A phase Ib dose allocation study of oral administration of lucitanib given in combination with fulvestrant in patients with estrogen receptor-positive and FGFR1-amplified or non-amplified metastatic breast cancer.

PURPOSE: The primary objective of this multicentric dose allocation and dose expansion study was to determine the MTD and the DLTs of the lucitanib (a tyrosine kinase inhibitor of the FGFR/VEGFR/PDFGR pathways)/fulvestrant combination. METHODS: Postmenopausal women with ER+/HER2- mBC, who have relapsed during or after treatment with fulvestrant, were eligible. The study had a dose allocation part to assess the tolerability of the combination followed by a dose expansion part. RESULTS: Eighteen patients with ER+, mBC were enrolled; median age was 66 years, 50% had a PS: 0 and all had received previous endocrine treatment. The study was prematurely terminated after 18 patients (15 in part 1 and 3 in part 2) based on preclinical experiments that failed to confirm the hypothesis that addition of lucitanib would reverse sensitivity to endocrine treatments. Based on data of global lucitanib development, it was decided to stop the dose allocation at 12.5 mg and to start the dose expansion part at 10 mg/day. The most common grade ≥ 3 toxicities (> 10% of patients) were hypertension (78%) and asthenia (22%). All patients required at ≥ 1 interruption, 13 patients (72%) required ≥ 1 dose reduction. Three patients (72%) withdrew from the study for AEs (at 10 mg). Three patients achieved a confirmed PR (10 mg n = 1; 12.5 mg n = 2). CONCLUSION: Although the combination is feasible it requires close monitoring of the patients for the management of adverse events. Further investigation is required to better understand the potential role of FGFR inhibition in reversing resistance to endocrine treatment.

Long-term clinical benefit from salvage EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer patients with EGFR wild-type tumors.

BACKGROUND: Erlotinib has been approved for the management of NSCLC patients after failure of the first or subsequent line of chemotherapy. Although the efficacy of erlotinib is clearly associated with the presence of EGFR mutations, there is a subset of patients with EGFR wild-type (EGFRwt) tumors who impressively respond. PATIENTS AND METHODS: Patients with EGFRwt NSCLC who received salvage (≥2nd line) treatment with erlotinib for a prolonged period (>6 months), were sought from the database of the Hellenic Oncology Research Group. We retrospectively analyzed the clinical, pathological and molecular characteristics of the patients with available tumor material. RESULTS: Forty-four patients that received erlotinib for >6 months (median 10.1 months) were enrolled in the study. The majority of them were male, never-smokers with adenocarcinoma histology and a good performance status. KRAS and PIK3CA mutations were detected in 21% (9/42 tested) and 13% (4/30 tested) of the patients, respectively. The ALK-EML4 translocation was found in 10% (2/20 tested); there was no patient with HER2 or BRAF mutated tumor. Twelve (54.5%) tumor specimens were considered positive for EGFR-overexpression. Eleven patients experienced a partial response (objective response rate 25%; 95% CI 12-38%) and the remaining 33 had stable disease. The median progression-free survival and overall survival were 10.1 (95% CI 8.6-11.6 months) and 24.1 (95% CI 11.2-37 months), respectively. CONCLUSIONS: Treatment with erlotinib significantly improves the clinical outcome in a subset of NSCLC patients with EGFRwt tumors. Further molecular analysis of such tumor specimens could provide a more comprehensive characterization of this particular group of patients. Nevertheless, the presence of other mutations should not prevent the treating physician from using erlotinib at later lines of salvage therapy for NSCLC patients.

Management of elderly patients with NSCLC; updated expert's opinion paper: EORTC Elderly Task Force, Lung Cancer Group and International Society for Geriatric Oncology.

Non-small-cell lung cancer (NSCLC) is a very common disease in the elderly population and its incidence in this particular population is expected to increase further, because of the ageing of the Western population. Despite this, limited data are available for the treatment of these patients and, therefore, the development of evidence-based treatment recommendations is challenging. In 2010, European Organization for Research and Treatment of Cancer (EORTC) took an initiative in collaboration with International Society of Geriatric Oncology (SIOG) and created an experts panel that provided an experts' opinion consensus paper for the management of elderly NSCLC patients. Since this publication, important new data are available and EORTC and SIOG recommended to update the 2010 recommendations. Besides recommendations for surgery, adjuvant chemotherapy and radiotherapy, treatment of locally advanced and metastatic disease, recommendations were expanded, to include data on patient preferences and geriatric assessment.

International validation of the EORTC QLQ-ELD14 questionnaire for assessment of health-related quality of life elderly patients with cancer.

BACKGROUND: Older people represent the majority of cancer patients but their specific needs are often ignored in the development of health-related quality of life (HRQOL) instruments. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-ELD15 was developed to supplement the EORTC's core questionnaire, the QLQ-C30, for measuring HRQOL in patients aged >70 years in oncology studies. METHODS: Patients (n=518) from 10 countries completed the QLQ-C30, QLQ-ELD15 and a debriefing interview. Eighty two clinically stable patients repeated the questionnaires 1 week later (test-retest analysis) and 107 others, with an expected change in clinical status, repeated the questionnaires 3 months later (response to change analysis, RCA). RESULTS: Information from the debriefing interview, factor analysis and item response theory analysis resulted in the removal of one item (QLQ-ELD15QLQ-ELD14) and revision of the proposed scale structure to five scales (mobility, worries about others, future worries, maintaining purpose and illness burden) and two single items (joint stiffness and family support). Convergent validity was good. In known-group comparisons, the QLQ-ELD14 differentiated between patients with different disease stage, treatment intention, number of comorbidities, performance status and geriatric screening scores. Test-retest and RCA analyses were equivocal. CONCLUSION: The QLQ-ELD14 is a validated HRQOL questionnaire for cancer patients aged 70 years. Changes in elderly patients' self-reported HRQOL may be related to both cancer evolution and non-clinical events.

Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of NSCLC.

Improvements in our understanding of the molecular biology of cancer have shifted management of lung cancer toward molecular-guided, individualized treatment. Development of epidermal growth factor receptor tyrosine kinase inhibitors, erlotinib and gefitinib, represent the best example of this approach. Erlotinib was tested as second/third line treatment in unselected population of patients and demonstrated a statistically significant prolongation of overall survival, while gefitinib was shown to be non-inferior to docetaxel as second line treatment. The discovery of EGFR activating mutations facilitated the selection of patients most likely to benefit from erlotinib/gefitinib. These drugs in patients with EGFR activating mutations offer an increased progression free survival and significantly higher response rates compared to chemotherapy. The purpose of this paper is to present the relevant clinical data, describe the predictive markers available for TKIs treatment in NSCLC, and describe the mechanisms associated with resistance to treatment with these agents.

Clinical relevance of circulating CK-19mRNA-positive tumour cells before front-line treatment in patients with metastatic breast cancer.

BACKGROUND: To investigate the clinical relevance of CK-19mRNA-positive circulating tumour cells (CTCs) detected before the initiation of front-line treatment in patients with metastatic breast cancer (MBC). METHODS: The presence of CTCs was detected in 298 patients with MBC using a real-time PCR (RT-PCR assay. In 44 patients, the detection of CTCs was evaluated by both the CellSearch and the RT-PCR assay. Interaction with known prognostic factors and association of CTCs with clinical outcome were investigated. RESULTS: There was a strong correlation between the detection of CTCs by both assays. CK-19mRNA-positive CTCs were detected in 201 (67%) patients and their detection was independent of various patients' clinico-pathological characteristics. The median progression-free survival (PFS; 9.2 vs 11.9 months (mo), P=0.003) and the overall survival (OS; 29.7 vs 38.9 mo, P=0.016) were significantly shorter in patients with detectable CK-19mRNA-positive CTCs compared with patients without detectable CTCs. Multivariate analysis demonstrated that oestrogen receptor status, performance status and detection of CTCs were emerged as independent prognostic factors associated with decreased PFS and OS. CONCLUSION: The detection of CK-19mRNA-positive CTCs in patients with MBC before front-line therapy could define a subgroup of patients with dismal clinical outcome.

A multicenter randomized phase III trial of vinorelbine/gemcitabine doublet versus capecitabine monotherapy in anthracycline- and taxane-pretreated women with metastatic breast cancer.

BACKGROUND: The Breast Cancer Study Group of the Hellenic Oncology Research Group conducted a phase III trial of single-agent capecitabine versus the vinorelbine/gemcitabine doublet in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. The primary objective was to demonstrate superiority of combination treatment in terms of progression-free survival (PFS). PATIENTS AND METHODS: Women with MBC were randomly assigned to receive either capecitabine (Cap arm: 1250 mg/m(2) twice daily, on days 1-14) or vinorelbine/gemcitabine doublet (VG arm: vinorelbine 25 mg/m(2); gemcitabine 1000 mg/m(2); both drugs on days 1 and 15). RESULTS: Seventy-four women were treated on each arm and median PFS was 5.4 versus 5.2 months (P = 0.736), for VG and Cap, respectively. Median overall survival was 20.4 months for the VG arm and 22.4 months for the Cap arm (P = 0.319). Overall response rate was 28.4% in the VG arm and 24.3% in the Cap arm (P = 0.576). Both regimens were generally well tolerated. Neutropenia and fatigue were more common with VG arm and hand-foot syndrome with Cap arm. CONCLUSIONS: This trial failed to demonstrate superiority of vinorelbine/gemcitabine doublet over single-agent capecitabine in terms of PFS. Given the favorable toxicity and convenience of oral administration, single-agent capecitabine is recommended for compliant patients.

Economic evaluation of pemetrexed versus erlotinib as second-line treatment of patients with advanced/metastatic non-small cell lung cancer in Greece: a cost minimization analysis.

OBJECTIVES: An economic evaluation was conducted in conjunction with a prospective, multicenter, randomized trial, to compare pemetrexed with erlotinib in pretreated patients with metastatic non-small cell lung cancer (NSCLC) in Greece. METHODS: The effectiveness of treatments examined was comparable; thus, cost minimization analysis was conducted to evaluate which option is less costly. Patient-level resource utilization data were combined with unit cost data, which were aggregated to compute the total treatment cost for each patient. The analysis was conducted with respect to the individual incurring the cost. Due to the limited life-expectancy of the patients, discounting was unnecessary. Since data were right censored, the Bang and Tsiatis method was employed to identify unbiased estimators of the mean cost per treatment arm, while other methods were employed for sensitivity analysis. To analyze uncertainty and to construct uncertainty intervals (UI), stochastic analysis was performed based on 5000 bootstrap replications. RESULTS: The one-year survival rate was 28.3% in the pemetrexed arm and 31.7% in the erlotinib arm, while the corresponding median survival over the follow-up period was 7.1 and 6.7 months, respectively (P = 0.765). Total cost in the pemetrexed arm was €10508 (95% UI: €9552-€11488), while in the erlotinib arm the cost was €9563 (95% UI: €8499-€10711); thus, no statistically significant difference was found between the comparators (P = 0.206). Results remained constant for all sensitivity analyses. CONCLUSIONS: There is no survival or cost difference between erlotinib and pemetrexed; thus, these therapies are equivalent. Further studies are needed to determine whether other parameters, such as quality of life, differ among treatment options.

Small cell ovarian cancer in adolescents: report of two cases and review of the literature.

Ovarian small cell carcinoma is a rare and highly malignant neoplasm carrying a poor prognosis. Although combination chemotherapy remains the cornerstone of treatment due to the rarity of these tumors, no regimen can be recommended as standard of care although in the majority of cases platinum-based regimens are used. Herein, we report two cases of small cell carcinoma of the ovaries along with a review of the relevant literature.

Are we treating enough elderly patients with early stage non-small cell lung cancer?

Despite the fact that non-small-cell lung cancer (NSCLC) is very common in the older population, these patients are frequently underrepresented in clinical trials evaluating new anti-cancer agents, and thus it is difficult to reach evidence-based recommendations for this special population. The purpose of the present paper is to present the currently available evidence regarding treatment of early-stages of NSCLC in older patients. Although, age is still considered as a negative factor influencing treatment decisions and curative cancer-directed surgery is often omitted in the older population several studies support that surgical resection is feasible in the older patient and that age per se is not a contraindication for various surgical procedures. Pneumonectomy is associated with a higher mortality in the older population and this issue should be taken into account when deciding whether a patient is suitable for pneumonectomy. Older patients should be considered for adjuvant chemotherapy after surgical resection although little information is available regarding the real benefit and tolerability of these regimens for patients over 75 years of age. Given the lack of demonstrated benefit for the use of adjuvant RT it is also not recommended in older population.

Biomarkers of clinical benefit for anti-epidermal growth factor receptor agents in patients with non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) remains by far the major cause of cancer-related death in the Western world in both men and women. The majority of patients will be diagnosed with metastatic disease, and chemotherapy doublets remain the cornerstone of treatment for these patients. However, chemotherapy has a minimal impact on long-term survival and prognosis remains poor for these patients. Further improvement in treatment is likely to require incorporation of novel targeted therapies. Among these agents, inhibitors of the epidermal growth factor receptor (EGFR) have demonstrated significant activity in the first-, second- or third-line treatment of NSCLC. The purpose of current paper is to present the evidence for using several proposed molecular biomarkers as a tool for selection of NSCLC patients for anti-EGFR treatment. According to current data, EGFR mutation status appears to be the strongest predictor for the selection of NSCLC patients to first-line treatment with EGFR tyrosine kinase inhibitors vs chemotherapy. Use of other biomarkers remains investigational.

Efficacy and treatment tolerance in older patients with NSCLC: a meta-analysis of five phase III randomized trials conducted by the Hellenic Oncology Research Group.

BACKGROUND: Approximately 50% of newly diagnosed cases of non-small-cell lung cancer (NSCLC) are observed in patients >65 years, while 30%-40% of cases occur in patients >70 years. PATIENTS AND METHODS: The objective of the current study was to determine (i) the number of elderly (>70 years) patients with advanced/metastatic NSCLC enrolled in phase III trials of the Hellenic Oncology Research Group, (ii) the treatment-related toxicity observed in these patients compared with their younger counterparts, and (iii) the differences in terms of response rate, time to tumor progression (TTP), and overall survival (OS) between younger and older patients. RESULTS: Pooled data from five clinical trials including 1845 patients were analyzed; 1421 (77%) and 424 (23%) were <70 years and ≥70 years, respectively. No difference was observed in terms of the overall response rate and TTP. There was an OS difference between young and older patients, with higher risk for death in older patients. However, when the analysis was carried out after omitting a trial that showed a different trend, no difference was observed. Older patients experienced higher toxicity. CONCLUSIONS: This report supports the feasibility of chemotherapy treatment for older NSCLC patients. Optimization of treatment of older NSCLC patients requires the design of prospective older-specific phase III trials for these patients.

Mechanisms of resistance to epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small-cell lung cancer: clinical and molecular considerations.

Non-Small-Cell Lung Cancer (NSCLC) with somatic mutations of the epidermal growth factor receptor (EGFR) is anticipated to respond to small-molecule tyrosine kinase inhibitors (TKIs) of the EGFR tyrosine kinase. There are, however, patients with EGFR mutated tumors who do not demonstrate tumor response. The most widely accepted mechanism of 'de novo' (inherent) resistance to these TKIs involves mutations of the KRAS gene. KRAS is a downstream mediator of EGFR-induced cell signaling, such mutations appear to be mutually exclusive from EGFR mutations in lung cancer. The first molecular modifier of resistance identified in patients who developed resistance (termed 'acquired resistance') to TK inhibition was a new acquired somatic EGFR mutation (T790M). Today there is an ever-growing series of molecular events that have recently come to the forefront to explain other instances of TKI resistance not attributable to T790M or KRAS. These include a number of molecules that interact with EGFR or form part of its downstream signaling pathway such as HER-2, IGFR-1, MET and B-RAF. Considering that the majority of studies carried out to date with respect to the identification of resistant clones have not used highly sensitive techniques (e.g. allelic discrimination to identify somatic mutations), coupled with the relatively low number of studies examining multiple molecular markers and the accepted molecular heterogeneity of NSCLC raise question as to the existence of 'acquired' versus 'de-novo' resistance. By examining the current knowledge base with respect to mechanisms of resistance to EGFR TKIs in NSCLC, we explore whether 'acquired' resistance is 'de-novo' resistance in disguise, and discuss the promises and limitations of molecular stratification with respect to strategies incorporating TKIs in the treatment of NSCLC.

EORTC workshop on clinical trial methodology in older individuals with a diagnosis of solid tumors.

BACKGROUND: Due to the aging of the population, the number of older patients diagnosed with a malignant disease is increasing. A multidisciplinary approach to the senior adult cancer patient is mandatory, to assure optimal diagnosis and therapeutic management. DESIGN: European Organisation for Research and Treatment of Cancer (EORTC) has currently defined senior adult oncology as one of its priorities and has established an active Elderly Task Force (ETF). Under the auspices of the EORTC, the ETF organized a workshop on clinical trial methodology in older cancer patients and in this article, we present the conclusions of this workshop. RESULTS: Besides the 'classical' efficacy end points, quality of life, functional status and independence of the patient should be assessed in clinical trials in older patients. The participants of the workshop agreed on the use of a minimum dataset for the assessment of global health and functional status in older cancer patients. The panel also recommended that optimization of collaboration with pharmaceutical industry requires reporting of age-related data (subgroup analyses of clinical trials, age-related pooled analyses and obligatory post-marketing studies in vulnerable and frail older patients). CONCLUSION: The identification of proper clinical outcomes and the validation of geriatric screening tools are needed for conducting sound and comparable clinical trials.

EORTC elderly task force position paper: approach to the older cancer patient.

As a result of an increasing life expectancy, the incidence of cancer cases diagnosed in the older population is rising. Indeed, cancer incidence is 11-fold higher in persons over the age of 65 than in younger ones. Despite this high incidence of cancer in older patients, solid data regarding the most appropriate approach and best treatment for older cancer patients are still lacking, mostly due to under-representation of these patients in prospective clinical trials. The clinical behaviour of common malignant diseases, e.g. breast, ovarian and lung cancers, lymphomas and acute leukaemias, may be different in older patients because of intrinsic variation of the neoplastic cells and the ability of the tumour host to support neoplastic growth. The decision to treat or not these patients should be based on patients' functional age rather than the chronological age. Assessment of patients' functional age includes the evaluation of health, functional status, nutrition, cognition and the psychosocial and economic context. The purpose of this paper is to focus on the influence of age on cancer presentation and cancer management in older cancer patients and to provide suggestions on clinical trial development and methodology in this population.

Questionnaires and instruments for a multidimensional assessment of the older cancer patient: what clinicians need to know?

Due to the ageing of the population in the Western world, a significant increase in the number of older patients diagnosed with neoplastic diseases is observed. Hence, there is an emerging need for tools to efficiently evaluate older patients' functional and global status. These tools can allow treating oncologists to better select patients, to propose treatment modifications, implement supportive measures and develop interventions to decrease the risk of toxicity and in general better tailor the treatment plan on an individual level. Currently significant uncertainty exists about the optimal tools and strategy for geriatric assessment, but on the other hand there is more than enough evidence that (some form of) geriatric assessment detects many previously unrecognised problems, and allows directed intervention which can improve outcome and compliance of proposed treatments. In the present paper, we discuss the most commonly used and studied tools for the assessment of functional status of older cancer patients.

Is age a negative prognostic factor for the treatment of advanced/metastatic non-small-cell lung cancer?

As a result of an increasing life expectancy, the incidence of non-small-cell lung cancer (NSCLC) in the older population is rising. As a consequence oncologists and their older patients commonly face the dilemma of whether or not to give/receive treatment for NSCLC. The current evidence supports the safety and efficacy of treatment for NSCLC cancer in fit older patients and demonstrates that treatment outcome can be similar to that of their younger counterparts and that chronological age per se is not a negative prognostic factor. However, it should be noted that these data are derived from retrospective studies which are likely to suffer from selection bias. Prospective data support the use of third generation single-agent (vinorelbine, gemcitabine, docetaxel) as first-line treatment for older NSCLC patients. Although cisplatin-based doublets represent the cornerstone of chemotherapy treatment for advanced/metastatic NSCLC their role in the treatment of older patients needs to be further elucidated. Despite a growing body of data, further work is still needed to establish optimal strategies to care for this special population and prospective specific trials for older NSCLC patients are clearly needed.

EORTC Elderly Task Force experts' opinion for the treatment of colon cancer in older patients.

As a result of an increasing life expectancy, the incidence of colon cancer in the older population is rising. As a consequence oncologists and their older patients commonly face the dilemma of whether or not to give/receive treatment for colon cancer. However, the paucity of large, well conducted prospective trials makes it difficult to provide evidence-based clinical recommendations for these patients. The current evidence supports the safety and efficacy of treatment for colon cancer in fit older patients and demonstrates that treatment outcome can be similar to that of their younger counterparts. However, it should be noted that these data are derived from retrospective studies which are likely to suffer from selection bias. Despite a growing body of data, further work is still needed to establish optimal strategies to care for this special population and prospective specific trials for older colon cancer patients are clearly needed.

EORTC Elderly Task Force and Lung Cancer Group and International Society for Geriatric Oncology (SIOG) experts' opinion for the treatment of non-small-cell lung cancer in an elderly population.

Non-small-cell lung cancer (NSCLC) represents a common health issue in the elderly population. Nevertheless, the paucity of large, well-conducted prospective trials makes it difficult to provide evidence-based clinical recommendations for these patients. The present paper reviews the currently available evidence regarding treatment of all stages of NSCLC in elderly patients. Surgery remains the standard for early-stage disease, though pneumonectomy is associated with higher incidence of postoperative mortality in elderly patients. Given the lack of demonstrated benefit for the use of adjuvant radiotherapy, it is also not recommended in elderly patients. Elderly patients seem to derive the same benefit from adjuvant chemotherapy as younger patients do, with no significant increase in toxicity. For locally advanced NSCLC, concurrent chemoradiotherapy may be offered to selected elderly patients as there is a higher risk for toxicity reported in the elderly population. Third-generation single-agent treatment is considered the standard of care for patients with advanced/metastatic disease. Platinum-based combination chemotherapy needs to be evaluated in prospective trials. Unfortunately, with the exception of advanced/metastatic NSCLC, prospective elderly-specific NSCLC trials are lacking and the majority of recommendations made are based on retrospective data, which might suffer from selection bias. Prospective elderly-specific trials are needed.

Economic evaluation of docetaxel-gemcitabine versus vinorelbine-cisplatin combination as front-line treatment of patients with advanced/metastatic non-small-cell lung cancer in Greece: a cost-minimization analysis.

BACKGROUND: An economic evaluation was undertaken, alongside a randomized phase III study, to assess docetaxel-gemcitabine (DG) relative to vinorelbine-cisplatin (VC) combination as front-line treatment of patients with advanced/metastatic non-small-cell lung cancer. METHODS: No differences were found in efficacy, thus a cost-minimization analysis was carried out. Treatment cost accounts for the administration of first- and second-line chemotherapy, for concomitant medications, for laboratory and biochemical examinations, and for hospitalizations due to adverse events. Unit prices used reflect 2008 and are common among National Health Service hospitals in Greece. RESULTS: The mean total cost of therapy in the DG group [14045 euros, 95% uncertainty interval (UI) 12628 euros-15390 euros], was significantly higher than in the VC group (8143 euros, 95% UI 7314 euros-9067 euros). CONCLUSIONS: Even though the combination VC has similar effectiveness compared with DG in patients with metastatic lung cancer, it is associated with a lower overall treatment cost and hence, it is preferable from an economic perspective. However, it should be noted that although VC is associated with lower cost, it is also more toxic than DG regimen, a significant parameter that should be considered in clinical decisions.