Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer

Background: The Lung Cancer Cetuximab Study is an open-label, randomized phase II pilot study of cisplatin and vinorelbine combined with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody cetuximab versus cisplatin and vinorelbine alone, in patients with advanced EGFR-expressing, non-small-cell lung cancer (NSCLC). End points of the study are activity, safety and pharmacokinetics. Patients and methods: Following randomization, for a maximum of eight cycles, patients received three-weekly cycles of cisplatin (80 mg/m2, day 1) and vinorelbine (25 mg/m2 on days 1 and 8) alone or following cetuximab treatment (initial dose 400 mg/m, followed by 250 mg/m2 weekly thereafter). Results: Eighty-six patients were randomly allocated to the study (43 per arm). Confirmed response rates were 28% in the cisplatin/vinorelbine arm (A) and 35% in the cetuximab plus cisplatin/vinorelbine arm (B). Median progression-free survival (PFS) was 4.6 months in arm A and 5.0 months in arm B, with PFS rates at 12 months of 0% and 15%, respectively. Median survival was 7.3 months in arm A and 8.3 months in arm B. The 24-month survival rates were 0% and 16%, respectively. The cetuximab combination was well tolerated. Conclusion: In the first-line treatment of advanced NSCLC, the combination of cetuximab plus cisplatin/vinorelbine demonstrated an acceptable safety profile and the potential to improve activity over cisplatin/vinorelbine alone. © 2007 European Society for Medical Oncology.

Crizotinib versus chemotherapy in advanced ALK-positive lung cancer

BACKGROUND: In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK ) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. METHODS: We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. RESULTS: The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. CONCLUSIONS: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.) Copyright © 2013 Massachusetts Medical Society.

Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer

OBJECTIVES: Four randomized phase II/III trials investigated the addition of cetuximab to platinum-based, first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). A meta-analysis was performed to examine the benefit/risk ratio for the addition of cetuximab to chemotherapy. MATERIALS AND METHODS: The meta-analysis included individual patient efficacy data from 2018 patients and individual patient safety data from 1970 patients comprising respectively the combined intention-to-treat and safety populations of the four trials. The effect of adding cetuximab to chemotherapy was measured by hazard ratios (HRs) obtained using a Cox proportional hazards model and odds ratios calculated by logistic regression. Survival rates at 1 year were calculated. All applied models were stratified by trial. Tests on heterogeneity of treatment effects across the trials and sensitivity analyses were performed for all endpoints. RESULTS: The meta-analysis demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival (HR 0.88, p=0.009, median 10.3 vs 9.4 months), progression-free survival (HR 0.90, p=0.045, median 4.7 vs 4.5 months) and response (odds ratio 1.46, p<0.001, overall response rate 32.2% vs 24.4%) compared with chemotherapy alone. The safety profile of chemotherapy plus cetuximab in the meta-analysis population was confirmed as manageable. Neither trials nor patient subgroups defined by key baseline characteristics showed significant heterogeneity for any endpoint. CONCLUSION: The addition of cetuximab to platinum-based, first-line chemotherapy for advanced NSCLC significantly improved outcome for all efficacy endpoints with an acceptable safety profile, indicating a favorable benefit/risk ratio.

Challenges of recruiting hospice patients with advanced cancer to research : reflections on a delirium screening study

Introduction Delirium research in palliative care, particularly in the dying phase, is possible but is frequently met with ethical and methodological challenges. This paper describes the challenges faced in a previous delirium screening study. Methods Within 72 hours of admission to an acute inpatient specialist palliative care unit one hundred consecutive patients over 18 years of age with advanced cancer were invited to be screened for delirium using validated screening tools. Results Of the 100 consecutive admissions 49 patients were unable to participate including seven who did not meet the inclusion criteria and nine (six families and three patients) who withheld consent. The remaining 33 patients were more unwell and closer to death than those who were recruited. Reasons for non- participation included being too unwell (ten), unresponsive (nine), died (two) or discharged (three) before recruitment and exceeding the 72hour time limit (nine). Conclusion Gate keeping and physical condition of patients were the main obstacles to recruitment and is consistent with barriers faced in previous studies involving palliative care and dying patients. While it is possible and necessary to conduct studies in palliative care, including the terminal phase, as reflective practitioners we must maintain the balance between the demands for evidence-based practice and our compassion and respect for our most vulnerable of patients.

Self-management associated with fatigue in patients with advanced cancer : a prospective longitudinal study

Cancer-related fatigue is one of the most distressing symptoms experienced by patients with advanced cancer. This doctoral study identified that patients with advanced cancer commonly use a number of self-management strategies in response to fatigue, although these strategies had varying levels of effectiveness in reducing the symptom. The study identified that enhancing self-efficacy and managing depressive symptoms are important factors to consider in the design of future interventions to support fatigue self-management.

2nd ESMO Consensus Conference on Lung Cancer : non-small-cell lung cancer first-line/second and further lines in advanced disease

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines in advanced disease, early stage disease and locally-advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on 1st line / 2nd and further lines of treatment in advanced disease. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Relationship between EGFR expression, EGFR mutation status, and the efficacy of chemotherapy plus cetuximab in FLEX study patients with advanced non-small-cell lung cancer

INTRODUCTION: The phase III FLEX study (NCT00148798) in advanced non-small-cell lung cancer indicated that the survival benefit associated with the addition of cetuximab to cisplatin and vinorelbine was limited to patients whose tumors expressed high levels of epidermal growth factor receptor (EGFR) (immunohistochemistry score of >/=200; scale 0-300). We assessed whether the treatment effect was also modulated in FLEX study patients by tumor EGFR mutation status. METHODS: A tumor mutation screen of EGFR exons 18 to 21 included 971 of 1125 (86%) FLEX study patients. Treatment outcome in low and high EGFR expression groups was analyzed across efficacy endpoints according to tumor EGFR mutation status. RESULTS: Mutations in EGFR exons 18 to 21 were detected in 133 of 971 tumors (14%), 970 of which were also evaluable for EGFR expression level. The most common mutations were exon 19 deletions and L858R (124 of 133 patients; 93%). In the high EGFR expression group (immunohistochemistry score of >/=200), a survival benefit for the addition of cetuximab to chemotherapy was demonstrated in patients with EGFR wild-type (including T790M mutant) tumors. Although patient numbers were small, those in the high EGFR expression group whose tumors carried EGFR mutations may also have derived a survival benefit from the addition of cetuximab to chemotherapy. Response data suggested a cetuximab benefit in the high EGFR expression group regardless of EGFR mutation status. CONCLUSIONS: The survival benefit associated with the addition of cetuximab to first-line chemotherapy for advanced non-small-cell lung cancer expressing high levels of EGFR is not limited by EGFR mutation status.

Delirium in advanced cancer : screening for the incidence on admission to an inpatient hospice unit

Background Delirium is a common underdiagnosed condition in advanced cancer leading to increased distress, morbidity, and mortality. Screening improves detection but there is no consensus as to the best screening tool to use with patients with advanced cancer. Objective To determine the incidence of delirium in patients with advanced cancer within 72 hours of admission to an acute inpatient hospice using clinical judgement and validated screening tools. Method One hundred consecutive patients with advanced cancer were invited to be screened for delirium within 72 hours of admission to an acute inpatient hospice unit. Two validated tools were used, the Delirium Rating Scale-Revised 98 (DRS-R-98) and the Confusion Assessment Method (CAM) shortened diagnostic algorithm. These results were compared with clinical assessment by review of medical charts. Results Of 100 consecutive admissions 51 participated and of these 22 (43.1%) screened positive for delirium with CAM and/or DRS-R-98 compared to 15 (29.4%) by clinical assessment. Eleven (21.6%) were identified as hypoactive delirium and 5 (9.8%) as subsyndromal delirium. Conclusion This study confirms that delirium is a common condition in patients with advanced cancer.While there remains a lack of consensus regarding the choice of delirium screening tool this study supports theCAMas being appropriate. Further research may determine the optimal screening tool for delirium enabling the development of best practice clinical guidelines for routinemedical practice.

CBCT-guided radiotherapy for locally advanced head and cancer: dosimetric impact of weight loss on VMAT and IMRT plans for selected organs at risk structures (OARs)

Purpose: It is common for head and neck patients to be affected by time trend errors as a result of weight loss during a course of radiation treatment. The objective of this planning study was to investigate the impact of weight loss on Volumetric Modulated Arc Therapy (VMAT) as well as Intensity modulated radiation therapy (IMRT) for locally advanced head and neck cancer using automatic co-registration of the CBCT. Methods and Materials: A retrospective analysis of previously treated IMRT plans for 10 patients with locally advanced head and neck cancer patients was done. A VMAT plan was also produced for all patients. We calculated the dose–volume histograms (DVH) indices for spinal cord planning at risk volumes (PRVs), the brainstem PRVs (SC+0.5cm and BS+0.5cm, respectively) as well as mean dose to the parotid glands. Results: The results show that the mean difference in dose to the SC+0.5cm was 1.03% and 1.27% for the IMRT and VMAT plans, respectively. As for dose to the BS+0.5, the percentage difference was 0.63% for the IMRT plans and 0.61% for the VMAT plans. The analysis of the parotid gland doses shows that the percentage change in mean dose to left parotid was -8.0% whereas that of the right parotid was -6.4% for the IMRT treatment plans. In the VMAT plans, the percentages change for the left and the right parotid glands were -6.6% and -6.7% respectively. Conclusions: This study shows a clinically significant impact of weight loss on DVH indices analysed in head and neck organs at risk. It highlights the importance of adaptive radiotherapy in head and neck patients if organ at risk sparing is to be maintained.

Adenoviral Gene Therapy for Advanced Head and Neck Cancer

Advanced stage head and neck cancers (HNC) with distant metastasis, as well as prostate cancers (PC), are devastating diseases currently lacking efficient treatment options. One promising developmental approach in cancer treatment is the use of oncolytic adenoviruses, especially in combination therapy with conventional cancer therapies. The safety of the approach has been tested in many clinical trials. However, antitumor efficacy needs to be improved in order to establish oncolytic viruses as a viable treatment alternative. To be able to test in vivo the effects on anti-tumor efficiency of a multimodal combination therapy of oncolytic adenoviruses with the standard therapeutic combination of radiotherapy, chemotherapy and Cetuximab monoclonal antibody (mAb), a xenograft HNC tumor model was developed. This model mimics the typical clinical situation as it is initially sensitive to cetuximab, but resistance develops eventually. Surprisingly, but in agreement with recent findings for chemotherapy and radiotherapy, a higher proportion of cells positive for HNC cancer stem cell markers were found in the tumors refractory to cetuximab. In vitro as well as in vivo results found in this study support the multimodal combination therapy of oncolytic adenoviruses with chemotherapy, radiotherapy and monoclonal antibody therapy to achieve increased anti-tumor efficiency and even complete tumor eradication with lower treatment doses required. In this study, it was found that capsid modified oncolytic viruses have increased gene transfer to cancer cells as well as an increased antitumor effect. In order to elucidate the mechanism of how oncolytic viruses promote radiosensitization of tumor cells in vivo, replicative deficient viruses expressing several promising radiosensitizing viral proteins were tested. The results of this study indicated that oncolytic adenoviruses promote radiosensitization by delaying the repair of DNA double strand breaks in tumor cells. Based on the promising data of the first study, two tumor double-targeted oncolytic adenoviruses armed with the fusion suicide gene FCU1 or with a fully human mAb specific for human Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) were produced. FCU1 encodes a bifunctional fusion protein that efficiently catalyzes the direct conversion of 5-FC, a relatively nontoxic antifungal agent, into the toxic metabolites 5-fluorouracil and 5-fluorouridine monophosphate, bypassing the natural resistance of certain human tumor cells to 5-fluorouracil. Anti-CTLA4 mAb promotes direct killing of tumor cells via apoptosis and most importantly immune system activation against the tumors. These armed oncolytic viruses present increased anti-tumor efficacy both in vitro and in vivo. Furthermore, by taking advantage of the unique tumor targeted gene transfer of oncolytic adenoviruses, functional high tumor titers but low systemic concentrations of the armed proteins were generated. In addition, supernatants of tumor cells infected with Ad5/3-24aCTLA4, which contain anti-CTLA4 mAb, were able to effectively immunomodulate peripheral blood mononuclear cells (PBMC) of cancer patients with advanced tumors. -- In conclusion, the results presented in this thesis suggest that genetically engineered oncolytic adenoviruses have great potential in the treatment of advanced and metastatic HNC and PC.

The development and preliminary testing of an instrument for assessing fatigue self-management outcomes in patients with advanced cancer

Background: Fatigue is one of the most distressing and commonly experienced symptoms in patients with advanced cancer. Although the self-management (SM) of cancer-related symptoms has received increasing attention, no research instrument assessing fatigue SM outcomes for patients with advanced cancer is available. Objectives: to describe the development and preliminary testing of an interviewer administered instrument for assessing the frequency, and perceived levels of effectiveness and self-efficacy associated with fatigue SM behaviors in patients with advanced cancer. Methods: The development and testing of the Self-efficacy in Managing Symptoms Scale- Fatigue Subscale for Patients with Advanced Cancer (SMSFS-A) involved a number of procedures: item-generation using a comprehensive literature review and semi-structured interviews, content validity evaluation using expert panel reviews, and face validity and test-retest reliability evaluation using pilot testing. Results: Initially, 23 items (22 specific behaviors with one global item) were generated from the literature review and semi-structured interviews. After two rounds of expert panel review, the final scale was reduced to 17 items (16 behaviors with one global item). Participants in the pilot test (n=10) confirmed that the questions in this scale were clear and easy to understand. Bland-Altman analysis showed agreement of results over a one-week interval. Conclusions: The SMSFS-A items were generated using multiple sources. This tool demonstrated preliminary validity and reliability. Implications for practice: The SMSFS-A has the potential to be used for clinical and research purposes. Nurses can use this instrument for collecting data to inform the initiation of appropriate fatigue SM support for this population.

Quality of life after early enteral feeding versus standard care for proven or suspected advanced epithelial ovarian cancer: Results from a randomised trial

Background Malnutrition is common in patients with advanced epithelial ovarian cancer (EOC), and is associated with impaired quality of life (QoL), longer hospital stay and higher risk of treatment-related adverse events. This phase III multi-centre randomised clinical trial tested early enteral feeding versus standard care on postoperative QoL. Methods From 2009 to 2013, 109 patients requiring surgery for suspected advanced EOC, moderately to severely malnourished were enrolled at five sites across Queensland and randomised to intervention (n = 53) or control (n = 56) groups. Intervention involved intraoperative nasojejunal tube placement and enteral feeding until adequate oral intake could be maintained. Despite being randomised to intervention, 20 patients did not receive feeds (13 did not receive the feeding tube; 7 had it removed early). Control involved postoperative diet as tolerated. QoL was measured at baseline, 6 weeks postoperatively and 30 days after the third cycle of chemotherapy. The primary outcome measure was the difference in QoL between the intervention and the control group. Secondary endpoints included treatment-related adverse event occurrence, length of stay, postoperative services use, and nutritional status. Results Baseline characteristics were comparable between treatment groups. No significant difference in QoL was found between the groups at any time point. There was a trend towards better nutritional status in patients who received the intervention but the differences did not reach statistical significance except for the intention-to-treat analysis at 7 days postoperatively (11.8 intervention vs. 13.8 control, p 0.04). Conclusion Early enteral feeding did not significantly improve patients' QoL compared to standard of care but may improve nutritional status.

Fatigue self-management behaviors in patients with advanced cancer: A prospective longitudinal survey

Purpose: To explore the fatigue self-management behaviors and factors associated with effectiveness of these behaviors in patients with advanced cancer. Design: Prospective longitudinal interviewer-administered survey. Setting: A tertiary cancer center in Queensland Australia. Sample: One hundred fifty two outpatients with metastatic breast, lung, colorectal and prostate cancer experiencing fatigue (>3/10) were recruited. Main Research Variables: Fatigue self-management behaviors outcomes (perceived effectiveness, self-efficacy and frequency), medical/demographic characteristics (including sites of primary cancer and metastasis, comorbidity, performance status), social support, depressive, anxiety, and other symptoms were assessed. Findings: The participants reported moderate levels of fatigue at baseline (M=5.85, SD 1.44), and maintained moderate levels at 4 weeks and 8 weeks. On average, participants consistently used approximately nine behaviors at each time point. Factors significantly associated with higher levels of perceived effectiveness of fatigue self-management behaviors were higher self-efficacy (p<.001), higher education level (p=.02), and lower levels of depressive symptoms (p=.04). Conclusions: The findings of this study demonstrate that patients with cancer, even with advanced disease, still want and are able to use a number of behaviors to control their fatigue. Self-management interventions that aim to enhance self-efficacy and address any concurrent depressive symptoms have the potential to reduce fatigue severity. Implications for Nursing: Nurses are well positioned to play a key role in supporting patients in their fatigue self-management. Knowledge Translation: This study particularly focused on the perspectives of patients about fatigue self-management, highlighting a number of issues requiring further attention in clinical practice and the potential for future research.

Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: Results of an open-label, randomized, controlled phase II study (CERTO)

Background: This multicentre, open-label, randomized, controlled phase II study evaluated cilengitide in combination with cetuximab and platinum-based chemotherapy, compared with cetuximab and chemotherapy alone, as first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: Patients were randomized 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (control), or combined with cilengitide 2000 mg 1×/week i.v. (CIL-once) or 2×/week i.v. (CIL-twice). A protocol amendment limited enrolment to patients with epidermal growth factor receptor (EGFR) histoscore ≥200 and closed the CIL-twice arm for practical feasibility issues. Primary end point was progression-free survival (PFS; independent read); secondary end points included overall survival (OS), safety, and biomarker analyses. A comparison between the CIL-once and control arms is reported, both for the total cohorts, as well as for patients with EGFR histoscore ≥200. Results: There were 85 patients in the CIL-once group and 84 in the control group. The PFS (independent read) was 6.2 versus 5.0 months for CIL-once versus control [hazard ratio (HR) 0.72; P = 0.085]; for patients with EGFR histoscore ≥200, PFS was 6.8 versus 5.6 months, respectively (HR 0.57; P = 0.0446). Median OS was 13.6 for CIL-once versus 9.7 months for control (HR 0.81; P = 0.265). In patients with EGFR ≥200, OS was 13.2 versus 11.8 months, respectively (HR 0.95; P = 0.855). No major differences in adverse events between CIL-once and control were reported; nausea (59% versus 56%, respectively) and neutropenia (54% versus 46%, respectively) were the most frequent. There was no increased incidence of thromboembolic events or haemorrhage in cilengitide-treated patients. αvβ3 and αvβ5 expression was neither a predictive nor a prognostic indicator. Conclusions: The addition of cilengitide to cetuximab/chemotherapy indicated potential clinical activity, with a trend for PFS difference in the independent-read analysis. However, the observed inconsistencies across end points suggest additional investigations are required to substantiate a potential role of other integrin inhibitors in NSCLC treatment.

Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): Pooled subset analyses from two randomized trials

Background: The irreversible epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in NSCLC patients with activating EGFR mutations, but it is unknown if they are superior to the reversible inhibitors. Dacomitinib is an oral, small-molecule irreversible inhibitor of all enzymatically active HER family tyrosine kinases. Methods: The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) studies randomized patients with locally advanced/metastatic NSCLC following progression with one or two prior chemotherapy regimens to dacomitinib or erlotinib. EGFR mutation testing was performed centrally on archived tumor samples. We pooled patients with exon 19 deletion and L858R EGFR mutations from both studies to compare the efficacy of dacomitinib to erlotinib. Results: One hundred twenty-one patients with any EGFR mutation were enrolled; 101 had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median progression-free survival was 14.6 months [95% confidence interval (CI) 9.0–18.2] with dacomitinib and 9.6 months (95% CI 7.4–12.7) with erlotinib [unstratified hazard ratio (HR) 0.717 (95% CI 0.458–1.124), two-sided log-rank, P = 0.146]. The median survival was 26.6 months (95% CI 21.6–41.5) with dacomitinib versus 23.2 months (95% CI 16.0–31.8) with erlotinib [unstratified HR 0.737 (95% CI 0.431–1.259), two-sided log-rank, P = 0.265]. Dacomitinib was associated with a higher incidence of diarrhea and mucositis in both studies compared with erlotinib. Conclusions: Dacomitinib is an active agent with comparable efficacy to erlotinib in the EGFR mutated patients. The subgroup with exon 19 deletion had favorable outcomes with dacomitinib. An ongoing phase III study will compare dacomitinib to gefitinib in first-line therapy of patients with NSCLC harboring common activating EGFR mutations (ARCHER 1050; NCT01774721). Clinical trials number: ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067).