy with checkpoint inhibitors was only tested in head and neck cancers (52%), non–small-cell lung cancer (NSCLC) (8.70%) and malignant melanoma (4%). A combination of radiotherapy/chemoradiotherapy with ICIs is assumed to be effective or very effective by >85% of all respondents. The treatment of intracranial metastatic disease by this combination is assumed to be very effective by most respondents (61%). The present survey shows great acceptance of new combined modality treatment paradigm. ICIs with radiotherapy and/or chemoradiotherapy are under investigation at >75% of all participating centres. Head and neck tumours, NSCLC and malignant melanoma are the most frequently tested cancer types.

Over 10% of small-cell lung cancer (SCLC) patients have brain metastases (BM) at initial diagnosis; more than 50% will develop BM within 2 years. BM are detected in up to 80% of all patients at autopsy. After primary treatment, prophylactic cranial irradiation (PCI) has been established as standard of care in SCLC patients responding to initial therapy. Based on level I evidence, PCI significantly decreases the risk of intracranial relapse and shows a modest survival benefit after 3 years. However, the role of PCI in defined patient subgroups such as resected SCLC, elderly and extensive stage patients with access to magnetic resonance imaging surveillance and stereotactic radiotherapy is yet to be fully clarified. Furthermore, strategies to effective prevention of neurocognitive decline after PCI remain unclear. All these factors significantly impact treatment decision making and should be evaluated in prospective settings. New concepts such as hippocampal avoidance and drug neuroprotection prevent chronic neurocognitive effects reducing treatment-related side effects of PCI. The aim of this review is to present a summary and update of the latest evidence for patient selection, efficacy and outcome of PCI.

Correction to: Strahlenther Onkol 2017 https://doi.org/10.1007/s00066-017-1229-3 Unfortunately, an incorrect reference was provided in Table 4. The corrected version of Table 4 can be found below. We apologize for any inconvenience …

Nivolumab is a feasible therapy option in patients with advanced non-small cell lung cancer (NSCLC) who progress on first-line treatment. However, there is limited information about an overlapping toxicity of PD-1 inhibitors when administered following thoracic radiotherapy (TRT). Three of 25 patients with advanced NSCLC were treated with palliative or curative intent. Nivolumab was initiated as second or third-line therapy after TRT for recurrent or progressive disease. All 3 patients developed grade 3 pneumonitis at some point during nivolumab therapy. Herein, we describe 3 cases of pneumonitis in patients with NSCLC started on nivolumab following TRT. Imaging analysis was strongly consistent with heterogenous lung parenchyma changes in the irradiated lung volume receiving a total dose of 15-20 Gy. Pulmonary toxicity was manageable; however, interruption of immunotherapy was necessary.

Adult medulloblastoma is a rare disease treated according to the current pediatric treatment guidelines. This retrospective analysis investigated the clinical outcomes and prognostic factors of adult medulloblastoma patients, who received multimodal therapy at our institution. Treatment charts of all patients over the age of 15 years of age with de novo medulloblastoma, who had been treated at our institution between 2001 and 2014, were retrospectively analyzed. Patients’ demographic parameters, initial symptoms, treatment modalities, toxicities, and survival outcomes were investigated. In all, 21 patients with a median age of 30.2 years were identified. The most frequent histologies were desmoplastic and classic, and the most common molecular subtype was sonic hedgehog (SHH). After tumor resection, all patients received craniospinal irradiation (median dose 35.2 Gy) and a boost to the posterior fossa (median dose 19.8 Gy). Simultaneous chemotherapy with vincristine was given to 20 patients and sequential chemotherapy to 15 patients. The most common side effects were hematological toxicities. Median overall survival (OS) has not been reached after a median follow-up of 92 months. Estimated 5‑ and 10-year OS was 89 and 80%, respectively. Estimated 5‑ and 10-year progression-free survival (PFS) was 89 and 81%, respectively. In univariate analysis, a shorter interval between tumor resection and end of irradiation was significantly associated with improved OS and PFS, anaplastic histology with worse OS and PFS. The combined modality treatment showed a good outcome in adults with medulloblastoma. Treatment time was revealed to be prognostic and should be kept as short as possible.

Positron emission tomography with 2‑deoxy-2-[fluorine-18] fluoro-d-glucose integrated with computed tomography (18F-FDG-PET/CT) has an established role in the initial diagnosis and staging of lung cancer. However, a prognostic value of PET/CT during multimodality treatment has not yet been fully clarified. This study evaluated the role of primary tumor metabolic volume (PT-MV) changes on PET/CT before, during, and after chemoradiotherapy (CRT). A total of 65 patients with non-small-cell lung cancer (NSCLC) UICC stage IIIA/B (TNM 7th Edition) were treated with definitive chemoradiotherapy (sequential or concurrent setting). PET/CT was acquired before the start, at the end of the third week, and 6 weeks following CRT. Median overall survival (OS) for the entire cohort was 16 months (95% confidence interval [CI]: 12–20). In all, 60 (92.3%) patients were eligible for pre-treatment (pre-PT-MV), 28 (43%) for mid-treatment (mid-PT-MV), and 53 (81.5%) for post-treatment (post-PT-MV) volume analysis. Patients with pre-PT-MV >63 cm3 had worse OS (p 15% improved OS (p = 0.001). In addition, patients with post-PT-MV > 25 cm3 had significantly worse outcome (p = 0.001). On multivariate analysis, performance status (p = 0.002, hazard ratio [HR] 0.007; 95% CI 0.00–0.158), pre-PT-MV1 15% (p = 0.004, HR 0.25; 95% CI 0.02–0.31) correlated with improved OS. Our results demonstrated that pre- and post-treatment PT-MV, as well as an at least 15% reduction in mid- to post-PT-MV, significantly correlates with OS in patients with inoperable locally advanced NSCLC.

Leptomeningeal metastases (LM) are found in approximately 3.8% of non-small cell lung cancer cases with an increased incidence in adenocarcinoma, and approximately one-third of patients will present with concomitant brain metastases. We report the case of a 50-year-old male patient with stage IV exon 19-del-EGFR mutant lung adenocarcinoma who progressed on second-generation TKI therapy with manifestation of symptomatic simultaneous diffuse brain and LM. Whole-brain radiotherapy with concurrent afatinib resulted in an almost complete regression of neurological symptoms as well as good, durable radiological response. Furthermore, treatment was well tolerated with no relevant adverse effects.

Visualization and metabolic analysis of acute inflammation in the lung parenchyma plays a crucial role for the prediction and diagnosis of radiation-induced lung injury and is particularly important in medically inoperable patients because of a priori very limited pulmonary function. This case confirms that a radiation-induced lung injury is accompanied by acute inflammatory reaction in the lung parenchyma irradiated with a total dose of 12-40 Gy. This well-defined inflammation component could be exactly characterized with FDG-PET/CT.