Tine McCulloch

EGFR mutation frequency and effectiveness of erlotinib: A prospective observational study in Danish patients with non-small cell lung cancer

OBJECTIVES In 2008, we initiated a prospective study to explore the frequency and predictive value of epidermal growth factor receptor (EGFR) mutations in an unselected population of Danish patients with non-small cell lung cancer offered treatment with erlotinib, mainly in second-line. MATERIALS AND METHODS Four hundred and eighty eight patients with advanced NSCLC were included. The mutation status was assessed using the cobas EGFR Mutation Test. Erlotinib was administrated (150 mg/d) until disease progression or unacceptable toxicities occurred. The primary endpoint was progression-free survival. Secondary endpoints were overall survival and response. RESULTS Biopsies were retrieved from 467 patients, and mutation results obtained for 462. We identified 57 (12%) patients with EGFR mutations: 33 exon 19 deletions, 13 exon 21 mutations, 5 exon 18 mutations, 3 exon 20 insertions, 1 exon 20 point mutation (S768I), and two complex mutations. Seven percent of the patients were never smokers. The differences in median progression-free survival and overall survival between the mutated group and the wild-type group were 8.0 vs. 2.5 months, p<0.001 and 12.1 vs. 3.9 months, p<0.001. Performance status (0-1 vs. 2-3) and line of treatment (1st vs. 2nd and 3rd) had no influence on outcome in EGFR-mutated patients. CONCLUSION We found a higher frequency of EGFR mutations than expected in a cohort with less than 10% never smokers. The outcome after treatment with erlotinib was much better in patients with EGFR mutations than in patients with wild-type EGFR and was independent of performance status and treatment line in EGFR-mutated patients.

Acute esophagitis for patients with local–regional advanced non small cell lung cancer treated with concurrent chemoradiotherapy

PURPOSE Esophagitis is common in patients treated with definitive radiotherapy for local-regional advanced non small cell lung cancer (NSCLC). The purpose of this study was to estimate the dose-effect relationship using clinical and dosimetric parameters in patients receiving intensity modulated radiotherapy (IMRT) and concomitant chemotherapy (CCT). METHODS Between 2009 and 2013, 117 patients with stages IIB-IIIB NSCLC were treated in a multicenter randomized phase II trial with 2 cycles of induction chemotherapy followed by IMRT and CCT. The esophagitis was prospectively scored using the Common Toxicity Criteria 3.0. Clinical and dosimetric variables were analyzed for the correlation with grade ⩾2 esophagitis through logistic regression. RESULTS Grade 2 esophagitis was experienced by 31 (27%). All models including gender, institution, a dosimetric parameter and a position parameter were significantly associated with esophagitis. The two models using the relative esophagus volume irradiated above 40 Gy (V40, OR=2.18/10% volume) or the length of esophagus irradiated above 40 Gy (L40, OR=4.03/5 cm) were optimal. The upper part of esophagus was more sensitive and females experienced more toxicity than men. CONCLUSION V40 and L40 were most effective dosimetric predictors of grade ⩾2 esophagitis. The upper part of esophagus was more sensitive.

Epigenetic predictive biomarkers for response or outcome to platinum-based chemotherapy in non-small cell lung cancer, current state-of-art

Platinum-based chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC). However, its efficacy is limited and no molecular biomarkers that predict response are available. In this review, we summarize current knowledge concerning potential epigenetic predictive markers for platinum-based chemotherapy response in NSCLC. A systematic search of PubMed and ClinicalTrials.gov using keywords “non-small cell lung cancer” combined with “chemotherapy predictive biomarkers”, “chemotherapy epigenetics biomarkers”, “chemotherapy microRNA biomarkers”, “chemotherapy DNA methylation” and “chemotherapy miRNA biomarkers” revealed 1740 articles from PubMed and 36 clinical trials. Finally, 22 papers and no trials fulfilled the review criteria. Among miRNA, combination of miR-1290, miR-196b and miR-135a in tumor tissue, and miR-21, miR-25, miR27b, and miR-326 in plasma were predictive for response to platinum-based chemotherapy in advanced NSCLC. RASSF1A methylation measured in tumor or blood was predictive for response to neoadjuvant chemotherapy. These biomarkers remain experimental and none have been tested in a prospective trial.

OC-0242: A randomized phase II trial of concurrent chemo-RT of oral vinorelbine and 60 Gy or 66 Gy, in locally advanced NSCLC

prescription dose was escalated to the maximum level achievable for each patient according to predefined organs at risk (OAR) toxicity and dose constraints. Radiobiological models were used to predict a patient-specific radiotherapy (RT) dose associated with a 10% risk of grade 3 and above pneumonitis which was then constrained to a prescription dose of 63-73 Gy in 30# for IDEAL-CRT (plus concurrent chemotherapy) and 55-65 Gy in 20# for I-START. These are the first multi-centre trials in the UK to investigate isotoxic dose escalation and as such incorporated a thorough Quality Assurance (QA) programme to ensure protocol compliance. Materials and Methods: RT plans were produced across 8 centres for IDEAL and 12 centres for I-START. Full 3D RT planning data was submitted to a central QA contact. All RT plans and plan assessment forms were analysed for quality and protocol compliance. Results: Between 2010 and 2014, 84 and 81 patients were recruited to IDEAL-CRT and I-START respectively. Table 1 shows the average doses received by OAR and targets compared to the doses stated in the protocol.

Effective ultra-low doses of erlotinib in patients with EGFR sensitising mutation

We describe three cases of patients with advanced adenocarcinoma of the lung and epidermal growth factor receptor (EGFR) mutation treated with erlotinib 25 mg/day and 25 mg every second day, being equal to one-sixth and one-twelfth of the recommended dose. The mean age of our patients was above 70 with a WHO performance status 1 before and during the treatment. The reasons for erlotinib dose reduction were rash, diarrhoea and fatigue. The decision was a result of lack of other treatment options and radiological response on standard doses. We did not observe any liver enzyme abnormalities. However, the post-treatment creatinine increased significantly. As of February 2014, our patients are still on treatment with tolerable side effects and improved quality of life. These findings indicate that some patients responding to erlotinib with noxious side effects could have clinical benefit in doses much lower than recommended.

A phase II study using vinorelbine and continuous 5-fluorouracil in patients with advanced head and neck cancer.

Seventy patients with advanced head and neck cancer were treated with vinorelbine and continuous 5-FU administered in a central venous catheter. Over all response was 36% with 9% complete responses. The most common grade 3 and 4 toxicities were stomatitis (13), infection (5), pain related to vinorelbine infusion (4), skin toxicity (3). Thirty one patients had grade 3 or 4 leukopenia. Treatment was complicated by venous thrombosis in the central venous catheter in one case. A majority of patients experienced dose reduction of one or both drugs or treatment delays due to toxicity. Median time to progression was 4.7 months and overall median survival 6.6 months. We conclude that the regimen is feasible and tolerated with moderate toxicity. Response rates and time to progression are comparable to other studies with multi agent treatment.