Patrizia Trenta

Randomized Trial of Two Induction Chemotherapy Regimens in Metastatic Colorectal Cancer: An Updated Analysis

BACKGROUND In a randomized trial with a median follow-up of 18.4 months, 6 months of induction chemotherapy with a three-drug regimen comprising 5-fluorouracil (by continuous infusion)-leucovorin, irinotecan, and oxaliplatin (FOLFOXIRI) demonstrated statistically significant improvements in response rate, radical surgical resection of metastases, progression-free survival, and overall survival compared with 6 months of induction chemotherapy with fluorouracil-leucovorin and irinotecan (FOLFIRI). METHODS From November 14, 2001, to April 22, 2005, we enrolled 244 patients with metastatic colorectal cancer. To evaluate if the superiority of FOLFOXIRI is maintained in the long term, we updated the overall and progression-free survival data to include events that occurred up to February 12, 2009, with a median follow-up of 60.6 months. We performed a subgroup and a risk-stratified analysis to examine whether outcomes differed in specific patient subgroups, and we analyzed the results of treatment after progression. Survival curves were estimated by the Kaplan-Meier method. Multivariable Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS FOLFOXIRI demonstrated statistically significant improvements in median progression-free survival (9.8 vs 6.8 months, HR for progression = 0.59, 95% CI = 0.45 to 0.76, P < .001) and median overall survival (23.4 vs 16.7 months, HR for death = 0.74, 95% CI = 0.56 to 0.96, P = .026) with a 5-year survival rate of 15% (95% CI = 9% to 23%) vs 8% (95% CI = 4% to 14%). The improvements in progression-free survival and, to a lesser extent, in overall survival were evident even when the analysis excluded patients who received radical resection of metastases. With regard to the risk-stratified analysis, FOLFOXIRI results in longer progression-free survival and overall survival than FOLFIRI in all risk subgroups. CONCLUSIONS Six months of induction chemotherapy with FOLFOXIRI is associated with a clinically significant improvement in the long-term outcome compared with FOLFIRI with an absolute benefit in survival at 5 years of 7%.

Targeted therapies and complete responses in first line treatment of metastatic renal cell carcinoma. A meta-analysis of published trials.

Antiangiogenic agents (AAs) have reported grater efficacy compared to interferon. Despite these advances, radiological complete response to therapy is rare. We meta-analyzed the incidence of complete response in patients treated with AAs and in controls in main randomized clinical trials for first-line therapy in metastatic renal cell carcinoma. PubMed was reviewed for phase II-III randomized clinical trials with AAs vs. non-AAs in patients with good or intermediate prognosis. We calculated the relative risk of events in patients assigned to AAs compared to control. Five RCTs were found; four were phase III and one was phase II. A total of 2747 patients was valuable for final analysis and randomized to receive AAs or control. Patients in the control-group had interferon (85%) or placebo (15%); patients in the AAs-group received bevacizumab (48%), sunitinib (26%), pazopanib (20%) or sorafenib (6%). The incidence of complete response in patients treated with AAs was 2.0% (95% CI, 1.2-2.8) compared to 1.4% (95% CI, 0.7-2.1) in the control arm. Comparing the different type of AAs, the incidence of complete response was 2.5% (95% CI, 1.2-3.8) in the bevacizumab group and 1.6% (95% CI, 0.1-2.5) in the TKIs group. The relative risk to have a complete response was 1.52 (95% CI, 0.85-2.73; p=0.16) in patients treated with AAs compared to controls; this was found higher in patients treated with TKIs compared to bevacizumab. The complete response is a rare event in metastatic kidney tumor, even if AAs reported greater efficacy in terms of progression-free survival and of overall response rate, they did not increase the curative rate of metastatic disease. Probably, some biologic factors other than angiogenesis may influence the complete response in this disease.

Incidence and relative risk of hepatic toxicity in patients treated with anti-angiogenic tyrosine kinase inhibitors for malignancy

The aim of this study is to investigate the incidence and risk of hepatic toxicity in patients receiving tyrosine kinase inhibitors (TKIs) through a large up‐to‐date meta‐analysis of available clinical trials.

Clinical and Pathological Features of Primary Neuroectodermal Tumor/Ewing Sarcoma of the Kidney

OBJECTIVE To collect and analyze clinical and pathological features of primitive neuroectodermal tumor (PNET)/Ewing sarcoma (EWS), a rare tumor occurring most commonly in bone and soft tissues of young people, which rarely occurs as a primary renal neoplasm and exhibits highly aggressive biological behavior. METHODS All cases of PNET/EWS published from 1975 to February 2012 were collected. When available, clinical and pathological data were extracted for each case. Survivals were estimated with the Kaplan-Meier method and compared with the log-rank test with 95% confidence interval (CI). RESULTS A total of 116 cases were found. All patients had clinical symptoms as first presentation of disease such as pain (54%), hematuria (29%), and bulky renal mass (28%). Sixty-six percent of patients had stage IV disease at diagnosis. Median disease-free survival (DFS) was 5.0 months (95% CI 2.4-7.6). The probability to be alive at 18 months was 60% and 85% for patients with metastatic disease (M1) or not (M0) at diagnosis, respectively. Median overall survival (OS) was 24 months (95% CI 4.5-15.1) in patients with M1 disease, whereas it was not reached in patients with M0 disease (P <.001). In patients with M0 disease, 50% received neoadjuvant chemotherapy and the 12-month OS was 93% compared to 75% of untreated patients (P = .092). In patients with M1 disease who underwent treatment, the median progression-free survival (PFS) was 22.0 months (95% CI 17.9-26.1) with a clinical benefit in 74% of cases. CONCLUSION Our findings suggest that PNET/EWS is a rare aggressive tumor affecting principally young people, with a poor prognosis for patients with M1 disease; chemotherapy is an effective strategy in M1 disease and probably also in M0 disease.

Clinical outcome and prognostic factors in renal medullary carcinoma: A pooled analysis from 18 years of medical literature

INTRODUCTION We describe clinical features and prognostic factors of renal medullary carcinoma (RMC) by performing a pooled analysis of all reported cases since 1995. METHODS A systematic search was performed to identify all articles describing patients with medullary renal cancer until February 2013. Survivals were estimated using Kaplan-Meier method with 95% confidence intervals and compared across the groups using the log-rank test. The following factors were evaluated using the Cox proportional hazards model: association of extension of disease at diagnosis, response to therapy, and surgical treatment of primary tumour with overall. RESULTS A total 47 articles were selected; these described 165 patients with RMC plus 1 from our centre. The median age was 21 years and 98% of cases had the sickle cell trait. The mean size of the primary tumours was 6.0 cm, with an involvement of loco-regional lymph nodes in 71% of cases. The overall survival at diagnosis was 4.0 months in metastatic patients and 17.0 months in non-metastatic patients. Patients who received platinum-paclitaxel-gemcitabine had longer control of the disease when compared to topoisomerase inhibitors or targeted therapies. The multivariate analysis confirmed that the advanced stage at diagnosis increased the risk of death of about threefold. CONCLUSION RMC is a tumour with poorer prognosis; based on these results, platinum-based chemotherapy is the preferred systemic treatment. Even if radical nephrectomy as an up-front strategy did not report a survival benefit, it may be considered to palliate local symptoms and to perform a correct diagnosis.

Molecular and Clinical Analysis of Predictive Biomarkers in Non-Small-Cell Lung Cancer

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-specific death in the USA and Europe. Over the last two decades, the pathogenetic mechanisms and the molecular alterations of NSCLC have been investigated more intensively, a number of potential therapeutic targets have been identified and new agents against specific molecular targets have been introduced in the treatment of NSCLC. Acquired abnormalities in the genes encoding RAS, p53, KRAS, EGFR and ALK, are particularly important in this field. Whenever targetable mutations are not found, the research of other genetic abnormalities can be useful to personalize chemotherapy. The attention has been focused, in particular, on the endonuclease excision repair cross-complementing1 and BRCA1 status. The use of antimetabolite drugs and the level of expression of their cellular targets seem to be correlated and influence the clinical efficacy of those agents. This review will focus on the role of predictive biomarkers for the treatment of non-small cell lung cancer.

EpCAM-expressing circulating tumor cells in colorectal cancer.

Background Several studies have raised the issue of the inadequacy of CellSearch® to detect the entire pool of circulating tumor cells (CTCs) from blood of cancer patients, suggesting that cells expressing low levels of epithelial cell adhesion molecule (EpCAM) are not recognized by the capture reagent. In this exploratory study, we aimed to evaluate the status of EpCAM in CTCs isolated from a group of metastatic colorectal cancer patients, in 40% of whom, CTC had been found to be undetected by the CellSearch® system. Methods CTCs were analyzed using both a microfiltration method (ScreenCell) and CellSearch® in parallel. Furthermore, since EpCAM exists in 2 different variants, we investigated the presence of both its intracellular domain (EpICD) and extracellular domain (EpEX) through immunofluorescence staining of CTCs on filters. Results Results from immunofluorescence experiments demonstrated that, overall, EpICD and/or EpEX was expressed in 176 CTCs detected by ScreenCell, while the CellSearch® system was able to capture only 10 CTCs. Conclusions This is the first demonstration that the low sensitivity of CellSearch® to detect CTCs in colorectal cancer patients is not due to the lack of EpCAM.

The impact of chemotherapy on the lymphatic system in thoracic oncology.

Non-small-cell lung cancer remains the leading cause of cancer-related mortality in the United States and Europe. Most patients are diagnosed with metastatic disease for which chemotherapy remains the cornerstone of treatment. In non-metastatic disease, surgery is the most potentially curative therapeutic option, but its outcome is still poor, in particular for patients with lymph node involvement. Therefore, several randomized adjuvant/neoadjuvant trials using chemotherapy and/or radiotherapy investigated the possibility of increasing the overall survival of patients with surgically treated lung cancer. The findings are reviewed in this article.

The Role of Systemic Chemotherapy

Development of peritoneal carcinomatosis (PC) in metastatic solid tumors is associated with poor prognosis and is usually more frequent in gynecological and gastrointestinal (GI) malignancies. No standard systemic or local treatment can eradicate PC definitively, and chemotherapy (CHT) and surgery alone seem unable to improve patient survival, so that PC is usually considered a terminal condition [1]. PC is commonly observed in ovarian cancer (OC), in which the spread of disease is primarily locoregional and then to visceral sites. In this pathology, complete PC removal is associated with improved survival. In GI tumors, such as gastric and colorectal cancer (CRC), PC is seen less frequently, and its cytoreduction is not considered mandatory due to the high percentage of short-term recurrence and no effect on survival rates [2]. Systemic CHT has a limited impact on the peritoneum, probably because the peritoneal cavity is a “pharmacological sanctuary” in which intravenously administered drug diffusion is difficult. This is due to a blood-peritoneal barrier, composed of stromal tissues between mesothelial and endothelial cells, of ∼90-μm thickness, which is difficult to overcome by many systemic agents [3]. Given this low effectiveness of systemic therapies or surgery alone and the necessity to improve the local action of drugs, in recent decades, new multimodal approaches have been developed based on the association of cytoreductive surgery (CRS) with intravenous (IV) (neoadjuvant or adjuvant) and/or intraperitoneal (IP) administration of CHT (IP-CHT). Different combinations and integrations of these treatments have been proposed and evaluated in randomized or nonrandomized trials in many cancer types.

1329TiPA RANDOMIZED PHASE III MULTICENTER TRIAL OF CUSTOMIZED CHEMOTHERAPY VERSUS STANDARD OF CARE FOR 1ST LINE TREATMENT OF ELDERLY PATIENTS WITH ADVANCED NON-SMALL-CELL LUNG CANCER (NSCLC): THE ELDERLY PATIENT INDIVIDUALIZED CHEMOTHERAPY (EPIC) TRIAL

ABSTRACT Background: Phase III trial aiming to compare first line pharmacogenomic-driven chemotherapy based on Excision-Repair-Cross-Complementing-1 (ERCC1, E), Ribonucleotide Reductase subunit M1 (RRM1, R) and Thymidylate Synthase (TS, T) gene expression versus standard treatment in elderly patients (pts) with advanced NSCLC. Trial design: pts aged ≥70 years, ECOG Performance Status 0 or 1, EGFR negative mutational status, chemonaive stage IV NSCLC will be evaluated. Pts will be randomized (2:1) to experimental arm (A) or standard arm (B). In arm A, treatment will be based on histology, E, R and T mRNA expression. The cut-off for high or low expression have been previously defined. Treatments for pts with squamous NSCLC: carboplatin for E low/R high, gemcitabine for E high/R low, carboplatin and gemcitabine for E low/R low, docetaxel or vinorelbine for E high/R high. Treatments for non-squamous NSCLC pts: carboplatin for E low/T high, pemetrexed for E high/T low, carboplatin and pemetrexed for E low/T low, gemcitabine for E high/T high/R low, docetaxel or vinorelbine for E high/T high/R high. In arm B treatment will be at the investigator discretion. The primary endpoint is overall survival. The secondary endpoints are progression-free survival, response rate (RECIST 1.1) and tolerability (CTCAE version 4.0). Feasibility of treatment selection based on pharmacogenomic parameters will be also assessed. Treatment will continue to a maximum of 6 cycles if tolerated or until disease progression. Assuming an exponential survival distribution for both arms and a median survival time of 8 months in the control arm, we anticipate to detect an improvement of 3 months in the median survival time in the experimental arm. To have 90% power to detect a three-month improvement in median survival at a significance level of 5% (2-sided) and assuming a 10% failure rate in gene analyses or loss to follow-up rate, a sample size of 567 patients is planned. Conclusion: To our knowledge, this is the first prospective pharmacogenomic-driven trial designed in elderly advanced NSCLC population. Disclosure: D. Cortinovis: Consultant for AZ, BI, Roche and Lilly; M. Papotti: Honoraria have been received from Eli Lilly; G. Scagliotti: Honoraria have been received from Eli Lilly, Roche, Pfizer and Astrazeneca. All other authors have declared no conflicts of interest.