Association of the advanced lung cancer inflammation index (ALI) with immune checkpoint inhibitor efficacy in patients with advanced non-small-cell lung cancer.

BACKGROUND: The advanced lung cancer inflammation index [ALI: body mass index × serum albumin/neutrophil-to-lymphocyte ratio (NLR)] reflects systemic host inflammation, and is easily reproducible. We hypothesized that ALI could assist guidance of non-small-cell lung cancer (NSCLC) treatment with immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: This retrospective study included 672 stage IV NSCLC patients treated with programmed death-ligand 1 (PD-L1) inhibitors alone or in combination with chemotherapy in 25 centers in Greece and Germany, and a control cohort of 444 stage IV NSCLC patients treated with platinum-based chemotherapy without subsequent targeted or immunotherapy drugs. The association of clinical outcomes with biomarkers was analyzed with Cox regression models, including cross-validation by calculation of the Harrell's C-index. RESULTS: High ALI values (>18) were significantly associated with longer overall survival (OS) for patients receiving ICI monotherapy [hazard ratio (HR) = 0.402, P < 0.0001, n = 460], but not chemo-immunotherapy (HR = 0.624, P = 0.111, n = 212). Similar positive correlations for ALI were observed for objective response rate (36% versus 24%, P = 0.008) and time-on-treatment (HR = 0.52, P < 0.001), in case of ICI monotherapy only. In the control cohort of chemotherapy, the association between ALI and OS was weaker (HR = 0.694, P = 0.0002), and showed a significant interaction with the type of treatment (ICI monotherapy versus chemotherapy, P < 0.0001) upon combined analysis of the two cohorts. In multivariate analysis, ALI had a stronger predictive effect than NLR, PD-L1 tumor proportion score, lung immune prognostic index, and EPSILoN scores. Among patients with PD-L1 tumor proportion score ≥50% receiving first-line ICI monotherapy, a high ALI score >18 identified a subset with longer OS and time-on-treatment (median 35 and 16 months, respectively), similar to these under chemo-immunotherapy. CONCLUSIONS: The ALI score is a powerful prognostic and predictive biomarker for patients with advanced NSCLC treated with PD-L1 inhibitors alone, but not in combination with chemotherapy. Its association with outcomes appears to be stronger than that of other widely used parameters. For PD-L1-high patients, an ALI score >18 could assist the selection of cases that do not need addition of chemotherapy.

Vascular endothelial growth factor polymorphisms and clinical outcome in patients with metastatic breast cancer treated with weekly docetaxel.

The aim of the study was to evaluate the association of vascular endothelial growth factor (VEGF) genotypes with treatment efficacy in a phase II trial. This study evaluated weekly docetaxel, as first-line treatment for metastatic breast cancer. Existing data from in vitro and animal model experiments suggest that docetaxel at low doses has anti-angiogenic activity. DNA was extracted from blood samples of 86 patients participating in the trial. Genotyping was performed for selected single-nucleotide polymorphisms (SNPs; VEGF-2578, -1498, -1154, and +936). Moreover, due to the highly polymorphic nature of the studied areas, we were able to analyze additional registered SNPs. All candidate genotypes were evaluated for associations with overall survival (OS), progression-free survival (PFS) and response rate. The VEGF-1154 GG genotype was more frequent in patients not responding to treatment compared with responders (42.9% vs 0.0%, P=0.048). Moreover, the VEGF-2578 AA genotype was associated with longer PFS compared with CC (hazard ratio (HR)=0.40; 95% confidence interval (CI) 0.17-0.98; pairwise P=0.0457). Patients with the VEGF-1190 GG genotype demonstrated shorter PFS compared with those with the alternative genotypes (GA and AA) combined (HR=3.85; 95% CI: 1.20-12.50; P=0.0224). In addition, the VEGF-2551/-2534 homozygous del18bp and VEGF-2430/-2425 homozygous ins1bp genotypes were associated with worse PFS compared with no deletion and no insertion, respectively (HR=2.49; 95% CI: 1.02-6.07; pairwise P=0.0442 and HR=2.57; 95% CI: 1.05-6.27; pairwise P=0.0385, respectively). Furthermore, patients with the VEGF-1498 CC genotype exhibited longer median OS compared with those with the alternatives genotypes (CT and TT) combined (HR=0.27; 95% CI: 0.08-0.89; P=0.0311). In multivariate analysis, the VEGF-2578 AA genotype retained its significance (P=0.0220) for PFS. Our results support the association of specific VEGF genotypes with clinical outcome in patients with metastatic breast cancer treated with a potentially anti-angiogenic regimen, such as weekly docetaxel. However, current results should be validated prospectively in larger cohorts.

Adjuvant therapy in primary GIST: state-of-the-art.

BACKGROUND: The management of primary gastrointestinal stromal tumours (GISTs) has evolved with the introduction of adjuvant therapy. Recently reported results of the SSG XVIII/AIO trial by the Scandinavian Sarcoma Group (SSG) and the German Working Group on Medical Oncology (AIO) represent a significant change in the evidence for adjuvant therapy duration. The objectives of this European Expert Panel meeting were to describe the optimal management and best practice for the systemic adjuvant treatment of patients with primary GISTs. MATERIALS AND METHODS: A panel of medical oncology experts from European sarcoma research groups were invited to a 1-day workshop. Several questions and discussion points were selected by the organising committee prior to the conference. The experts reviewed the current literature of all clinical trials available on adjuvant therapy for primary GISTs, considered the quality evidence and formulated recommendations for each discussion point. RESULTS: Clinical issues were identified and provisional clinical opinions were formulated for adjuvant treatment patient selection, imatinib dose, duration and patient recall, mutational analysis and follow-up of primary GIST patients. Adjuvant imatinib 400 mg/day for 3 years duration is a standard treatment in all patients with significant risk of recurrence following resection of primary GISTs. Patient selection for adjuvant therapy should be based on any of the three commonly used patient risk stratification schemes. R1 surgery (versus R0) alone is not an indication for adjuvant imatinib in low-risk GIST. Recall and imatinib restart could be proposed in patients who discontinued 1-year adjuvant imatinib within the previous 3 months and may be considered on a case-by-case basis in patients who discontinued within the previous year. Mutational analysis is recommended in all cases of GISTs using centralised laboratories with good quality control. Treatment is not recommended in an imatinib-insensitive D842V-mutated GIST. During adjuvant treatment, patients are recommended to be clinically assessed at 1- to 3-month intervals. Upon discontinuation, computed tomography scan (CT) scans are recommended every 3 to 4 months for 2 years when the risk of relapse is highest, followed by every 6 months until year 5 and annually until year 10 after treatment discontinuation. CONCLUSIONS: Key points in systemic adjuvant treatment and clinical management of primary GISTs as well as open questions were identified during this European Expert Panel meeting on GIST management.

Zoledronic acid in patients with stage IIIA/B NSCLC: results of a randomized, phase III study.

BACKGROUND: Bone metastases are common in patients with advanced non-small-cell lung cancer (NSCLC) and can have devastating consequences. Preventing or delaying bone metastases may improve outcomes. PATIENTS AND METHODS: This study evaluated whether zoledronic acid (ZOL) delayed disease progression or recurrence in patients with controlled stage IIIA/B NSCLC after first-line therapy. Patients received vitamin D and calcium supplementation and were randomized to i.v. ZOL (every 3-4 weeks) or no treatment (control). The primary end point was progression-free survival (PFS). RESULTS: No significant intergroup differences were observed in PFS or overall survival (OS). Median PFS was 9.0 months with ZOL versus 11.3 months for control. Fifteen ZOL-treated (6.6%) and 19 control patients (9.0%) developed bone metastases. Estimated 1-year OS was 81.8% for each group. ZOL safety profile was consistent with previous clinical data, but with higher discontinuations versus control. Fifteen ZOL-treated (6.6%) and five control patients (2.3%) had renal adverse events. Two cases of osteonecrosis of the jaw were reported. CONCLUSIONS: ZOL did not significantly affect PFS or OS in stage IIIA/B NSCLC patients with controlled disease, with a trend toward worsening PFS in the longer-term follow-up. Few patients experienced bone metastases, possibly limiting the potential ZOL impact on disease course.

Third CECOG consensus on the systemic treatment of non-small-cell lung cancer.

The current third consensus on the systemic treatment of non-small-cell lung cancer (NSCLC) builds upon and updates similar publications on the subject by the Central European Cooperative Oncology Group (CECOG), which has published such consensus statements in the years 2002 and 2005 (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer--update 2004. Lung Cancer 2005; 50: 129-137). The principle of all CECOG consensus is such that evidence-based recommendations for state-of-the-art treatment are given upon which all participants and authors of the manuscript have to agree (Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). This is of particular importance in diseases in which treatment options depend on very particular clinical and biologic variables (Zielinski CC, Beinert T, Crawford J et al. Consensus on medical treatment of non-small-cell lung cancer--update 2004. Lung Cancer 2005; 50: 129-137; Beslija S, Bonneterre J, Burstein HJ et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 2009; 20 (11): 1771-1785). Since the publication of the last CECOG consensus on the medical treatment of NSCLC, a series of diagnostic tools for the characterization of biomarkers for personalized therapy for NSCLC as well as therapeutic options including adjuvant treatment, targeted therapy, and maintenance treatment have emerged and strongly influenced the field. Thus, the present third consensus was generated that not only readdresses previous disease-related issues but also expands toward recent developments in the management of NSCLC. It is the aim of the present consensus to summarize minimal quality-oriented requirements for individual patients with NSCLC in its various stages based upon levels of evidence in the light of a rapidly expanding array of individual therapeutic options.

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.

EGFR gene copy number as a predictive biomarker for patients receiving tyrosine kinase inhibitor treatment: a systematic review and meta-analysis in non-small-cell lung cancer.

INTRODUCTION: We conducted a systematic review and meta-analysis to assess epidermal growth factor receptor (EGFR) gene copy number as a potential biomarker of survival for patients with advanced non-small-cell lung cancer (NSCLC) receiving single-agent treatment with EGFR tyrosine kinase inhibitors (TKIs). METHODS: We systematically identified articles investigating EGFR gene copy number by fluorescent or chromogenic in situ hybridization in patients with advanced or recurrent NSCLC treated with the TKIs erlotinib or gefitinib, (last search: 31 June 2009). Eligible studies had to report on overall survival (OS), progression-free survival (PFS) or time-to-progression (TTP), stratified by EGFR gene copy number. Summary hazard ratios (HRs) were calculated using random-effects models. RESULTS: Among 255 identified studies, 20 (1689 patients, 594 with increased gene copy number), 10 (822 patients, 290 with increased gene copy number) and 5 (294 patients, 129 with increased gene copy number) were eligible for the OS, PFS and TTP meta-analyses, respectively. Increased EGFR gene copy number was associated with increased OS (HR = 0.77; 95% CI 0.66-0.89; P = 0.001), PFS (HR = 0.60; 95% CI 0.46-0.79; P<0.001) and TTP (HR = 0.50; 95% CI 0.28-0.91; P = 0.02). Among predominantly white populations, increased EGFR gene copy number was strongly associated with improved survival (HR = 0.70; 95% CI 0.59-0.82; P<0.001), whereas it did not influence survival in East Asians (HR = 1.11; 95% CI 0.82-1.50; P=0.50). This difference was statistically significant (P=0.02). CONCLUSION: Among TKI-treated patients, increased EGFR gene copy number appears to be associated with improved survival outcomes. The effect on OS appears to be limited to patients of non-Asian descent.

Paclitaxel and gemcitabine versus paclitaxel and vinorelbine in patients with advanced non-small-cell lung cancer. A phase III study of the Hellenic Cooperative Oncology Group (HeCOG).

BACKGROUND: Paclitaxel (Taxol) and vinorelbine have shown synergism of cytotoxic effects in vitro and clinical activity in phase I and II studies. This combination was compared prospectively with the paclitaxel/gemcitabine regimen in non-operable non-small-cell lung cancer. PATIENTS AND METHODS: Chemotherapy-naive patients, stage IIIbwet and IV with performance status (0-1), were randomized to receive paclitaxel 200 mg/m(2) on day 1 plus gemcitabine 1 gm/m(2) (group A) on days 1 and 8 every 3 weeks or paclitaxel 80 mg/m(2) plus vinorelbine 22.5 mg/m(2) (group B) on days 1, 8 and 15 every 4 weeks. RESULTS: A total of 398 out of 415 patients were eligible for analysis on intent-to-treat basis (group A: 196, group B: 202). Progression-free survival (PFS) was 5.0 months [95% confidence interval (CI) 4.3-5.6] and 4.4 months (95% CI 3.7-5.2) for groups A and B respectively (P=0.365). Median survival was 11.1 months (95% CI 9.2-13.0) and 8.6 months (95% CI 7.0-10.2) for groups A and B respectively (P = 0.147). Grade 3/4 neutropenia and leukopenia were worse in group B (P<0.001, in both cases). Febrile neutropenia and severe infections were more prominent (P<0.001, P=0.029 respectively) in group B. CONCLUSION: Although response rate, PFS and survival were non-different in both groups, toxicity was significantly worse in group B and therefore further investigation of P-Vin is of no value.

Non small cell lung cancer in the elderly: clinico-pathologic, management and outcome characteristics in comparison to younger patients.

It is controversial whether non-small cell lung cancer (NSCLC) in the elderly constitutes a distinct clinico-biological entity compared to younger counterparts. As reported data are scant and discordant, we sought to analyze retrospectively the medical records of Hellenic NSCLC patients aged >70 years and compare them with those of age (70-45 years) and younger (<45 years) patients. Records were abstracted from the Hellenic Cooperative Oncology Group (HeCOG) cancer registry database. Presentation, management and outcome data of 417 elderly patients aged > or =70, 1374 age 70-45 years old and 115 patients aged < or =45 years old with histologically confirmed NSCLC managed from 1989 until 2004 were retrieved and compared. Elderly patients differed significantly in terms of presence of symptoms (p<0.001), including thoracic pain (p=0.003), dyspnea (p<0.001), cough (p<0.001) and fatigue (p<0.001), eastern Cooperative Oncology Group performance status (PS) 2-3 (p<0.001), and histological type (more commonly diagnosed with squamous cell carcinoma (p<0.002) and less frequently with adenocarcinoma). Although elderly patients had significantly higher rates of PS 2-3, they had significantly better median time to disease progression (TTP) compared to the younger counterpart (6.4 versus 4.3 months p=0.047). Overall survival (OS) was not significantly different between elderly and young patients (median OS 11.8 versus 11.5 months; p=0.6), but platinum-based chemotherapy and radiotherapy were variables associated favorably with TTP and survival in the elderly. This large retrospective series presents strong evidence that NSCLC constitutes a similar clinicopathologic entity in elderly and young individuals with discretely differing biological behavior and that elderly symptomatic patients should be considered for effective anticancer treatment whenever possible.

A randomized phase III study comparing three anthracycline-free taxane-based regimens, as first line chemotherapy, in metastatic breast cancer: a Hellenic Cooperative Oncology Group study.

BACKGROUND: Effective anthracycline-free combinations need to be evaluated in metastatic breast cancer (MBC), due to the increased number of patients treated with anthracycline-based adjuvant chemotherapy. PATIENTS AND METHODS: Patients with MBC were randomized to paclitaxel and carboplatin (PCb) every 3 weeks or docetaxel and gemcitabine (GDoc) every 3 weeks or weekly paclitaxel (Pw). Trastuzumab was given to patients with HER-2 over-expressing tumors. The primary endpoint of the study was survival. Quality of life (QoL) and cost were assessed. RESULTS: Totally, 416 eligible patients entered the study. Median survival times were 29.9 months for PCb, 26.9 for GDoc and 41.0 for Pw (P = 0.037). According to multivariate analysis, adjuvant chemotherapy, >1 metastatic sites, lack of maintenance hormonal therapy, and worse performance status (PS) were significant adverse prognostic factors for survival, while Pw when compared to GDoc improved survival (P = 0.03), as well as when compared to PCb in the subgroup of patients with PS = 1 (P = 0.01, treatment by PS interaction P = 0.03). No significant differences in terms of time to progression were found. Severe myelotoxicity and mucositis were more frequent with GDoc, while severe neuropathy with PCb and Pw. QoL changes did not differ significantly between treatment groups, while cost analysis favored Pw. CONCLUSIONS: Pw appears to be the most preferable choice among the 3 anthracycline-free taxanes-based regimens tested in the present study.

Paclitaxel and gemcitabine versus carboplatin and gemcitabine in patients with advanced non-small-cell lung cancer. A phase III study of the Hellenic Cooperative Oncology Group.

BACKGROUND: This phase III study was designed to compare the combination paclitaxel (Taxol)-gemcitabine (PG) versus carboplatin-gemcitabine (CG) in patients with advanced inoperable non-small-cell lung cancer. METHODS: Chemotherapy-naive patients with performance status of zero or one were randomized to gemcitabine 1 gm/m(2) on days 1 and 8 plus either paclitaxel 200 mg/m(2) on day 1 (arm A) or carboplatin at an area under the concentration-time curve of 6 mg on day 1 (arm B) every 3 weeks. Primary end point was overall survival (OS). Secondary end points included objective response (OR), time to progression and toxicity. RESULTS: A total of 512 patients were enrolled and 452 eligible (arm A, 225; arm B, 227) were analyzed. All characteristics were well balanced with the exception of vena cava obstruction symptoms and lymph node involvement. Median survival was 9.97 months [95% confidence interval (CI) 8.74-12.0] for group A and 10.49 (95% CI 9.04-11.94) for group B. There was no difference in the OS, 1-year survival, OR and TtP. However, statistically significant differences were seen in toxicity. CONCLUSION: The two regimens are equally active. Myelotoxicity is worse in the CG group whereas alopecia, myalgia and neurotoxicity worse in the PG group.

Combination chemotherapy with cisplatin, etoposide and irinotecan in patients with extensive small-cell lung cancer: A phase II study of the Hellenic Co-operative Oncology Group.

OBJECTIVE: The purpose of this study was to evaluate the efficacy and toxicity of cisplatin, etoposide and irinotecan as first-line treatment in patients with extensive small-cell lung cancer (E-SCLC). PATIENTS AND METHODS: Chemo-naïve adult patients with a performance status (PS) of 0-2 and adequate organ function were eligible. Patients received cisplatin 20mg/m(2) i.v. daily for three consecutive days, etoposide 75mg/m(2) i.v. daily for three consecutive days and irinotecan 120mg/m(2) i.v. on day 2, every 21 days for six to eight cycles. Administration of G-CSF was given in the presence of febrile neutropenia and as a 5-day prophylaxis around the recorded nadir day in patients who developed grades 3-4 neutropenia. RESULTS: Fifty-six patients were assessable. The median age was 62.2 years; 96.4% had PS 0-1, 33.5% had >3 metastatic sites. The overall response rate was 80.4% with 8 (14.3%) patients achieving a complete response. The median time to tumor progression was 7.8 months [95% confidence interval (CI), 7.1-8.6 months] with a median survival of 15.1 months [95% CI, 9.7-20.5 months] and 1-year survival rate of 56.5%. One patient died from toxicity. Grades 3-4 neutropenia occurred in 37.5% of patients, grades 3-4 thrombocytopenia occurred in 10.9% of patients and 11 (19.6%) patients developed febrile neutropenia. Grades 3-4 non-hematological toxicities were primarily nausea-vomiting 3.6%, diarrhea 7.1% and fatigue 3.6%. CONCLUSION: This study strongly suggests that cisplatin, etoposide and irinotecan combination is very effective for the treatment of E-SCLC with good safety profile. The triplet regimen currently seems a promising regimen and has to be further explored in phase III trials.

Simultaneous deregulation of p16 and cyclin D1 genes in pancreatic ductal adenocarcinoma: a combined immunohistochemistry and image analysis study based on tissue microarrays.

PURPOSE: Deregulation of cell cycle control molecules, such as cyclins and their inhibitors, is a crucial event in the carcinogenetic process. Our aim was to identify potential correlations between p16 and cyclin D1 expression in pancreatic ductal adenocarcinoma (PDAC) that affect the biological behavior of this neoplasm. MATERIALS AND METHODS: Using tissue microarray (TMA) technology, 50 paraffin-embedded tissue samples of histologically confirmed primary PDACs were cored twice and re-embedded to the final recipient block. Immunohistochemistry (IHC) was performed using monoclonal anti-p16 and anti-cyclin D1 antibodies. Protein expression levels were determined by performing computerized image analysis (CIA; estimation of Nuclear Labeling Index-NLI). SPSS (chi square test and interrater Cohen's kappa) was used for statistical analysis. RESULTS: Cyclin D1 overexpression was observed in 24/50 (48%) of the examined carcinomas, whereas p16 loss or reduced expression was detected in 40/50 (80%) cases. Statistical significance was noted when correlating grade to cyclin D1 (p=0.038), stage to p16 (p=0.012) and also to cyclin D1 (p=0.011). Interestingly, combined protein alterations (p16 loss and cyclin D1 overexpression) were observed in 23/50 (46%) cases associated with advanced stage (p=0.019). Overall combined expression of the two molecules demonstrated a significantly low value (kappa=0.012; 95% confidence interval-CI: 0.010-0.014). CONCLUSION: A significant proportion of PDACs is characterized by simultaneous protein alterations regarding p16 and cyclin D1 genes. This mechanism of genetic deregulation in cell cycle potentially explains in part the aggressive phenotype of this neoplasm.

Combination chemotherapy with paclitaxel and gemcitabine followed by concurrent chemoradiotherapy in non-operable localized non-small cell lung cancer. A hellenic cooperative oncology group (HeCOG) phase II study.

UNLABELLED: Concurrent chemoradiotherapy has become a standard therapy for locoregionally advanced inoperable nonsmall cell lung cancer (NSCLC). The purpose of this phase II trial was to evaluate the efficacy and toxicity of concurrent chemoradiotherapy following induction with non-platinum chemotherapy in patients with inoperable locally advanced NSCLC. PATIENTS AND METHODS: All patients with locally advanced inoperable NSCLC ECOG performance status (PS): 0-1 following staging received paclitaxel 200 mg/m2 in a 3-h infusion on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8 every 21 days for two cycles. The patients with a response or stable disease (SD) continued to receive paclitaxel 60 mg/m2 weekly and radiotherapy 63 Gy given at 1.8 Gy once a day for 7 weeks. RESULTS: Forty-three eligible patients entered the study. The median age was 63 years (range 42-76), male 93%, IIIB 63% and IIIA 37%. Following induction 15 (36.5%) of the patients responded: complete response (CR), 2%; partial response (PR), 33%; and 19 (46.5%) SD. From those with SD, 7 (37%) improved to a PR following concurrent chemoradiotherapy. With a median follow-up of 44 months (95% CI: range 36-53) the median survival was 20.8 months (95% CI: range 15.4-26.3) and time-to-progression 8.4 months (95% CI: range 6.2-10.6). The median survival of those who had improved response from SD to PR was 31.4 months (95% CI: range 18.7-44.1) versus 20.8 months (95% CI: range 5.5-11.3) for those who had no improvement (p=0.20). The commonest grade 3/4 toxicity in induction was neutropenia 12% with 2 febrile neutropenic patients whereas in the concurrent chemoradiotherapy neutropenia, neurotoxicity and oesophagitis were observed in 6% of the patients. CONCLUSION: Concurrent chemoradiotherapy following induction chemotherapy in patients with stage III NSCLC is feasible with reasonable efficacy and acceptable toxicity.

Non-small cell lung cancer in the young: a retrospective analysis of diagnosis, management and outcome data.

BACKGROUND: Non-small cell lung cancer (NSCLC) in young patients is uncommon and is thought to constitute a distinct oncological entity with characteristic clinicopathological patterns. Since the reported data are scant and discordant, the presentation, management and outcome data of NSCLC patients aged under 45 years of age were analyzed and compared with those of patients over 45 years old. Prognostic factors for risk classification were also evaluated. MATERIALS AND METHODS: The data were abstracted from the Hellenic Cooperative Oncology Group (HeCOG) cancer registry database. The presentation, management and outcome data of patients with histologically confirmed NSCLC, managed from 1989 until 2004 in HeCOG participating centers, were retrospectively analyzed. The clinicopathological characteristics of patients aged < and > than 45 years old were compared and evaluated for prognostic significance regarding outcome. RESULTS: The data for NSCLC patients (1906), of whom 115 were aged <45, were retrieved. In comparative analysis, the young patients were more frequently asymptomatic at diagnosis, while older patients presented significantly higher rates of thoracic pain, cough and fatigue (p<0.01). The young patients were more commonly diagnosed with adenocarcinoma and less frequently with squamous cancer than patients aged over 45. Although the stage distribution was distinct, with older patients presenting higher rates of stage IV disease (21.9% vs. 12.2%), the rates of early lung cancer (stages I-IIIa) were similar. The overall survival (OS) was not significantly different (median OS 12 vs. 11.5 months, p=0.277). Among patients who underwent first-line palliative chemotherapy, young individuals had a significantly shorter time to progression: 4.3 vs. 5.8 months (p=0.0049). Univariate and multivariate regression analyses established the prognostic usefulness of the performance status, disease stage and disease-free interval for the risk of death, both in the total number of patients (1906) and in young patients (115). CONCLUSION: This large retrospective series failed to present strong evidence that NSCLC among young individuals constitutes a distinct clinicopathological entity with differing biological behavior, since the same clinicopathological prognostic factors were valid in both age groups. Molecular phenotypic studies are needed to shed light on this controversial subject.

Mitoxantrone plus gemcitabine in pretreated patients with metastatic breast cancer.

Gemcitabine and mitoxantrone have both shown significant antitumor activity in patients with breast cancer. The aim of this study was to evaluate the efficacy and safety of this combination as second or third-line treatment in patients with metastatic breast cancer (MBC). Forty-six previously treated patients with MBC were enrolled from June 2000 to November 2002. Mean age was 56 years and ECOG performance status was < or =2. All patients received mitoxantrone 10 mg/m2, D8 and gemcitabine 1000 mg/m2, D1+8 every 21 days for 6 cycles. There were no complete responders. Objective response was observed in 12 patients (26%), 15 (33%) patients had stable disease, 15 (33%) had progressive disease and 4 (9%) were non-evaluable. At median follow-up of 27.8 months, overall survival was 13.3 months (range 0.6-33.8+) and the median time to disease progression (TTP) was 4.4 months (range 0.2-33.8). Toxicities (grade 3-4) were as follows: leukopenia 18 (39%), neutropenia 19 (41%), thrombocytopenia 4 (8.5%), anemia 6 (13%) and alopecia 1 (2%). Febrile neutropenia was recorded in 2 (4%) patients. There were no treatment related deaths. The authors conclude that the combination of mitoxantrone and gemcitabine is an effective regimen in pretreated patients with metastatic breast cancer. Toxicity was manageable.

Vinflunine -- an active chemotherapy for treatment of advanced non-small-cell lung cancer previously treated with a platinum-based regimen: results of a phase II study.

A multicentre, single-arm, phase II trial designed to determine the efficacy of single-agent vinflunine in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with a platinum-based regimen. The objectives were to assess efficacy in terms of tumour response rate (primary end point), duration of response, progression-free survival (PFS) and overall survival (OS), and to evaluate the toxicity associated with this treatment. Patients with advanced NSCLC with progressive disease having failed prior platinum-based first-line treatment for advanced disease. Five responses out of the 63 treated patients were documented by WHO criteria and validated by an independent panel review (IRP), yielding a response rate of 7.9% (95% CI: 2.6-17.6) in the intent-to-treat analysis and 8.3% (95% CI: 2.8-18.4) in the evaluable population. Disease control was achieved in 35 out of 60 evaluable patients (58.3%). The median duration of response (complete response+partial response), according to modified WHO criteria was 7.8 months (95% CI: 4.6-NR). Median PFS was 2.6 months (95% CI: 1.4-3.8), and the median survival was 7.0 months (95% CI: 5.8-9.2). Grades 3-4 neutropenia was reported in 50% of patients; febrile neutropenia was observed in two patients (3.2%); grades 3-4 myalgia and grade 3 constipation were experienced by 10 (15.9%) and six (9.5%) of patients, respectively. Constipation was manageable, non-cumulative and could be prevented with laxative prophylaxis. The encouraging results from this phase II study with vinflunine warrant further investigations in phase III trials as second- or first-line treatment of advanced non-small-cell lung carcinoma, as a single agent or in combination with other active drugs.

Epoetin alfa in platinum-treated ovarian cancer patients: results of a multinational, multicentre, randomised trial.

This multicentre, open-label, controlled clinical trial assessed the effects of epoetin alfa treatment on haematologic and quality of life (QOL) parameters in 182 anaemic (Hb< or = 12 g dl(-1)) ovarian cancer patients receiving platinum chemotherapy. Patients were randomised 2 : 1 to receive epoetin alfa 10,000-20 000 IU three times weekly plus best standard treatment (BST) or BST only. Main study end points were changes from baseline in haemoglobin (Hb) level, transfusion requirements, and QOL. For the epoetin alfa group, mean Hb increased by 1.8 g dl(-1) by weeks 4-6 and was significantly increased from baseline through study end (P<0.001). The mean change in Hb from baseline was significantly (P<0.001) greater for epoetin alfa than BST patients at all post-baseline evaluations. Significantly fewer epoetin alfa than BST patients required transfusion(s) after the first 4 weeks of treatment (7.9 vs 30.5%; P<0.001). Also, significant (P< or = 0.04) differences favouring the epoetin alfa group over the BST group were found for all three median CLAS scores (Energy Level, Ability to Do Daily Activities, Overall QOL) and the median average CLAS score during chemotherapy. These findings support use of epoetin alfa to increase Hb levels, reduce transfusion use, and improve QOL in anaemic ovarian cancer patients receiving platinum chemotherapy.