A Randomized Phase I/II Trial to Compare Weekly Usage with Triple Weekly Usage of Paclitaxel in Concurrent Radiochemotherapy for Patients with Locally Advanced Non-small Cell Lung Cancer

Background and objective Although the guidelines of the National Comprehensive Cancer Network of USA recommend that the standard therapy for locally advanced non-small cell lung cancer (LANSCLC) is concurrent chemoradiotherapy. There is ongoing controversy about the treatment regimen which combines chemotherapy concurrently with radiotherapy. The aim of this study is to compare weekly usage with triple weekly usage of paclitaxel in concurrent radiochemotherapy for patients with LANSCLC, and to obtain the best paclitaxel regimen in the concurrent radiochemotherapy. Methods From April 2006 to April 2009, some LANSCLC patients in multicenter were randomly divided into weekly usage (45 mg/m2, 1 times/week, a total of 270 mg/m2 in six weeks) and triple weekly usage (15 mg/m2, 3 times/week, a total of 270 mg/m2 in six weeks) group of paclitaxel by a random number table. All patients were treated with 3D radiotherapy, and 95% planning target volume (PTV) received a prescription dose of (60-70) Gy/(30-35)times/(6-7)weeks, (1.8-2.0) Gy/fraction. Then the side effects, response and overall survival rate were compared between two groups of patients. Results Thirty-eight LANSCLC patients were enrolled. Weekly usage and triple weekly usage group were 20 and 18 patients, respectively. In the triple weekly usage group, the side effects were 12 patients had radiation esophagitis of I-II degree, 1 patient had radiation esophagitis of III degree, 2 patients had radiation pneumonitis of I degree, 1 patient had radiation pneumonitis of II degree, 1 patient had radiation pneumonitis of III degree and died of respiratory failure, 2 patients developed weight loss of I degree. In the weekly usage group, the side effects were 11 patients had radiation esophagitis of I-III degree, 6 patients had radiation pneumonitis of II-III degree, 2 patients developed weight loss of I degree, 6 patients developed leucopenia of III-IV degree. The response rate of two groups was 88.8% and 50.0%, respectively (P=0.026). 1-year survival rate of two groups was 79% and 67%, respectively (P=0.607). Conclusion Although the preliminary results did not show the merits of survival in triple weekly usage, but preliminary results show that triple weekly usage was more safe and effective than weekly usage of paclitaxel in concurrent radiochemotherapy for patients with LANSCLC

Analysis of clinical and dosimetric factors associated with severe acute radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with concurrent chemotherapy and intensity-modulated radiotherapy

<p>Abstract</p> <p>Background</p> <p>To evaluate the association between the clinical, dosimetric factors and severe acute radiation pneumonitis (SARP) in patients with locally advanced non-small cell lung cancer (LANSCLC) treated with concurrent chemotherapy and intensity-modulated radiotherapy (IMRT).</p> <p>Methods</p> <p>We analyzed 94 LANSCLC patients treated with concurrent chemotherapy and IMRT between May 2005 and September 2006. SARP was defined as greater than or equal 3 side effects and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.</p> <p>The clinical and dosimetric factors were analyzed. Univariate and multivariate logistic regression analyses were performed to evaluate the relationship between clinical, dosimetric factors and SARP.</p> <p>Results</p> <p>Median follow-up was 10.5 months (range 6.5-24). Of 94 patients, 11 (11.7%) developed SARP. Univariate analyses showed that the normal tissue complication probability (NTCP), mean lung dose (MLD), relative volumes of lung receiving more than a threshold dose of 5-60 Gy at increments of 5 Gy (V5-V60), chronic obstructive pulmonary disease (COPD) and Forced Expiratory Volume in the first second (FEV1) were associated with SARP (<it>p </it>< 0.05). In multivariate analysis, NTCP value (<it>p </it>= 0.001) and V10 (<it>p </it>= 0.015) were the most significant factors associated with SARP. The incidences of SARP in the group with NTCP > 4.2% and NTCP ≤4.2% were 43.5% and 1.4%, respectively (<it>p </it>< 0.01). The incidences of SARP in the group with V10 ≤50% and V10 >50% were 5.7% and 29.2%, respectively (<it>p </it>< 0.01).</p> <p>Conclusions</p> <p>NTCP value and V10 are the useful indicators for predicting SARP in NSCLC patients treated with concurrent chemotherapy and IMRT.</p

Current Status of Stereotactic Ablative Radiotherapy (SABR) for Early-stage Non-small Cell Lung Cancer

High level evidence from randomized studies comparing stereotactic ablative radiotherapy (SABR) to surgery is lacking. Although the results of pooled analysis of two randomized trials for STARS and ROSEL showed that SABR is better tolerated and might lead to better overall survival than surgery for operable clinical stage I non-small cell lung cancer (NSCLC), SABR, however, is only recommended as a preferred treatment option for early stage NSCLC patients who cannot or will not undergo surgery. We, therefore, are waiting for the results of the ongoing randomized studies [Veterans affairs lung cancer surgery or stereotactic radiotherapy in the US (VALOR) and the SABRTooth study in the United Kingdom (SABRTooths)]. Many retrospective and case control studies showed that SABR is safe and effective (local control rate higher than 90%, 5 years survival rate reached 70%), but there are considerable variations in the definitions and staging of lung cancer, operability determination, and surgical approaches to operable lung cancer (open vs video-assisted). Therefore, it is difficult to compare the superiority of radiotherapy and surgery in the treatment of early staged lung cancer. Most studies demonstrated that the efficacy of the two modalities for early staged lung cancer is equivalent; however, due to the limited data, the conclusions from those studies are difficult to be evidence based. Therefore, the controversies will be focusing on the safety and invasiveness of the two treatment modalities. This article will review the ongoing debate in light of these goals

Stereotactic Radiotherapy for Non-small Cell Lung Cancer with Small Lesions Applying A Flattening Filter Free Clinac

Background and objective With the rapid development of technology, stereotactic radiotherapy has been widely used. In a cohort of medically operable non-small cell lung cancer patients receiving stereotactic body radiation therapy (SBRT) survival rates “potentially equivalent to those of surgery” have been reported. Removing the field flattening filter, Clinac is capable of delivering dose rates much higher than conventional linac as well as reducing the treatment time. The goals of this work were to report safety and efficacy of SBRT treatment using a flattening filter-free model for non-small cell lung cancer (NSCLC) with small lesions. Methods From December 2011 to December 2013, 31 NSCLC patients who were T1-2N0M0, solitary pulmonary recurrence after surgery, and stage IV with oligo metastasis were enrolled, receiving SBRT treatment (60 Gy/8 f or 48 Gy/4 f) applying a flattening filter-free model. Results Compared with conventional technique, flattening filter-free model shortened the treating time with equivalent target dose and normal tissue dose. The median follow-up time is 19.4 mo. The 1-yr local control, regional control, distant control, progression free survival and overall survival rates were 96.8%, 96.8%, 83.9%, 77.4% and 96.8%. The most common side effects were radiation pneumonitis (29% grade 1, 3.2% grade 2) and chest pain (12.9% grade 1, 6.5% grade 2). Conclusion The use of flattening filter-free model in SBRT for small lesions of NSCLC patients is safe and effective. Long time follow-up and additional studies are still needed to validate our conclusions

A Phase I/II Study of Chemotherapy Concurrent with Twice-daily Radiotherapy Schedules by Intensity Modulated Radiation Therapy Using Simultaneous Integrated Boost for Limited-stage Small Cell Lung Cancer

Background and objective Twice-daily radiation concurrent with chemotherapy is one of the standard methods for limited-stage small cell lung cancer. The study was to evaluate the feasibility of chemotherapy concurrent with dose-escalating twice-daily radiotherapy by simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) approach in patients with limited-stage small cell lung cancer. Methods Patients with limited-stage small cell lung cancer were included, treated with twice-daily radiotherapy by SIB-IMRT concurrent with chemotherapy of etoposide plus cisplatin. Dose escalation was conducted by “classical” 3+3 methods with three patients enrolled in each dose level. The therapeutic gross tumor volume (GTV) was treated according to three consecutive dose levels i.e., 45 Gy at 1.5 Gy twice daily, 50 Gy at 1.67 Gy twice daily and 54 Gy at 1.8 Gy twice daily. The planning target volume (PTV) received a dose of 45 Gy delivered in 30 fractions of 1.5 Gy. The primary endpoints were acute toxicities. The secondary endpoints included overall survival (OS), progression-free survival (PFS) and loco-regional failure-free survival (LRFFS) at 1-year of follow-up. Results Twenty men and six women were included. The median age was 52 (30-68) months. 12 patients experienced grade 2 acute esophagitis, and 1 patient developed grade 3 acute esophagitis. Only 3 patients developed Grade 2 pneumonitis. Grade 3 or higher radiation-related pneumonia was not observed. None died of treatment-related causes. With median follow-up of 11.2 months (3.2-36.2 months), 1-year OS, PFS and LRFFS were 89.0%, 51.0% and 85.0%, respectively. Conclusion Dose escalation for twice-daily radiation concurrent with chemotherapy in LS-SCLC has been safely achieved up to 54 Gy for GTV using SIB-IMRT technique

Phase I Study of Etoposide and Cisplatin Chemotherapy Dose Escalation with Concurrent Twice-daily Radiotherapy for Patients with Limited-stage Small Cell Lung Cancer

Background and objective Concurrent twice-daily radiotherapy with chemotherapy of EP regimen is one of the current standard treatments for limited-stage small cell lung cancer. However, the safely tolerated dose of standard chemotherapy for Chinese patients is not decided. This study was to evaluate the toxicity and the maximum tolerated dose (MTD) of etoposide and cisplatin concurrent with thoracic radiation therapy for patients with limited-stage small cell lung cancer. Methods Patients with histologically proven limited-stage small cell lung cancer (LS-SCLC) were eligible. The patients underwent thoracic radiotherapy (45 Gy, 1.5 Gy bid, 30 fractions for 3 weeks) delivered concurrently with etoposide (100 mg/m2 iv, days 1-3) and cisplatin dose escalating from the two levels ( 70 mg/m2 and 75 mg/m2 on d1). The primary endpoints were hematologic toxicities during treatment. The secondary endpoints were non-hematologic toxicities, overall survival (OS) and progression-free survival (PFS). According to Common Terminology Criteria for Adverse Events 4.0 (CTC-AE 4.0), maximum tolerant dosage (MTD) was defined as the highest safely tolerated dose at which no more than one patient out of six experiences dose-limiting toxicity (Grades 4 hematologic), with the next higher dose having at least two out of six patients experience dose-limiting toxicity. Results From January 2013 to August 2016, 20 patients were enrolled in this study. The median age was 49.5 (30-68). After the first 6 patients were enrolled in Arm 1 (70 mg/m2 on d1), one patient had Grade 4 neutropenia. Another 14 patients were enrolled in Arm 2 (75 mg/m2 on d1), one patient had Grade 4 neutropenia. The MTD was determined to be etoposide (100 mg/m2 iv, d1-d3) and cisplatin dose (75 mg/m2 on d1). 4 patients had ≥Grade 3 neutropenia and 1 patients had ≥Grade 3 acute esophagitis in Arm 1. 10 patients had ≥Grade 3 neutropenia and no patient had ≥Grade 3 acute esophagitis in Arm 2. All patients with a median follow-up time was 9.0 months, median OS and PFS were not achieved, 1-year OS and PFS were 91% and 61%, respectively. Conclusion The MTD of RT with concurrent chemotherapy of EP regimen for patients with LS-SCLC was etoposide (100 mg/m2 iv, d1-d3) and cisplatin dose (75 mg/m2 on d1)

Study on the Mechanism of Ionic Liquids Improving the Extraction Efficiency of Essential Oil Based on Experimental Optimization and Density Functional Theory: The Fennel (Foeniculi fructus) Essential Oil Case

In this work, microwave-assisted ionic liquids treatment, followed by hydro-distillation (MILT-HD), as an efficient extraction technology, was used to extract essential oil. The purpose for this was to use multivariate analysis (MVA) models to investigate the effects of potential critical process parameters on the extraction efficiency of essential oil, and explore the mechanism of ionic liquids (ILs). According to the design of experiment (DoE), under optimal process conditions, the extraction efficiency of essential oil was dramatically enhanced, and had low energy demands. Since little is known regarding those mechanisms, according to the non-covalent interaction analysis, the underlying mechanism for ILs improving extraction efficiency was explored based on the density functional theory (DFT). The results showed that ILs could form intense non-covalent bond interaction with cellulose. It helped destroy the network hydrogen bond structure of cellulose in plant cells and caused the essential oils in the cells to be more easily exposed to the extraction solution, thereby accelerating extraction efficiency. Based on this work, it is conducive to understand the MILT-HD process better and gain knowledge of the mechanism of ILs