Radiotherapy (RT) plays a crucial role in all stages of lung cancer. Data on recent real-world RT patterns and main drivers of RT decisions in lung cancer in Romania is scarce; we aimed to address these knowledge gaps through this physician-led medical chart review in 16 RT centers across the country. Consecutive patients with lung cancer receiving RT as part of their disease management between May–October 2019 (pre-COVID-19 pandemic) were included. Descriptive statistics were generated for all variables. This cohort included 422 patients: median age 63 years, males 76%, stages I–II 6%, III 43%, IV 50%, mostly adeno- and squamous cell carcinoma (76%), ECOG 0-1 50% at the time of RT. Curative intent RT was used in 36% of cases, palliative RT in 64%. Delays were reported in 13% of patients, mostly due to machine breakdown (67%). Most acute reported RT toxicity was esophagitis (19%). Multiple disease-, patient-, physician- and context-related drivers counted in the decision-making process. This is the first detailed analysis of RT use in lung cancer in Romania. Palliative RT still dominates the landscape. Earlier diagnosis, coordinated multidisciplinary strategies, and the true impact of the multimodal treatments on survival are strongly needed to improve lung cancer outcomes.

Immunotherapy (IT) and especially immune checkpoint blockade (ICB) changed the therapeutic approach in non-small cell lung cancer (NSCLC). Nevertheless, primary or secondary resistance and a percentage of long responders and survivors have been observed. The aim of this study is to gain a deeper understanding of the complex mechanisms of primary and secondary resistance to IT, involving tumor cells, the tumor microenvironment (TME), and the host, in order to find strategies to overcome it. With this aim in mind, a search for key words has been performed to identify relevant evidence in the literature. The most widely used approach is the combination of IT with chemotherapy (CT) and/or radiotherapy (RT), relying on the synergistic effect on the enhancement of immunogenic cell death. Since a dual role has been observed, a lot of questions are yet to be answered regarding the complex effect of these therapies, especially on the TME. Preclinical and clinical studies investigate the best sequencing and timing of chemoradiation with IT, and the optimal RT volumes, sites, and dose/fractionation regimens to favor immune stimulation over suppression on the TME. Moving forward, multiple agents addressing coinhibitory or costimulatory receptors on immune or tumor cells are under evaluation. The huge potential of combination therapies becoming apparent. Questions regarding targets, selection of patients, and time and sequence of administration are yet to be answered, considering the complex mechanisms of resistance. Dynamic biomarkers to guide personalized treatment decisions are needed.

"Two randomized phase III studies provided cumulated long-term results, comparing second line treatment with Nivolumab versus Docetaxel in advanced non-small cell lung cancer (NSCLC). With the advent of modern immunotherapy (IO), the potential for even more immune activation by radiation therapy, inducing tumor specific immunity led to a novel role for radiotherapy in systemic disease. This case proposes to evaluate the benefit of second line immunotherapy with Nivolumab, a PD-1 checkpoint inhibitor, and hypofractionated radiotherapy, in a patient with advanced oligometastatic adenocarcinoma of the lung, with progressive disease after first line chemotherapy, and the analysis of a possible abscopal effect. A 50-year-old male, heavy smoker with a 30 years-pack index, presented with a history of left posterior thoracic pain. MRI identified an osteolytic lesion on the 10th rib and CT scan showed an additional 25 mm nodule in the left upper lobe (LUL) and a 7 mm nodule in the left lower lobe (LLL). Atypical resections of the nodules and resection of the osteolytic lesion of the rib were performed. The pathological examination revealed a G2 adenocarcinoma of the lung (ALK and EGFR negative) pT4Nx pM1 with metastases in the rib and pleura, with unspecified margins. Chemotherapy was administered, with complete response on imaging after 6 cycles of Gemcitabine/Carboplatin, and hematologic toxicity. After 7 ½ months a regional and distant progression of the disease with metastases on the 7th and 10th rib was revealed on PET-CT. Palliative hypofractionated radiotherapy was administered to a dose of 20 Gy/ 5 fr to the painful 7th rib metastasis and the patient started second line treatment with Nivolumab, 240 mg iv q2wks. Three years later, at his last follow-up in Nov 2021, the patient maintains a (PET)-CT complete response, with no adverse events. A possible abscopal effect may be suspected in this case."

Immunotherapy (IT) and especially immune checkpoint blockade (ICB) changed the therapeutic approaches in non-small cell lung cancer (NSCLC). Still, primary or second-ary resistance and a percentage of long responders and survivors have been observed. The objective is to have a deeper understanding of the complex mechanisms of primary and secondary resistance to IT involving tumor cells, TME and host, to find strategies to over-come it. In this aim a search of the key words has been performed to identify the relevant evidence in the literature. The most available approach thus far is the combination of IT with chemotherapy (CT) and/or radiotherapy (RT), relying on the synergistic effect in enhancement of immunogenic cell death. Even so, a lot of questions are to be answered, as a dual role has been observed, considering the complex effect, especially on the TME. Preclinical and clinical studies investigate the best sequencing and timing of chemoradiation with IT, the optimal RT volumes, sites, dose/fractionation regimens, to favor immunostimulation over suppression on the TME. Moving forward, multiple agents addressing coinhibitory or costimulatory receptors, on immune or tumor cells, are under evalua-tion. In perspective, a huge potential of combination therapies is arising, but to which tar-get, to what patient, at what time and sequence to be administered, considering the complex mechanisms of resistance, needs dynamic biomarkers to guide the decisions, to-wards more personalized treatments.