Evaluation of Radiation Therapy Treatment Plans in a Randomized Phase 2 Trial Comparing 2 Schedules of Twice-Daily Thoracic Radiation Therapy in Limited Stage Small Cell Lung Cancer.

PURPOSE: There is limited clinical data for recommendations on how to deliver thoracic radiation therapy (TRT) concurrently with chemotherapy in limited-stage small cell lung cancer. We reviewed radiation therapy treatment plans in a randomized phase 2 trial comparing high-dose with standard-dose twice-daily TRT to assess treatment planning techniques, dose-volume data for target volumes and organs at risk (OARs), evaluate compliance with the protocol, associations with radiation-induced toxicity, and whether an imbalance in treatment planning parameters might be a reason for the large survival benefit of the higher dose (median overall survival 43.6 vs 22.6 months). METHODS AND MATERIALS: In the study, 170 patients were to receive 4 courses of platinum/etoposide and were randomized to receive twice-daily TRT of 60 Gy/40 fractions (fx) or 45 Gy/30 fx. TRT treatment plans for those who received 1 or more fx of TRT (n = 166) were analyzed. RESULTS: The most common treatment planning technique was 3-dimensional conformal radiation therapy (67%). The 75th percentile of the reported dose-volume parameters for the OARs were within the protocol-recommended limits for both groups. Mean doses to the esophagus of 25.5 Gy (IQR, 20.2-31.3; 60 Gy/40 fx) and 24.3 Gy (IQR, 20.3-27.5; 45 Gy/30 fx) were associated with 21% and 18% ≥ grade 3 acute esophagitis, respectively. In the 60 Gy/40 fx group, a mean dose to the lungs of 16.5 Gy (IQR, 15.8-16.9), V20 Gy of 29.5% (IQR, 28.8-30.4), and V5 Gy of 65.6% (IQR, 61.5-68.7) led to ≥ grade 3 pneumonitis in 4% of the patients. There was no ≥ grade 3 pneumonitis in the 45 Gy/30 fx group. The treatment planning techniques, the percentage change in volumes between original and redelineated OARs, planning target volumes, relative doses, and laterality were well balanced between the randomly assigned groups. CONCLUSIONS: Considering the incidences of severe radiation-induced toxicities were within the range of other recent trials, the reported doses to the OARs appear to be safe. Treatment planning parameters were well balanced between the randomly assigned groups, supporting that the survival benefit of the twice-daily 60 Gy/40 fx TRT schedule was due to the higher dose.

Fragmentation assessment of FFPE DNA helps in evaluating NGS library complexity and interpretation of NGS results.

Formalin-fixed paraffin-embedded (FFPE) tissue remains the most common source for DNA extraction from human tissue both in research and routine clinical practice. FFPE DNA can be considerably fragmented, and the amount of DNA measured in nanograms may not represent the amount of amplifiable DNA available for next-generation sequencing (NGS). Two samples with similar input DNA amounts in nanograms can yield NGS analyses of considerably different quality. Nevertheless, many protocols for NGS library preparation from FFPE DNA describe input DNA in nanograms without indication of a minimum requirement of amplifiable genome equivalent DNA. An important NGS quality metric is the library complexity, reflecting the number of DNA fragments from the original specimen represented in the final library. Aiming to illustrate the relationship between DNA fragmentation degree and library complexity, we assessed the fragmentation degree of 116 lung cancer FFPE DNA samples to calculate the amount of amplifiable input DNA used for library preparation. Mean unique coverage, coverage uniformity, and mean number of PCR duplicates with the same unique molecular identifier were used to evaluate library complexity. We showed that the amount of amplifiable input DNA predicted library complexity better than the input measured in nanograms. The frequent discrepancy between DNA amount in nanograms and the amount of amplifiable DNA indicate that the fragmentation degree should be considered when performing NGS of FFPE DNA. Importantly, the fragmentation assessment may help when interpreting NGS data and be a useful tool for evaluating library complexity in the absence of unique molecular identifiers.

Prognostic Value of Post First-Line Chemotherapy Glasgow Prognostic Score in Advanced Non-Small Cell Lung Cancer.

Background: The Glasgow prognostic score (GPS) is an established inflammatory prognostic index in cancer patients. Most studies have only measured GPS at baseline (B-GPS). Effective cancer therapy may reduce inflammation, and we investigated whether re-assessing GPS after first-line chemotherapy (E-GPS) provided more prognostic information than B-GPS in a phase III trial of advanced non-squamous non-small cell lung cancer (NSCLC). Methods: Glasgow prognostic score was assessed before and after carboplatin/vinorelbine chemotherapy. When assessing GPS, C-reactive protein (CRP) ⩾ 10 mg/L and albumin < 35 mg/L are defined as abnormal values. GPS 0: both values normal, GPS 1: one abnormal value, and GPS 2: both values abnormal. Results: Glasgow prognostic score at baseline and E-GPS were available in 138 patients. Median age was 67 years, 51% were women, and 94% had performance status 0-1. B-GPS was not a statistically significant prognostic factor (B-GPS 1 vs 0: hazard ratio [HR] = 1.32, 95% confidence interval [CI] = 0.9-2.0; B-GPS 2 vs 0: HR = 1.46, 95% CI = 0.9-2.3), while E-GPS was (E-GPS 1 vs 0: HR = 1.57, 95% CI = 1.0-2.4; E-GPS 2 vs 0: HR = 2.77, 95% CI = 1.7-4.5). E-GPS was associated with treatment response (P < .01), whereas B-GPS was not. Conclusion: Glasgow prognostic score at baseline after first-line chemotherapy provided more prognostic information than baseline GPS in patients with advanced non-squamous NSCLC and was associated with treatment response. ClinicalTrialsgov Identifier: NCT02004184.

Prognostic value of absolute quantification of mutated KRAS in circulating tumour DNA in lung adenocarcinoma patients prior to therapy.

Droplet digital polymerase chain reaction (ddPCR) is a highly sensitive and accurate method for quantification of nucleic acid sequences. We used absolute quantification of mutated v-Ki-ras2 Kirsten rat sarcoma viral oncogene homology gene (KRAS) by ddPCR to investigate the prognostic role of mutated KRAS in patients with KRAS-mutated lung adenocarcinomas. Pre-treatment plasma samples from 60 patients with stages I-IV KRAS-mutated lung adenocarcinomas were analysed for KRAS mutations. The associations between survival, detectable KRAS mutations in plasma, and the plasma concentration of mutated KRAS were assessed. Overall, 23 of 60 (38%) patients had detectable KRAS mutation in plasma. The percentage of patients with detectable mutation was 8% in stage I, 30% in stage II, 71% in stage III, and 73% in stage IV. Estimated overall median progression-free survival (PFS) and overall survival (OS) were 26.2 months [95% confidence interval (CI) 12.5-39.9] and 50.8 months (95% CI 0-107.3), respectively. Patients with detectable mutations in plasma had significantly worse median PFS compared to patients with undetectable mutation (13.1 versus 70.1 months) and shorter median OS (20.7 versus not reached). High circulating tumour DNA (ctDNA) concentrations of mutated KRAS were significantly associated with shorter PFS [hazard ratio (HR) 1.008, 95% CI 1.004-1.012] and OS (HR 1.007, 95% CI 1.003-1.011). All associations remained statistically significant in multivariable analyses. In conclusion, ddPCR is an accurate and easily feasible technique for quantification of KRAS mutations in ctDNA. The presence of detectable KRAS mutation in plasma at baseline was associated with worse PFS and OS. High concentration of mutated KRAS in ctDNA was an independent negative prognostic factor for both PFS and OS.

Timing of Severe Toxicity from Chemotherapy in Patients With Lung Cancer.

BACKGROUND/AIM: The aim of this study was to investigate the timing of severe toxicity in lung cancer patients receiving chemotherapy. PATIENTS AND METHODS: Patients with advanced non-small cell lung cancer or limited disease small cell lung cancer included in two randomized controlled trials were analysed. Severe toxicity was defined as grade 3-5 toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. RESULTS: We analysed 569 patients and 433 (76.1%) experienced severe toxicity. Of these, 249 (57.5%) experienced the first episode of severe toxicity after the first, 109 (25.2%) after the second, 54 (12.5%) after the third and 18 (4.2%) after the fourth course of chemotherapy. Performance status (PS 2 vs. 0-1; p=0.046) and treatment arm were independent predictive factors for severe toxicity. CONCLUSION: Severe toxicity was most frequent after the first chemotherapy course, but some patients did not experience severe toxicity until after the fourth course. Accounting for timing might be important when studying factors predicting severe toxicity.

Randomized phase III trial comparing switch-maintenance pemetrexed with observation followed by pemetrexed at progression in advanced NSCLC.

Objectives: Two phase III trials show that maintenance pemetrexed therapy after platinum-doublet chemotherapy prolongs overall survival (OS) and progression free survival (PFS) in advanced non-squamous non-small-cell lung cancer (NSCLC). However, few patients in the control arms received pemetrexed at progression in these trials, performance status (PS) two patients were ineligible and few of the participants were elderly. Thus, we designed this study comparing immediate switch-maintenance pemetrexed therapy with pemetrexed at progression after platinum-doublet chemotherapy.Methods: Patients with stage IIIB/IV non-squamous NSCLC, ≥18 years, PS 0-2, and non-progression after four courses of carboplatin/vinorelbine were randomized to receive immediate maintenance pemetrexed therapy or observation followed by pemetrexed at progression. The primary endpoint was OS, secondary endpoints were PFS, toxicity and health related quality of life (HRQoL).Results: 105 patients were randomized between May 2014 and September 2017. Median age was 67 years, 36% were >70 years, 9% had PS 2, 91% stage IV and 47% were women. In the observation arm, 73% received pemetrexed at progression. Patients in the maintenance arm had a numerically longer OS (median 12.0 vs. 10.0 months; p = .10) and a statistically significant longer PFS (median 3.1 vs. 1.9 months; p < .01). In multivariable analyses adjusting for baseline characteristics, there was a trend toward improved OS (HR 0.65, 95% CI 0.42-1.01); p = .05), and a significantly improved PFS (HR 0.53, 95% CI 0.35-0.80; p < .01). There were no significant differences in toxicity or HRQoL between the treatment arms.Conclusion: There was a trend toward prolonged OS and significantly longer PFS from switch- maintenance pemetrexed therapy when 73% of patients in the control arm received pemetrexed at progression. ClinicalTrials.gov Identifier: NCT02004184.

Randomized phase II trial comparing twice daily hyperfractionated with once daily hypofractionated thoracic radiotherapy in limited disease small cell lung cancer.

BACKGROUND: Concurrent chemotherapy and thoracic radiotherapy (TRT) is recommended for limited disease small cell lung cancer (LD SCLC). Twice daily TRT is well documented, but not universally implemented - probably mainly due to inconvenience and concerns about toxicity. A schedule of three-week hypofractionated TRT is a commonly used alternative. This is the first randomized trial comparing twice daily and hypofractionated TRT in LD SCLC. MATERIAL AND METHODS: Patients received four courses of cisplatin/etoposide (PE) and were randomized to TRT of 42 Gy in 15 fractions (once daily, OD) or 45 Gy in 30 fractions (twice daily, BID) between the second and third PE course. Good responders received prophylactic cranial irradiation of 30 Gy in 15 fractions. RESULTS: 157 patients were enrolled between May 2005 and January 2011 (OD: n = 84, BID: n = 73). Median age was 63 years, 52% were men, 84% had performance status 0-1, 72% had stage III disease and 11% non-malignant pleural effusion. The treatment arms were well balanced. The response rates were similar (OD: 92%, BID: 88%; p = 0.41), but more BID patients achieved a complete response (OD: 13%, BID: 33%; p = 0.003). There was no difference in one-year progression-free survival (PFS) (OD: 45%, BID: 49%; p = 0.61) or median PFS (OD: 10.2 months, BID: 11.4 months; p = 0.93). The median overall survival in the BID arm was 6.3 months longer (OD: 18.8 months, BID: 25.1 months; p = 0.61). There were no differences in grade 3-4 esophagitis (OD: 31%, BID: 33%, p = 0.80) or pneumonitis (OD: 2%, BID: 3%, p = 1.0). Patients on the BID arm reported slightly more dysphagia at the end of the TRT. CONCLUSION: There was no difference in severe toxicity between the two TRT schedules. The twice daily schedule resulted in significantly more complete responses and a numerically longer median overall survival, but no firm conclusions about efficacy could be drawn from this phase II trial.

Frailty modelling of testicular cancer incidence using Scandinavian data.

The incidence of testicular cancer is highest among young men, and then decreases sharply with age. This points towards a frailty effect, where some men have a much greater risk of testicular cancer than the majority of the male population. Those with the highest risk get cancer, drain the group of individuals at risk, and leave a healthy male population which has approximately zero risk of testicular cancer. This leads to the observed decrease in incidence. We discuss a frailty model, where the frailty is compound-Poisson-distributed. This allows for a non-susceptible group (of zero frailty). The model is successfully applied to incidence data from the Danish and Norwegian registries. It is indicated that there was a decrease in incidence for males born during World War II in both countries. Bootstrap analysis is used to find the degree of variation in the estimates. In the Armitage-Doll multistage model, the estimated number of transitions needed for a cell to become malignant is close to 3 for non-seminomas and 4 for seminomas in both the Danish and Norwegian data. This paper demonstrates that a model including a frailty effect fits the incidence data well and gives interesting results and interpretations, although this is no proof of the effect's truth.