Do ethnic patients report longer lung cancer intervals than Anglo-Australian patients?: Findings from a prospective, observational cohort study.

OBJECTIVE: Lung cancer patients from ethnic minorities have poorer outcomes than their Caucasian counterparts. We compared lung cancer intervals between culturally and linguistically diverse (CALD) and Anglo-Australian patients to identify ethnic disparities. METHODS: This was a prospective, observational cohort study comprising a patient survey and reviews of patients' hospital and general practice records. Across three states, 577 (407 Anglo-Australian and 170 CALD) patients were recruited and their hospital records reviewed. The survey was returned by 189 (135 Anglo-Australian and 54 CALD) patients, and a review was completed by general practitioners (GPs) of 99 (76 Anglo-Australian and 23 CALD) patients. Survival and Cox regression analyses were conducted. RESULTS: CALD patients had longer hospital diagnostic interval [median 30 days, 95% confidence interval (CI) 26-34] than Anglo-Australian patients (median 17, 95% CI 14-20), p = 0.005, hazard ratio (HR) = 1.32 (95% CI 1.09-1.60). This difference persisted after relevant factors were taken into consideration, adjusted HR = 1.26 (95% CI 1.03-1.54, p = 0.022). CALD patients also reported longer prehospital intervals; however, these differences were not statistically significant. CONCLUSION: Target interventions need to be developed to address ethnic disparity in hospital diagnostic interval.

Correction to: Differences in cancer survival by sex: a population-based study using cancer registry data.

In the original publication of the article, the concluding paragraph of the Discussion section was inadvertently missed and is provided below.

Differences in cancer survival by sex: a population-based study using cancer registry data.

PURPOSE: Few large-scale studies have investigated sex differences in cancer survival and little is known about their temporal and age-related patterns. METHODS: We used cancer registry data for first primary cancers diagnosed between 1982 and 2015 in Victoria, Australia. Cases were followed until the end of 2015 through linkage to death registries. Differences in survival were assessed for 25 cancers using the Pohar-Perme estimator of net survival and the excess mortality rate ratio (EMRR) adjusting for age and year of diagnosis. RESULTS: Five-year net survival for all cancers combined was lower for men (47.1%; 95% CI 46.9-47.4) than women (52.0%; 95% CI 51.7-52.3); EMRR 1.13 (95% CI 1.12-1.14; p < 0.001). A survival disadvantage for men was observed for 11 cancers: head and neck, esophagus, colorectum, pancreas, lung, bone, melanoma, mesothelioma, kidney, thyroid, and non-Hodgkin lymphoma. In contrast, women had lower survival from cancers of the bladder, renal pelvis, and ureter. For the majority of cancers with survival differences, the EMRR decreased with increasing age at diagnosis; for colorectal, esophageal, and kidney cancer, the EMRR increased with time since diagnosis. CONCLUSION: Identifying the underlying reasons behind sex differences in cancer survival is necessary to address inequalities, which may improve outcomes for men and women.

Reducing Artifactual EGFR T790M Mutations in DNA from Formalin-Fixed Paraffin-Embedded Tissue by Use of Thymine-DNA Glycosylase.

BACKGROUND: False-positive EGFR T790M mutations have been reported in formalin-fixed lung tumors, but the cause of the false positives has not been identified. The T790M mutation results from a C>T change at the cytosine of a CpG dinucleotide. The presence or absence of methylation at this cytosine has different consequences following deamination, resulting in a thymine or uracil, respectively, both of which however result in an artifactual change. Uracil-DNA glycosylase (UDG) can be used to eliminate DNA templates with uracil residues but is not active against artifactual thymines. We therefore investigated the use of thymine-DNA glycosylase (TDG) to reduce artifactual T790M mutations. METHODS: Formalin-fixed normal lung tissues and lung squamous cell carcinomas were tested to measure the frequency of false-positive EGFR mutations by use of droplet digital PCR before and after treatment with either UDG or TDG. Methylation at the cytosine at EGFR T790 was assessed by pyrosequencing and by analysis of public databases. RESULTS: Artifactual EGFR T790M mutations were detected in all of the archival formalin-fixed normal lung and lung squamous cell carcinomas at mutant allele frequencies of 1% or lower. The cytosine at EGFR T790 showed high levels of methylation in all lung cancer samples and normal tissues. Pretreatment of the formalin-fixed DNA with either UDG or TDG reduced the false EGFR T790M mutations, but a greater reduction was seen with the TDG treatment. CONCLUSIONS: Both U:G and T:G lesions in formalin-fixed tissue are sources of false-positive EGFR T790M mutations. This is the first report of the use of TDG to reduce sequence artifacts in formalin-fixed DNA and is applicable to the accurate detection of mutations arising at methylated cytosines.

Digital PCR of Genomic Rearrangements for Monitoring Circulating Tumour DNA.

Identifying circulating tumour DNA (ctDNA) for monitoring of cancer therapy is dependent on the development of readily designed, sensitive cancer-specific DNA markers. Genomic rearrangements that are present in the vast majority of cancers provide such markers.Tumour DNA isolated from two fresh-frozen lung tumours underwent whole genome sequencing. Genomic rearrangements were detected using a new computational algorithm, GRIDSS. Four genomic rearrangements from each tumour were chosen for further study using rearrangement-specific primers. Six of the eight rearrangements tested were identified as tumour-specific, the remaining two were present in the germline. ctDNA was quantified using digital PCR for the tumour genomic rearrangements in patient blood. Interestingly, one of the patients had no detectable ctDNA either prior to or post surgery although the rearrangements were readily detectable in the tumour DNA.This study demonstrates the feasibility of using digital PCR based on genomic rearrangements for the monitoring of minimal residual disease. In addition, whole genome sequencing provided further information enabling therapeutic choices including the identification of a cryptic EGFR exon 19 deletion in one patient and the identification of a high somatic mutation load in the other patient. This approach can be used as a model for all cancers with rearranged genomes.

Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial.

BACKGROUND: Effective maintenance therapies after chemoradiotherapy for lung cancer are lacking. Our aim was to investigate whether the MUC1 antigen-specific cancer immunotherapy tecemotide improves survival in patients with stage III unresectable non-small-cell lung cancer when given as maintenance therapy after chemoradiation. METHODS: The phase 3 START trial was an international, randomised, double-blind trial that recruited patients with unresectable stage III non-small-cell lung cancer who had completed chemoradiotherapy within the 4-12 week window before randomisation and received confirmation of stable disease or objective response. Patients were stratified by stage (IIIA vs IIIB), response to chemoradiotherapy (stable disease vs objective response), delivery of chemoradiotherapy (concurrent vs sequential), and region using block randomisation, and were randomly assigned (2:1, double-blind) by a central interactive voice randomisation system to either tecemotide or placebo. Injections of tecemotide (806 µg lipopeptide) or placebo were given every week for 8 weeks, and then every 6 weeks until disease progression or withdrawal. Cyclophosphamide 300 mg/m(2) (before tecemotide) or saline (before placebo) was given once before the first study drug administration. The primary endpoint was overall survival in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00409188. FINDINGS: From Feb 22, 2007, to Nov 15, 2011, 1513 patients were randomly assigned (1006 to tecemotide and 507 to placebo). 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Median overall survival was 25.6 months (95% CI 22.5-29.2) with tecemotide versus 22.3 months (19.6-25.5) with placebo (adjusted HR 0.88, 0.75-1.03; p=0.123). In the patients who received previous concurrent chemoradiotherapy, median overall survival for the 538 (65%) of 829 patients assigned to tecemotide was 30.8 months (95% CI 25.6-36.8) compared with 20.6 months (17.4-23.9) for the 268 (65%) of 410 patients assigned to placebo (adjusted HR 0.78, 0.64-0.95; p=0.016). In patients who received previous sequential chemoradiotherapy, overall survival did not differ between the 291 (35%) patients in the tecemotide group and the 142 (35%) patients in the placebo group (19.4 months [95% CI 17.6-23.1] vs 24.6 months [18.8-33.0], respectively; adjusted HR 1.12, 0.87-1.44; p=0.38). Grade 3-4 adverse events seen with a greater than 2% frequency with tecemotide were dyspnoea (49 [5%] of 1024 patients in the tecemotide group vs 21 [4%] of 477 patients in the placebo group), metastases to central nervous system (29 [3%] vs 6 [1%]), and pneumonia (23 [2%] vs 12 [3%]). Serious adverse events with a greater than 2% frequency with tecemotide were pneumonia (30 [3%] in the tecemotide group vs 14 [3%] in the placebo group), dyspnoea (29 [3%] vs 13 [3%]), and metastases to central nervous system (32 [3%] vs 9 [2%]). Serious immune-related adverse events did not differ between groups. INTERPRETATION: We found no significant difference in overall survival with the administration of tecemotide after chemoradiotherapy compared with placebo for all patients with unresectable stage III non-small-cell lung cancer. However, tecemotide might have a role for patients who initially receive concurrent chemoradiotherapy, and further study in this population is warranted. FUNDING: Merck KGaA (Darmstadt, Germany).

Lung cancer in Victoria: are we making progress?

OBJECTIVES: To identify areas to improve patient management in lung cancer, which remains the greatest cause of death from cancer in Australia. DESIGN AND SETTING: Retrospective survey of all cases of lung cancer reported to the Victorian Cancer Registry from 1 January to 30 June 2003 and followed up for 5 years. MAIN OUTCOME MEASURES: Patient and disease characteristics, investigations, staging, treatment, cause of death, survival. RESULTS: 841 patients were included. Smoking data were available for 799, of whom 63 (7.9%) had never smoked. Of 655 non-small cell lung cancer (NSCLC) cases, 198 (30.2%) were treated with curative intent, 125 (19.1%) by surgery and 73 (11.1%) by radiotherapy with or without chemotherapy. Only 7 (6.9%) of surgical patients with complete R0 resection had adjuvant chemotherapy. Of 101 small cell lung cancer (SCLC) cases, a third had limited stage disease which was mostly treated with curative intent by chemotherapy with or without radiotherapy. Patients whose cases were discussed at a multidisciplinary meeting (MDM) were significantly more likely to receive anticancer treatment and had longer survival; on multivariate analysis, MDM discussion was an independent prognostic factor. Compared with a similar survey 10 years earlier, the median age of patients diagnosed with lung cancer had increased by almost 3 years, the proportion of affected men decreased and adenocarcinoma was more frequent, while 10% of patients continued to have no pathologically confirmed diagnosis and 26% continued to receive no anticancer treatment. The number of patients with NSCLC who went on to a definitive surgical procedure fell with no detriment to survival, which likely reflected better staging with the introduction of positron emission tomography scanning. CONCLUSIONS: Opportunities to improve patient management included increasing the proportion with a pathologically confirmed diagnosis and greater use of postsurgical adjuvant chemotherapy. A high proportion of patients received no treatment, with underuse of chemotherapy and radiotherapy. Critically, the low rate of case discussions at MDMs needs to increase. However, effective strategies are required to identify cases early, as over two-thirds currently present with incurable disease.

Sunvozertinib, a Selective EGFR Inhibitor for Previously Treated Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations.

Epidermal growth factor receptor exon 20 insertion mutations (EGFRexon20ins) are detected in approximately 2% of patients with non-small cell lung cancer (NSCLC). Due to a lack of effective therapy, the prognosis of these patients is typically poor. Sunvozertinib (DZD9008) was designed as an oral, potent, irreversible, and selective EGFR tyrosine kinase inhibitor, showing activity against EGFRexon20ins and other mutations. In both cell lines and xenograft models, sunvozertinib shows potent antitumor activity. In the two ongoing phase I clinical studies, sunvozertinib was tolerated up to 400 mg once daily. The most common drug-related adverse events included diarrhea and skin rash. Antitumor efficacy was observed at the doses of 100 mg and above in patients with EGFRexon20ins NSCLC across different subtypes, with prior amivantamab treatment as well as with baseline brain metastasis. The median duration of response has not been reached. SIGNIFICANCE: We report the discovery and early clinical development of sunvozertinib, a potential treatment option for the unmet medical need of EGFRexon20ins NSCLC. This article is highlighted in the In This Issue feature, p. 1599.

Impact of Radiotherapy on the Efficacy and Toxicity of anti-PD-1 Inhibitors in Metastatic NSCLC.

BACKGROUND: The impact of radiotherapy (RT) on the efficacy and toxicity of immune checkpoint inhibitors (ICIs) in patients with metastatic non-small-cell lung cancer (NSCLC) is unclear. MATERIALS AND METHODS: We identified patients with metastatic NSCLC treated with the anti-programmed death 1 antibodies nivolumab or pembrolizumab between January 2016 and May 2019 at 3 tertiary centers, who were also treated with palliative RT either during or within 3 months of starting anti-programmed death 1 treatment. Patient demographics, tumor characteristics, and treatment history were collected. Response rates, progression-free survival (PFS), and overall survival (OS) were analyzed and correlated with RT use. RESULTS: A total of 269 patients were identified, with a median follow-up of 19.4 months. The median age was 70 years (range, 35-90 years), and they were 63% male, 60% smokers, and 65% had adenocarcinoma histology. At the commencement of ICI treatment, the majority (86%) had ≥ 1 line of prior therapy and 34% had brain metastases. A total of 102 (38%) patients received RT within 3 months of starting ICI or subsequently during ICI treatment. Of patients that received RT, 86 (84%) received conventional hypofractionated RT, and, in the majority, 81 (79%) the intent of RT was symptom control. The use of RT did not increase grade 3/4 immune-related adverse events. The overall median PFS was 2.0 months (95% confidence interval, 1.3-2.6 months) and the median OS was 9.0 months (95% confidence interval, 6.4-9.5 months). There were no significant differences in median PFS (3.0 vs. 2.0 months; P = .515) and median OS (9.0 vs. 9.0 months; P = .917) in the patients who received RT versus those that did not. CONCLUSIONS: In patients with metastatic NSCLC, the addition of RT to ICI was not associated with increased toxicity or improved survival.

Credentialing of vertebral stereotactic ablative body radiotherapy in a multi-centre trial.

PURPOSE/OBJECTIVE: Stereotactic ablative body radiotherapy (SABR) in multi-centre trials requires rigorous quality assurance to ensure safe and consistent treatment for all trial participants. We report results of vertebral SABR dosimetry credentialing for the ALTG/TROG NIVORAD trial. MATERIAL/METHODS: Centres with a previous SABR site visit performed axial film measurement of the benchmarking vertebral plan in a local phantom and submitted radiochromic film images for analysis. Remaining centres had on-site review of SABR processes and axial film measurement of the vertebral benchmarking plan. Films were analysed for dosimetric and positional accuracy: gamma analysis (>90% passing 2%/2mm/10% threshold) and ≤ 1 mm positional accuracy at target-cord interface was required. RESULTS: 19 centres were credentialed; 11 had on-site measurement. Delivery devices included linear accelerator, TomoTherapy and CyberKnife systems. Five centres did not achieve 90% gamma passing rate. Of these, three were out of tolerance (OOT) in low (<5Gy) dose regions and > 80% passing rate and deemed acceptable. Two were OOT over the full dose range: one elected not to remeasure; the other also had positional discrepancy greater than 1 mm and repeat measurement with a new plan was in tolerance. The original OOT was attributed to inappropriate MLC constraints. All centres delivered planned target-cord dose gradient within 1 mm. CONCLUSION: Credentialing measurements for vertebral SABR in a multi-centre trial showed although the majority of centres delivered accurate vertebral SABR, there is high value in independent audit measurements. One centre with inappropriate MLC settings was detected, which may have resulted in delivery of clinically unacceptable vertebral SABR plans.

NTRK and ALK rearrangements in malignant pleural mesothelioma, pulmonary neuroendocrine tumours and non-small cell lung cancer.

OBJECTIVES: Gene rearrangements involving NTRK1, NTRK2, NTRK3, ROS1 and ALK have been identified in many types of cancer, including non-small cell lung cancer (NSCLC). Data in malignant pleural mesothelioma (MPM), lung neuroendocrine tumors (NETs) and small-cell lung cancer (SCLC) are lacking. Given the activity of NTRK, ROS-1 and ALK inhibitors in tumors harboring gene fusions, we sought to explore such rearrangements in these less common tumors in addition to NSCLC. METHODS: Archival tumor tissue from patients with MPM, lung NETs, SCLC and NSCLC were used to create tissue microarrays. Immunohistochemistry (IHC) was performed using a cocktail of antibodies against TRK, ROS1 and ALK. IHC positive samples underwent RNA sequencing using the ArcherDX FusionPlex CTL diagnostic assay. Clinical data were obtained through retrospective chart review. RESULTS: We performed IHC on 1116 samples: 335 MPMs, 522 NSCLCs, 105 SCLCs and 154 lung NETs. There were 23 IHC positive cases (2.1%) including eight MPMs (2.4%), eight NETs (5.2%), five SCLC (4.8%) and two NSCLC (0.4%). The following fusions were detected: one MPM with an NTRK ex10-TPM3 ex8, another MPM with an ALK ex20-EML4ex13, one lung intermediate-grade NET (atypical carcinoid) with an ALK ex20-EML4 ex6/intron6, and two NSCLCs with an ALK ex20-EML4 ex6/intron6 rearrangement. None of the patients received targeted treatment. CONCLUSIONS: To our knowledge, we report for the first time NTRK and ALK rearrangements in a small subset of MPM. An ALK rearrangement was also detected in lung intermediate-grade NET (or atypical carcinoid). Our data suggest that IHC could be a useful screening test in such patients to ensure that all therapeutic strategies including targeted therapy are utilized.

High resolution melting analysis for rapid and sensitive EGFR and KRAS mutation detection in formalin fixed paraffin embedded biopsies.

BACKGROUND: Epithelial growth factor receptor (EGFR) and KRAS mutation status have been reported as predictive markers of tumour response to EGFR inhibitors. High resolution melting (HRM) analysis is an attractive screening method for the detection of both known and unknown mutations as it is rapid to set up and inexpensive to operate. However, up to now it has not been fully validated for clinical samples when formalin-fixed paraffin-embedded (FFPE) sections are the only material available for analysis as is often the case. METHODS: We developed HRM assays, optimised for the analysis of FFPE tissues, to detect somatic mutations in EGFR exons 18 to 21. We performed HRM analysis for EGFR and KRAS on DNA isolated from a panel of 200 non-small cell lung cancer (NSCLC) samples derived from FFPE tissues. RESULTS: All 73 samples that harboured EGFR mutations previously identified by sequencing were correctly identified by HRM, giving 100% sensitivity with 90% specificity. Twenty five samples were positive by HRM for KRAS exon 2 mutations. Sequencing of these 25 samples confirmed the presence of codon 12 or 13 mutations. EGFR and KRAS mutations were mutually exclusive. CONCLUSION: This is the first extensive validation of HRM on FFPE samples using the detection of EGFR exons 18 to 21 mutations and KRAS exon 2 mutations. Our results demonstrate the utility of HRM analysis for the detection of somatic EGFR and KRAS mutations in clinical samples and for screening of samples prior to sequencing. We estimate that by using HRM as a screening method, the number of sequencing reactions needed for EGFR and KRAS mutation detection can be reduced by up to 80% and thus result in substantial time and cost savings.

Population pharmacokinetics of gemcitabine and its metabolite in patients with cancer: effect of oxaliplatin and infusion rate.

UNLABELLED: What is already known about this subject. Gemcitabine is an anticancer drug which is metabolized to a number of metabolites, administered using different dosing regimens and increasingly used in combination with oxaliplatin. the impact of dosing strategies and combination therapy on the pharmacokinetics of gemcitabine and its main metabolite is not clearly understood. what this study adds. this study has characterized the pharmacokinetics of gemcitabine and its main metabolite in people with cancer, including the variability between patients and on different occasions. gemcitabine metabolite (but not gemcitabine) pharmacokinetics were significantly affected by co-administration with oxaliplatin and were dependent on the order of administration. the clinical implications of this observation remain to be established. AIMS: To characterize the population pharmacokinetics of gemcitabine and its metabolite (dfdu) in patients with cancer and identify factors that are influential in gemcitabine dose regimen design. METHODS: Gemcitabine and dfdu plasma concentration-time and clinical data from 94 patients with cancer and nonlinear mixed effect modelling were used to characterize gemcitabine and metabolite pharmacokinetic variability and identify influential covariates. RESULTS: Gemcitabine and dFdU pharmacokinetics were described by a two-compartment model with first-order elimination. The population mean (and between-subject variability, CV%) for clearance and volume of distribution of the central compartment (V(C)) for gemcitabine were 2.7 l min(-1) (31%) and 15 l (39%), respectively, and 0.04 l min(-1) (35%) and 46 l (15%), respectively, for dFdU. Oxaliplatin co-administration significantly decreased dFdU V(C) by 35% when gemcitabine was administered first and by 46% when oxaliplatin was administered first compared with patients who received gemcitabine alone. CONCLUSIONS: Co-administration of gemcitabine with oxaliplatin significantly affected the pharmacokinetics of dFdU. The clinical significance of this observation in the context of gemcitabine safety and efficacy is worthy of further investigation.

Mannan-MUC1-pulsed dendritic cell immunotherapy: a phase I trial in patients with adenocarcinoma.

PURPOSE: Tumor antigen-loaded dendritic cells show promise for cancer immunotherapy. This phase I study evaluated immunization with autologous dendritic cells pulsed with mannan-MUC1 fusion protein (MFP) to treat patients with advanced malignancy. EXPERIMENTAL DESIGN: Eligible patients had adenocarcinoma expressing MUC1, were of performance status 0 to 1, with no autoimmune disease. Patients underwent leukapheresis to generate dendritic cells by culture ex vivo with granulocyte macrophage colony-stimulating factor and interleukin 4 for 5 days. Dendritic cells were then pulsed overnight with MFP and harvested for reinjection. Patients underwent three cycles of leukapheresis and reinjection at monthly intervals. Patients with clinical benefit were able to continue with dendritic cell-MFP immunotherapy. RESULTS: Ten patients with a range of tumor types were enrolled, with median age of 60 years (range, 33-70 years); eight patients were of performance status 0 and two of performance status 1. Dendritic cell-MFP therapy led to strong T-cell IFNgamma Elispot responses to the vaccine and delayed-type hypersensitivity responses at injection sites in nine patients who completed treatments. Immune responses were sustained at 1 year in monitored patients. Antibody responses were seen in three patients only and were of low titer. Side effects were grade 1 only. Two patients with clearly progressive disease (ovarian and renal carcinoma) at entry were stable after initial therapy and went on to further leukapheresis and dendritic cell-MFP immunotherapy. These two patients have now each completed over 3 years of treatment. CONCLUSIONS: Immunization produced T-cell responses in all patients with evidence of tumor stabilization in 2 of the 10 advanced cancer patients treated. These data support further clinical evaluation of this dendritic cell-MFP immunotherapy.

Addition of gabapentin to a modified FOLFOX regimen does not reduce oxaliplatin-induced neurotoxicity.

BACKGROUND: Sensory neurotoxicity is dose limiting for oxaliplatin, an effective drug in the treatment of colorectal cancer (CRC) and other malignancies. This study assessed the impact of gabapentin on oxaliplatin dose intensity and neurotoxicity. PATIENTS AND METHODS: Patients with previously untreated metastatic CRC were recruited sequentially to 2 cohorts: the first used a modified FOLFOX6 (fluorouracil/leucovorin/oxaliplatin) regimen alone with oxaliplatin 100 mg/m(2) every 2 weeks (mFOLFOX; n = 40), and the second included the addition of gabapentin (mFOLFOX+G; n = 41). Gabapentin commenced at 300 mg daily, increasing to a maximum of 600 mg 3 times daily to decrease neurotoxicity. RESULTS: Doses of gabapentin were increased in 31 of 41 patients, with 39% of patients receiving >or= 900 mg daily. The median relative dose intensity of oxaliplatin and requirement for dose reductions or delays because of neurotoxicity were similar in the 2 cohorts. There was no grade 4 neurotoxicity. Whereas grade 3 neurotoxicity was observed in 10% of patients treated with gabapentin versus 21% of patients treated with mFOLFOX alone, there was no statistically significant difference in the severity of neurotoxicity between the 2 cohorts (P = 0.89) or the time to recover from grade 2/3 neurotoxicity (P = 0.97). There were also no significant differences in nonneurologic toxicity or antitumor efficacy between the 2 cohorts. CONCLUSION: This study does not support a role for gabapentin in reducing the incidence or severity of oxaliplatin-induced sensory neurotoxicity.

A phase 1 and pharmacokinetic study of gemcitabine and oxaliplatin in patients with solid tumors.

PURPOSE: This dose escalation study aimed to determine the recommended doses, toxicity and pharmacokinetics of oxaliplatin and gemcitabine given on days 1 and 8 every 21 days. This schedule may maximize dose intensity of both drugs with acceptable or reduced toxicity. PATIENT AND METHODS: Eligible patients had solid malignancies, no more than two prior courses of chemotherapy, ECOG performance status 0-2, neurotoxicity < or = NCI-CTC grade 1 and adequate organ function. Dose escalation commenced at oxaliplatin 40 mg/m(2) and gemcitabine 750 mg/m(2), both given on days 1 and 8 every 21 days, and reached oxaliplatin 80 mg/m(2) and gemcitabine 1,500 mg/m(2). The two highest dose levels were each expanded to six patients to gain additional toxicity data. RESULTS: There were no dose limiting toxicities related to treatment and an MTD was not reached. Five patients (24%) had grade 3 neutropenia, without associated infection, and seven patients (33%) had grade 3/4 thrombocytopenia. Neurotoxicity was mild and no worse than grade 1. Two patients with mesothelioma (10%) had partial responses and 11 patients (52%) had disease stabilization. No pharmacokinetic interaction between oxaliplatin and gemcitabine was detected. Dose intensity was maximal at level 4 (oxaliplatin 70 mg/m(2) and gemcitabine 1,250 mg/m(2)). CONCLUSIONS: This schedule allows oxaliplatin and gemcitabine to be delivered at the full dose intensity of each drug with excellent tolerability and predictable pharmacokinetics. The recommended doses for phase II studies are oxaliplatin 70 mg/m(2) and gemcitabine 1,250 mg/m(2) on days 1 and 8 every 21 days.

A critical re-assessment of DNA repair gene promoter methylation in non-small cell lung carcinoma.

DNA repair genes that have been inactivated by promoter methylation offer potential therapeutic targets either by targeting the specific repair deficiency, or by synthetic lethal approaches. This study evaluated promoter methylation status for eight selected DNA repair genes (ATM, BRCA1, ERCC1, MGMT, MLH1, NEIL1, RAD23B and XPC) in 56 non-small cell lung cancer (NSCLC) tumours and 11 lung cell lines using the methylation-sensitive high resolution melting (MS-HRM) methodology. Frequent methylation in NEIL1 (42%) and infrequent methylation in ERCC1 (2%) and RAD23B (2%) are reported for the first time in NSCLC. MGMT methylation was detected in 13% of the NSCLCs. Contrary to previous studies, methylation was not detected in ATM, BRCA1, MLH1 and XPC. Data from The Cancer Genome Atlas (TCGA) was consistent with these findings. The study emphasises the importance of using appropriate methodology for accurate assessment of promoter methylation.