Xiaojuan Zhou

Planning analysis for locally advanced lung cancer: dosimetric and efficiency comparisons between intensity-modulated radiotherapy (IMRT), single-arc/partial-arc volumetric modulated arc therapy (SA/PA-VMAT)

PurposeTo analyze the differences between the intensity-modulated radiotherapy (IMRT), single/partial-arc volumetric modulated arc therapy (SA/PA-VMAT) techniques in treatment planning for locally advanced lung cancer.Materials and methods12 patients were retrospectively studied. In each patients case, several parameters were analyzed based on the dose-volume histograms (DVH) of the IMRT, SA/PA-VMAT plans respectively. Also, each plan was delivered to a phantom for time comparison.ResultsThe SA-VMAT plans showed the superior target dose coverage, although the minimum/mean/maximum doses to the target were similar. For the total and contralateral lungs, the higher V5/10, lower V20/30 and mean lung dose (MLD) were observed in the SA/PA-VMAT plans (p < 0.05, respectively). The PA-VMAT technique improves the dose sparing (V20, V30 and MLD) of the controlateral lung more notably, comparing to those parameters of the IMRT and SA-VMAT plans respectively. The delivered monitor units (MUs) and treatment times were reduced significantly with VMAT plans, especially PA-VMAT plans (for MUs: mean 458.3 vs. 439.2 vs. 435.7 MUs, p < 0.05 and for treatment time: mean 13.7 vs. 10.6 vs. 6.4 minutes, p < 0.01).ConclusionsThe SA-VMAT technique achieves highly conformal dose distribution to the target. Comparing to the IMRT plans, the higher V5/10, lower V20/30 and MLD were observed in the total and contralateral lungs in the VMAT plans, especially in the PA-VMAT plans. The SA/PA-VMAT plans also reduced treatment time with more efficient dose delivering. But the clinical benefit of the VMAT technique for locally advanced lung cancer needs further investigations.

Evaluation of positioning accuracy of four different immobilizations using cone-beam CT in radiotherapy of non-small-cell lung cancer.

PURPOSE To evaluate the positioning accuracy of four different immobilizations by use of cone-beam computed tomography guidance for radiotherapy of non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS Sixty-seven patients with NSCLC received conventional or stereotactic body radiotherapy. Of these, 30 were immobilized with a thermoplastic frame (TF), 16 with a thermoplastic frame and active breathing control (TF-ABC), 7 with a stereotactic body frame (SBF), and 14 with a stereotactic body frame and active breathing control (SBF-ABC). Cone-beam computed tomography scans at initial setup and after correction were registered to planning computed tomography. The positional errors in the left-to-right, superior-inferior, and anterior-posterior directions were analyzed. The planning target volume margins were calculated. RESULTS The precorrection systematic and random errors ranged from 1.9 to 4.2 mm for TF, 1.9 to 4.3 mm for SBF, 1.2 to 5.8 mm for TF-ABC, and 2.3 to 3.9 mm for SBF-ABC. The postcorrection systematic and random errors ranged from 0.3 to 1.9 mm for the four immobilizations. The planning target volume margins (conventional vs. stereotactic body radiotherapy) were 15.6 vs. 13.9 mm (TF), 14.9 vs. 14.8 mm (TF-ABC), 14.4 vs. 13.4 mm (SBF), and 9.9 vs. 9.4 mm (SBF-ABC) before correction and 7.3 vs. 6.9 mm (TF), 4.0 vs. 3.8 mm (TF-ABC), 7.5 vs. 7.1 mm (SBF), and 4.5 vs. 4.2 mm (SBF-ABC) after correction. CONCLUSIONS The positioning accuracies of SBF and TF were similar. Active breathing control increased positioning error but reduced internal margin. Cone-beam computed tomography online correction improved the positioning accuracy of NSCLC patients.

Impact of whole brain radiation therapy on CSF penetration ability of Icotinib in EGFR-mutated non-small cell lung cancer patients with brain metastases: Results of phase I dose-escalation study

OBJECTIVES Whole-brain radiation therapy (WBRT) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are both treatment options for EGFR-mutated non-small cell lung cancer (NSCLC) patients with brain metastases. However, the dose-escalation toxicity and efficacy of combination therapy, and the effect of WBRT on cerebrospinal fluid (CSF) penetration of EGFR-TKIs are still unclear. MATERIALS AND METHODS EGFR-mutated NSCLC patients with brain metastases were enrolled in this study, and the cohorts were constructed with a 3+3 design. The patients received icotinib with escalating doses (125-625mg, tid), and the concurrent WBRT (37.5Gy/15f/3weeks) started a week later. The CSF penetration rates of icotinib were tested before, immediately after, and 4 weeks after WBRT, respectively. Potential toxicities and benefits from dose-escalation treatment were analyzed. RESULTS Fifteen patients were included in this study, 3 at each dose level from 125mg-375mg and 6 at 500mg with 3 occurred dose-limiting toxicities. The maximal tolerated dose of icotinib was 375mg tid in this combination therapy. There was a significant correlation between icotinib concentration in the CSF and plasma (R(2)=0.599, P<0.001). The CSF penetration rate of icotinib, from 1.2% to 9.7%, reached a maximum at 375mg (median, 6.1%). There was no significant difference for CSF penetration rates among the three test points (median, 4.1% vs. 2.8% vs. 2.8%, P=0.16). The intracranial objective response rate and median intracranial progression free survival are 80% and 18.9 months. CONCLUSIONS WBRT plus concurrent icotinib is well tolerated in EGFR-mutated NSCLC patients with brain metastases, up to an icotinib dose of 375mg tid. The icotinib CSF concentration seemed to have a potential ceiling effect with the dose escalation, and WBRT seemed to have no significant impact on CSF penetration of icotinib till 4 weeks after the treatment.

Primary mediastinal sarcoma: surgical outcomes of 21 cases

OBJECTIVES Primary sarcomas of the mediastinum are relatively rare. This article reviews the surgical outcomes of 21 cases diagnosed with localized mediastinal sarcomas receiving multidisciplinary treatment modalities in Sichuan province, China, from January 1996 to January 2011. METHODS Twenty-one cases of histologically diagnosed primary mediastinal sarcoma undergoing surgical treatment were reviewed retrospectively. Disease-free survival (DFS) and overall survival (OS) were statistically analysed. All the patients presented with localized tumours consisting of 5 females and 16 males with a median age of 41.0 years (range: 9.0-68.0 years). Among all cases, 17 (81.0%) had an Eastern Cooperative Oncology Group performance status score of ≤1 at diagnosis. Eight (38.1%) underwent macroscopically complete resection (R0-R1) and 13 (61.9%) had incomplete resection (R2). Ten (47.6%) received postoperative radiotherapy and 7 (33.3%) postoperative chemotherapy. RESULTS The median DFS was 17 months (range: 0.4-79.8 months) and the median OS was 27.2 months (range: 0.4-79.8 months). Patients receiving complete resection showed significantly improved DFS (P = 0.031) and OS (P = 0.035) compared with those with incomplete resection. Neither postoperative radiotherapy nor chemotherapy significantly improved DFS (P = 0.770, P = 0.756) or OS (P = 0.905, P = 0.738). However, 7 patients (R2) and 2 (R0-R1 and grade 3) had improved local control with a local recurrence-free survival of 28.9 months (range: 7.6-73.2 months). CONCLUSIONS Complete resection should be preferentially attempted compared with incomplete resection and postoperative radiotherapy might yield good local control.

Efficacy of epidermal growth factor receptor–tyrosine kinase inhibitors for lung squamous carcinomas harboring EGFR mutation: A multicenter study and pooled analysis of published reports

Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinoma (ADC) but rare in squamous cell carcinoma (SQC). The efficacy of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) for SQC with EGFR mutations is unclear. The aim of this study was to evaluate the efficacy of EGFR-TKIs for these patients. We performed a retrospective matched-pair case-control study from 3 cancer centers, including 44 SQC and 44 ADC patients with EGFR mutation who were treated with EGFR-TKI. Subsequently, we performed a pooled analysis on the efficacy of EGFR-TKIs for EGFR-mutant SQC in 115 patients, including 71 patients selected from 25 published reports. In our multicenter study, EGFR-mutant SQC and ADC patients had similar objective response rate (ORR) (43.2% vs. 54.5%, p = 0.290), but SQC patients had lower disease control rate (DCR) (71.3% vs. 100%, p = 0.001), significant shorter median progression free survival (PFS) (5.1 vs. 13.0 months, p = 0.000) and median overall survival (OS) (17.2 vs. 23.6 months, p = 0.027). In pooled analysis, the ORR, DCR, PFS and OS of SQC patients were 39.1%, 71.3%, 5.6 months and 15.0 months, respectively. Performance status was the only independent predictor of PFS and erlotinib treatment was associated with a better survival. In conclusion, EGFR-TKI was less effective in EGFR-mutant SQC than in ADC but still has clinical benefit for SQC patients. Further study is need to evaluate the using of EGFR-TKIs in these SQC patients.

Malignant Pleural Effusion and ascites Induce Epithelial-Mesenchymal Transition and Cancer Stem-like Cell Properties via the Vascular Endothelial Growth Factor (VEGF)/Phosphatidylinositol 3-Kinase (PI3K)/Akt/Mechanistic Target of Rapamycin (mTOR) Pathway.

Malignant pleural effusion (PE) and ascites, common clinical manifestations in advanced cancer patients, are associated with a poor prognosis. However, the biological characteristics of malignant PE and ascites are not clarified. Here we report that malignant PE and ascites can induce a frequent epithelial-mesenchymal transition program and endow tumor cells with stem cell properties with high efficiency, which promotes tumor growth, chemoresistance, and immune evasion. We determine that this epithelial-mesenchymal transition process is mainly dependent on VEGF, one initiator of the PI3K/Akt/mechanistic target of rapamycin (mTOR) pathway. From the clinical observation, we define a therapeutic option with VEGF antibody for malignant PE and ascites. Taken together, our findings clarify a novel biological characteristic of malignant PE and ascites in cancer progression and provide a promising and available strategy for cancer patients with recurrent/refractory malignant PE and ascites.

Comparison of chemotherapy plus bevacizumab vs. chemotherapy alone as third-line treatment or beyond for advanced non-small cell lung cancer: A propensity score-matched analysis

The addition of bevacizumab to chemotherapy has demonstrated efficacy as a first-line treatment for non-small cell lung cancer (NSCLC). Whether this combination is effective as a salvage treatment for patients with NSCLC remains unclear. The present retrospective study was designed to compare the efficacy and safety of chemotherapy plus bevacizumab with chemotherapy alone as a third-line, or continuing, treatment for patients with NSCLC. Between January 2011 and June 2016, a total of 38 patients with stage IV NSCLC who had received chemotherapy plus bevacizumab subsequent to failure of ≥2 prior regimens were matched with 38 patients who had received chemotherapy alone using propensity score matching from a dataset of 165 patients. The variables that were analyzed included age, sex, smoking history, histology, epithelial growth factor receptor mutation status, number of prior regimens and type of chemotherapy regimen. Univariate and multivariate analyses were used to evaluate the prognostic factors for survival outcomes and tumor response, and toxicity analyses were performed. The objective response rate (ORR) and disease control rate (DCR) were improved in patients who underwent chemotherapy-bevacizumab treatment compared with chemotherapy alone (ORR, 23.7 vs. 5.3%, P<0.001; DCR, 65.8 vs. 31.6%, P<0.001). Progression-free survival was prolonged in the chemotherapy-bevacizumab group compared with the chemotherapy-alone group (median, 3.9 vs. 2.2 months; HR, 0.54; 95% CI, 0.32–0.89, P=0.014). Incidence of ≥grade 3 adverse events was low and similar across the groups. The combination of chemotherapy and bevacizumab is a potentially effective and safe alternative salvage treatment for patients with NSCLC who have not received bevacizumab treatment previously.

Concurrent brain radiotherapy and EGFR-TKI may improve intracranial metastases control in non-small cell lung cancer and have survival benefit in patients with low DS-GPA score

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) has intracranial activity in EGFR-mutant Non-Small Cell Lung Cancer (NSCLC). The optimal timing of brain radiotherapy (RT) and appropriate patients who need early brain RT remains undetermined. This is a retrospective study of EGFR-mutant NSCLC patients with newly diagnosed brain metastases (BMs) before EGFR-TKI initiation. Intra-cranial progression free survival (IC-PFS) and overall survival (OS) were measured from the date of EGFR-TKI treatment. A total of 113 patients were eligible, 49 received concurrent early brain RT with EGFR-TKI and 64 were treated with EGFR-TKI alone as initial therapy, including 27 with salvage RT upon BM progression. The patients with early brain RT had superior IC-PFS than those without early brain RT (21.4 vs 15.0 months, P=0.001), which remained significant in multivariate analysis (HR 0.30, P<0.001). The median overall survival (OS) for early RT, EGFR-TKI alone and salvage RT groups was 28.1, 24.5, and 24.6 months, respectively (P=0.604). Similar IC-PFS (23.6 vs 21.4 months, P=0.253) and OS (24.6 vs 28.1 months, P=0.385) were observed between salvage RT and early RT groups. For patients with Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) score of 0 to 2, early brain RT was the independent factor for improved OS (HR 0.33, P=0.025). In conclusion, concurrent early brain RT with EGFR-TKI may improve intracranial disease control in EGFR-mutant NSCLC with BM and have survival benefit in patients with low DS-GPA score. Salvage brain RT upon BM progression may be acceptable in some patients.

Assessment of programmed cell death ligand-1 expression with multiple immunohistochemistry antibody clones in non-small cell lung cancer

Background Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have been identified as novel targets for immunotherapy, with PD-L1 as a potential predictive biomarker. However, a specific antibody for PD-L1 expression is an immediate requirement. Meanwhile, the clinicopathological identification of patients with positive PD-L1 remains unclear. Methods The present study adopted three anti-PD-L1 IHC antibodies, SP142, SP263, and UMAB228 to test PD-L1 expression in 84 non-small cell lung cancer (NSCLC) specimens. The concordance among antibodies was examined by analytical comparison, and the association between PD-L1 expression and clinicopathological factors was assessed. Results The samples from 41 (48.8%), 51 (60.7%), and 50 (59.5%) patients were detected as PD-L1 positive evaluated by antibody SP142, SP263, and UMAB228, respectively. The kappa coefficient was 0.53, 0.58, and 0.46 for SP263 vs. SP142, SP263 vs. UMAB228, and SP142 vs. UMAB228, respectively. On the other hand, the univariate analysis of consensus cases indicated that the PD-L1 expression was significantly correlated with tobacco use (χ2=4.25, P=0.04). Conclusions The analytical comparison showed moderate concordance between SP142, SP263 and UMAB228, whereas SP263 exhibited higher overall positive rate. Moreover, PD-L1 positive rate was significantly higher in patients with smoking history, which might help in identifying patients who would benefit from PD-1/PD-L1 checkpoint inhibitors.

Dosimetric effect of beam arrangement for intensity-modulated radiation therapy in the treatment of upper thoracic esophageal carcinoma

To evaluate the lung sparing in intensity-modulated radiation therapy (IMRT) for patients with upper thoracic esophageal tumors extending inferiorly to the thorax by different beam arrangement. Overall, 15 patient cases with cancer of upper thoracic esophagus were selected for a retrospective treatment-planning study. Intensity-modulated radiation therapy plans using 4, 5, and 7 beams (4B, 5B, and 7B) were developed for each patient by direct machine parameter optimization (DMPO). All plans were evaluated with respect to dose volumes to irradiated targets and normal structures, with statistical comparisons made between 4B with 5B and 7B intensity-modulated radiation therapy plans. Differences among plans were evaluated using a two-tailed Friedman test at a statistical significance of p < 0.05. The maximum dose, average dose, and the conformity index (CI) of planning target volume 1 (PTV1) were similar for 3 plans for each case. No significant difference of coverage for planning target volume 1 and maximum dose for spinal cords were observed among 3 plans in present study (p > 0.05). The average V5, V13, V20, mean lung dose, and generalized equivalent uniform dose (gEUD) for the total lung were significantly lower in 4B-plans than those data in 5B-plans and 7B-plans (p < 0.01). Although the average V30 for the total lung were significantly higher in 4B-plans than those in 5B-plans and 7B-plans (p < 0.05). In addition, when comparing with the 4B-plans, the conformity/heterogeneity index of the 5B- and 7B-plans were significantly superior (p < 0.05). The 4B-intensity-modulated radiation therapy plan has advantage to address the specialized problem of lung sparing to low- and intermediate-dose exposure in the thorax when dealing with relative long tumors extended inferiorly to the thoracic esophagus for upper esophageal carcinoma with the cost for less conformity. Studies are needed to compare the superiority of volumetric modulated arc therapy with intensity-modulated radiation therapy technique.