Showing papers by "Keith A. Cengel published in 2023"
TL;DR: In this paper , the authors investigated an alternative endpoint, death without cancer progression (DWP), which is potentially more specific than OS and more sensitive than cardiac events for understanding CRT toxicity.
1 citations
TL;DR: In this paper , a preclinical model of surgically mediated tumor injury (TI) was developed to support the surgical inflammation hypothesis and showed that myeloid derived suppressor cells in the tumor appeared to increase pro-inflammatory cytokines plasma levels from surgery prior to intraoperative photodynamic therapy.
TL;DR: In this article , the authors evaluated outcomes after the initiation of pembrolizumab monotherapy in the treatment of adults with peritoneal mesothelioma (DMPM).
Abstract: Importance
Diffuse malignant peritoneal mesothelioma (DMPM) represents a rare and clinically distinct entity among malignant mesotheliomas. Pembrolizumab has activity in diffuse pleural mesothelioma but limited data are available for DMPM; thus, DMPM-specific outcome data are needed.
Objective
To evaluate outcomes after the initiation of pembrolizumab monotherapy in the treatment of adults with DMPM.
Design, Setting, and Participants
This retrospective cohort study was conducted in 2 tertiary care academic cancer centers (University of Pennsylvania Hospital Abramson Cancer Center and Memorial Sloan Kettering Cancer Center). All patients with DMPM treated between January 1, 2015, and September 1, 2019, were retrospectively identified and followed until January 1, 2021. Statistical analysis was performed between September 2021 and February 2022.
Exposures
Pembrolizumab (200 mg or 2 mg/kg every 21 days).
Main Outcomes and Measures
Median progression-free survival (PFS) and median overall survival (OS) were assessed using Kaplan-Meier estimates. The best overall response was determined using RECIST (Response Evaluation Criteria in Solid Tumors) criteria, version 1.1. The association of disease characteristics with partial response was evaluated using the Fisher exact test.
Results
This study included 24 patients with DMPM who received pembrolizumab monotherapy. Patients had a median age of 62 years (IQR, 52.4-70.6 years); 14 (58.3%) were women, 18 (75.0%) had epithelioid histology, and most (19 [79.2%]) were White. A total of 23 patients (95.8%) received systemic chemotherapy prior to pembrolizumab, and the median number of lines of prior therapy was 2 (range, 0-6 lines). Of the 17 patients who underwent programmed death ligand 1 (PD-L1) testing, 6 (35.3%) had positive tumor PD-L1 expression (range, 1.0%-80.0%). Of the 19 evaluable patients, 4 (21.0%) had a partial response (overall response rate, 21.1% [95% CI, 6.1%-46.6%]), 10 (52.6%) had stable disease, and 5 (26.3%) had progressive disease (5 of 24 patients [20.8%] were lost to follow-up). There was no association between a partial response and the presence of a BAP1 alteration, PD-L1 positivity, or nonepithelioid histology. With a median follow-up of 29.2 (95% CI, 19.3 to not available [NA]) months, the median PFS was 4.9 (95% CI, 2.8-13.3) months and the median OS was 20.9 (95% CI, 10.0 to NA) months from pembrolizumab initiation. Three patients (12.5%) experienced PFS of more than 2 years. Among patients with nonepithelioid vs epithelioid histology, there was a numeric advantage in median PFS (11.5 [95% CI, 2.8 to NA] vs 4.0 [95% CI, 2.8-8.8] months) and median OS (31.8 [95% CI, 8.3 to NA] vs 17.5 [95% CI, 10.0 to NA] months); however, this did not reach statistical significance.
Conclusions and Relevance
The results of this retrospective dual-center cohort study of patients with DMPM suggest that pembrolizumab had clinical activity regardless of PD-L1 status or histology, although patients with nonepithelioid histology may have experienced additional clinical benefit. The partial response rate of 21.0% and median OS of 20.9 months in this cohort with 75.0% epithelioid histology warrants further investigation to identify those most likely to respond to immunotherapy.
TL;DR: In this article , the proportion of patients with stage III non-small cell lung cancer (NSCLC) who initiate consolidation durvalumab or other immune checkpoint inhibitors (ICIs) after concurrent chemoradiotherapy (cCRT), as well as reasons for nonreceipt and prognostic implications were evaluated.
TL;DR: The CTXXXX trial as mentioned in this paper evaluated proton beam therapy (PBT) with concurrent chemotherapy as part of trimodality management for resectable stage IIIA or superior sulcus non-small cell lung cancer (NSCLC).
Abstract: This is the first prospective clinical trial (NCTXXXX) evaluating proton beam therapy (PBT) with concurrent chemotherapy as part of trimodality management for resectable stage IIIA or superior sulcus non-small cell lung cancer (NSCLC).The starting PBT dose level was 50.4 Gy in 1.8 Gy fractions (feasibility study), followed by sequential dose escalation to determine maximum tolerated dose (MTD) of PBT based on dose-limiting toxicities (DLTs) (phase I/II study). DLTs were defined as 30-day postoperative mortality, grade ≥4 hematologic toxicity requiring >14-day treatment breaks, or any grade ≥3 non-hematologic/esophagitis/pneumonitis toxicities attributable to PBT. Primary outcomes included feasibility, MTD, and pathologic complete response (pCR) rate.Twenty patients underwent neoadjuvant PBT and chemotherapy, of which 19 subsequently underwent surgery. There were 13 patients in the feasibility study (at 50.4 Gy) and 6 in the phase I/II study (at 59.4 Gy). The trial closed early due to slow accrual prior to reaching the MTD. Treatment was deemed feasible. There were no DLTs, including no post-operative deaths within 30 days. Two patients (10%) experienced PBT-related acute grade 3 adverse events (post-operative atrial fibrillation and esophagitis/dysphagia); no grade 4-5 acute non-hematologic adverse events were noted. Overall and nodal pCR rates were 5/19 (26%) and 8/18 (44%), respectively; nodal pCR was 4/13 (31%) at 50.4 Gy versus 4/5 (80%) at 59.4 Gy (p=0.12). Median follow-up was 8.5 years. Median and 5-year progression-free survival were 1.8 years and 25%, and median and 5-year overall survival were 3.6 years and 40%, respectively. Eleven patients experienced disease failure, most with a distant component (10 of 11).Concurrent PBT and chemotherapy is feasible as part of trimodality management with favorable oncologic outcomes and low toxicity rates.
TL;DR: A searchable abstracts of presentations at key conferences in endocrinology can be found in this article , where the abstracts are extracted from the corresponding abstracts from the conference proceedings.
Abstract: Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
TL;DR: In this article , the authors found that PBT is associated with fewer acute hospitalizations compared to IMRT in the era of ICI consolidation for LA-NSCLC patients.
Abstract: 8573 Background: Prior work found that PBT is associated with fewer acute hospitalizations compared to photons for a variety of cancers. Patients (pts) with LA-NSCLC treated with concurrent chemoradiation (cCRT) and ICI consolidation are at high risk for treatment-related toxicity and acute hospitalizations. We hypothesized that PBT is associated with fewer acute unplanned hospitalizations as compared to IMRT in the era of ICI consolidation. Methods: This single institution, multi-site retrospective study included consecutive pts with LA-NSCLC treated with definitive cCRT with either PBT or IMRT from October 2017 to December 2021. Pts were evaluated for consolidative ICI. Primary endpoint was unplanned hospitalization within 90 days of first radiation (RT) treatment. Secondary endpoints included grade 3+ pneumonitis, grade 3+ esophagitis, PFS, and OS. Logistic regression was used to assess associations with 90-day hospitalization. Competing risk regression was used for grade 3+ pneumonitis and esophagitis and Cox regression for PFS and OS. Inverse probability treatment weighting (IPTW) was applied to adjust for differences in PBT and IMRT groups. Results: 316 pts were included: 117 (37%) received PBT and 199 (63%) IMRT. Median age was 68.5 yrs; median RT dose 66.6 Gy (IQR 65.9-70.0). PBT group was older (median 71.1 vs 67.2 yrs, p < 0.005) and had a higher Charlson comorbidity index (CCI) (median 4 vs 3, p = 0.02). There was no difference in receipt of ICI consolidation (66.7% vs 68.3%, p = 0.76). PBT group had lower mean heart dose (5.9 vs 10.8 Gy, p < 0.001), LAD V15 (0 vs 6%, p = 0.001), mean lung dose (14.7 vs 15.7 Gy, p < 0.008) and effective dose to immune circulating cells (median 3.7 vs 4.9 Gy, p < 0.001) but not mean esophagus dose. PBT was associated with fewer unplanned 90-day hospitalizations (23.9% vs 34.7%; aOR 0.52, 95% CI 0.30-0.90, p = 0.02). This difference persisted on IPTW analysis (OR 0.48, 95% 0.33-0.70, p = 0.0002) after adjusting for CCI, ECOG, smoking pack yrs, T stage, N stage, target volume, concurrent chemotherapy agent and histology. Reasons for hospitalization in PBT and IMRT groups included progression (1.4% vs 1.6%), definite/probable toxicity from cCRT (11.4% vs 18.2%), possible toxicity from cCRT (7.3% vs 12.8%) or unrelated to cCRT (2.5% vs 2.3%). There was no significant difference between PBT and IMRT groups in G3+ pneumonitis (1-year 6.0% vs 9.1%, p = 0.49), G3+ esophagitis (1-year 6.0% vs 6.5%, p = 0.71), PFS (median 14.4 vs 15.1 months, p = 0.69), or OS (median 34.2 vs 29.4 months, p = 0.41); results remained unchanged in IPTW analysis. Conclusions: Among pts with LA-NSCLC treated with cCRT in the era of ICI consolidation, PBT was associated with fewer acute unplanned hospitalizations compared to IMRT.
TL;DR: The first prospective trial of Proton Beam Therapy (PBT) re-RT followed by pembro was reported in this article , where patients with isolated thoracic recurrences of NSCLC in/near previously irradiated fields were enrolled.
Abstract: 8552 Background: Isolated thoracic recurrences of NSCLC in/near previously irradiated fields present a therapeutic challenge. One treatment option is re-RT with proton beam therapy (PBT) to minimize normal tissue exposure; however, distant failure is common. Herein, we report the first prospective trial of PBT re-RT followed by pembro. Methods: This phase II, single-arm trial ( NCT03087760 ) enrolled patients (pts) with isolated locoregional recurrences of NSCLC in/near previously irradiated fields. Key inclusion were definitive thoracic RT > 6 months (mo) prior, ECOG 0-1, and clinical target volume (CTV) < 250 cc. Key exclusion were extrathoracic metastases, prior grade ≥3 pneumonitis, and prior immunotherapy < 30 days from re-RT start. 4-12 weeks after completion of 60-70 Gy PBT re-RT, pts without progressive disease started pembro 200 mg IV q21 days for up to 12 mo. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and CTCAE v5.0 toxicity. PFS and OS were measured from re-RT start and estimated using Kaplan-Meier method. Results: Between November 2017 and April 2021, 32 pts were consented; 10 were excluded most commonly due to CTV ≥250cc (N = 3) or separate primary (N = 3). 22 were eligible and initiated PBT re-RT. Trial closed early due to slow accrual. Median age was 68 years. All recurrences were biopsy-proven; 8 (36%) were squamous. Recurrences were primary tumor (N = 4), nodal (N = 8), and both (N = 10). 8 pts (36%) received prior durvalumab. Median interval from prior RT end to re-RT start was 20 mo (range 10.2-74.8). Median delivered re-RT dose and dose/fraction were 60 Gy (range 18-70) and 2 Gy (range 1.8-4), respectively; 21 pts (95%) received concurrent chemotherapy. 15 pts (68%) initiated consolidation pembro on trial and received a median of 3 cycles (range 2-17). Pembro was discontinued due to completion of 1 year (N = 3), disease progression (N = 4), toxicity (N = 5; 2 pembro-related [grade 2 pneumonitis after cycle 3 and grade 3 mucositis after cycle 13, the former also re-RT-related]), death without progression (N = 2; NSTEMI and unknown), and pt decision (N = 1). Median follow-up was 38.7 mo. Median PFS and OS were 8.8 mo (95% CI 4.2-23.7) and 22.8 mo (95% CI 6.9-not reached) for all pts, respectively, and 13.5 mo (95% CI 4.2-25.3) and 22.8 mo (95% CI 6.5-not reached) for pts who started pembro. Receipt of > 3 cycles pembro (N = 7) associated with better OS (median 46.7 vs 13.8 mo, log-rank p = 0.007). 10 pts (46%) had grade ≥3 toxicity; 2 were pembro-related (grade 3 lymphopenia and mucositis). 1 pt had grade 5 toxicity (aortic fistula), from re-RT. Conclusions: In the first prospective trial of PBT re-RT + consolidation pembro, treatment proved feasible and PFS was acceptable though the capacity to administer pembro was limited. This approach may be considered in selected patients with isolated thoracic recurrences of NSCLC. Clinical trial information: NCT03087760 .
TL;DR: In this paper , the authors found that post-chemoradiation (CRT) cardiac events may be higher among those who experience postchemoradiation cardiac events, and that dose to specific cardiovascular substructures-the great vessels, atria, ventricles, and left anterior descending coronary artery-may be lower with proton versus photon-based RT.
Abstract: Radiation therapy (RT) plays a critical role in treating locally advanced non-small cell lung cancer but has been associated with deleterious cardiac effects. We hypothesized that RT dose to certain cardiovascular substructures may be higher among those who experience post-chemoradiation (CRT) cardiac events, and that dose to specific substructures-the great vessels, atria, ventricles, and left anterior descending coronary artery-may be lower with proton- versus photon-based RT.In this retrospective review, we selected 26 patients who experienced cardiac events after CRT for locally advanced non-small cell lung cancer and matched them to 26 patients who did not experience cardiac events after CRT. Matching was done based on RT technique (protons vs photons), age, sex, and cardiovascular comorbidity. For each patient, the whole heart and 10 cardiovascular substructures on the RT planning computerized tomography scan were manually contoured. Dosimetric comparisons were made between those who did and did not experience cardiac events and between the proton and photon groups.There was no significant difference in heart or any cardiovascular substructure dose between those patients who experienced post-treatment cardiac events and those who did not (P > .05 for all). The mean heart dose in the patients receiving proton therapy was significantly lower than the mean heart dose in the patients receiving photon therapy (P = .032). The left ventricle, right ventricle, and the left anterior descending artery also had significantly lower doses (by multiple measures) when treated with protons (P = .0004, P < .0001, and P = .0002, respectively).Proton therapy may have a significant effect on decreasing dose to individual cardiovascular substructures compared with photon therapy. There was no significant difference in heart dose or dose to any cardiovascular substructure between patients who did and did not experience post-treatment cardiac events. Further research should be done to assess the association between cardiovascular substructure dose and post-treatment cardiac events.
TL;DR: In this article , the authors established the POF in mNSCLC treated with first line pembrolizumab, identified the frequency of oligoprogression (OPD), and characterized the use of RT in patients with OPD.
Abstract: e21054 Background: The patterns of failure (POF) for patients (pts) with mNSCLC treated with immunotherapy are not well established. These POF inform treatment decisions and may identify candidates for radiotherapy (RT). The primary objective of this study was to establish the POF in mNSCLC treated with first line pembrolizumab, identify the frequency of oligoprogression (OPD), and characterize the use of RT in patients with OPD. Methods: We retrospectively identified pts with mNSCLC who received first line pembrolizumab +/- chemotherapy between January 2015 – January 2021 at a single institution. We defined POF at the time of first disease progression (PD) after pembrolizumab infusion according to two classifications: 1) local, regional, or distant failure, or 2) failure in existing lesions, new lesions, or a combination. OPD was defined as PD in < 3 distinct sites of failure in any number of organs. Overall survival (OS) was measured via the Kaplan Meier method. Multivariable Cox modeling was used to correlate pt characteristics with OS. Logistic regression was used to predict pt variables associated with OPD. Results: Of the 298 pts who received first line pembrolizumab +/- chemotherapy for mNSCLC, 198 had PD at median follow up of 46.3 months. Using POF classification 1, most failures were distant (n = 87, 43.9%) or a combination of locoregional and distant (n = 68, 34.4%). For POF classification 2, failures occurred in a combination of new and existing lesions (n = 89, 45.0%), existing lesions alone (n = 66, 33.3%), or in new lesions only (n = 42, 21.7%). OPD occurred in 79 (39.9%) pts. At the time of progression, 52 pts (27.3%) had PD at 1 site, 50 pts (25.2%) had PD at 2-3 sites, 37 pts (18.7%) had PD at 4-5 sites, and 57 pts (28.8%) had PD at > 5 sites. Most PD occurred in a solitary organ (n = 93, 47.0%) or in 2-3 different organs (n = 81, 40.9%). Median OS was higher in the following groups: PD in existing lesions vs new or new + existing lesions (28.7 vs 20.2 vs 13.9 months, p < 0.001), locoregional failure vs distant or both (39.1 vs 17.4 vs 14.3 months, p < 0.001) and OPD vs polyprogression (35.1 vs. 12.2 months, p < 0.001). Among pts with OPD (n = 79), median OS was better for those who received RT to all sites of PD than for those who changed systemic therapy (66.2 vs 22.9 months, p = 0.007). Pts with oligometastatic disease at diagnosis (OR 2.94, 95% CI 1.19-7.56, p = 0.02) and PR as best response to ICI (OR 2.48, 95% CI 1.04-6.14, p = 0.04) were more likely to develop OPD. On multivariable analysis, receipt of RT at time of OPD (HR 0.35, 95% CI 0.20-0.62, p < 0.01) and higher number of ICI cycles received (HR 0.94, 95% CI 0.92-0.96, p < 0.001) were associated with improved OS. Conclusions: For pts with mNSCLC treated with pembrolizumab, PD outside of existing lesions is infrequent. OPD is common and occurs in 40% of PD. Randomized data are needed to define the benefits of RT in mNSCLC with OPD.
14 Mar 2023
TL;DR: In this paper , a 3D surface acquisition protocol was developed for a life-sized human phantom model using handheld threedimensional (3D) surface acquisition devices. This technology was utilized to develop light fluence modeling of the internal pleural cavity space during Photodynamic therapy (PDT) of malignant mesothelioma.
Abstract: We have developed a novel scanning protocol for a life-sized human phantom model using handheld threedimensional (3D) surface acquisition devices. This technology will be utilized to develop light fluence modeling of the internal pleural cavity space during Photodynamic Therapy (PDT) of malignant mesothelioma. The external aspect of the chest cavity phantom was prefabricated of a hardened synthetic polymer resembling ordinary human anatomy (pleural cavity space) and the internal aspect remained hollow without any characterizations. Both surfaces were layered with non-reflective adhesive paper to create non-uniformed surface topographies. These surface characteristics were established in randomized X-Y-Z coordinates ranging in dimensions from 1-15mm. This protocol utilized the handheld Occipital Scanner and the MEDIT i700. The Occipital device required a minimum scanner-to-surface distance of 24cm and the MEDIT device 1cm respectively. The external and internal aspects of the phantom model were successfully scanned acquiring digital measurements in actual value and converted into a digital image file. The initial surface rendering was acquired by the Occipital device and applied with proprietary software to guide the MEDIT device to fill voided areas. This protocol is accompanied by a visualization tool that allows for real-time inspection of surface acquisition in 2D and 3D. This scanning protocol can be utilized to scan the pleural cavity for real-time guidance for light fluence modeling during PDT, which will be expanded to ongoing clinical trials.