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Effects of selenomethionine on acute toxicities from concurrent chemoradiation for inoperable stage III non-small cell lung cancer.

ABSTRACT: AIM:To prospectively determine the safety and tolerability of oral L-selenomethionine (SLM) with concurrent chemoradiation (CCRT) for Stage III non-small cell lung cancer (NSCLC) and estimate if the incidence and/or severity of adverse events could be reduced by its use. METHODS:Sixteen patients with stage III NSCLC were accrued to this single arm, phase II study. CCRT consisted of radiation given at 2 Gy per fraction for 30-33 fractions, 5 d per week with concurrent weekly IV paclitaxel 50 mg/m(2) followed by carboplatin dosed at an area under the time-concentration curve of 2. SLM was dosed in a loading phase at 4800 ?g twice daily for one week prior to CCRT followed by once daily dosing during treatment. RESULTS:No selenium-related toxicity was observed. Analysis revealed grade 3 or higher esophagitis in 3 of 16 patients (19%), pneumonitis in 0, leukopenia in 2 (12.5%), and anemia in 1 (6%); the latter two were significantly reduced when compared to the protocol-stated expected rate of 35% (P = 0.045 for leukopenia, and P < 0.01 for anemia). Median overall survival was 14.9 mo and median failure-free survival was 9 mo (95%CI: 3.3-21.5). CONCLUSION:There may be some protective benefit of selenium in the setting of CCRT for inoperable NSCLC. The data suggests decreased rates of myelosuppression when compared to similarly-treated historical and contemporary controls. Further evaluation of selenium in this setting may be warranted.

SUBMITTER: Mix M

PROVIDER: S-EPMC4600190 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Effects of selenomethionine on acute toxicities from concurrent chemoradiation for inoperable stage III non-small cell lung cancer.

Mix Michael M Ramnath Nithya N Gomez Jorge J de Groot Charles C Rajan Saju S Dibaj Shiva S Tan Wei W Rustum Youcef Y Jameson Michael B MB Singh Anurag K AK

World journal of clinical oncology 20151001 5

<h4>Aim</h4>To prospectively determine the safety and tolerability of oral L-selenomethionine (SLM) with concurrent chemoradiation (CCRT) for Stage III non-small cell lung cancer (NSCLC) and estimate if the incidence and/or severity of adverse events could be reduced by its use.<h4>Methods</h4>Sixteen patients with stage III NSCLC were accrued to this single arm, phase II study. CCRT consisted of radiation given at 2 Gy per fraction for 30-33 fractions, 5 d per week with concurrent weekly IV pac ...[more]

PMID: 26468452

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Project description:PurposeThis study aimed to investigate the association between target volume margins and clinical outcomes for patients with inoperable non-small cell lung cancer (NSCLC) treated with concurrent chemoradiation therapy.Methods and materialsWe reviewed the records of 82 patients with inoperable NSCLC treated between 2009 and 2016 with concurrent chemoradiation. All patients received positron emission tomography-based treatment planning, 4-dimensional computed tomography simulation to define an internal target volume, and daily cone beam computed tomography. We quantified variations in target volume margins with a margin deviation index (MDI), calculated as the percentage change in equivalent uniform dose between the original planning target volume (PTV) and a standard reference PTV 10 mm beyond the original gross tumor volume, consistent with the minimum margins mandated by recent NSCLC trials. Greater MDIs equated to smaller effective target volume margins. We dichotomized patients by the upper tercile MDI value (5.8%). Endpoints included time to locoregional progression and time to grade ≥ 3 radiation esophagitis (RE3) or radiation pneumonitis (RP3), modelled with the Fine-Gray method.ResultsMedian follow-up was 37.8 months (range, 5.9-58.1 months). Larger MDIs correlated with smaller clinical target volume (CTV) + PTV margins, larger gross tumor volumes, later treatment year, and intensity modulated radiation therapy use. The risk of locoregional progression did not differ for MDI ≥5.8% versus <5.8% (adjusted hazard ratio: 0.88; P = .76), but the risk of RE3 or RP3 was decreased for MDI ≥5.8% (adjusted hazard ratio: 0.27; P = .027). Patients with MDI ≥5.8% were treated with smaller CTV + PTV margins (median, 5.6 vs 8 mm; P < .0001) and a marginally lower volume of esophagus receiving ≥50 Gy (median, 31.1% vs 35.3%; P = .069).ConclusionsSmaller margins were used for larger tumors but were not associated with an increase in locoregional failures. Additional studies could clarify whether smaller margins, when used alongside modern radiation therapy techniques, decrease treatment-related toxicity for inoperable NSCLC.

Project description:BackgroundDurvalumab as maintenance treatment after platinum-based concurrent chemoradiotherapy (cCRT) has become the standard of care in inoperable stage III non-small cell lung cancer (NSCLC). In this nationwide survey, we solicited members of the German Radiation Oncology Society to review the current distribution and clinical settings of durvalumab treatment after cCRT, observed side effects and summarize follow-up management.MethodsWe surveyed radiation oncology institutions in Germany via an anonymous online questionnaire sent by e-mail to all members of the German Radiation Oncology Society which agreed their willingness to participate.ResultsWe received a total of 255 responses (response rate: 18%). Of which 203 (80%) were completed and returned and thus eligible for further evaluation. The respondents work in 87 different cities and 44% in a private medical practice, 29% in university and 22% in a general hospital. Durvalumab was implemented in clinical routine by 70% of respondents. Major reasons for failed implementation in clinical practice reported by the respondents were patient's ineligibility (42%), lack of required PD-L1 status (25%), decision of medical oncologists (7%) or absence of updated German guidelines (7%). Thirty-six percent of all respondents report low (≤30%) PD-L1 testing before cCRT based on IHC assay. No respondent had applied durvalumab in less than 14 days after the completion of CRT. Severe side effects requiring hospital admission in more than 10% of all patients were reported by 12% of all respondents.ConclusionsDurvalumab maintenance is already implemented in the radiation oncology community and administered by the absolute majority of respondents. Low testing rates of PD-L1 at initial diagnosis were observed and should be considered a major barrier to universal adoption and integration in the clinical work-flow in countries with durvalumab approval restricted to PD-L1 positive patients. No respondent applies durvalumab in less than 14 days after cCRT.

Project description:PurposeOf newly diagnosed patients with non-small-cell lung cancer (NSCLC), stage III accounts for 30%. Most patients are treated with concurrent chemoradiation therapy, but the addition of consolidation chemotherapy (CC) is debatable. We examined the effect of CC in Brazilian patients with stage III NSCLC treated in routine clinical practice.MethodsWe retrospectively collected data for patients from five different Brazilian cancer institutions who had stage III NSCLC and who were treated with chemoradiation therapy followed or not by CC. Eligible patients were age 18 years or older and must have been treated with cisplatin-carboplatin plus etoposide, paclitaxel, or vinorelbine, concurrently with thoracic radiation therapy (RT). Patients treated with surgery or neoadjuvant chemotherapy were excluded. The primary end point was overall survival (OS). Associations between CC and clinical variables and demographics were evaluated by using Pearson's χ2 test. Survival curves were calculated by using the Kaplan-Meier method and were compared using the log-rank test. Univariable and multivariable analysis used a Cox proportional hazards model.ResultsWe collected data from 165 patients. Median age was 60 years. Most patients were male (69.1%), white (77.9%), current or former smokers (93.3%), and had stage IIIB disease (52.7%). Adenocarcinoma was the most common histology (47.9%). Weight loss of more than 5% was observed in 39.1% and Eastern Cooperative Oncology Group performance status of 2 was observed in 14.6%. The only variable associated with CC was T stage ( P = .022). We observed no statistically significant difference in OS between patients treated or not with CC ( P = .128). A total delivered RT dose ≥ 61 Gy was the only variable independently associated with improved survival ( P = .012).ConclusionBrazilian patients with locally advanced NSCLC who were treated with standard treatment achieved OS similar to that reported in randomized trials. CC did not improve OS in patients with stage III NSCLC after concurrent chemoradiation therapy. An RT dose of less than 61 Gy had a negative effect on OS.

Project description:Administration of pembrolizumab plus concurrent chemoradiation therapy (cCRT) may provide treatment benefit to patients with locally advanced, stage III non-small cell lung cancer (NSCLC). To evaluate treatment outcomes and safety of pembrolizumab plus cCRT in stage III NSCLC. The phase 2, nonrandomized, 2-cohort, open-label KEYNOTE-799 study enrolled patients between November 5, 2018, and July 31, 2020, from 52 academic facilities and community-based institutions across 10 countries. As of October 28, 2020, median (range) follow-up was 18.5 (13.6-23.8) months in cohort A and 13.7 (2.9-23.5) months in cohort B. Of 301 patients screened, 216 eligible patients with previously untreated, unresectable, and pathologically/radiologically confirmed stage IIIA/IIIB/IIIC NSCLC with measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) were enrolled. Patients in cohort A (squamous/nonsquamous) received 1 cycle (3 weeks) of carboplatin (area under the curve [AUC] 6 mg/mL/min), paclitaxel (200 mg/m2), and pembrolizumab (200 mg), followed by carboplatin (AUC 2 mg/mL/min) and paclitaxel (45 mg/m2) once weekly for 6 weeks and 2 cycles of pembrolizumab plus standard thoracic radiotherapy. Patients in cohort B (nonsquamous) received 3 cycles of cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and pembrolizumab (200 mg) every 3 weeks and thoracic radiotherapy in cycles 2 and 3. Patients received 14 additional cycles of pembrolizumab. Coprimary end points were objective response rate per RECIST v1.1 by blinded independent central review and incidence of grade 3 to 5 pneumonitis. A total of 112 patients received treatment in cohort A (76 men [67.9%]; median [range] age, 66.0 [46-90] years; 66 patients [58.9%] with programmed cell death ligand 1 [PD-L1] tumor proportion score ≥1%) and 102 patients received treatment in cohort B (62 men [60.8%]; median [range] age, 64.0 [35-81] years; 40 patients [39.2%] with PD-L1 tumor proportion score ≥1%). Objective response rate was 70.5% (79 of 112; 95% CI, 61.2%-78.8%) in cohort A and 70.6% (72 of 102; 95% CI, 60.7%-79.2%) in cohort B. Median duration of response was not reached, but 79.7% and 75.6%, respectively, had response duration of 12 months or longer. Grade 3 or higher pneumonitis occurred in 9 of 112 patients (8.0%) in cohort A and 7 of 102 (6.9%) in cohort B. Grade 3 to 5 treatment-related adverse events occurred in 72 of 112 (64.3%) and 51 of 102 (50.0%) patients, respectively. The findings of this phase 2, nonrandomized, 2-cohort study suggest promising antitumor activity of pembrolizumab plus cCRT and manageable safety in patients with previously untreated, locally advanced, stage III NSCLC.

Project description:BackgroundRadiation with platinum-based chemotherapy is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). Despite aggressive treatment, progression-free survival and overall survival remain poor. It is unclear whether any tumor genetic mutations are associated with response to chemoradiation therapy.MethodsWe retrospectively reviewed clinical outcomes of patients with stage III NSCLC treated with definitive radiation who had undergone tumor molecular profiling through a next-generation DNA sequencing platform. Cox proportional hazards model was used to investigate associations between clinical outcomes and genetic mutations detected by next-generation sequencing.Results110 patients were identified with stage III NSCLC and underwent definitive radiation between 2013 and 2017 and tumor molecular profiling. Concurrent or sequential chemotherapy was given in 104 patients (95%). Unbiased genomic analyses revealed a significant association between AKT2 mutations and decreased local-regional tumor control and overall survival (hazard ratios [HR] 12.5 and 13.7, P = .003 and P = .003, respectively). Analyses restricted to loss-of-function mutations identified KMT2C and KMT2D deleterious mutations as negative prognostic factors for overall survival (HR 13.4 and 7.0, P < .001 and P < .001, respectively). Deleterious mutations in a panel of 38 DNA damage response and repair pathway genes were associated with improved local-regional control (HR 0.32, P = .049).ConclusionsThis study coupled multiplexed targeted sequencing with clinical outcome and identified mutations in AKT2, KMT2C, and KMT2D as negative predictors of local-regional control and survival, and deleterious mutations in damage response and repair pathway genes were associated with improved local-regional disease control after chemoradiation therapy. These findings will require validation in a larger cohort of patients with prospectively collected and detailed clinical information.

Project description:BACKGROUND:Loco-regional and distant failure are common in inoperable stage III non small-cell lung cancer (NSCLC) after chemoradiotherapy (CRT). However, there is limited real-world data on failure pattern, patient prognosis and salvage options. METHODS:We analysed 99 consecutive patients with inoperable stage III NSCLC treated with CRT between 2011 and 2016. Follow up CT scans from date of the first-site failure were matched with the delivered radiation treatment plans. Intra-thoracic loco-regional relapse was defined as in-field (IFR) vs. out-of-field recurrence (OFR) [in- vs. outside 50Gy isodose line in the involved lung], respectively. Extracranial distant (DMs) and brain metastases (BMs) as first site of recurrence were also evaluated. Using the Kaplan-Meier method, impact of salvage surgery (sS), radiotherapy (sRT), chemotherapy (sCT) and immunotherapy (sIO) on patient survival was assessed. RESULTS:Median follow-up was 60.0?months. Median PFS from the end of CRT for the entire cohort was 7.5 (95% CI: 6.0-9.0?months) months. Twenty-six (26%) and 25 (25%) patients developed IFR and OFR. Median time to diagnosis of IFR and OFR was 7.2 and 6.2?months. In the entire cohort, onset of IFR and OFR did not influence patient outcome. However, in 73 (74%) patients who survived longer than 12?months after initial diagnosis, IFR was a significant negative prognostic factor with a median survival of 19.3 vs 40.0?months (p <?0.001). No patients with IFR underwent sS and/or sRT. 18 (70%) and 5 (19%) patients with IFR underwent sCT and sIO. Three (12%) patients with OFR underwent sS and are still alive with 3-year survival rate of 100%. 5 (20%) patients with OFR underwent sRT with a median survival of 71.2 vs 19.1?months (p =?0.014). Four (16%) patients with OFR received sIO with a numerical survival benefit (64.6 vs. 26.4?months, p =?0.222). DMs and BMs were detected in 27 (27%) and 16 (16%) patients after median time of 5.8 and 5.13?months. Both had no impact on patient outcome in the entire cohort. However, patients with more than three BMs showed significantly poor OS (9.3 vs 26.0?months; p =?0.012). CONCLUSIONS:After completion of CRT, IFR was a negative prognostic factor in those patients, who survived longer than 12?months after initial diagnosis. Patients with OFR benefit significantly from salvage local treatment. Patients with more than three BMs as first site of failure had a significantly inferior outcome.

Dataset Information

Effects of selenomethionine on acute toxicities from concurrent chemoradiation for inoperable stage III non-small cell lung cancer.

Publications

Effects of selenomethionine on acute toxicities from concurrent chemoradiation for inoperable stage III non-small cell lung cancer.

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