Vasari Scoring System in Discerning between Different Degrees of Glioma and IDH Status Prediction: A Possible Machine Learning Application?

(1) The aim of our study is to evaluate the capacity of the Visually AcceSAble Rembrandt Images (VASARI) scoring system in discerning between the different degrees of glioma and Isocitrate Dehydrogenase (IDH) status predictions, with a possible application in machine learning. (2) A retrospective study was conducted on 126 patients with gliomas (M/F = 75/51; mean age: 55.30), from which we obtained their histological grade and molecular status. Each patient was analyzed with all 25 features of VASARI, blinded by two residents and three neuroradiologists. The interobserver agreement was assessed. A statistical analysis was conducted to evaluate the distribution of the observations using a box plot and a bar plot. We then performed univariate and multivariate logistic regressions and a Wald test. We also calculated the odds ratios and confidence intervals for each variable and the evaluation matrices with receiver operating characteristic (ROC) curves in order to identify cut-off values that are predictive of a diagnosis. Finally, we did the Pearson correlation test to see if the variables grade and IDH were correlated. (3) An excellent ICC estimate was obtained. For the grade and IDH status prediction, there were statistically significant results by evaluation of the degree of post-contrast impregnation (F4) and the percentage of impregnated area (F5), not impregnated area (F6), and necrotic (F7) tissue. These models showed good performances according to the area under the curve (AUC) values (>70%). (4) Specific MRI features can be used to predict the grade and IDH status of gliomas, with important prognostic implications. The standardization and improvement of these data (aim: AUC > 80%) can be used for programming machine learning software.

Evaluation of the Molecular Landscape in PD-L1 Positive Metastatic NSCLC: Data from Campania, Italy.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have increased and improved the treatment options for patients with non-oncogene-addicted advanced stage non-small cell lung cancer (NSCLC). However, the role of ICIs in oncogene-addicted advanced stage NSCLC patients is still debated. In this study, in an attempt to fill in the informational gap on the effect of ICIs on other driver mutations, we set out to provide a molecular landscape of clinically relevant oncogenic drivers in programmed death-ligand 1 (PD-L1) positive NSCLC patients. METHODS: We retrospectively reviewed data on 167 advanced stage NSCLC PD-L1 positive patients (≥1%) who were referred to our clinic for molecular evaluation of five driver oncogenes, namely, EGFR, KRAS, BRAF, ALK and ROS1. RESULTS: Interestingly, n = 93 (55.7%) patients showed at least one genomic alteration within the tested genes. Furthermore, analyzing a subset of patients with PD-L1 tumor proportion score (TPS) ≥ 50% and concomitant gene alterations (n = 8), we found that n = 3 (37.5%) of these patients feature clinical benefit with ICIs administration, despite the presence of a concomitant KRAS gene alteration. CONCLUSIONS: In this study, we provide a molecular landscape of clinically relevant biomarkers in NSCLC PD-L1 positive patients, along with data evidencing the clinical benefit of ICIs in patient NSCLC PD-L1 positive alterations.

Epigenetic Regulation in Melanoma: Facts and Hopes.

Cutaneous melanoma is a lethal disease, even when diagnosed in advanced stages. Although recent progress in biology and treatment has dramatically improved survival rates, new therapeutic approaches are still needed. Deregulation of epigenetics, which mainly controls DNA methylation status and chromatin remodeling, is implied not only in cancer initiation and progression, but also in resistance to antitumor drugs. Epigenetics in melanoma has been studied recently in both melanoma preclinical models and patient samples, highlighting its potential role in different phases of melanomagenesis, as well as in resistance to approved drugs such as immune checkpoint inhibitors and MAPK inhibitors. This review summarizes what is currently known about epigenetics in melanoma and dwells on the recognized and potential new targets for testing epigenetic drugs, alone or together with other agents, in advanced melanoma patients.

Bone Metastases from Gastric Cancer: What We Know and How to Deal with Them.

Gastric cancer (GC) is the third cause of cancer-related death worldwide; the prognosis is poor especially in the case of metastatic disease. Liver, lymph nodes, peritoneum, and lung are the most frequent sites of metastases from GC; however, bone metastases from GC have been reported in the literature. Nevertheless, it is unclear how the metastatic sites may affect the prognosis. In particular, knowledge about the impact of bone metastases on GC patients' outcome is scant, and this may be related to the rarity of bone lesions and/or their underestimation at the time of diagnosis. In fact, there is still a lack of specific recommendation for their detection at the diagnosis. Then, the majority of the evidences in this field came from retrospective analysis on very heterogeneous study populations. In this context, the aim of this narrative review is to delineate an overview about the evidences existing about bone metastases in GC patients, focusing on their incidence and biology, the prognostic role of bone involvement, and their possible implication in the treatment choice.

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Status and Novel Perspectives.

Immune checkpoint inhibitors (ICIs) represent a promising treatment for many kinds of cancers, including hepatocellular carcinoma (HCC). The rationale for using ICIs in HCC is based on the immunogenic background of hepatitis and cirrhosis and on the observation of high programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes in this cancer. Promising data from phase I/II studies in advanced HCC, showing durable objective response rates (~20% in first- and second-line settings) and good safety profile, have led to phase III studies with ICIs as single agents or in combination therapy, both in first and second line setting. While the activity of immunotherapy agents as single agents seems to be limited to an "ill-defined" small subset of patients, the combination of the anti PD-L1 atezolizumab and anti-vascular endothelial growth factor bevacizumab revealed a benefit in the outcomes when compared to sorafenib in the first line. In addition, the activity and efficacy of the combinations between anti-PD-1/anti-PD-L1 antibody and other ICIs, tyrosine kinase inhibitors, or surgical and locoregional therapies, has also been investigated in clinical trials. In this review, we provide an overview of the role of ICIs in the management of HCC with a critical evaluation of the current status and future directions.

Impact of COVID-19 outbreak on cancer immunotherapy in Italy: a survey of young oncologists.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has overwhelmed the health systems worldwide. Data regarding the impact of COVID-19 on cancer patients (CPs) undergoing or candidate for immune checkpoint inhibitors (ICIs) are lacking. We depicted the practice and adaptations in the management of patients with solid tumors eligible or receiving ICIs during the COVID-19 pandemic, with a special focus on Campania region. METHODS: This survey (25 questions), promoted by the young section of SCITO (Società Campana di ImmunoTerapia Oncologica) Group, was circulated among Italian young oncologists practicing in regions variously affected by the pandemic: high (group 1), medium (group 2) and low (group 3) prevalence of SARS-CoV-2-positive patients. For Campania region, the physician responders were split into those working in cancer centers (CC), university hospitals (UH) and general hospitals (GH). Percentages of agreement, among High (H) versus Medium (M) and versus Low (L) group for Italy and among CC, UH and GH for Campania region, were compared by using Fisher's exact tests for dichotomous answers and χ2 test for trends relative to the questions with 3 or more options. RESULTS: This is the first Italian study to investigate the COVID-19 impact on cancer immunotherapy, unique in its type and very clear in the results. The COVID-19 pandemic seemed not to affect the standard practice in the prescription and delivery of ICIs in Italy. Telemedicine was widely used. There was high consensus to interrupt immunotherapy in SARS-CoV-2-positive patients and to adopt ICIs with longer schedule interval. The majority of the responders tended not to delay the start of ICIs; there were no changes in supportive treatments, but some of the physicians opted for delaying surgeries (if part of patients' planned treatment approach). The results from responders in Campania did not differ significantly from the national ones. CONCLUSION: Our study highlights the efforts of Italian oncologists to maintain high standards of care for CPs treated with ICIs, regardless the regional prevalence of COVID-19, suggesting the adoption of similar solutions. Research on patients treated with ICIs and experiencing COVID-19 will clarify the safety profile to continue the treatments, thus informing on the most appropriate clinical conducts.

Multicenter Single-Arm, Two-Stage Phase 2 Study of Panitumumab in Patients With Cetuximab-Refractory Metastatic Colorectal Cancer: The PACER Trial.

PURPOSE: To assess whether panitumumab is active in patients with cetuximab-refractory metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Eligible patients had pretreated RAS (renin-angiotensin system) wild-type mCRC that progressed after cetuximab treatment, after having shown either objective response or stable disease. A minimax two-stage design was applied, with progression-free rate at 2 months as the primary end point. At least 12 of 28 and 21 of 41 successes at the first and second stage, respectively, were required for a positive result. Panitumumab 6 mg/kg was provided every 2 weeks, until progression or unacceptable toxicity. RESULTS: Overall, 52 patients with KRAS (Kirsten rat sarcoma viral oncogene) wild-type disease were enrolled, but 11 were found to have mutated disease after all-RAS retesting. Among 41 eligible patients, median time since diagnosis was 38 months, and 71% experienced an objective response to previous cetuximab. First stage was passed with 12 of 28 patients alive without progression at 2 months. At the second stage, 17 of 41 patients were alive without progression at 2 months. At a median follow-up of 21.8 months, 35 patients experienced disease progression, and 26 died. Median progression-free survival was 2.1 months (95% confidence interval, 1.8-3.6) and median overall survival 6.8 months (95% confidence interval, 4.6-16.6). Most of the patients experienced no adverse reactions; 25% of patients had grade 3 rash. CONCLUSION: According to our study design, panitumumab was not effective in patients with cetuximab-refractory RAS wild-type mCRC.

The role of radiation therapy and systemic therapies in elderly with breast cancer.

The focus of this review deals with the management of elderly patients with early stage breast cancer, discussing the role of systemic therapies [endocrine therapy (ET), chemotherapy, novel agents] and radiation therapy (RT). Several studies have evaluated in elderly low risk patients the possibility of omitting the RT but, at the same time, higher locoregional relapse (LR) rates without significant impact on overall survival (OS) were observed in all studies when RT was excluded. Technological improvements [intensity-modulated RT (IMRT), volumetric modulated arc therapy (VMAT), high dose brachy therapy (HDBT)] are very useful in order to reduce cosmetic outcome and improve quality of life of frail patients. The optimal sequence of ET, concomitant or sequential to RT, is currently under investigation, and specifically in the elderly it is questioned the possible choice of prolonged therapy after standard 5 years. Data regarding chemotherapy suggesting no benefit of OS in endocrine responsive diseases, whereas endocrine non-responsive breast cancer still showed a better outcome. Cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen is recognized as the standard protocol, although age-dependent increase in therapy related mortality was reported. Neoadjuvant chemotherapy in elderly showed a lower ratio of pathological complete response in comparison to younger patients, but triple negative breast cancer patients showed a good prognosis regarding OS, comparable to younger patients. The risk of cardiotoxicity seems to increase with age, so the use trastuzumab in this setting is much debated. Currently, other anti-HER2 agents (pertuzumab, lapatinib) are used in neoadjuvant setting, but the data on elderly are still premature. Novel molecules are rapidly changing the clinical management of breast cancer patients but are tested especially in locally advanced and metastatic setting. Among these, particularly interesting are inhibitors of CDK4 and 6, alpelisib (PI3K enzymes mutations), immune checkpoint (PD1, PDL1, CTLA4) inhibitors, atezolizumab. Elderly patients are under-represented in clinical trials, although ageing can be frequently correlated with a decrease in the effectiveness of the immune system. For elderly women, treatment decisions should be individually decided, taking into account the geriatric assessment and limited life expectancy and tumor characteristics.

Progress and challenges in the treatment of small cell lung cancer.

Small cell lung cancer (SCLC) is a very aggressive malignancy characterized by high cellular proliferation and early metastatic spread. In fact, although SCLC is a chemosensitive and radiosensitive disease, the initial responsiveness to chemotherapy is usually followed by development of resistance and the prognosis remains poor with a median survival of less than 12 months in patients with extensive disease (ED-SCLC). Furthermore, no significant progress has been made over the last years, with no newly approved drug. For all these reasons, SCLC represents for the oncologists a major challenge and an exciting field of clinical research. In this review, we analyze the most promising advances in development for SCLC with a special focus on antiangiogenic treatments, immunotherapy, novel chemotherapeutic and targeted agents.

Afatinib: An overview of its clinical development in non-small-cell lung cancer and other tumors.

Afatinib is an oral, irreversible, tyrosine kinase inhibitor (TKI) of EGFR, HER2 and HER4. According to phase I studies, the recommended dose of afatinib was 50mg daily. Rash, acne, diarrhea and stomatitis were the most common adverse events. Afatinib failed to demonstrate an improvement in overall survival in unselected heavily pretreated NSCLC patients (Lux-Lung-1). On the contrary, the Lux-Lung-3 and -6 trials met the primary end point, demonstrating a significant increase in terms of PFS with afatinib compared with chemotherapy in the first line treatment of EGFR mutant patients. Moreover, in both studies, afatinib improved overall survival in patients with exon 19 EGFR deletion (31.7 vs 20.7 months; HR: 0.59, p=0.0001). The results of ongoing randomized trials should further clarify the efficacy of afatinib compared with first-generation TKIs in advanced NSCLC, its activity in the adjuvant and neoadjuvant settings, as well as its efficacy in other tumors.

How can we improve prognostic models in renal cell carcinoma?

The therapeutic improvements in renal cell carcinoma brought about by the transition from the 'cytokine era' to the 'targeted agents era', have not affected the peculiar prognostic heterogeneity of the disease, nor have they diminished the importance of risk group classification based on easily assessable and commonly available laboratory and clinical variables. In the landmark study conducted by Motzer et al. before biological agents were available, the median survival of patients in the good prognosis group was 20 months, while the patients in the poor-risk group had a median survival time of only 4 months. With the introduction of anti-VEGF agents, overall survival has approximately doubled in all risk classes. In a population-based analysis of 670 patients treated with anti-VEGF agents, either in the first-line setting or in the second-line setting after cytokines, stratification according to the Database Consortium model showed that patients in the favorable risk group had a median overall survival of 43.2 months, while patients in the poor-risk group had a median overall survival of 7.8 months.

Treatment of small cell lung cancer.

Treatment of small cell lung cancer (SCLC) remains a significant challenge for the oncologists. Attempts to improve the results of first-line treatment have all failed so far and no real progress has been made in last years, emphasizing the need for novel strategies of treatment and the development of validated biomarkers. Patients with limited disease and good performance status should be considered for concomitant chemoradiotherapy, followed by prophylactic cranial irradiation. Patients with extensive disease should be treated with a platinum-based chemotherapy (cisplatin or carboplatin); chest radiotherapy can be considered in patients achieving extra-thoracic complete response and prophylactic cranial irradiation is recommended for patients responsive to initial chemotherapy. A large number of molecular-targeted drugs and immunomodulators are currently in clinical development: however, only a better understanding of molecular biology of SCLC and the identification of molecular markers predictive of response to targeted agents will lead to advances in the treatment of SCLC.

New biological treatments for gynecological tumors: focus on angiogenesis.

INTRODUCTION: Gynecological tumors are a group of heterogeneous malignancies, with only modest results having been observed thus far with chemotherapy in advanced disease. New insights from pathobiology of these tumors have shed new light on potential new therapeutic targets. Angiogenesis is one of the most important processes involved in tumorigenesis, and effective treatments targeting the angiogenic machinery are now available. AREAS COVERED: In this review, we will focus on angiogenesis as a therapeutic target in gynecological cancer patients. After a brief introduction on the angiogenesis machinery involvement in these malignancies, the most recent clinical data will be discussed. EXPERT OPINION: Although clinical data with antiangiogenics are groundbreaking in several tumors such as ovarian epithelial cancer, overall efficacy of these agents is far from what was initially envisaged. As with other molecular targeted agents, selection of patients who may benefit from these agents will surely contribute to demonstrating better results. However, this does not diminish the clinical relevance of the above-mentioned results in a difficult field such as gynecological malignancies.

Combining anti-Epidermal Growth Factor Receptor (EGFR) and anti-angiogenic strategies in advanced NSCLC: we should have known better .

Drugs directed against Epidermal Growth Factor Receptor (EGFR), namely tyrosine kinase inhibitors erlotinib and gefitinib, and anti-angiogenic agents, namely the anti-Vascular Endothelial Growth Factor (VEGF) antibody bevacizumab, have independently demonstrated clinical benefit in the treatment of patients with advanced non-small cell lung cancer (NSCLC), and are currently approved for use in clinical practice. Pre-clinical studies have shown promising results with the combination of anti-EGFR and anti-angiogenesis drugs in different tumor models, including NSCLC. Several clinical trials have been conducted to verify if the combination of the two therapeutic strategies could improve the outcome in the setting of advanced NSCLC. The largest body of evidence has been produced testing the combination of erlotinib plus bevacizumab, or erlotinib plus a multi-targeted receptor tyrosine kinase inhibitor, namely sunitinib or sorafenib. Furthermore, several dual inhibitors, targeting both EGFR and VEGFR, have been tested in advanced NSCLC, with the greatest body of evidence produced with vandetanib. However, despite an intriguing pre-clinical background, the combination strategy has not yet produced clinically relevant results. Several phase III trials showed an improvement in progression-free survival, underlining some activity of targeting both pathways concurrently, but no trial has demonstrated an impact on overall survival to date. Unfortunately, the vast majority of trials conducted in this setting have been performed without any selection criteria based on molecular characteristics, compromising the chance of detecting a potentially relevant benefit in selected subgroup of patients. In recent years, the important interaction between the efficacy of EGFR inhibitors and the presence of EGFR activating mutations in tumor cells has been repeatedly demonstrated. On the other hand, we still have no clear idea about predictive factors of efficacy for bevacizumab and other anti-angiogenic drugs. This is probably the real challenge to optimize the use of these drugs and to fully evaluate the real clinical potential of a combination strategy.

Advanced non-small-cell lung cancer with epidermal growth factor receptor mutations: current evidence and future perspectives.

The identification of activating mutations in the tyrosine kinase domain of the EGF receptor (EGFR) predictive of response to tyrosine kinase inhibitors (TKIs) led to a therapeutic revolution in the treatment of patients with metastatic non-small-cell lung cancer (NSCLC). To date, eight randomized clinical trials have demonstrated that first-line treatment with TKIs in advanced NSCLC patients harboring activating EGFR mutations is associated with significant improvement in response rate, progression-free survival, quality of life and tolerability, compared with platinum-based chemotherapy. These results prompted the EGFR TKIs as the current standard first-line treatment of patients with advanced NSCLC harboring activating EGFR mutations. However, there are several questions that need to be addressed, including the best choice among different EGFR TKIs, the treatment of resistant disease and of patients with specific clinical conditions. Ongoing and future, well-designed trials should answer all these questions.

Early PET/CT scan is more effective than RECIST in predicting outcome of patients with liver metastases from colorectal cancer treated with preoperative chemotherapy plus bevacizumab.

UNLABELLED: Markers predictive of treatment effect might be useful to improve the treatment of patients with metastatic solid tumors. Particularly, early changes in tumor metabolism measured by PET/CT with (18)F-FDG could predict the efficacy of treatment better than standard dimensional Response Evaluation Criteria In Solid Tumors (RECIST) response. METHODS: We performed PET/CT evaluation before and after 1 cycle of treatment in patients with resectable liver metastases from colorectal cancer, within a phase 2 trial of preoperative FOLFIRI plus bevacizumab. For each lesion, the maximum standardized uptake value (SUV) and the total lesion glycolysis (TLG) were determined. On the basis of previous studies, a ≤ -50% change from baseline was used as a threshold for significant metabolic response for maximum SUV and, exploratively, for TLG. Standard RECIST response was assessed with CT after 3 mo of treatment. Pathologic response was assessed in patients undergoing resection. The association between metabolic and CT/RECIST and pathologic response was tested with the McNemar test; the ability to predict progression-free survival (PFS) and overall survival (OS) was tested with the Log-rank test and a multivariable Cox model. RESULTS: Thirty-three patients were analyzed. After treatment, there was a notable decrease of all the parameters measured by PET/CT. Early metabolic PET/CT response (either SUV- or TLG-based) had a stronger, independent and statistically significant predictive value for PFS and OS than both CT/RECIST and pathologic response at multivariate analysis, although with different degrees of statistical significance. The predictive value of CT/RECIST response was not significant at multivariate analysis. CONCLUSION: PET/CT response was significantly predictive of long-term outcomes during preoperative treatment of patients with liver metastases from colorectal cancer, and its predictive ability was higher than that of CT/RECIST response after 3 mo of treatment. Such findings need to be confirmed by larger prospective trials.

Randomized phase III trial of gemcitabine and cisplatin vs. gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: the CAPPA-2 study.

Platinum-based chemotherapy is the standard treatment for patients with advanced non-small cell lung cancer (NSCLC), but the evidence of its efficacy among ECOG performance status (PS)2 patients is weak because these patients are usually excluded from clinical trials; concern exists about tolerability and feasibility of standard chemotherapy in these patients. No prospective randomized trial has tested the addition of cisplatin to single-agent chemotherapy in patients with advanced NSCLC and PS2. CAPPA-2 was a multicenter, randomized phase 3 study for first-line treatment of PS2 patients with advanced NSCLC. Patients, aged 18-70, were eligible if they had stage IV or IIIB with malignant pleural effusion or metastatic supraclavicular nodes (TNM VI edition) and adequate organ function. Patients in standard arm received gemcitabine 1200 mg/m(2) days 1 and 8. Patients in experimental arm received cisplatin 60 mg/m(2) day 1 plus gemcitabine 1000 mg/m(2) days 1 and 8. All treatments were repeated every 3 weeks, up to 4 cycles, unless disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS). To have 80% power of detecting hazard ratio (HR) 0.71, corresponding to an increase in median OS from 4.8 to 6.8 months, 285 deaths were required. The study was stopped in June 2012 after the enrolment of 57 patients, due to the slow accrual and the report of positive results from a similar study. Median OS was 3.0 months with single-agent gemcitabine and 5.9 months with cisplatin plus gemcitabine (HR 0.52, 95% CI 0.28-0.98, p = 0.039). Combination chemotherapy produced longer PFS (median 1.7 vs. 3.3 months, HR 0.49, 95% CI 0.27-0.89, p = 0.017) and higher response rate (4% vs. 18%, p = 0.19), without substantial increase in toxicity. The addition of cisplatin to single-agent gemcitabine improves survival as first-line treatment of PS2 patients with advanced NSCLC.

Integrated therapeutic approaches in the treatment of locally advanced non-small cell lung cancer.

Treatment of locally advanced non-small cell lung cancer (NSCLC) remains a significant challenge for oncologists, despite progress made in recent years in early diagnosis and therapy. This review focuses on integrated therapeutic approaches of patients with locally advanced NSCLC, summarizing the available evidence for patients with potentially resectable disease (stage IIIA-0/3) and with unresectable disease (stage IIIA-4/IIIB) and discussing several key questions related to the use of integrated approaches in NSCLC. Based on current evidence, neoadjuvant platinum-based combination chemotherapy is a treatment option in patients with potentially resectable stage IIIA-0/3: a 2-drug combination of platinum combined with a third-generation drug seems preferable, and at least 3 cycles of chemotherapy should be administered. There are no definitive evidences of clear superiority of surgery compared to radiotherapy for patients obtaining a response with neoadjuvant treatment: however, surgery is associated with a better local control, and subgroup analyses of randomized trials suggest improved outcome in patients in whom a complete resection could be obtained with a lobectomy, avoiding the increased surgical mortality associated with pneumonectomy. Standard treatment for patients with locally advanced, unresectable NSCLC is currently represented by combination of chemotherapy and radiotherapy. Concomitant approach has been proven superior to the sequential administration, although it is associated with higher risk of toxicity. All patients should be evaluated by a multidisciplinary team, skilled in multimodality treatment and should be counselled about risks and potential benefits of the different therapeutic approaches.

Pharmacokinetic evaluation of capecitabine in breast cancer.

INTRODUCTION: Capecitabine , an oral prodrug of 5-fluorouracil (5-FU), is adsorbed in its intact form through the intestine and metabolized to 5-FU in tumour cells. In metastatic breast cancer (MBC), capecitabine is an effective and well-tolerated therapeutic option both in monotherapy and in combination with chemotherapeutic or molecular-targeted agents. AREAS COVERED: We summarized data on pharmacokinetics and pharmacodynamics of capecitabine. We also produced a general review of the most relevant clinical studies of capecitabine in MBC. A literature search was performed using PubMed database including selected articles published in English language up to October 2012. EXPERT OPINION: The unique pharmacodynamic/pharmacokinetic features represent the bases of the reduced toxicity and the activity of capecitabine in several tumours. Although during the past 10 years there has been an increasing use of this drug in MBC both as single agent and in combination, encouraging results of well tolerated and active combinations with novel agents will lead to a more extensive and protracted use of capecitabine. In view of this, some aspects should be further clarified such as the optimal starting dose and the introduction of alternative schedules of treatment.

Prognostic impact of education level of patients with advanced non-small cell lung cancer enrolled in clinical trials.

BACKGROUND: Socioeconomic status can potentially affect prognosis of cancer patients. Our aim was to describe potential differences in demographic and clinical characteristics, treatment, and survival by education level in patients with advanced non-small cell lung cancer (NSCLC) enrolled in clinical trials of first-line treatment. METHODS: Individual data of Italian patients with advanced NSCLC (stage IV, or IIIB with supraclavicular nodes or malignant pleural effusion), ECOG performance status (PS) 0-2, enrolled in four phase III randomized trials conducted between 1996 and 2005 were pooled. Information about education was available for 1680 of 1709 patients (98.3%). Patients were divided in two groups according to education level: high (patients with at least high school diploma) or low (those with less than high school diploma). Survival analyses were stratified by treatment arm within trial. RESULTS: There were 312 (19%) and 1368 (81%) patients with high and low education, respectively. Education level was significantly different among birth cohorts, with a time-trend toward higher education level. Patients with high education were significantly younger (median age 65 vs. 70), were less frequently unfit at diagnosis (ECOG PS2 5% vs. 16%), and their tumor type was more frequently adenocarcinoma (47% vs. 37%). Number of treatment cycles received was not significantly different between education groups. Median survival was 9.4 and 7.6 months in high and low education, respectively (p=0.012). At multivariable analysis, female sex, better PS and high education level (Hazard Ratio 0.85, 95%CI 0.73-0.99, p=0.03) were independently associated with longer survival. CONCLUSIONS: In Italian patients enrolled in four randomized trials of first-line chemotherapy for advanced NSCLC, high education was significantly more frequent among younger patients, and was associated with lower proportion of PS2 patients. Education level did not significantly affect number of chemotherapy cycles received. Overall survival was longer in patients with high education, after adjustment for PS and other prognostic factors. The exact underlying mechanisms of the independent prognostic role of education level are substantially unknown, but lead-time bias (anticipation in diagnosis and time to inclusion in the trial), differences in adherence to care outside the trial procedures, differences in comorbidities and life-style factors may all contribute.