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Abstract: The interpretation of gap fraction in terms of LAI from optical in situ methods is based on light extinction models, which link LAI and canopy architecture to the penetration of solar radiation through the canopy. The selection of the most appropriate LAI inversion model to calculate LAI from gap fraction data extracted from high-dynamic range digital hemispherical photographs is a crucial step in the development of a standardized protocol for the digital hemispherical camera. Three currently available light extinction models, all based on different assumptions concerning the foliage distribution, were tested in this study with respect to the appropriateness of the respective canopy elements distribution theories for LAI inversion. Reference LAI values (L_exact) from virtual 3-D forest stands were compared to indirectly measured LAI values (L_HP) obtained from simulated hemispherical photographs taken in the virtual stands. A regression between the reference LAI and the indirectly measured LAI selected the Markov model as most optimal inversion model. Fractal dimension (FD) was tested as a correction parameter for the deviation of forest canopies from assumed theoretical foliage distributions. Inclusion of a FD correction parameter improved the goodness-of-fit of the indirect LAI versus reference LAI from 86.7% to 97%. Virtual 3-D forest stands generated by L-systems provided a very appropriate validation environment for this research. Finally, the validity of the FD correction parameter was also tested with actual forest stand data. [Copyright &y& Elsevier]

Concurrent chemotherapy and radiotherapy (CCRT) followed by durvalumab immune therapy in appropriate patients is considered to be the standard of care in most fit stage III non-small-cell lung cancer (NSCLC) patients. However, CCRT is a toxic treatment that affects all organ systems and may cause acute and permanent side effects, some of which may be lethal. Supportive care is therefore of utmost importance in this clinical setting. A group of experts from the European Society for Therapeutic Radiology and Oncology (ESTRO) and the European Society of Medical Oncology (ESMO) identified the following items of importance for further improvement of supportive care: smoking cessation; nutrition before and during CCRT (including treatment and prevention of anorexia); physical exercise before and during CCRT; prevention and treatment of acute esophagitis and dysphagia; treatment of cough and dyspnea; treatment of skin reactions; treatment of fatigue; prophylaxis of nausea and emesis; prevention, diagnosis, and treatment of cardiac disease and damage; and optimization of radiotherapy techniques and chemotherapy adjustments to reduce toxicity in the era of immune therapy. The resulting recommendations are summarized in this manuscript and knowledge gaps identified, in which future investments are needed to improve supportive care and hence quality of life and survival for our stage III NSCLC patients. • Supportive care is an integral part of CCRT. • All aspects are important. • A multi-disciplinary approach is mandatory. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: While the overall prognosis of non-molecularly selected advanced non-small cell lung cancer (NSCLC) patients is poor, a subset of these patients has durable survival. We examined which clinical factors might be predictive for this favourable outcome. Patients and methods: Long-term NSCLC survivors (LTS, i.e. >2 years) were retrieved from all our out- and in-patient contacts in a 6 month period (March–August 2009). LTS records were compared with a group of short-term survivors (STS). Both baseline clinical factors (sex, age, smoking status, weight loss, performance status, co-morbidity, histological subtype, place and number of metastasis) and treatment-related features (number and type of therapeutic lines, response, duration of treatment-free interval) were compared. Results: 31 LTS were retrieved (stage IV patients with potentially radical treatment options, e.g. solitary brain or adrenal metastasis, were excluded), and compared with 34 STS. In the LTS group, median survival was 53 months, with 47% of patients alive at 5 years, in the STS patients this was 9.7 months, with 24% alive at 1-year. Baseline factors had little predictive value, but response to 1st line therapy (P =0.0001), response duration (P =0.009), and the number of systemic lines (P =0.0023) were of importance. Conclusion: These data confirm the existence of LTS in patients with advanced NSCLC. There are very little clinical factors at the time of diagnosis that help to distinguish future LTS from STS patients. Factors related to the effect of 1st line treatment are important, and further prospects of patients achieving a 2-year survival are in general quite good. [Copyright &y& Elsevier]

Concurrent chemotherapy and thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) is the standard treatment in limited-disease small-cell lung cancer (LD-SCLC), with 5-year overall survival (OS) of only 25% to 33%. STIMULI is a 1:1 randomised phase II trial aiming to demonstrate superiority of consolidation combination immunotherapy versus observation after chemo-radiotherapy plus PCI (protocol amendment-1). Consolidation immunotherapy consisted of four cycles of nivolumab [1 mg/kg, every three weeks (Q3W)] plus ipilimumab (3 mg/kg, Q3W), followed by nivolumab monotherapy (240 mg, Q2W) for up to 12 months. Patient recruitment closed prematurely due to slow accrual and the statistical analyses plan was updated to address progression-free survival (PFS) as the only primary endpoint. Of the 222 patients enrolled, 153 were randomised (78: experimental; 75: observation). Among the randomised patients, median age was 62 years, 60% males, 34%/65% current/former smokers, 31%/66% performance status (PS) 0/1. Up to 25 May 2020 (median follow-up 22.4 months), 40 PFS events were observed in the experimental arm, with median PFS 10.7 months [95% confidence interval (CI) 7.0-not estimable (NE)] versus 42 events and median 14.5 months (8.2-NE) in the observation, hazard ratio (HR) = 1.02 (0.66-1.58), two-sided P = 0.93. With updated follow-up (03 June 2021; median: 35 months), median OS was not reached in the experimental arm, while it was 32.1 months (26.1-NE) in observation, with HR = 0.95 (0.59-1.52), P = 0.82. In the experimental arm, median time-to-treatment-discontinuation was only 1.7 months. CTCAE v4 grade ≥3 adverse events were experienced by 62% of patients in the experimental and 25% in the observation arm, with 4 and 1 fatal, respectively. The STIMULI trial did not meet its primary endpoint of improving PFS with nivolumab-ipilimumab consolidation after chemo-radiotherapy in LD-SCLC. A short period on active treatment related to toxicity and treatment discontinuation likely affected the efficacy results. • First randomised trial comparing nivolumab/ipilimumab versus observation after standard chemo-radiotherapy and PCI in LD-SCLC. • Period on active treatment was short with a median time to nivolumab/ipilimumab discontinuation <2 months. • No improvement for PFS and OS for immunotherapy consolidation over observation. • Higher OS benefit observed for patients on twice daily radiotherapy schedule (versus once daily), female sex and ECOG PS 1. [ABSTRACT FROM AUTHOR]

Purpose To investigate if selective compared to elective pleural irradiation of malignant pleural mesothelioma (MPM) can allow dose escalation. Patients and methods Twelve consecutive stage I-IV MPM patients (6 consecutive left-sided and 6 consecutive right-sided) were retrospectively identified from a prospective institutional database and included. In all patients, the staging computed tomography and the staging magnetic resonance imaging (MRI) were used for gross tumor volume (GTV) definition. The patients had not received chemotherapy. An MRI-based pleural GTV was contoured and a planning target volume (PTV) was generated. Two sets of PTVs were generated for each patient: (1) a “selective” PTV (S-PTV), originating from a 5-mm isotropic expansion from the GTV, and (2) an “elective” PTV (E-PTV), originating from a 5-mm isotropic expansion from the whole ipsilateral pleural space. Two sets of volumetric modulated arc therapy (VMAT) treatment plans were generated for each patient: a “selective” pleural irradiation plan (SPI plan) and an “elective” pleural irradiation plan (EPI plan). Results In the SPI plans, the median dose to the S-PTV was 53.6 Gy (SD: 5.4, range: 41–63.6 Gy). In 4/12 patients it was possible to escalate the dose to the S-PTV to > 58 Gy. In the EPI plans, the median dose to the E-PTV was 48.6 Gy (SD: 5.8, range: 38.5–58.7), with a median dose to the S-PTV of 49 Gy (SD: 6, range: 38.6–59.5 Gy). No significant dose escalation was achievable. Conclusion The omission of elective irradiation of the whole ipsilateral pleural space allows dose escalation from 49 Gy to more than 58 Gy in 4/12 chemo-naive MPM patients. This strategy may form the basis for non-surgical radical combined modality treatment of MPM. [ABSTRACT FROM AUTHOR]

Abstract: Disease-specific mortality is the final outcome of a lung cancer screening trial, therefore cause of death verification is crucial. The use of death certificates for this purpose is debated because of bias, inaccurate completion and incorrect ante mortem diagnoses. A cause of death evaluation process was designed to ensure a uniform and unbiased determination of the graduation of certainty that lung cancer was the underlying cause of death. An independent clinical expert committee will review the medical files of all deceased participants once diagnosed with lung cancer and will make use of a flow chart and predetermined criteria. A pilot study of fifty cases was conducted to determine the performance of this process and to compare the outcome with the official death certificates. The independent review has shown an agreement of 90% (kappa 0.65), which demonstrates a uniform classification. The sensitivity and specificity of the death certificates for lung cancer specific mortality were 95.2 and 62.5%. This demonstrates a limited distinctive character of the death certification process in lung cancer patients. Our results imply that the final outcome of a lung cancer screening trial cannot reliably be established without predetermined criteria and an independent review of blinded cases. [Copyright &y& Elsevier]

Abstract: Background: The objectives were to determine the maximum tolerated dose (MTD) of pemetrexed and cisplatin with concurrent radiotherapy. Secondary objectives include incidence and nature of acute and late toxicities, tumor response and overall survival. Patients and methods: Treatment naïve patients received 1 cycle of cisplatin 80mg/m2 in study I (stage III NSCLC), 75mg/m2 in study II (LD-SCLC) and pemetrexed 500mg/m2 before the phase I part. In study I, patients were treated in cohorts with escalating cisplatin doses (60–80mg/m2), pemetrexed doses (400–500mg/m2) and concurrent escalating radiotherapy doses (66Gy in 33–27 fractions). In study II, patients were treated with cisplatin 75mg/m2 and escalating pemetrexed doses (400–500mg/m2) with concurrent escalating radiotherapy doses (50–62Gy). Results: The trials closed prematurely: study I because of poor accrual, study II because of sponsor decision. Thirteen patients were treated: 4 with NSCLC, 9 with LD-SCLC. No dose-limiting toxicity was observed. There was no grade 4 toxicity, grade 3 hematological toxicity was mild. One patient developed grade 3 acute esophagitis, but was able to complete radiotherapy without delay. Two patients experienced grade 2 late pulmonary toxicity, 1 complete response, 6 partial responses and 1 progressive disease were observed. Conclusions: Although the studies stopped too early to assess MTD, we have demonstrated that the combination of cisplatin and pemetrexed with concurrent radiotherapy up to 66Gy (33×2Gy) is well tolerated and this new combination shows activity in NSCLC. Pemetrexed is the first 3rd generation cytotoxic found to be tolerable at full dose with concurrent radiotherapy. [Copyright &y& Elsevier]

We investigated the activity and toxicity of raltitrexed (Tomudex®) as a single agent treatment in patients with Malignant Pleural Mesothelioma (MPM) in a multicentre phase II European Organization for Research and Treatment of Cancer (EORTC) study. This study enrolled chemonaı¨ve patients with histologically-confirmed measurable MPM. Raltitrexed was administered at the dose of 3 mg/m2 intravenous (i.v.) bolus on an outpatient basis every 3 weeks. A maximum of eight cycles was planned in cases with an absence of progression or unacceptable toxicity. 24 patients received a total of 104 courses. 5 patients (20.8%, 95% confidence interval (CI) 7.1–42.2%) had a partial response (PR), which was confirmed by an independent radiology committee. Toxicity was mild, with diarrhoea, nausea, vomiting, fatigue and neutropenia as the major side-effects, but not exceeding grade 3 toxicity. We conclude that raltitrexed has activity as a single agent in the treatment of MPM, and that further studies with this drug in MPM are warranted. [Copyright &y& Elsevier]

The greatest news of the past year in this field was the first large-scale early detection trial that could prove a 20% reduction in lung cancer-related mortality by screening high-risk individuals with low-dose computed tomography (LDCT). Several expert groups and medical societies have assessed the data and concluded that LDCT screening for lung cancer is, however, not ready for large-scale population-based implementation. Too many open questions remain, such as definition of the at-risk population, timing and intervals of screening, optimal method of acquisition and interpretation of the images, how to handle (false) positive findings, and especially cost-effectiveness in relation to other lung cancer prevention strategies, mainly smoking cessation. Further analyses and several ongoing European trials are eagerly awaited. Much hope also resides in the use of biomarkers, as their use in, e.g., blood or exhaled air may provide more easy-to-use tests to better stratify high-risk populations for screening studies. While exciting research is ongoing in this domain—e.g. with microRNAs—none of the tests has yet reached sufficient validation for clinical use. Early central lung cancers are more difficult to visualise by CT. For these patients, standard bronchoscopy, complemented by autofluoresence endoscopy, has been studied in different screening and follow-up settings. [ABSTRACT FROM AUTHOR]