Michela Tiberi

Prognostic models to predict survival in patients with advanced non-small cell lung cancer treated with first-line chemo- or targeted therapy

Background We aimed to assess the prognostic role of neutrophilia, lymphocytopenia and the neutrophil-to-lymphocyte ratio (NLR), and to design models to define the prognosis of patients receiving first-line chemo- or targeted therapy for advanced non-small cell lung cancer (NSCLC). Materials and Methods We retrospectively analysed 401 consecutive patients with advanced NSCLC treated with first line chemo- or targeted therapy. Patients were stratified into two groups with pre-treatment NLR ≥ 3.7 (Group A) vs. < 3.7 (Group B). The best NLR cut-off was identified by ROC curve analysis. Results At baseline 264 patients had NLR≥3.7 (Group A), whilst 137 had lower NLR (Group B). Median OS was 10.8 months and 19.4 months in the two groups (p < 0.001), while median PFS was 3.6 months and 5.6 months, respectively (p = 0.012). At multivariate analysis, ECOG-PS≥2, stage IV cancer, non-adenocarcinoma histology, EGFR wild-type status and NLR were predictors of worse OS. Stage IV cancer, wild type EGFR status and NLR≥3.7 were independent prognostic factors for worse PFS. Patients were stratified according to the presence of 0-1 prognostic factors (8%), 2-3 factors (73%) and 4-5 factors (19%) and median OS in these groups was 33.7 months, 14.6 months and 6.6 months, respectively (p < 0.001). Similarly, patients were stratified for PFS based on the presence of 0-1 prognostic factor (15%), 2 factors (41%) and 3 factors (44%). The median PFS was 8.3 months, 4.6 months and 3.3 months respectively (p < 0.001). Conclusion Pre-treatment NLR is an independent prognostic factor for patients with advanced NSCLC treated with first-line therapies.

Locally advanced rectal cancer: The importance of a multidisciplinary approach

Rectal cancer accounts for a relevant part of colorectal cancer cases, with a mortality of 4-10/100000 per year. The development of locoregional recurrences and the occurrence of distant metastases both influences the prognosis of these patients. In the last two decades, new multimodality strategies have improved the prognosis of locally advanced rectal cancer with a significant reduction of local relapse and an increase in terms of overall survival. Radical surgery still remains the principal curative treatment and the introduction of total mesorectal excision has significantly achieved a reduction in terms of local recurrence rates. The employment of neoadjuvant treatment, delivered before surgery, also achieved an improved local control and an increased sphincter preservation rate in low-lying tumors, with an acceptable acute and late toxicity. This review describes the multidisciplinary management of rectal cancer, focusing on the effectiveness of neoadjuvant chemoradiotherapy and of post-operative adjuvant chemotherapy both in the standard combined modality treatment programs and in the ongoing research to improve these regimens.

Preoperative maximum oxygen consumption is associated with prognosis after pulmonary resection in stage I non-small cell lung cancer.

BACKGROUND The objective of this investigation was to evaluate whether maximum oxygen consumption (VO2max) is a reliable prognostic factor after lung resection for pathologic stage I non-small cell lung cancer (NSCLC). METHODS Observational analysis of 157 patients undergoing pulmonary lobectomy or segmentectomy for pathologic stage I (T1 or T2-N0 only) NSCLC, with preoperative measurement of Vo2max and complete follow-up (2006-2011). Survival was calculated by the Kaplan-Meier method. The log-rank test was used to assess differences in survival between groups. The relationships between survival and several baseline and clinical variables were determined by Cox multivariate analyses. RESULTS The median follow-up time was 40 months. The average preoperative Vo2max was 16.1 mL/kg · min and 69% of predicted value. Sixty-two (40%) patients had a Vo2max below 60%. The median and 5-year overall survivals of patients with preoperative Vo2max above 60% were significantly longer than in those with Vo2max below 60% (median not reached vs 48 months: 73% vs 40%, p=0.0004). Cox regression model showed that an age older than 70 years (p=0.005, hazard ratio 2.3) and Vo2max below 60% (p=0.001, hazard ratio 2.4) were independent prognostic factors significantly associated with overall survival. Cancer-specific survival was also longer in patients with Vo2max above 60% (81% vs 61%, p=0.01). CONCLUSIONS Exercise tolerance may influence the physiologic outcomes associated with cancer that can potentially affect survival. Physical rehabilitation aimed at improving exercise tolerance can possibly improve the long-term prognosis after operations for lung cancer.

Patient satisfaction with health-care professionals and structure is not affected by longer hospital stay and complications after lung resection: a case-matched analysis

OBJECTIVES The objective of this investigation was to assess satisfaction with care of patients with long hospital stay (LHS) or complications after pulmonary resection in comparison with case-matched counterparts with a regular postoperative course. METHODS This is a prospective observational analysis on 171 consecutive patients submitted to pulmonary resections (78 wedges, 8 segmentectomies, 83 lobectomies, 3 pneumonectomies) for benign (35), primary (93) or secondary malignant (43) diseases. A hospital stay >7 days was defined as long (LHS). Major cardiopulmonary complications were defined according to the ESTS database. Patient satisfaction was assessed by the administration of the EORTC IN-PATSAT32 module at discharge. The questionnaire is a 32-item self-administered survey including different scales, reflecting the perceived level of satisfaction about the care provided by doctors, nurses and other personnel. To minimize selection bias, propensity score case-matching technique was applied to generate two sets of matched patients: patients with LHS with counterparts without it; patients with complications with counterparts without it. RESULTS Median length of postoperative stay was 4 days (range 2-43). Forty-one patients (24%) had a hospital stay>7 days and 21 developed cardiopulmonary complications (12%). Propensity score yielded two well-matched groups of 41 patients with and without LHS. There were no significant differences in any patient satisfaction scale between the two groups. The comparison of the results of the patient satisfaction questionnaire between the two matched groups of 21 patients with and without complications did not show significant differences in any scale. CONCLUSIONS Patients experiencing poor outcomes such as long hospital stay or complications have similar perception of quality of care compared with those with regular outcomes. Patient-reported outcome measures are becoming increasingly important in the evaluation of the quality of care and may complement more traditional objective indicators such as morbidity or length of stay.

Hyponatremia normalization as an independent prognostic factor in patients with advanced non-small cell lung cancer treated with first-line therapy.

The aim of the study was to assess, for the first time, the prognostic role of hyponatremia and sodium normalization in patients receiving first-line chemo- or targeted therapy for advanced non-small cell lung cancer. Four hundred thirty-three patients with advanced non small cell lung cancer were treated with first line chemo- or targeted therapy between 2006 and 2015 at our institutions. Patients were stratified in two groups, with or without hyponatremia (group A and B, respectively). Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method. A Cox regression model was carried out for univariate and multivariate analyses. Sixty-nine patients (16%) presented with hyponatremia at the start of first-line therapy. The median OS was 8.78 months in Group A and 15.5 months in Group B (p < 0.001), while the median PFS was 4.1 months and 6.3 months respectively (p = 0.24). In Group A, median OS was significantly higher in patients who normalized their sodium levels (11.6 vs. 4.7 months, p = 0.0435). Similarly, the median PFS was significantly higher in patients who normalized their sodium levels (6.7 vs. 3.3 months, p = 0.011). At multivariate analysis, sodium normalization was an independent prognostic factor for both OS and PFS. Sodium normalization during first-line therapy is an independent prognostic factor for OS and PFS in patients with advanced lung cancer treated with first-line therapies. Frequent clinical monitoring and prompt treatment of hyponatremia should be emphasized to optimize the outcome of these patients.

Recurrent air leak soon after pulmonary lobectomy: an analysis based on an electronic airflow evaluation†.

OBJECTIVES The objective of this analysis was to evaluate the incidence and risk factors of recurrent air leak (RAL) occurring soon after pulmonary lobectomy based on electronic airflow measurements. METHODS A prospective observational analysis of 129 consecutive patients managed with a single chest tube connected with an electronic chest drainage system. The incidence and timing of RAL among patients who had an air leak sealed within the first 24 postoperative hours was recorded. Stepwise logistic regression and bootstrap analyses were used to test the association of several baseline and surgical variables with RAL. RESULTS A total of 95 patients (68%) had their air leak stopped within 24 h after the operation. Twelve patients had RAL (13%) after the first stop. All RALs occurred within the first 24 h from operation. Logistic regression showed that the presence of moderate-to-severe chronic obstructive pulmonary disease [COPD; forced expiratory volume in 1 s (FEV1) <80% and FEV1/forced vital capacity ratio <0.7] was an independent risk factor associated with RAL (P = 0.02, bootstrap frequency 83%). Seven of 27 (26%) patients with COPD had RAL, a proportion significantly higher than in patients without COPD (5 of 68, 7.3%, P = 0.03). CONCLUSIONS A large proportion of patients with COPD developed RAL. In this high-risk group, we advise against chest tube removal in the first 24 h after operation, even in the case of absence or cessation of air leak.

Clinical and pathologic predictors of clinical outcome of malignant pleural mesothelioma.

Aims and background Although worldwide use of asbestos has decreased, the incidence of malignant pleural mesothelioma (MPM) is expected to increase over the next few decades. A number of scoring systems has been proposed to assess clinicopathologic features and to predict the prognosis. We assessed the relationship between patients’ features and disease evolution in order to choose the best treatment able to prolong overall survival (OS) and progression-free survival (PFS). Methods We retrospectively analyzed patients with locally advanced or metastatic MPM, treated at the Department of Medical Oncology, Università Politecnica Marche, Italy, from January 2003 to September 2013. Data on age, sex, smoking history, asbestos exposure, performance status, tumor stage, histology, type of treatment, and routine laboratory tests including complete blood count panel, date of death, or censored status were collected. The OS and PFS were estimated using Kaplan-Meier method and Cox analysis was performed to analyze the prognostic relevance of clinical parameters. Results We enrolled a total of 62 patients. Univariate analysis showed that histologic type, performance status, response to first-line therapy, pretreatment hemoglobin levels, and plasmatic Ca125 were significant prognostic factors. Conversely, no significant correlation was found between age, sex, smoking history, reported exposure to asbestos, stages at diagnosis, treatments, and OS and PFS. Conclusions Our results showed that anemia and increased Ca125 might be considered negative prognostic parameters in MPM patients and confirmed the prognostic role of histotype, performance status, and response to first-line chemotherapy.

Video-assisted thoracic surgery lobectomy does not offer any functional recovery advantage in comparison to the open approach 3 months after the operation: a case matched analysis†

OBJECTIVES The objective of the present study was to compare functional loss [forced expiratory volume in one second to forced vital capacity ratio (FEV1), DLCO and VO2max reduction] after VATS versus open lobectomies. METHODS We performed a prospective observational study on 195 patients who had a pulmonary lobectomy from June 2010 to November 2014 and who were able to complete a 3-months functional evaluation follow-up program. Since the VATS technique was our first choice for performing lobectomies from January 2012, we divided the patients into two groups: the OPEN group (112 patients) and the VATS group (83 patients). The open approach was intended as a muscle sparing/nerve sparing lateral thoracotomy. Fourteen baseline factors were used to construct a propensity score to match the VATS-group patients with their OPEN-group counterparts. These two matched groups were then compared in terms of reduction of FEV1, DLCO and VO2max (Mann-Whitney test). RESULTS The propensity score analysis yielded 83 well-matched pairs of OPEN and VATS patients. In both groups, 3 months postoperatively, we found a reduction in FEV1, DLCO and VO2max values (OPEN patients: FEV1-10%, DLCO -11.9%, VO2max - 5.5%; VATS patients: FEV1-7.2%, DLCO-10.6%, VO2max-6.9%). The reductions in FEV1, DLCO and VO2max were similar to those in the two matched groups, with a Cohen effect size <0.2 for all the comparisons. CONCLUSIONS In 3 months, both OPEN patients and VATS patients experienced a reduction in their preoperative functional parameters. VATS lobectomy does not offer any advantages in terms of FEV1, DLCO and exercise capacity recovery in comparison to the muscle-sparing thoracotomy approach.

Clinical pathway for thoracic surgery in an Italian centre

Clinical care pathways are developed to standardize postoperative patient care and the main impetus is to improve quality of care, decrease variation in care and reduce costs. We report the clinical pathway of care adopted at our centre since the introduction of Uniportal VATS program for major lung resections.

Abstract 2220: Impact of single-nucleotide polymorphisms (SNPs) on thymic hyperplasia and tumors outcome

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Thymic Hyperplasia refers to an enlargement of the thymus, while thymomas display significant heterogeneity from morphologic point of view, clinical behaviour, expression of immunohistochemical markers and molecular profiling. Therefore improving our understanding of the molecular biology of thymic disorders represents a key challenge in the treatment of these rare diseases. Methods: The genomic DNA of 93 consecutive patients undergoing total thymectomy at our Institution was extracted from paraffin-embedded tissue. We selected the following SNPs: Hypoxia Inducible Factor-1 alpha (HIF1a: rs2057482T>C, rs1951795A>C, rs2301113C>A, rs10873142C>T, rs11158358G>C, rs12434438G>A, rs11549465C>T, rs11549467G>A), Vascular Endothelial Growth Factor-A (VEGF-A: rs2010963G>C, rs699947A>C), VEGF Receptor 2 (VEGFR-2: rs2305948C>T, rs1870377T>A), VEGFR-3 (rs307826T>C, rs307821C>A), Platelet-Derived Growth Factor-A (PDGFR-A: rs35597368C>T). Gene polymorphisms were determined by Real-Time PCR using TaqMan assays. Results: 93 patients were included into the study, 58 females and 35 males. The patients underwent surgery: 43 for thymomas, 14 for thymic carcinomas, 36 for thymic hyperplasia. The frequency of PDGFRa rs35597368T (95.24%) was significantly higher in thymic malignancies if compared with data available for population (86%, p=0.012), thus suggesting that it may represent a risk factor for this type of disease. On the other hand, the frequency of several HIF-1a polymorphisms (rs2057482C, rs11549465C, rs1951795C, rs2301113A, rs10873142T, rs11158358C, rs12434438A) resulted lower in our study than in the general population (p<0.05). In particular, frequencies of HIF1a rs1951795C, rs2301113A, rs12434438A were significantly lower in thymic malignancy than in thymic hyperplasia and moreover these were lower than population, according to available literature data on other types of tumors, suggesting a protective role. Furthermore, VEGFR3 rs307821C polymorphism was higher in thymoma than in thymic carcinoma (79.5% vs 72%, p=0.0371), and therefore it seems to be related to a lower grade of malignancy. Finally, the following factors were significantly correlated with a better overall survival: VEGFR-3 rs307826C, VEGFR-2 rs1870377A, PDGFR-A rs35597368T/C, HIF1a rs2301113C, rs2057482C/T, rs1951795C, rs11158358G/C and rs10873142T/C (p<0.05). Conclusion: To the best of our knowledge this is the largest monocentric study analyzing the angiogenetic variants in thymic hyperplasia and tumors representing a further asset in the definition of high-risk patients after curative resection, also driving the selection of more aggressive adjuvant treatment in this subgroup of patients. The selection tool deriving from this analysis may allow an optimal use of innovative treatment strategies in thymic malignancies including targeted agents such as sunitinib, sorafenib or pazopanib. Citation Format: Rossana Berardi, Silvia Pagliaretta, Alessandro Brunelli, Vittorio Paolucci, Gaia Goteri, Majed Refai, Cecilia Pompili, Agnese Savini, Giulia Marcantognini, Mariangela Torniai, Michela Tiberi, Consuelo Ferrini, Francesca Morgese, Miriam Caramanti, Silvia Rinaldi, Azzurra Onofri, Antonio Zizzi, Paola Mazzanti, Stefano Cascinu. Impact of single-nucleotide polymorphisms (SNPs) on thymic hyperplasia and tumors outcome. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2220. doi:10.1158/1538-7445.AM2014-2220