Response and toxicity prediction by MALDI-TOF-MS serum peptide profiling in patients with non-small cell lung cancer.

PURPOSE: We validated a previously reported proteomic signature, associated with treatment outcome, in an independent cohort of patients with non-small cell lung cancer (NSCLC). A novel peptide signature was developed to predict toxicity. EXPERIMENTAL DESIGN: Using automated magnetic C18 bead-assisted serum peptide capture coupled to MALDI-TOF MS, we conducted serum peptide profiling of 50 NCSLC patients participating in a phase II trial of erlotinib and sorafenib. On the obtained peptide mass profiles, we applied a previously described proteomic classification algorithm. Additionally, associations between observed side effects and peptide profiles were investigated. RESULTS: Application of the previously acquired algorithm successfully classified the new cohort of patients in groups significantly associated with the outcome. The "poor" group exhibited shorter median progression-free survival (PFS) and overall survival (OS) of 1.35 and 1.98 months (with p = 0.00677 and p = 0.00002, respectively) while the "good" group had significantly longer PFS and OS (10.63 and 14.4 months with p = 0.00142 and p = 0.00002, respectively), compared to average OS and PFS. Two specific peptides were detected in the sera of all patients that developed severe toxicity. CONCLUSIONS AND CLINICAL RELEVANCE: Our results provide an algorithm that, following prospective validation in larger cohorts, could assist treatment selection of patients with NSCLC in the first line setting.

Time for reappraisal of extracranial treatment options? Synchronous brain metastases from nonsmall cell lung cancer.

BACKGROUND: The optimal treatment of the primary tumor in patients with brain metastases (BM) from newly diagnosed nonsmall cell lung cancer (NSCLC) remains unclear. The authors aimed to identify patient groups with synchronous BM for whom radical treatment of the primary site may be appropriate. METHODS: The medical records of 167 patients treated at our center between November 2000 and June 2009 for newly diagnosed NSCLC and synchronous BM were reviewed. All patients underwent surgery/radiosurgery (n = 86) or whole-brain radiotherapy (WBRT; n = 81) for BM. Univariate and multivariate analyses assessed prognostic factors significant for overall survival (OS). RESULTS: Median OS of patients undergoing surgery/radiosurgery for BM was 12.1 months. Those undergoing "radical" thoracic treatment (n = 24) had a longer median OS (28.4 months) than those undergoing chemotherapy (n = 74; 12.1 months) or supportive therapy (n = 69; 5.6 months, P < .01). Patients with stage I thoracic disease (n = 23) had a longer median OS (18.5 months) than those with stage III (n = 43; 9.4 months) or with intra/extra-thoracic metastases other than BM (stage IV; n = 20; 2.7 months, P < .01). Median OS of WBRT patients was 3.7 months. One patient underwent radical thoracic treatment. Patients undergoing chemotherapy (n = 42) had a longer median OS (5.7 months) than patients undergoing supportive therapy only (n = 38; 1.6 months, P < .01). Performance status and age were also associated with OS. CONCLUSIONS: Radical thoracic treatments may be justified in selected patients <65-years-old, eligible to undergo surgery/radiosurgery for synchronous BM from NSCLC, even when stage III thoracic disease is present.

Dynamic contrast-enhanced CT in patients treated with sorafenib and erlotinib for non-small cell lung cancer: a new method of monitoring treatment?

OBJECTIVE: We investigated the feasibility of serial dynamic contrast-enhanced computed tomography (DCE-CT) in patients with advanced/metastatic non-small cell lung cancer (NSCLC) receiving anti-angiogenic (sorafenib) and anti-EGFR (erlotinib) treatment, and correlated tumour blood flow (BF) with treatment outcome. METHODS: DCE-CTs were performed at baseline and 3 and 6 weeks after starting treatment. Tumour BF, calculated with the maximum slope method, and percentage change were measured in 23 patients (14 male; median age 59 years). Tumour BF was compared at baseline and weeks 3 and 6; the relation with RECIST/Crabb response and progression-free survival (PFS) was assessed. RESULTS: Mean tumour perfusion decreased from 39.2 ml/100 g/min at baseline to 15.1 ml/100 g/min at week 3 (p < 0.001) and 9.4 ml/100 g/min at week 6 (p < 0.001). Tumour perfusion was lower in RECIST and Crabb responders versus non-responders at week 3 (4.2 versus 17.7 ml/100 g/min, p = 0.03) and week 6 (0 versus 13.4 ml/100 g/min, p = 0.04). Patients with a decrease larger than the median at week 6 tended to have a longer PFS (7.1 versus 5.7 months, p = 0.06). CONCLUSION: Serial DCE-CTs are feasible in patients with NSCLC and demonstrated a significant decrease in tumour BF following sorafenib/erlotinib therapy. Early changes in tumour BF correlated with objective response and showed a trend towards longer PFS.

A multicenter phase II study of erlotinib and sorafenib in chemotherapy-naive patients with advanced non-small cell lung cancer.

PURPOSE: This multicenter, phase II study evaluates the efficacy and safety of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, plus sorafenib, a multityrosine kinase inhibitor against vascular endothelial growth factor receptors, in patients with previously untreated advanced non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Chemotherapy-naïve patients with stage IIIB/IV NSCLC received erlotinib (150 mg once a day) and sorafenib (400 mg twice a day) until disease progression or unacceptable toxicity. The primary end point was the rate of nonprogression at 6 weeks. Secondary end points included objective response rate (ORR), time to progression, overall survival, and adverse events. Exploratory end points included pretreatment EGFR and KRAS mutation status, pharmacokinetics, and cytochrome P450 polymorphisms. RESULTS: Fifty patients initiated therapy. The nonprogression rate at 6 weeks was 74%: 12 (24%) partial response and 25 (50%) stable disease. Ultimately, the ORR was 28%. Median time to progression was 5.0 months [95% confidence interval (95% CI), 3.2-6.8 months]. Median overall survival was 10.9 months (95% CI, 3.8-18.1 months). Grade 3/4 adverse events included fatigue (16%), hand-foot skin reaction (16%), rash (16%), diarrhea (14%), and hypophosphatemia (42%). There was one treatment-related fatal pulmonary hemorrhage. Patients with wild-type EGFR had a higher ORR (19%) than previously reported for single-agent erlotinib/sorafenib. Erlotinib levels were lowered. This was associated with CYP3A4 polymorphism and was possibly due to sorafenib. CONCLUSION: Despite a possible drug interaction, sorafenib plus erlotinib has promising clinical activity in patients with stage IIIB/IV NSCLC and has an acceptable safety profile. Further evaluation of this combination as potential salvage therapy in EGFR mutation-negative patients and the possible drug interaction is warranted.

Osteoblastic bone lesions developing during treatment with erlotinib indicate major response in patients with non-small cell lung cancer: a brief report.

BACKGROUND: The osteoblastic bone flare or response is the paradoxical phenomenon of increase in the quantity and/or density of bone lesions in the presence of well-documented disease response to treatment in other tumor sites. It results from the rapid repair and increased osteoblastic activity in bone metastases responding to therapy and therefore represents treatment efficacy. Nevertheless, no reliable markers can differentiate an osteoblastic flare or response from disease progression. In non-small cell lung cancer (NSCLC) osteoblastic bone flare or response has been reported in only a few patients. METHODS: Pre- and posttreatment CT scans of NSCLC patients with osteolytic bone lesions and treated with erlotinib as a single treatment modality were reviewed. RESULTS: In 3 cases fulfilling these criteria and responding to erlotinib according to RECIST criteria, an osteoblastic bone response was found. With the increasing use of epidermal growth factor receptor tyrosine kinase inhibitors in patients with NSCLC harboring mutations predicting a good response, the osteoblastic response will likely be increasingly seen. Awareness of this phenomenon with epidermal growth factor receptor tyrosine kinase inhibitors is important for physicians treating patients with NSCLC, so that it is not misinterpreted as progressive disease resulting in premature cessation of effective therapy.

Dramatic response to low-dose erlotinib of epidermal growth factor receptor mutation-positive recurrent non-small cell lung cancer after severe cutaneous toxicity.

Erlotinib is increasingly being used for the treatment of non-small cell lung cancer. The recommended dose is 150 mg/day and no efficacy data is available for lower doses. We describe a case of dramatic tumor response to 50 mg erlotinib in a patient with EGFR mutation positive NSCLC who developed a severe rash on full dose erlotinib. Rash is known to correlate with response and survival in patients treated with erlotinib. Our case suggests that in the presence of rash, dose reductions to "subtherapeutic" levels remain effective and may prevent unnecessary early treatment termination.

Phase I study of concurrent whole brain radiotherapy and erlotinib for multiple brain metastases from non-small-cell lung cancer.

PURPOSE: Erlotinib has shown activity in patients with brain metastases from non-small-cell lung cancer. The present dose-escalation Phase I trial evaluated the toxicity of whole brain radiotherapy (WBRT) with concurrent and maintenance erlotinib in this patient group. METHODS AND MATERIALS: Erlotinib (Cohort 1, 100 mg/d; Cohort 2, 150 mg/d) was started 1 week before, and continued during, WBRT (30 Gy in 10 fractions). Maintenance erlotinib (150 mg/d) was continued until unacceptable toxicity or disease progression. RESULTS: A total of 11 patients completed WBRT, 4 in Cohort 1 and 7 in Cohort 2. The median duration of erlotinib treatment was 83 days. No treatment-related neurotoxicity was observed. No treatment-related Grade 3 or greater toxicity occurred in Cohort 1. In Cohort 2, 1 patient developed a Grade 3 acneiform rash and 1 patient had Grade 3 fatigue. Two patients in Cohort 2 developed erlotinib-related interstitial lung disease, contributing to death during maintenance therapy. The median overall survival and interval to progression was 133 and 141 days, respectively. Six patients developed extracranial progression; only 1 patient had intracranial progression. In 7 patients with follow-up neuroimaging at 3 months, 5 had a partial response and 2 had stable disease. CONCLUSION: WBRT with concurrent erlotinib is well tolerated in patients with brain metastases from non-small-cell lung cancer. The suggestion of a high intracranial disease control rate warrants additional study.

Angiogenesis inhibitors in the treatment of non-small cell lung cancer.

A therapeutic plateau seems to have been reached with the standard treatment of cytotoxic chemotherapy alone for advanced stage non-small cell lung cancer (NSCLC) and new treatment options are urgently needed. Recent insight into the molecular biology of cancer has identified angiogenesis as one of the key biological processes. The major player in tumor angiogenesis is the vascular endothelial growth factor (VEGF) pathway. VEGF is expressed in the majority of NSCLC and overexpression is associated with a poor prognosis. The VEGF pathway can be inhibited in two main ways: targeting VEGF directly or inhibiting the VEGF receptors. The development of angiogenesis inhibitors has shown great promise in the treatment of NSCLC. Bevacizumab, an anti-VEGF antibody, has been approved for the treatment of advanced NSCLC and other drugs are undergoing phase III investigation. However, a number of unresolved issues remain. In this review, we discuss the main angiogenesis inhibitors in development for the treatment of NSCLC focusing on the VEGF pathway.

Fatal interstitial lung disease after erlotinib for non-small cell lung cancer.

The use of erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, is considered safe in the treatment of non-small cell lung cancer. Recently, cases of erlotinib-associated interstitial lung disease have been reported. This disease entity remains poorly understood and the histopathology is rarely documented. We describe two cases of histologically confirmed fatal interstitial lung disease after erlotinib treatment for non-small cell lung cancer. After starting erlotinib treatment both patients developed clinical and radiologic signs of interstitial lung disease resulting in respiratory failure and death. Autopsy confirmed diffuse alveolar damage. As the use of erlotinib is increasing, physicians should be aware of this potentially fatal complication. The sparse data on the clinical presentation, radiographic patterns, and histologic findings of epidermal growth factor receptor tyrosine kinase inhibitor-associated interstitial lung disease are discussed.

Accuracy and feasibility of point-of-care and continuous blood glucose analysis in critically ill ICU patients.

INTRODUCTION: To obtain strict glucose regulation, an accurate and feasible bedside glucometry method is essential. We evaluated three different types of point-of-care glucometry in seriously ill intensive care unit (ICU) patients. The study was performed as a single-centre, prospective, observational study in a 12-bed medical ICU of a university hospital. METHODS: Patients with an expected ICU stay of more than 48 hours were included. Because the reference laboratory delivers glucose values after approximately 30 to 60 minutes, which is too slow to use in a glucose regulation protocol and for calibration of the subcutaneous continuous glucose monitoring system (CGMS) (CGMS System Gold), we first validated the ICU-based blood gas/glucose analyser ABL715 (part 1 of the study). Subsequently, part 2 was performed: after inserting (and calibrating) the subcutaneous CGMS, heparinised arterial blood samples were drawn from an arterial line every 6 hours and analysed on both the Precision PCx point-of-care meter using test strips and on the blood gas/glucose analyser ABL715. CGMS glucose data were downloaded after 24 to 72 hours. The results of the paired measurements were analysed as a scatter plot by the method of Bland and Altman and were expressed as a correlation coefficient. RESULTS: Part 1: Four hundred and twenty-four blood samples were drawn from 45 critically ill ICU patients. The ICU-based blood gas/glucose analyser ABL715 provided a good estimate of conventional laboratory glucose assessment: the correlation coefficient was 0.95. In the Clarke error grid, 96.8% of the paired measurements were in the clinically acceptable zones A and B. Part 2: One hundred sixty-five paired samples were drawn from 19 ICU patients. The Precision PCx point-of-care meter showed a correlation coefficient of 0.89. Ninety-eight point seven percent of measurements were within zones A and B. The correlation coefficient for the subcutaneous CGMS System Gold was 0.89. One hundred percent of measurements were within zones A and B. CONCLUSION: The ICU-based blood glucose analyser ABL715 is a rapid and accurate alternative for laboratory glucose determination and can serve as a standard for ICU blood glucose measurements. The Precision PCx is a good alternative, but feasibility may be limited because of the blood sample handling. The subcutaneous CGMS System Gold is promising, but real-time glucose level reporting is necessary before it can be of clinical use in the ICU. When implementing a glucose-insulin algorithm in patient care or research, one should realise that the absolute glucose level may differ systematically among various measuring methods, influencing targeted glucose levels.