Continuous and bilevel positive airway pressure may improve radiotherapy delivery in patients with intra-thoracic tumors.

Background: Minimizing tumor motion in radiotherapy for intra-thoracic tumors reduces side-effects by limiting radiation exposure to healthy tissue. Continuous or Bilevel Positive Airway Pressure (CPAP/BiPAP) could achieve this, since it could increase lung inflation and decrease tidal volume variability. We aim to identify the better CPAP/BiPAP setting for minimizing tumor motion. Methods: In 10 patients (5 with lung cancer, 5 with other intra-thoracic tumors), CPAP/BiPAP was tested with the following settings for 10 min each: CPAP 5, 10 and 15 cmH2O and BiPAP 14/10 cmH2O with a lower (7 breaths/min) and higher back-up respiratory rate (BURR initially 1 breath/min above the spontaneous breathing frequency, with the option to adjust if the patient continued to initiate breaths). Electrical impedance tomography was used to analyse end-expiratory lung impedance (EELI) as an estimate of end-expiratory lung volume and tidal impedance variation (TIV) as an estimate of tidal volume. Results: Nine out of ten patients tolerated all settings; one patient could not sustain CPAP-15. A significant difference in EELI was observed between settings (χ2 22.960, p < 0.001), with most increase during CPAP-15 (median (IQR) 1.03 (1.00 - 1.06), normalized to the EELI during spontaneous breathing). No significant differences in TIV and breathing variability were found between settings. Conclusions: This study shows that the application of different settings of CPAP/BiPAP in patients with intra-thoracic tumors is feasible and tolerable. BiPAP with a higher BURR may offer the greatest potential for mitigating tumor motion among the applied settings, although further research investigating tumor motion should be conducted.

Safety and tolerability of stereotactic radiotherapy combined with durvalumab with or without tremelimumab in advanced non-small cell lung cancer, the phase I SICI trial.

INTRODUCTION: This phase I study primarily addresses the safety and tolerability of Stereotactic radiotherapy on the primary tumor combined with double Immune Checkpoint Inhibition (SICI) in patients with non-small cell lung cancer (NSCLC). Increasing the release of neoantigens by radiotherapy might enhance response to immunotherapy. Especially, by targeting trunk mutations in the primary tumor. MATERIALS AND METHODS: In three sequential cohorts, immunotherapy regimes combined with stereotactic body radiotherapy (SBRT) on the primary tumor (1x20 Gy on 9 cc) were studied in stage IIIB/IV NSCLC patients progressing on chemotherapy. The first cohort (n = 3) received durvalumab. The second (n = 6) received a combination of tremelimumab and durvalumab followed by durvalumab monotherapy. The third cohort (n = 6) was similar except that the combination was reversed. Descriptive statistics were used to assess safety parameters and the exploratory outcomes of efficacy. Adverse events were reported using NCI CTCAE version 4.03. Exhaled breath was analyzed at baseline. RESULTS: Fifteen patients were included. Median irradiated volume was 9.13 cc, on a median primary tumor volume of 79 cc. There were seven patients with grade 1-2, and two patients with grade 3 treatment related adverse events. There was 1 dose limiting toxicity (colitis) with double immunotherapy. CONCLUSION: The combination of SBRT to the primary tumor and double immunotherapy in advanced NSCLC patients is safe and feasible.

Hypoxia and tumor metabolism in radiation oncology: targets visualized by positron emission tomography.

Due to the amazing leap of technology in radiation oncology in the past few years, cancer treatment will become more individualized. Molecular imaging with PET contributed to this with its many tracers available, each of them visualizing a specific feature of a tumor and its microenvironment revealing the biological characteristics of cancer. Hypoxia is of interest as hypoxic tumor cells are associated with lower disease control because of an increased resistance to cytotoxic treatment. This is especially the case for radiotherapy. Treatment adaptations overcoming the negative effect of hypoxia have shown promising results. Several hypoxia tracers are available of which [18F]FMISO is studied most extensively, however other tracers are studied as well and the search for highly specific and reproducible PET tracers is still ongoing. Wide experience has been gained with the use of [18F]FDG PET as it is used on a routine basis for diagnosing and staging of cancer. Although not a specific marker for hypoxia, increased metabolic rate reflects increased proliferation and glycolysis indicating increased treatment resistance. Molecular imaging by means of PET creates an opportunity to provide personalized care, with optimal disease control, minimal toxicity and best cost-effectiveness.

Factors influencing the activity and fate of benzodiazepines in the body.

1 The clinical pharmacokinetics of the many benzodiazepines used to treat numerous and varied clinical conditions can be influenced by many factors. 2 Combinations of drugs efficacious in the central nervous system can change the onset, intensity and duration of effect as a result of pharmacological, physiological and pharmacokinetic actions. 3 Pharmacokinetic considerations indicate that short to medium long-acting benzodiazepines that depend on only glucuronidation for their major metabolic pathway are the drugs of choice in this category.