Hongqing Zhuang

Phase II study of whole brain radiotherapy with or without erlotinib in patients with multiple brain metastases from lung adenocarcinoma

The aim of this paper is to explore the efficacy of whole brain radiotherapy (WBRT) versus WBRT concurrent with erlotinib in patients with multiple brain metastases of lung adenocarcinoma. WBRT was administered at 30Gy/10f in both arms. In the combination arm, 150 mg erlotinib was given each day, starting the first day of radiotherapy and continuing for 1 month following the end of radiotherapy. Thereafter, pemetrexed or docetaxel monotherapy or the best supportive therapy was given to both arms. The intracranial objective response rate and the local progression-free survival (LPFS) were primary endpoints. Toxicity, progression-free survival (PFS) and overall survival (OS) were secondary endpoints. Thirty-one patients in the WBRT group and 23 patients in the combination group were enrolled from November 2009 to December 2011. In the WBRT and the combination arms, respectively, the objective response rate was 54.84% and 95.65% (P = 0.001), the median local progression-free survival was 6.8 months and 10.6 months (P = 0.003), the median PFS was 5.2 months and 6.8 months (P = 0.009), and median OS was 8.9 months and 10.7 months (P = 0.020). In the combination group, there were no differences of LPFS, PFS, and OS between the epidermal growth factor receptor (EGFR) mutation patients and EGFR wild-type patients. No Grade 4 or higher side effects were observed in either group. A multivariate analysis indicated that erlotinib was the most important prognostic factor for a prolonged survival. Data showed that erlotinib in combination with WBRT had a tolerable toxicity profile and prolonged the LPFS, PFS, and OS of lung adenocarcinoma patients with multiple brain metastases compared with WBRT monotherapy.

The theoretical foundation and research progress for WBRT combined with erlotinib for the treatment of multiple brain metastases in patients with lung adenocarcinoma

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung adenocarcinoma, and a theoretical basis exists for utilising whole brain radiotherapy (WBRT) combined with erlotinib for the treatment for brain metastases in patients with lung adenocarcinoma. This therapeutic regimen has the potential to be a revolutionary treatment for which the most appropriate indication is lung adenocarcinoma. Currently, there is no difference in the treatment of brain metastasis, especially multiple brain metastases, in patients with lung adenocarcinoma of patients with other lung carcinomas. Furthermore, limited clinical trials that combine a TKI with WBRT to treat multiple lung adenocarcinoma metastases have been conducted, and many clinical questions remain unanswered. Lung adenocarcinoma has a high propensity to metastasize to the brain, and targeted therapy has been widely used; however, clinical trials are necessary to provide data to support the combination of erlotinib and WBRT.

Progress of clinical research on targeted therapy combined with thoracic radiotherapy for non-small-cell lung cancer

The combination of radiotherapy and targeted therapy is an important approach in the application of targeted therapy in clinical practice, and represents an important opportunity for the development of radiotherapy itself. Numerous agents, including epidermal growth factor receptor, monoclonal antibodies, tyrosine kinase inhibitors, and antiangiogenic therapies, have been used for targeted therapy. A number of studies of radiotherapy combined with targeted therapy in non-small-cell lung carcinoma have been completed or are ongoing. This paper briefly summarizes the drugs involved and the important related clinical research, and indicates that considerable progress has been made with the joint efforts of the two disciplines. Many issues, including drug selection, identification of populations most likely to benefit, timing of administration of medication, and side effects of treatment require further investigation. However, further fundamental research and accumulation of clinical data will provide a more comprehensive understanding of these therapies. Targeted therapy in combination with radiotherapy has a bright future.

Influence of different image-guided tracking methods upon the local efficacy of CyberKnife treatment in lung tumors

The aim of this study was to explore the influence of image‐guided tumor localization modality (Synchrony tracking vs. Xsight spine‐based localization) on the local efficacy of CyberKnife treatment in lung cancer and lung metastases.

Stereotactic body radiation therapy induces fast tumor control and symptom relief in patients with iliac lymph node metastasis.

The CyberKnife is a robotic stereotactic body radiotherapy (SBRT) system which has shown promising results for many malignances with good efficacy and low toxicity. This study aims to evaluate the response and local control (LC) obtained with CyberKnife in the management of iliac lymph node metastases (ILNM). Twenty-two patients with 27 ILNM were treated by CyberKnife from May 2010 to May 2016. Median follow-up time was 33 months (8–97). The complete response, partial response, stable disease and progression disease rates were 37.0%, 48.0%, 7.5% and 7.5% respectively. The 1-, 2-, and 3-year LC rates were all 90.6%, and overall survival rates were 78.8%, 60.6%, and 43.3% respectively. All patients with pelvic pain and ureter obstruction achieved good and fast symptom relief, while leg edema persisted in 2 patients. The general treatment tolerance was acceptable and no severe toxicities were reported. No factors were found correlated with local failure. While overall survival (OS) was better for patients who had received a total dose more than 30 Gy or prior systemic treatment, and whose symptoms were relieved. Taken together, CyberKnife is an effective therapeutic option for ILNM, providing high LC rate and good symptom relief with minimal toxicity.

Analysis of clinical efficacy of CyberKnife® treatment for locally advanced pancreatic cancer

Objective To evaluate the efficacy and safety of CyberKnife® treatment for locally-advanced pancreatic cancer (LAPC). Methods The efficacy of CyberKnife® treatment was analyzed in 59 LAPC patients treated between October 2006 and September 2014. The median tumor volume was 27.1 mL (13.0–125.145 mL). The median prescribed dose was 45 Gy (35–50 Gy), delivered in 5 fractions (3–8 fractions). The overall survival (OS) rates and freedom from local progression (FFLP) rates were estimated using the Kaplan–Meier survival curve. Results The median follow-up for all patients was 10.9 months (3.2–48.7 months) and 15.6 months (3.9–37.6 months) among surviving patients. The median OS was 12.5 months, and the 1-year and 2-year survival rates were 53.9% and 35.1%, respectively. The 1-year FFLP rate was 90.8% based on the computed tomography (CT) evaluation. Grade 1–2 acute and late-stage gastrointestinal (GI) reactions were observed in 61% of the patients. One patient experienced grade 3 toxicity. Conclusion Excellent clinical efficacy was obtained after treatment of LAPC using CyberKnife®, with minimal toxicity.

Robotic stereotactic irradiation and reirradiation for spinal metastases: Safety and efficacy assessment

Background Spine is the most common site of bone metastases in patients with cancer. Conventional external beam radiotherapy lacks precision to allow delivery of large fraction radiation but simultaneously limit the dose to spinal cord. The purpose of this study was to evaluate the safety and efficacy of CyberKnife® radiation therapy for spinal metastases. Methods Seventy‐three lesions in 62 patients treated with CyberKnife radiotherapy from September 2006 to June 2010 for spinal metastases were retrospectively reviewed. Thirteen tumors in 12 patients had received prior radiation. Patients were followed clinically and radiographically for at least 12 months or until death. In all patients, the spinal cord and thecal sac were contoured for dose‐volume constraints, and maximum doses to 0.1, 0.5, 1, 2, and 5‐ml volumes were analyzed. Results Using the CyberKnife System, 20‐48 Gy in one to five fractions for unirradiated patients, and 21‐38 Gy in one to five fractions for the previously irradiatied patients, were delivered. Median 2‐Gy normalized Biological Equvalent Dose (nBED) of unirradiated targets and irradiated targets were 49.6 Gy10/2 (range, 31.25‐74.8 Gy10/2) and 46.9 Gy10/2 (range, 29.8‐66 Gy10/2), respectively. With a median follow‐up of 9.4 months (range, 2.5‐45 months), twenty‐nine patients (46.7%) were alive, whereas the others died of progressive disease. Fifty‐six patients (93.3%) reported complete or partial reduction of pain after CyberKnife radiotherapy at one‐month follow‐up, 17 patients (28.3%) reported some degree of pain relief after first fraction of the treatment course. Two patients experienced local recurrence at fifth and ninth months postradiotherapy. Median maximum nBED for spinal cord and thecal sac of naive targets were 68.6 Gy2/2 (range, 8.3‐154.5 Gy2/2) and 83.5 Gy2/2 (range, 10.5‐180.5 Gy2/2), respectively. Median maximum nBED for spinal cord and thecal sac for the re‐irradiated targets were 58.6 Gy2/2 (range, 17.7‐140 Gy2/2) and 70.5 Gy2/2 (range, 21.7‐141.3 Gy2/2), respectively. No patient developed radiation related myelopathy during the follow‐up period. Conclusion Cyberknife radiotherapy is clinically effective and safe for spinal metastases, even in previously irradiated patients.

The different radiosensitivity when combining erlotinib with radiation at different administration schedules might be related to activity variations in c-MET-PI3K-AKT signal transduction

Objectives The aim of this paper was to investigate the efficacy and activity variation associated with phosphoinositide 3-kinase (PI3K) signal transduction when combining erlotinib with radiation, using different administration schedules. Materials and methods Erlotinib was delivered to A973 cancer cells in the following three ways: (1) irradiation after administration, (2) irradiation upon administration, and, (3) irradiation before administration. The cell-survival rates were detected using colony-forming assays, while cell apoptosis was detected with flow cytometry. The expression levels of C-MET, p-C-MET, AKT, and p-AKT were determined via Western blotting analysis, under 6 Gy irradiation with/ without erlotinib. Results The sensitizer enhancement ratios (SERs) of erlotinib irradiation after administration, irradiation upon administration, and irradiation before administration groups were 2.19, 1.53, and 1.38, respectively. A higher apoptosis rate was observed when irradiation was delivered after erlotinib. In addition, changes in cell apoptosis were found to be related to concurrent changes in C-MET, p-C-MET, AKT, and p-AKT expression. Protein expression increased in the combination groups, with trends showing a negative relationship with cell apoptosis. Conclusion The radiosensitive effect of erlotinib varied because of the different administration schedules; this variation may be related to PI3K signal transduction and its associated regulating effect.

A study on the evaluation method and recent clinical efficacy of bevacizumab on the treatment of radiation cerebral necrosis

In order to investigate the efficacy of bevacizumab on the treatment of radiation cerebral necrosis, patients who were diagnosed with radiation cerebral necrosis by imaging after stereotactic radiotherapy were collected. Bevacizumab was applied at a dose of 5 mg/kg once every three weeks at least three times. The changes in cerebral necrosis symptoms before and after treatment, the cerebral edema volume, the cerebral necrosis volume, and the changes in magnetic resonance imaging (MRI) strengthening phase signals of cerebral necrosis were used as the first observation point. The side effects of bevacizumab were used as the second observation point. Total of 14 radiation cerebral necrosis patients were treated with bevacizumab between June 2011 and February 2013 were collected. There were 12 symptomatic patients, of whom 10 patients (83.3%) had reduced symptoms. The edema index grades of nine patients (64.29%) improved. The cerebral necrosis volumes of 13 patients (92.86%) decreased. The T1 phase signal strengths of the intracranial enhanced MRIs of 12 patients (85.71%) significantly decreased. The clinical side effects of bevacizumab were mild. In conclusion, Preliminary results showed that treatment of radiation cerebral necrosis using bevacizumab was safe and effective. This treatment measure is worthy of further study.

MTOR inhibition reversed drug resistance after combination radiation with erlotinib in lung adenocarcinoma

Objective To investigate the effects of mTOR inhibition on drug resistance in lung adenocarcinoma after combined radiation and erlotinib therapy. Results Combined radiation and erlotinib therapy produced clear radiosensitization effects both in vitro and in vivo; however, tumor cells remained drug resistant. Additionally, combined radiation and erlotinib therapy significantly increased p-AKT and p-P70 levels. After mTOR inhibition, the number of surviving cells significantly decreased compared with that before inhibition, and the in vivo growth curve was significantly reduced. Methods The effects of combined radiation and erlotinib therapy on tumor inhibition and drug resistance were evaluated by in vitro survival curves in PC9 lung adenocarcinoma cell line and in vivo growth curves in nude mouse xenograft tumor model respectively. The association between tumor drug resistance and the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K-AKT-mTOR) pathway was measured by western blot, assessing the changes in protein kinase B (AKT), phosphor-AKT (p-AKT), P70, and p-P70 protein levels. MTOR was inhibited using everolimus, and changes in AKT, p-AKT, P70, and p-P70 levels were observed. Furthermore, changes in in vitro survival curves, and in vivo growth curves before and after mTOR inhibition were evaluated to confirm its effects on drug resistance in lung adenocarcinoma after combined radiation and TKI therapy. Conclusion mTOR was associated with drug resistance in lung adenocarcinoma after radiation combined with TKI, and MTOR inhibition reversed drug resistance in lung adenocarcinoma after combined radiation and TKI therapy.