First-site-metastasis pattern in patients with inoperable stage III NSCLC treated with concurrent chemoradiotherapy with or without immune check-point inhibition: a retrospective analysis.

PURPOSE: The aim of this study was to investigate a first-site-metastasis pattern (FSMP) in unresectable stage III NSCLC after concurrent chemoradiotherapy (cCRT) with or without immune checkpoint inhibition (ICI). METHODS: We defined three patient subgroups according to the year of initial multimodal treatment: A (2011-2014), B (2015-2017) and C (2018-2020). Different treatment-related parameters were analyzed. Observed outcome parameters were brain metastasis-free survival (BMFS), extracranial distant metastasis-free survival (ecDMFS) and distant metastasis-free survival (DMFS). RESULTS: 136 patients treated between 2011 and 2020 were included with ≥ 60.0 Gy total dose and concurrent chemotherapy (cCRT); thirty-six (26%) received ICI. Median follow-up was 49.7 (range:0.7-126.1), median OS 31.2 (95% CI:16.4-30.3) months (23.4 for non-ICI vs not reached for ICI patients, p = 0.001). Median BMFS/ecDMFS/DMFS in subgroups A, B and C was 14.9/16.3/14.7 months, 20.6/12.9/12.7 months and not reached (NR)/NR/36.4 months (p = 0.004/0.001/0.016). For cCRT+ICI median BMFS was 53.1 vs. 19.1 months for cCRT alone (p = 0.005). Median ecDMFS achieved 55.2 vs. 17.9 (p = 0.003) and median DMFS 29.5 (95% CI: 1.4-57.6) vs 14.93 (95% CI:10.8-19.0) months (p = 0.031), respectively. Multivariate analysis showed that age over 65 (HR:1.629; p = 0.036), GTV ≥ 78 cc (HR: 2.100; p = 0.002) and V20 ≥ 30 (HR: 2.400; p = 0.002) were negative prognosticators for BMFS and GTV ≥ 78 cc for ecDMFS (HR: 1.739; p = 0.027). After onset of brain metastasis (BM), patients survived 13.3 (95% CI: 6.4-20.2) months and 8.6 months (95% CI: 1.6-15.5) after extracranial-distant-metastasis (ecDM). Patients with ecDM as FSMP reached significantly worse overall survival of 22.1 (range:14.4-29.8) vs. 40.1 (range:18.7-61.3) months (p = 0.034) in the rest of cohort. In contrast, BM as FSMP had no impact on OS. CONCLUSION: This retrospective analysis of inoperable stage III NSCLC patients revealed that age over 65, V20 ≥ 30 and GTV ≥ 78 cc were prognosticators for BMFS and GTV ≥ 78 cc for ecDMFS. ICI treatment led to a significant improvement of BMFS, ecDMFS and DMFS. ecDM as FSMP was associated with significant deterioration of OS, whereas BM as FSMP was not.

Metabolic patterns on [18F]FDG PET/CT in patients with unresectable stage III NSCLC undergoing chemoradiotherapy ± durvalumab maintenance treatment.

PURPOSE: In patients with unresectable stage III non-small-cell lung cancer (NSCLC), durvalumab maintenance treatment after chemoradiotherapy (CRT) significantly improves survival. So far, however, metabolic changes of tumoral lesions and secondary lymphoid organs under durvalumab are unknown. Hence, we assessed changes on [18F]FDG PET/CT in comparison to patients undergoing CRT alone. METHODS: Forty-three patients with [18F]FDG PET/CT both before and after standard CRT for unresectable stage III NSCLC were included, in 16/43 patients durvalumab maintenance treatment was initiated (CRT-IO) prior to the second PET/CT. Uptake of tumor sites and secondary lymphoid organs was compared between CRT and CRT-IO. Also, readers were blinded for durvalumab administration and reviewed scans for findings suspicious for immunotherapy-related adverse events (irAE). RESULTS: Initial uptake characteristics were comparable. However, under durvalumab, diverging metabolic patterns were noted: There was a significantly higher reduction of tumoral uptake intensity in CRT-IO compared to CRT, e.g. median decrease of SUVmax -70.0% vs. -24.8%, p = 0.009. In contrast, the spleen uptake increased in CRT-IO while it dropped in CRT (median + 12.5% vs. -4.4%, p = 0.029). Overall survival was significantly longer in CRT-IO compared to CRT with few events (progression/death) noted in CRT-IO. Findings suggestive of irAE were present on PET/CT more often in CRT-IO (12/16) compared to CRT (8/27 patients), p = 0.005. CONCLUSION: Durvalumab maintenance treatment after CRT leads to diverging tumoral metabolic changes, but also increases splenic metabolism and leads to a higher proportion of findings suggestive of irAE compared to patients without durvalumab. Due to significantly prolonged survival with durvalumab, survival analysis will be substantiated in correlation to metabolic changes as soon as more clinical events are present.

Pooled analysis on image-guided moderately hypofractionated thoracic irradiation in inoperable node-positive/recurrent patients with non-small cell lung cancer with poor prognostic factors and severely limited pulmonary function and reserve.

BACKGROUND: The objective of this study was to investigate the feasibility and efficacy of image-guided moderately hypofractionated thoracic radiotherapy (hypo-IGRT) in patients with non-small cell lung cancer (NSCLC) with poor performance status and severely limited pulmonary function and reserve. METHODS: Consecutive inoperable patients who had node-positive, stage IIB-IIIC (TNM, 8th edition) or recurrent NSCLC, had an Eastern Cooperative Oncology Group performance status ≥1, and had a forced expiratory volume in 1 second (FEV1 ) ≤1.0 L, had a single-breath diffusing capacity of the lung for carbon monoxide (DLCO-SB) ≤40% and/or on long-term oxygen therapy were analyzed. All patients received hypofractionated IGRT to a total dose of 42.0 to 49.0 Gy/13 to 16 fractions (2.8-3.5 Gy/fraction) (equivalent dose in 2-Gy fractions/biologically effective dose [α/ß = 10] = 45.5-55.1 Gy/54.6-66.2 Gy) alone. Patients were monitored closely for nonhematological toxicity, which was classified per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Between 2014 and 2021, 47 consecutive patients with a median age of 72 years (range, 52.2-88 years) were treated. At baseline, the median FEV1 , vital capacity, and DLCO-SB were 1.17 L (range, 0.69-2.84 L), 2.34 L (range, 1.23-3.74 L), and 35% predicted (range, 13.3%-69.0%), respectively. The mean and median planning target volumes were 410.8 cc (SD, 267.1 cc) and 315.4 cc (range, 83.4-1174.1 cc). With a median follow-up of 28.9 months (range, 0.5-90.6 months) after RT, the median progression-free survival (PFS)/overall survival (OS) and 6- and 12-month PFS/OS rates were 10.4 months (95% CI, 7-13.8 months)/18.3 months (95% CI, 9.2-27.4 months), 70%/89.4%, and 38.8%/66%, respectively. Treatment was well tolerated with only 1 case each of grade 3 pneumonitis and esophagitis. No toxicity greater than grade 3 was observed. CONCLUSIONS: Patients with inoperable node-positive NSCLC, a poor performance status, and severely limited lung function can be safely and effectively treated with individualized moderately hypofractionated IGRT. The achieved survival rates for this highly multimorbid group of patients were encouraging.

Planning target volume as a predictor of disease progression in inoperable stage III non-small cell lung cancer patients treated with chemoradiotherapy and concurrent and/or sequential immune checkpoint inhibition.

BACKGROUND: The present study evaluates outcome after chemoradiotherapy (CRT) with concurrent and/or sequential Programmed Cell Death 1 (PD-1) or Ligand 1 (PD-L1) immune checkpoint inhibition (CPI) for inoperable stage III NSCLC patients depending on planning target volume (PTV). METHOD AND PATIENTS: Prospective data of thirty-three consecutive patients with inoperable stage III NSCLC treated with CRT and sequential durvalumab (67%, 22 patients) or concurrent and sequential nivolumab (33%, 11 patients) were analyzed. Different PTV cut offs and PTV as a continuous variable were evaluated for their association with progression-free (PFS), local-regional progression-free (LRPFS), extracranial distant metastasis-free (eMFS) and brain-metastasis free-survival (BMFS). RESULTS: All patients were treated with conventionally fractionated thoracic radiotherapy (TRT); 93% to a total dose of at least 60 Gy, 97% of patients received two cycles of concurrent platinum-based chemotherapy. Median follow-up for the entire cohort was 19.9 (range: 6.0-42.4) months; median overall survival (OS), LRFS, BMFS and eMFS were not reached. Median PFS was 22.8 (95% CI: 10.7-34.8) months. Patients with PTV ≥ 900ccm had a significantly shorter PFS (6.9 vs 22.8 months, p = 0.020) and eMFS (8.1 months vs. not reached, p = 0.003). Furthermore, patients with PTV ≥ 900ccm and stage IIIC disease (UICC-TNM Classification 8th Edition) achieved a very poor outcome with a median PFS and eMFS of 3.6 vs 22.8 months (p < 0.001) and 3.6 months vs. not reached (p = 0.001), respectively. PTV as a continuous variable also had a significant impact on eMFS (p = 0.048). However, no significant association of different PTV cut-offs or PTV as a continuous variable with LRPFS and BMFS could be shown. The multivariate analysis that was performed for PTV ≥ 900ccm and age (≥ 65 years), gender (male), histology (non-ACC) as well as T- and N-stage (T4, N3) as covariates also revealed PTV ≥ 900ccm as the only factor that had a significant correlation with PFS (HR: 5.383 (95% CI:1.263-22.942, p = 0.023)). CONCLUSION: In this prospective analysis of inoperable stage III NSCLC patients treated with definitive CRT combined with concurrent and/or sequential CPI, significantly shorter PFS and eMFS were observed in patients with initial PTV ≥ 900ccm.

Consequences of the COVID-19 pandemic on lung cancer care and patient health in a German lung cancer center: results from a cross-sectional questionnaire.

BACKGROUND: The novel coronavirus SARS-CoV-2 has caused a global COVID-19 pandemic, leading to worldwide changes in public health measures. In addition to changes in the public sector (lockdowns, contact restrictions), hospitals modified care to minimize risk of infection and to mobilize resources for COVID-19 patients. Our study aimed to assess the impact of these measures on access to care and behaviour of patients with thoracic malignancies. METHODS: Thoracic oncology patients were surveyed in October 2020 using paper-based questionnaires to assess access to ambulatory care services and tumor-directed therapy during the COVID-19 pandemic. Additionally, behaviour regarding social distancing and wearing of face masks were assessed, as well as COVID-19 exposure, testing and vaccination. Results are presented as absolute and relative frequencies for categorical variables and means with standard deviation for numerical variables. We used t-test, and ANOVA to compare differences in metric variables and Chi2-test to compare proportions between groups. RESULTS: 93 of 245 (38%) patients surveyed completed the questionnaire. Respiration therapy and physical therapy were unavailable for 57% to 70% of patients during March/April. Appointments for tumor-directed therapy, tumor imaging, and follow-up care were postponed or cancelled for 18.9%, 13.6%, and 14.8% of patients, respectively. Patients reported their general health as mostly unaffected. The majority of patients surveyed did not report reducing their contacts with family. The majority reduced contact with friends. Most patients wore community masks, although a significant proportion reported respiratory difficulties during prolonged mask-wearing. 74 patients (80%) reported willingness to be vaccinated against SARS-CoV-2. CONCLUSIONS: This survey provides insights into the patient experience during the second wave of the COVID-19 pandemic in Munich, Germany. Most patients reported no negative changes to cancer treatments or general health; however, allied health services were greatly impacted. Patients reported gaps in social distancing, but were prepared to wear community masks. The willingness to get vaccinated against SARS-CoV-2 was high. This information is not only of high relevance to policy makers, but also to health care providers.

Differential role of residual metabolic tumor volume in inoperable stage III NSCLC after chemoradiotherapy ± immune checkpoint inhibition.

BACKGROUND: The PET-derived metabolic tumor volume (MTV) is an independent prognosticator in non-small cell lung cancer (NSCLC) patients. We analyzed the prognostic value of residual MTV (rMTV) after completion of chemoradiotherapy (CRT) in inoperable stage III NSCLC patients with and without immune checkpoint inhibition (ICI). METHODS: Fifty-six inoperable stage III NSCLC patients (16 female, median 65.0 years) underwent 18F-FDG PET/CT after completion of standard CRT. rMTV was delineated on 18F-FDG PET/CT using a standard threshold (liver SUVmean + 2 × standard deviation). 21/56 patients underwent additional ICI (CRT-IO, 21/56 patients) thereafter. Patients were divided in volumetric subgroups using median split dichotomization (MTV ≤ 4.3 ml vs. > 4.3 ml). rMTV, clinical features, and ICI-application were correlated with clinical outcome parameters (progression-free survival (PFS), local PFS (LPFS), and overall survival (OS). RESULTS: Overall, median follow-up was 52.0 months. Smaller rMTV was associated with longer median PFS (29.3 vs. 10.5 months, p = 0.015), LPFS (49.9 vs. 13.5 months, p = 0.001), and OS (63.0 vs. 23.0 months, p = 0.003). CRT-IO patients compared to CRT patients showed significantly longer median PFS (29.3 vs. 11.2 months, p = 0.034), LPFS (median not reached vs. 14.0 months, p = 0.016), and OS (median not reached vs. 25.2 months, p = 0.007). In the CRT subgroup, smaller rMTV was associated with longer median PFS (33.5 vs. 8.6 months, p = 0.001), LPFS (49.9 vs. 10.1 months, p = 0.001), and OS (63.0 vs. 16.3 months, p = 0.004). In the CRT-IO subgroup, neither PFS, LPFS, nor OS were associated with MTV (p > 0.05 each). The findings were confirmed in subsequent multivariate analyses. CONCLUSION: In stage III NSCLC, smaller rMTV is highly associated with superior clinical outcome, especially in patients undergoing CRT without ICI. Patients with CRT-IO show significantly improved outcome compared to CRT patients. Of note, clinical outcome in CRT-IO patients is independent of residual MTV. Hence, even patients with large rMTV might profit from ICI despite extensive tumor load.

Primary radiation therapy in stage I/II indolent orbital lymphoma - a comprehensive retrospective recurrence and toxicity analysis.

PURPOSE OR OBJECTIVE: To provide a comprehensive recurrence and toxicity analysis of patients treated with radiotherapy alone for stage I/II (Ann-Arbor classification) indolent orbital lymphoma. MATERIAL AND METHODS: We retrospectively reviewed the medical charts of 46 patients (and 51 orbits) treated at our centre with radiotherapy between 1995 and 2012 for biopsy-proven stage I/IIE primary orbital lymphomas. We evaluated treatment response and performed a comprehensive toxicity analysis with correlation to delivered radiation dose. RESULTS: At diagnosis, the median age was 63.5 years (range: 20-92). At initial diagnosis 43 and 3 patients had unilateral, synchronous bilateral involvement while there were 2 cases of contralateral metachronous failure. The predominant histological subtype was extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue in 42 (91.3%), follicular in 1 (2.2%), lymphoplasmacytic lymphoma in 1 (2.2%) and other indolent histology in 2 (4.3%) patients. Most lymphomas were located in the conjunctiva (18/35.3%) or eyelids (18/35.3%). Thirty-eight (82.6%) patients presented with stage I while 8/46 (17.4%) with stage II disease. The median radiation dose was 39.6 Gy (range: 21.6-48.6 Gy) delivered in 1.8-2 Gy single fractions. At a median follow-up of 83 months (range: 7-258 months), the complete remission rate was 98%. A local relapse was observed in 2/51 (3.9%) orbits and 4/46 (8.7%) patients had systemic relapse. The 5- and 10-year PFS rates were 79.2% (95% CI: 73.0%-85.4%) and 67.6% (95% CI: 59.4%-75.8%); 5- and 10-year OS was 83.6% (95% CI: 77.9%-89.3%) and 76.5% (95% CI: 69.4%-83.6%), respectively. In total, 66 acute toxicity events (all-grade) were observed: 5/51 (9.8%) ≥G2 acute conjunctivitis, 2/51 (3.9%) cases of G2 acute keratitis, 1/51 (2%) cases of ≥G2 ophthalmagia and 12/51 (23.5%) cases of ≥G2 xerophthalmia. Furthermore, 45 chronic adverse events were observed in 34/51 (66.7%) irradiated orbits with 30 late adverse events attributed to cataract. CONCLUSION: Our analysis confirms the role of radiotherapy alone at lower doses in the treatment of indolent orbital lymphomas. Further research is required to assess the efficacy of ultra-low-dose radiotherapy and anti-CD20 monoclonal antibodies to further mitigate long-term sequelae.

WITHDRAWN: lncRNA Linc00173 modulates glucose metabolism and multidrug chemoresistance in SCLC: Potential molecular panel for targeted therapy.

This article has been withdrawn at the request of the editor-in-chief. Following publication of this article, the editor-in-chief discovered evidence of image duplication in Figures 1I, 1J, 3F, S5B, and S6B. Given the duplication of several western blots representing several gene products, the editor-in-chief has lost faith in the findings presented in this article. The authors maintain that these image duplications were the result of errors in file management and do not affect the conclusions of the study. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Real-world prospective analysis of treatment patterns in durvalumab maintenance after chemoradiotherapy in unresectable, locally advanced NSCLC patients.

The aim of this prospective study is to evaluate the clinical use and real-world efficacy of durvalumab maintenance treatment after chemoradiotherapy (CRT) in unresectable stage, locally advanced non-small cell lung cancer (NSCLC). All consecutive patients with unresectable, locally advanced NSCLC and PD-L1 expression (≥1%) treated after October 2018 were included. Regular follow up, including physical examination, PET/CT and/or contrast-enhanced CT-Thorax/Abdomen were performed every three months after CRT. Descriptive treatment pattern analyses, including reasons of discontinuation and salvage treatment, were undertaken. Statistics were calculated from the last day of thoracic irradiation (TRT). Twenty-six patients were included. Median follow up achieved 20.6 months (range: 1.9-30.6). Durvalumab was initiated after a median of 25 (range: 13-103) days after completion of CRT. In median 14 (range: 2-24) cycles of durvalumab were applied within 6.4 (range 1-12.7) months. Six patients (23%) are still in treatment and seven (27%) have completed treatment with 24 cycles. Maintenance treatment was discontinued in 13 (50%) patients: 4 (15%) patients developed grade 3 pneumonitis according to CTCAE v5 after a median of 3.9 (range: 0.5-11.6) months and 7 (range: 2-17) cycles of durvalumab. Four (15%) patients developed grade 2 skin toxicity. One (4%) patient has discontinued treatment due to incompliance. Six and 12- month progression-free survival (PFS) rates were 82% and 62%, median PFS was not reached. No case of hyperprogression was documented. Eight (31%) patients have relapsed during maintenance treatment after a median of 4.8 (range: 2.2-11.3) months and 11 (range: 6-17) durvalumab cycles. Two patients (9%) developed a local-regional recurrence after 14 and 17 cycles of durvalumab. Extracranial distant metastases and brain metastases as first site of failure were detected in 4 (15%) and 2 (8%) patients, respectively. Three (13%) patients presented with symptomatic relapse. Our prospective study confirmed a favourable safety profile of durvalumab maintenance treatment after completion of CRT in unresectable stage, locally advanced NSCLC in a real-world setting. In a median follow-up time of 20.6 months, durvalumab was discontinued in 27% of all patients due to progressive disease. All patients with progressive disease were eligible for second-line treatment.

PET/CT imaging for evaluation of multimodal treatment efficacy and toxicity in advanced NSCLC-current state and future directions.

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.

External Validation of a Survival Score for Limited-Stage Small Cell Lung Cancer Patients Treated with Chemoradiotherapy.

PURPOSE: 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. METHODS: 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. RESULTS: 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 < 0.001), whereas the difference between the 14 and 18 points and the 19-26 points group was not significant (p = 0.602, p = 0.770). CONCLUSION: The score was reproducible to estimate the 2-year survival rate of patients with LS-SCLC, especially in the high- and intermediate-risk subgroups. In order to improve the differentiation between patients with an intermediate and favorable survival prognosis, the scoring system needs further development.

Correction to: Analysis of primary tumor metabolic volume during chemoradiotherapy in locally advanced non-small cell lung cancer.

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 ….

Analysis of primary tumor metabolic volume during chemoradiotherapy in locally advanced non-small cell lung cancer.

PURPOSE: Positron emission tomography with 2­deoxy-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). METHODS: 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. RESULTS: 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 < 0.0001). A reduction from mid-PT-MV to post-PT-MV of >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 < 63 cm3 (p = 0.027, HR 3.98; 95% CI 1.17-13.49), post-PT-MV < 25 cm3 (p = 0.013, HR 11.90; 95% CI 1.70-83.27), and a reduction from mid-PT-MV to post-PT-MV > 15% (p = 0.004, HR 0.25; 95% CI 0.02-0.31) correlated with improved OS. CONCLUSIONS: 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.

How much primary tumor metabolic volume reduction is required to improve outcome in stage III NSCLC after chemoradiotherapy? A single-centre experience.

PURPOSE: 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). METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Prognostic role of patient gender in limited-disease small-cell lung cancer treated with chemoradiotherapy.

BACKGROUND: Previous studies have demonstrated that female gender could be a prognostic factor in limited-disease (LD) small-cell lung cancer (SCLC), but the correlation between patient gender and survival parameters remains unclear. PATIENTS AND METHODS: Data from 179 LD SCLC patients treated with definitive chemoradiotherapy (CRT) were reviewed. Influence of patient gender on time to progression (TTP), local control (LC), brain metastasis-free (BMFS), distant metastasis-free (DMFS) and overall survival (OS) was analysed. RESULTS: Definitive CRT was completed by 179 (110 men/69 women) patients. Of these, 68 (38%; 34 men/34 women) patients were treated in concurrent and 111 (62%; 76 men/35 women) in sequential mode. Prophylactic cranial irradiation (PCI) was subsequently applied in 70 (39%; 36 men/34 women) patients with partial or complete response after CRT. Median OS was 20 (95% confidence interval [CI] 10-22) and 14 (95% CI 10-18) months in female and male patients, respectively (p = 0.021). In subgroups defined by remission status (complete and partial response) after CRT, an OS benefit for females compared to males was also detected. There was no correlation between patient gender and TTP, LC or DMFS, and no difference in OS in the female and male subgroups treated with PCI. The incidence of metachronous brain metastases (BMs) in the male and female subgroups differed significantly (40/110 men vs. 18/69 women, p = 0.03). Also, mean BMFS was significantly longer in women (p = 0.023). Patient gender also significantly correlated with OS on multivariate analysis after adjustment for other prognostic factors (p = 0.04, HR 1.38, 95% CI 1.08-1.92). CONCLUSION: In this heterogeneous LD SCLC patient cohort treated with definitive CRT, female gender was significantly associated with longer BMFS and OS, as well as with a lower incidence of metachronous brain failure.

Prefraction displacement and intrafraction drift of the prostate due to perineal ultrasound probe pressure.

OBJECTIVE: In image-guided EBRT of the prostate, transperineal ultrasound (US) probes exert pressure on the perineum both during planning and treatment. Through tissue deformation and relaxation, this causes target and risk organ displacement and drift. In this study, prefraction shift and intrafraction drift of the prostate are quantified during robotic transperineal 4DUS. METHODS: The position of the prostate was recorded for different positions of the probe before treatment in 10 patients (16 series of measurements). During treatment (15 patients, 273 fractions), intrafraction motion of the prostate was tracked (total of 27 h and 24 min) with the transperineal probe in place. RESULTS: Per 1 mm shift of the US probe in the cranial direction, a displacement of the prostate by 0.42 ± 0.09 mm in the cranial direction was detected. The relationship was found to be linear (R² = 0.97) and highly significant (p < 0.0001). After initial contact of the probe and the perineum (no pressure), a shift of the probe of about 5-10 mm was typically necessary to achieve good image quality, corresponding to a shift of the prostate of about 2-4 mm in the cranial direction. Tissue compression and prostate displacement were well visible. During treatment, the prostate drifted at an average rate of 0.075 mm/min in the cranial direction (p = 0.0014). CONCLUSION: The pressure applied by a perineal US probe has a quantitatively similar impact on prostate displacement as transabdominal pressure. Shifts are predominantly in the cranial direction (typically 2-4 mm) with some component in the anterior direction (typically <1 mm). Slight probe pressure can improve image quality, but excessive probe pressure can distort the surrounding anatomy and potentially move risk organs closer to the high-dose area.

Comparison of prostate positioning guided by three-dimensional transperineal ultrasound and cone beam CT.

OBJECTIVE: The accuracy of a transperineal three-dimensional ultrasound system (3DUS) was assessed for prostate positioning and compared to fiducial- and bone-based positioning in kV cone beam computed tomography (CBCT) during definitive radiotherapy of prostate cancer. METHODS: Each of the 7 patients had three fiducial markers implanted into the prostate before treatment. Prostate positioning was simultaneously measured by 3DUS and CBCT before each fraction. In total, 177 pairs of 3DUS and CBCT scans were collected. Bone-match and seed-match were performed for each CBCT. Using seed-match as a reference, the accuracy of 3DUS and bone-match was evaluated. Systematic and random errors as well as optimal setup margins were calculated for 3DUS and bone-match. RESULTS: The discrepancy between 3DUS and seed-match in CBCT (average ± standard deviation) was 0.0 ± 1.7 mm laterally, 0.2 ± 2.0 mm longitudinally, and 0.3 ± 1.7 mm vertically. Using seed-match as a reference, systematic errors for 3DUS were 1.2 mm, 1.1 mm, and 0.9 mm; and random errors were 1.4 mm, 1.8 mm, and 1.6 mm, on lateral, longitudinal, and vertical axes, respectively. By analogy, the difference of bone-match to seed-match was 0.1 ± 1.1 mm laterally, 1.3 ± 3.8 mm longitudinally, and 1.3 ± 4.5 mm vertically. Systematic errors were 0.5 mm, 2.2 mm, and 2.6 mm; and random errors were 1.0 mm, 3.1 mm, and 3.9 mm on lateral, longitudinal, and vertical axes, respectively. The accuracy of 3DUS was significantly higher than that of bone-match on longitudinal and vertical axes, but not on the lateral axis. CONCLUSION: Image-guided radiotherapy of prostate cancer based on transperineal 3DUS was feasible, with overall small discrepancy to seed-match in CBCT in this retrospective study. Compared to bone-match, transperineal 3DUS achieved higher accuracy on longitudinal and vertical axes.

Clinical relevance of the M1b and M1c descriptors from the proposed TNM 8 classification of lung cancer.

OBJECTIVE: The TNM 8 lung cancer staging system reclassifies patients with a solitary extrathoracic metastasis as M1b and two or more extrathoracic metastases as M1c. This study investigates the clinical relevance of this change. METHODS: Advanced lung cancer patients were retrospectively restaged according to the TNM8 M1b and M1c classifiers. Overall survival was compared in M1b and M1c patients staged with and without PET-CT. We then summarized the TNM 8 staging classification and the relevant literature on the treatment of oligometastatic lung cancer. RESULTS: In all, 82 patients with metastatic lung cancer were reclassified according to the TNM 8: 14 had M1b and 58 had M1c disease. Those with M1b disease lived significantly longer than those with M1c disease (15.2 vs. 7.3 months, p = 0.0029). Among those with M1b disease, survival was the highest when M1b status was confirmed by PET-CT (21.4 vs. 7 months). M1c patients with 4 or less distant metastases had a trend to longer survival vs. M1c patients with 5 or more metastases (9.4 vs. 7.3 months), especially when PET-CT staging was used (13.9 months). CONCLUSIONS: We confirmed the prognostic value of the M1b and M1c descriptors in a Western European tertiary care population. The use of PET-CT seems to increase the prognostic value of the M descriptor and may define an additional oligometastatic subgroup of M1c patients. Clinical trials investigating the treatment of patients with varying degrees of metastatic disease are needed and should be based on PET-CT staging.

Evaluation of the role of remission status in a heterogeneous limited disease small-cell lung cancer patient cohort treated with definitive chemoradiotherapy.

BACKGROUND: The role of remission status in limited disease (LD) small-cell lung cancer (SCLC) patients treated with definitive chemoradiotherapy (CRT) remains to be finally clarified. METHODS: Individual data from 184 patients treated with definitive CRT concurrently or sequentially were retrospectively reviewed. Kaplan-Meier analysis as well as univariate and multivariate Cox regression models were used to describe survival within patient subgroups defined by remission status. RESULTS: 71 (39%) patients were treated in the concurrent, 113 (61%) in the sequential CRT mode. Prophylactic cranial irradiation (PCI) was applied in 71 (39%) patients. 37 (20%) patients developed local, while 89 (48%) distant recurrence. 58 (32%) patients developed metachronous brain metastases. Complete, partial remission and non-response (defined as stable and progressive disease) were documented in 65 (35%), 77 (42%), and 37 (20%) patients, respectively. In complete responders median overall survival was 21.8 months (95CI: 18.6 - 25) versus 14.9 (95% CI: 11.7 - 18.2) (p = 0.041, log-rank test) and 11.5 months (95% CI: 8.9 - 15.0) (p < 0.001, log-rank test) in partial and non-responders, respectively. The same effect was documented for the time to progression and distant metastasis-free survival. In the multivariate analysis achievement of complete remission as a variable shows a trend for the prolonged time to progression (p = 0.1, HR 1.48) and distant metastasis-free survival (p = 0.06, HR 1.63) compared to partial responders and was highly significant compared to non-responders. CONCLUSION: In this treated heterogeneous LD SCLC patient cohort complete remission was associated with longer time to progression, distant metastasis-free and overall survival compared to the non- and especially partial responders.