Real world experience on treatment, outcome and toxicity of crizotinib in patients with anaplastic lymphoma kinase positive advanced non-small cell lung cancer.

BACKGROUND: Crizotinib has been the standard treatment for patients with anaplastic lymphoma kinase (ALK)-rearranged advanced non-small cell lung cancer (NSCLC). It demonstrated superior progression-free survival (PFS) and higher objective response rates (ORRs) vs. chemotherapy in previously treated and untreated patients with ALK-positive advanced NSCLC. This retrospective analysis reports real-world experience in treatment outcome and toxicity of crizotinib in this group of patients, with a focus on the cardiac toxicity and its management. METHODS: Twenty-two patients diagnosed with ALK-positive NSCLC, either by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), treated at Johns Hopkins Singapore International Medical Centre (JHSIMC) and Tan Tock Seng Hospital (TTSH) in Singapore, were identified and followed for a median of 18 months. Data were collected and analyzed for baseline demographics, PFS, ORR, duration of response, toxicity and overall survival (OS). RESULTS: Clinical profile of patients included in the study was similar with clinical trials on crizotinib. Most patients were young of mean age 42, non-smokers and with good performance status. Fifty-nine percent had prior chemotherapy. Fifty percent of patients had brain metastases (BM), either de novo or on progression. ORR of crizotinib was 64% with median total duration of treatment of 8.5 months (range, 2-73+ months). Median PFS for patients treated with first-line crizotinib was 15 months. Most patients with BM had brain radiation. Median time for intracranial progression from the start of crizotinib was 11 months. Those with stable or responding extracranial disease continued crizotinib after radiotherapy to the brain. Median duration of response in this group of patients was 14 months (range, 2-31 months). Median OS among patients treated with upfront crizotinib was not reached, with 7 out of 11 patients still alive at the time of data analysis (n=11, range, 1-73+). Toxicity was manageable with moderate rate of grade 3 or worse toxicity (n=7, 31.8%). Three patients had grade 3-4 neutropenia. Eighteen percent (n=4) of patients developed cardiotoxicities such as bradycardia, prolonged QTc interval and complete heart block. One patient who developed complete heart block required pacemaker insertion. Two patients are long term responders who have been on crizotinib for 68+ and 73+ months. CONCLUSIONS: This retrospective analysis of a real-world experience confirms the therapeutic benefit of crizotinib in advanced ALK-positive NSCLC. Our data showed crizotinib is tolerable and effective, comparable with literature report. Occasional serious cardiac toxicity requires attention.

Phase II study of neo-adjuvant chemotherapy for locally advanced gastric cancer.

BACKGROUND: Neoadjuvant chemotherapy improves survival of locally advanced gastric cancer patients. However, benefit is limited and the best regimen remains controversial. OBJECTIVES: Our primary objective of this prospective, multicenter phase 2 study was to evaluate the pathological complete response rate (PCR) with 2 cycles of docetaxel and capecitabine. METHODS: To be eligible, patients had to have histologically documented gastric cancer, a ECOG performance status 0 or 1, T3or4 Nany M0 staging after oesophagogastroduodenoscopy (OGD), endoscopic ultrasound (EUS), CT scan of thorax and abdomen, and negative laparoscopic examination and peritoneal washing. Eligible patients received two cycles of intravenous docetaxel 60 mg/m(2) on day 1 and oral capecitabine 900 mg/m(2) two times per day from day 1 to day 14 every 3 weeks. We evaluated the response by CT scan and EUS. The patients underwent curative resection with D2 lymphadenectomy subsequently. RESULTS: 18 patients were enrolled in the study: 66% were male and the median age was 60 years. 17 patients had T3 disease at diagnosis. There was no pCR noted. 4 patients had a partial response of 22% (95% CI: 7-42%), 8 patients had stable disease and 3 patients had disease progression. The median survival was 17.1 months with 3 long-term survivors after at least 3 years of follow-up. The treatment was well tolerated with neutropenia being the most common toxicity. We observed 22% grade III and 33% grade IV neutropenia, but no neutropenic fever or death was observed from chemotherapy. CONCLUSION: Neo-adjuvant chemotherapy with docetaxel and capecitabine has limited activity against GC. More effective treatment regimens are needed urgently. TRIAL REGISTRATION NUMBER: NCT00414271.

Silica-shell cross-linked micelles encapsulating fluorescent conjugated polymers for targeted cellular imaging.

A bioinspired silification approach was successfully used to encapsulate fluorescent conjugated polymers inside silica-shell cross-linked polymeric micelles (CP-SSCL) in the highly benign synthesis environment of room temperature and near-neutral aqueous environment. Four different conjugated polymers were employed to demonstrate the versatility of the bioinspired silification, resulting in the formation of CP-SSCL with different emission wavelengths across the visible spectrum. The CP-SSCL are characterized by a large absorption coefficient and high quantum yield, indicating that they exhibit the required high fluorescence brightness for cellular imaging application. In addition, the CP-SSCL also exhibit a high colloidal stability and low cytotoxicity. The in vitro studies of using MDA-MB-231 breast cancer cells show that the CP-SSCL are successfully uptaken by the cancer cells and located at the cytoplasm of the cells. Furthermore, by conjugating folic acid on their surfaces, the uptake of CP-SSCL by MDA-MB-231 cells was enhanced significantly, suggesting their great potential for targeted imaging and early detection of cancer cells.

Clinical experience with gefitinib in Indian patients.

INTRODUCTION: Treatment options are limited in patients with advanced or refractory non-small cell lung cancer and lead to suboptimal outcome and/or benefit. The epidermal growth factor tyrosine kinase inhibitor gefitinib (IRESSA) has been approved in many countries. Increased responsiveness to gefitinib has been demonstrated in particular subsets of patients, for example never smokers and patients of Asian origin. However, to date, little is known of its use specifically in patients from India. METHODS: Retrospective ad hoc analysis of clinical data from experience with gefitinib in patients with advanced NSCLC from India enrolled in the IRESSA Survival Evaluation in Lung (ISEL) study (n = 77) or included in the gefitinib expanded-access program in India (n = 133). RESULTS: Among Indian patients enrolled in the ISEL study, median survival was 6.4 months with gefitinib and 5.1 month with placebo. The objective response rate in Indian patients was 14% with gefitinib versus 0% with placebo. In ISEL, tolerability data from Indian patients were consistent with the overall study population. In the Indian gefitinib expanded-access program, median survival was 6 months and gefitinib was well tolerated. CONCLUSIONS: Gefitinib seems well tolerated in Indian patients with advanced NSCLC, with some clinical benefit observed.

Detection and comparison of epidermal growth factor receptor mutations in cells and fluid of malignant pleural effusion in non-small cell lung cancer.

Cells or cell-free fluid of malignant pleural effusion could be important clinical specimen for epidermal growth factor receptor (EGFR) mutation screening in advanced non-small cell lung cancer (NSCLC) patients. However, their usefulness in mutation detection has not been well compared. In this study we recruited 26 East Asian NSCLC patients with malignant pleural effusion, determined the mutation status of EGFR in both cells and matched cell-free fluid with the use of sequencing and mutant-enriched PCR. After comparing the mutation spectrums, we found both the cells and cell-free pleural fluid may be feasible clinical specimen for EGFR mutation detection in unresectable NSCLC given sensitive genotyping assays employed. Direct sequencing could miss a significant portion of mutations in these heterogeneous specimens. More sensitive methods, such as mutant-enriched PCR and gene scan, could provide more reliable mutational information.

Differential reactions of microglia to brain metastasis of lung cancer.

The brain is a common metastatic site for various types of cancers, especially lung cancer. Patients with brain metastases have a poor prognosis in spite of radiotherapy and/or chemotherapy. It is postulated that immune cells in the brain may play a major role in cancer metastasis, dormancy, and relapse. Although microglia may serve as a major component in the brain immune system, the interaction between metastatic cancer cells and microglia is still largely unknown and remains to be elucidated. In this study, we have investigated microglial reactions in brain tissues with metastatic lung cancer cells and evaluated the cytotoxic effects of lipopolysaccharide (LPS)-activated microglia on metastatic lung cancer cells in vitro. In the vicinity of metastatic lung cancer mass in the brain, microglia showed signs of significant activation. There was an obvious increase in the number of microglia labeled with ionized calcium binding adaptor molecule 1 (Iba-1) antibody, a specific marker of microglia. The microglia were observed to form a clear boundary between the tumor mass and normal brain tissue. In the region where the tumor mass was situated, only a few microglia expressed inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha), indicating differential activation in those microglia. The supernatant from LPS-activated microglia induced apoptosis of metastatic lung cancer cells in vitro in a dose- and time-dependent manner. However, at lower concentrations of activated microglial supernatant, trophic effects on cancer cells were observed, some lung cancer cells being insensitive to microglial cytotoxicity. Together with the observation that TNF-alpha alone induced proliferation of the tumor cells, the findings provide possible clues to the mechanism involved in metastasis of lung cancer cells to the brain.