Docetaxel and nedaplatin twice a week with concurrent definitive radiotherapy in inoperable esophageal squamous cell carcinoma: A phase I trial (GASTO-1021).

PURPOSE: This phase I trial aimed to determine the maximal tolerated dose (MTD) of incorporating a twice-weekly docetaxel and nedaplatin regimen into definitive concurrent chemoradiotherapy (CCRT) as radiosensitizers in patients with inoperable esophageal squamous cell carcinoma (ESCC). METHODS: The CCRT regimen included docetaxel (5 mg/m2, 10 mg/m2, or 15 mg/m2) and nedaplatin (5 mg/m2, 10 mg/m2, or 15 mg/m2) twice-weekly based on the traditional 3 + 3 dose escalation strategy, and radiotherapy (64 Gy in 32 fractions). The primary goals were to determine the MTD of concurrent chemotherapy and the dose limiting toxicities (DLTs). In-field objective response rate (ORR) was investigated. RESULTS: Fifteen patients had been recruited and analyzed. DLT involving persistent grade 3 esophagitis over 1 week was observed in all three patients (3/3) at dose level 3 (15 mg/m2), and two patients (2/6) experienced DLTs in the dose level 2 (10 mg/m2) due to esophageal fistula and persistent grade 3 esophagitis over 1 week, while one patient (1/6) treated at dose level 1 (5 mg/m2) exhibited DLT owing to Grade 3 increased liver enzymes, suggesting a MTD of 5 mg/m2. The in-filed ORR was both 100% in all patients and those receiving MTD. The 1-year loco-regional recurrence-free survival rate was 83.3%, 83.3% and 66.7% in dose level 1, 2, and 3, respectively. CONCLUSIONS: The MTD of twice-weekly docetaxel and nedaplatin regimen was 5 mg/m2 in inoperable ESCC patients treated with definitive CCRT. Low dose concurrent docetaxel and nedaplatin showed promising radiosensitizing effect on in-filed disease control and good tolerability.

Developing and validating an integrated gross tumor volume (GTV)-TNM stratification system for supplementing unresectable locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy.

PURPOSE: The gross tumor volume (GTV) could be an independent prognostic factor for unresectable locally advanced non-small cell lung cancer (LANSCLC). We aimed to develop and validate a novel integrated GTV-TNM stratification system to supplement LANSCLC sub-staging in patients treated with concurrent chemoradiotherapy (CCRT). METHODS: We performed a retrospective review of 340 patients with unresectable LANSCLC receiving definitive CCRT. All included patients were divided into two randomized cohorts. Then the Kaplan-Meier method and Cox regression were calculated to access the prognostic value of the integrated GTV-TNM stratification system, which was further validated by the area under the receiver operating characteristic curve (AUC) score and F1-score. RESULTS: The optimal outcome-based GTV cut-off values (70 and 180 cm3) of the modeling cohort were used to determine each patient's integrated GTV-TNM stratum in the whole cohort. Our results indicated that a lower integrated GTV-TNM stratum could had better overall survival and progression-free survival (all P < 0.001), which was recognized as an independent prognostic factor. Also, its prognostic value was robust in both the modeling and validation cohorts. Furthermore, the prognostic validity of the integrated GTV-TNM stratification system was validated by significantly improved AUC score (0.636 vs. 0.570, P = 0.027) and F1-score (0.655 vs. 0.615, P < 0.001), compared with TNM stage. CONCLUSIONS: We proposed a novel integrated GTV-TNM stratification system to supplement unresectable LANSCLC sub-staging due to its prognostic value independent of TNM stage and other clinical characteristics, suggesting that it could be considered in individual treatment decision-making process.

Plasma Epstein-Barr Virus-Deoxyribonucleic Acid Copy Number Predicts Disease Progression in Stage I-III Pulmonary Lymphoepithelioma-Like Carcinoma.

Purpose: To investigate the predictive values of plasma Epstein-Barr Virus (EBV)- deoxyribonucleic acid (DNA) copy number on disease progression and survival in stage I-III pulmonary lymphoepithelioma-like carcinoma (LELC). Patients and Methods: Patients with pathologically confirmed, initially diagnosed or locally recurrent stage I-III pulmonary LELC, who received locally radical treatment and had plasma EBV-DNA results, were retrospectively reviewed. Risk factors of progression-free survival (PFS) and overall survival (OS) were assessed, including the predictive value of pre- and post-treatment EBV-DNA levels. The EBV-DNA change during follow-up was analyzed to determine its association with tumor progression and survival. Results: A total of 102 patients were included in analysis. Eighty-eight patients had initially-diagnosed and 14 had locally recurrent disease. There were 33 patients treated with radical surgery, 55 with definite radiotherapy and 14 with both. EBV-DNA was tested pre-treatment (N = 66), post-treatment (N = 93) and/or during follow-up (N = 58). Forty-one patients had complete EBV-DNA results of all three time points. The overall 2-year PFS and OS were 66.3 and 96.0%, respectively. Pre-treatment EBV-DNA copy number > 10,000 copies/mL was a risk factor of PFS (2-year PFS, > 10,000 vs. ≤ 10,000 copies/mL, 37.2 vs. 75.1%, p = 0.007). Positive post-treatment EBV-DNA also indicated a worse PFS in univariable (2-year PFS, > 0 vs. 0 copy/mL, 25.6 vs. 76.8%, p < 0.001) and multivariable analysis (HR = 3.44, 95% CI, 1.52-7.78; p = 0.003). In the follow-up set, an increasing EBV-DNA exceeding 1,000 copies/mL strongly predicted disease progression within 3 months, with a specificity of 97.5% (95% CI: 86.8-99.6%) and was associated with impaired OS (2-year OS, > 1,000 vs. ≤ 1,000 copies/mL, 72.9 vs. 100%, p < 0.001). Conclusions: Regular testing of EBV-DNA is suggested for pulmonary LELC to predict disease progression. If EBV-DNA copy number was increasing and beyond 1,000 copies/mL during follow-up, intensive radiologic evaluations are recommended.

Investigating the loco-regional control of simultaneous integrated boost intensity-modulated radiotherapy with different radiation fraction sizes for locally advanced non-small-cell lung cancer: clinical outcomes and the application of an extended LQ/TCP model.

BACKGROUND: To investigate the loco-regional progression-free survival (LPFS) of intensity-modulated radiotherapy (IMRT) with different fraction sizes for locally advanced non-small-cell lung cancer (LANSCLC), and to apply a new radiobiological model for tumor control probability (TCP). METHODS: One hundred and three LANSCLC patients treated with concurrent radiochemotherapy were retrospectively analyzed. Factors potentially predictive of LPFS were assessed in the univariate and multivariate analysis. Patients were divided into group A (2.0 ≤ fraction size<2.2Gy), B (2.2 ≤ fraction size<2.5Gy), and C (2.5 ≤ fraction size≤3.1Gy) according to the tertiles of fraction size. A novel LQRG/TCP model, incorporating four "R"s of radiobiology and Gompertzian tumor growth, was developed to predict LPFS and compared with the classical LQ/TCP model. RESULTS: With a median follow-up of 22.1 months, the median LPFS was 23.8 months. Fraction size was independently prognostic of LPFS. The median LPFS of group A, B and C was 13.8, 35.7 months and not reached, respectively. Using the new LQRG/TCP model, the average absolute and relative fitting errors for LPFS were 6.9 and 19.6% for group A, 5.5 and 8.8% for group B, 6.6 and 9.5% for group C, compared with 9.5 and 29.4% for group A, 16.6 and 36.7% for group B, 24.8 and 39.1% for group C using the conventional LQ/TCP model. CONCLUSIONS: Hypo-fractionated IMRT could be an effective approach for dose intensification in LANSCLC. Compared with conventional LQ model, the LQRG model showed a better performance in predicting follow-up time dependent LPFS.