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Introduction: Single-agent monoclonal antibody therapy against programmed death-ligand 1 (PD-L1) has modest effects in malignant pleural mesothelioma. Radiation therapy can enhance the antitumor effects of immunotherapy. Nevertheless, the safety of combining anti-PD-L1 therapy with stereotactic body radiation therapy (SBRT) is unknown. We present the results of a phase 1 trial to evaluate the safety of the anti-PD-L1 antibody avelumab plus SBRT in patients with malignant pleural mesothelioma. Methods: This was a single-arm, investigator-initiated trial in patients who progressed on prior chemotherapy. Avelumab was delivered every other week, and SBRT was delivered to one lesion in three to five fractions (minimum of 30 Gy) followed by continuation of avelumab up to 24 months or until disease progression. The primary end point of the study was safety on the basis of grade 3+ nonhematologic adverse events (AEs) within 3 months of SBRT. Results: Thirteen assessable patients received a median of seven cycles (range: 2–26 cycles) of avelumab. There were 27 grade 1, 17 grade 2, four grade 3, and no grade 4 or 5 avelumab-related AEs. The most common were infusion-related allergic reactions (n = 6), anorexia or weight loss (n = 6), fatigue (n = 6), thyroid disorders (n = 5), diarrhea (n = 3), and myalgia or arthralgias (n = 3). There were 10 grade 1, four grade 2, one grade 3, and no grade 4 or 5 SBRT-related AEs. The most common were diarrhea (n = 3), chest pain/myalgia (n = 2), fatigue (n = 2), cough (n = 2), dyspnea (n = 2), and nausea/vomiting (n = 2). Conclusions: Combination avelumab plus SBRT seems tolerable on the basis of the prespecified toxicity end points of the first stage of this Simon two-stage design phase 1 study.

Most patients with metastatic cancer eventually develop resistance to systemic therapy, with some having limited disease progression (ie, oligoprogression). We aimed to assess whether stereotactic body radiotherapy (SBRT) targeting oligoprogressive sites could improve patient outcomes. We did a phase 2, open-label, randomised controlled trial of SBRT in patients with oligoprogressive metastatic breast cancer or non-small-cell lung cancer (NSCLC) after having received at least first-line systemic therapy, with oligoprogression defined as five or less progressive lesions on PET-CT or CT. Patients aged 18 years or older were enrolled from a tertiary cancer centre in New York, NY, USA, and six affiliated regional centres in the states of New York and New Jersey, with a 1:1 randomisation between standard of care (standard-of-care group) and SBRT plus standard of care (SBRT group). Randomisation was done with a computer-based algorithm with stratification by number of progressive sites of metastasis, receptor or driver genetic alteration status, primary site, and type of systemic therapy previously received. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, measured up to 12 months. We did a prespecified subgroup analysis of the primary endpoint by disease site. All analyses were done in the intention-to-treat population. The study is registered with ClinicalTrials.gov , NCT03808662 , and is complete. From Jan 1, 2019, to July 31, 2021, 106 patients were randomly assigned to standard of care (n=51; 23 patients with breast cancer and 28 patients with NSCLC) or SBRT plus standard of care (n=55; 24 patients with breast cancer and 31 patients with NSCLC). 16 (34%) of 47 patients with breast cancer had triple-negative disease, and 51 (86%) of 59 patients with NSCLC had no actionable driver mutation. The study was closed to accrual before reaching the targeted sample size, after the primary efficacy endpoint was met during a preplanned interim analysis. The median follow-up was 11·6 months for patients in the standard-of-care group and 12·1 months for patients in the SBRT group. The median progression-free survival was 3·2 months (95% CI 2·0–4·5) for patients in the standard-of-care group versus 7·2 months (4·5–10·0) for patients in the SBRT group (hazard ratio [HR] 0·53, 95% CI 0·35–0·81; p=0·0035). The median progression-free survival was higher for patients with NSCLC in the SBRT group than for those with NSCLC in the standard-of-care group (10·0 months [7·2–not reached] vs 2·2 months [95% CI 2·0–4·5]; HR 0·41, 95% CI 0·22–0·75; p=0·0039), but no difference was found for patients with breast cancer (4·4 months [2·5–8·7] vs 4·2 months [1·8–5·5]; 0·78, 0·43–1·43; p=0·43). Grade 2 or worse adverse events occurred in 21 (41%) patients in the standard-of-care group and 34 (62%) patients in the SBRT group. Nine (16%) patients in the SBRT group had grade 2 or worse toxicities related to SBRT, including gastrointestinal reflux disease, pain exacerbation, radiation pneumonitis, brachial plexopathy, and low blood counts. The trial showed that progression-free survival was increased in the SBRT plus standard-of-care group compared with standard of care only. Oligoprogression in patients with metastatic NSCLC could be effectively treated with SBRT plus standard of care, leading to more than a four-times increase in progression-free survival compared with standard of care only. By contrast, no benefit was observed in patients with oligoprogressive breast cancer. Further studies to validate these findings and understand the differential benefits are warranted. National Cancer Institute. [ABSTRACT FROM AUTHOR]

1. Consider tracheostomy decannulation as part of withdrawal of life-prolonging technologies. We present a 76-year-old man with a prior right MCA stroke, CAD, HF, AF, DM, and stage 4 CKD who was hospitalized after a neurologically devastating left MCA infarction requiring intubation for airway protection. A tracheostomy was performed on HD 15 due to inability to wean from mechanical ventilation. Weeks later, seeing no improvement in neurological status, the family requested cessation of life-sustaining technologies. On HD 48, the patient was disconnected from mechanical ventilation but still continued to breathe spontaneously via the trach. The family felt that the patient was suffering in this liminal state, and with their consent, the tracheostomy cannula was removed on HD 57. Roughly 2 hours after the decannulation, the patient's tracheostomy site had completely closed, and he was breathing solely through his mouth with signs of partial pharyngeal obstruction. Opiates were given as needed to treat perceived dyspnea, and the patient died 12 hours after decannulation. The family expressed gratitude for removing the tracheostomy tube. Palliative extubation is a commonly performed procedure at the end of life when the stated goals are to discontinue life-sustaining technologies. For patients with tracheostomies, our practice has typically been to leave the trach tube in place while disconnecting the ventilator circuit. This case highlights how the tracheostomy cannula itself can act as a life-sustaining technology, and leaving it in place can prolong patient and family suffering. Thus, we recommend that tracheostomy decannulation be considered when the goals of care are to remove life-sustaining technologies. If decannulation is pursued, families should be counseled about the possibility of hearing obstructive noises, the unpredictability of time course, and that opiates can be given as needed for dyspnea. [ABSTRACT FROM AUTHOR]

To assess if stereotactic body radiotherapy (SBRT) for oligoprogressive metastatic lung or breast cancer prolongs progression-free survival (PFS), overall survival (OS), and alters circulating tumor (ct)DNA profile. We enrolled patients with metastatic non-small-cell lung cancer (NSCLC) or breast cancer with ≤5 oligoprogressive lesions after ≥1 line of systemic therapy. Stratification factors included number of oligoprogressive lesions, prior immunotherapy, primary site, and receptor/mutation status. Patients were randomized 1:1 to standard of care (SOC) with or without SBRT to all progressive sites. The primary endpoint was PFS. Secondary endpoints included OS, toxicity, and quality-of-life (QoL). Blood was collected at baseline and at 8 weeks for ctDNA analysis. A hybridization capture and deep sequencing assay was used to identify genomic alterations and calculate estimated variant allele frequencies (VAFs) of tumor-derived mutations. Patients were followed for 12 months for PFS and until death or last contact for OS. One-sided stratified log-rank test was used to assess survival outcomes. From January 2019 to July 2021, 106 patients were randomized - 59 with NSCLC and 47 with breast cancer. Most (75%) had >1 site of oligoprogression and 47% had >5 total lesions. The majority of NSCLCs (86%) had no actionable driver mutation and 66% of breast cancers were triple-negative. Median PFS was 3.2 months in SOC arm vs. 7.2 months in SBRT arm (p=0.002). Stratified analysis showed that NSCLC patients derived substantial PFS benefit from SBRT (2.2 months in SOC vs. 10 months in SBRT arm; p=0.002), whereas breast cancer patients did not (4.2 vs. 4.4 months, p=0.2). No difference in OS between arms has yet been seen in either cohort. Grade ≥2 toxicities occurred in 8 patients after SBRT. There was no difference in QoL between treatment arms. The study was closed to accrual after a preplanned interim analysis crossed a prespecified efficacy threshold. Analysis of 52 pairs of baseline and 8-week blood samples with detectable ctDNA showed significant reduction of median VAFs over time comparing SBRT to SOC in the NSCLC cohort (p=0.03), but not the breast cancer cohort (p=0.56). Increasing median VAFs at 8 weeks was predictive of subsequent disease progression (Hazard Ratio: 1.17, 95% CI: 1.02-1.36, p=0.03), independent of treatment arm or primary site. In this first and largest randomized trial of radiotherapy for oligoprogressive metastatic cancer, we observed a more than 4-fold PFS benefit in patients with oligoprogressive metastatic NSCLC receiving SBRT, with corresponding decrease in ctDNA VAFs. There was no PFS benefit or change in ctDNA after SBRT for breast cancer, suggesting a more diffusely systemic pathophysiology. The benefit of SBRT in oligoprogressive metastatic NSCLC will require validation in a larger study and the distinction in oligoprogressive biology between these diseases warrants further evaluation. [ABSTRACT FROM AUTHOR]

We hypothesize that there is an oligoprogressive state in metastatic cancer, in which disease control can be improved with local therapy to progressive lesions only. This study therefore evaluated the impact of stereotactic body radiotherapy (SBRT) to sites of oligoprogression in patients with metastatic non-small-cell lung cancer (NSCLC) and breast cancer with 1-5 progressive lesions. We enrolled patients with metastatic NSCLC or breast cancer who received ≥ 1 line of systemic therapy and had oligoprogressive lesions amenable to SBRT. There was no upper limit of non-progressive lesions. Oligoprogression was defined as Response Evaluation or Positron Emission Tomography Response Criteria in Solid Tumors documented progression ≤ 5 individual lesions. Stratification factors included number of progressive sites (1 vs. 2-5), prior systemic therapy (immunotherapy vs. other), primary tumor (NSCLC vs. breast), and tumor marker status (driver mutation and hormone receptor status). Patients were randomized 1:1 between SBRT to all progressive sites plus palliative standard of care (SOC) vs. palliative SOC only. Systemic therapy was per physician's discretion. The primary endpoint was progression-free survival (PFS). We used a randomized phase II design with a one-sided alpha of 0.05 and a power of 0.80, yielding a target accrual of 160 patients. PFS was compared using one-sided stratified log-rank test. One interim analysis was planned. From January 2019 to May 2021, 102 patients were randomized - 58 NSCLC (30 in the SBRT arm) and 44 breast (22 in each arm). Median age was 67. Most patients (75%) had > 1 site of oligoprogression and 47% had > 5 total metastatic lesions. Fifty-five (54%) patients received immunotherapy. The majority of NSCLC (86%) did not harbor an actionable driver mutation and 32% of breast cancer were triple negative. Baseline factors were balanced between arms. At a median follow-up of 51 weeks, 71 patients progressed and 30 died. Median PFS was 22 weeks in the SBRT arm vs. 10 weeks in the palliative SOC arm (p=0.005). This was driven entirely by the PFS benefit from SBRT in the NSCLC patients (44 weeks with SBRT vs. 9 weeks with SOC; p=0.004). No difference in median PFS was seen in the breast cohort (18 weeks with SBRT vs. 17 weeks with SOC; p=0.5). In multivariable Cox model inclusive of stratification factors, age, sex, lines of systemic therapy, and change of systemic therapy, the PFS benefit of SBRT remained substantial in the NSCLC cohort (Hazard Ratio: 0.38; 95% CI: 0.18-77; p=0.007). Grade ≥2 adverse events occurred in 8 patients in the SBRT arm, including 1 grade 3 pneumonitis. Inthis pre-planned interim analysis of the first and largest randomized trial of radiotherapy for oligoprogressive metastatic NSCLC and breast cancer, we demonstrated the benefit of SBRT to sites of oligoprogression on overall PFS, meeting the primary endpoint. The mechanism of the differential benefits between NSCLC and breast cohorts merits further evaluation. [ABSTRACT FROM AUTHOR]