Low RNA disruption during neoadjuvant chemotherapy predicts pathologic complete response absence in patients with breast cancer.

In previously reported retrospective studies, high tumor RNA disruption during neoadjuvant chemotherapy predicted for post-treatment pathologic complete response (pCR) and improved disease-free survival at definitive surgery for primary early breast cancer. The BREVITY (Breast Cancer Response Evaluation for Individualized Therapy) prospective clinical trial (NCT03524430) seeks to validate these prior findings. Here we report training set (Phase I) findings, including determination of RNA disruption index (RDI) cut points for outcome prediction in the subsequent validation set (Phase II; 454 patients). In 80 patients of the training set, maximum tumor RDI values for biopsies obtained during neoadjuvant chemotherapy were significantly higher in pCR responders than in patients without pCR post-treatment (P = .008). Moreover, maximum tumor RDI values ≤3.7 during treatment predicted for a lack of pCR at surgery (negative predictive value = 93.3%). These findings support the prospect that on-treatment tumor RNA disruption assessments may effectively predict post-surgery outcome, possibly permitting treatment optimization.

Progression after First-Line Cyclin-Dependent Kinase 4/6 Inhibitor Treatment: Analysis of Molecular Mechanisms and Clinical Data.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6iss) are widely used in first-line metastatic breast cancer. For patients with progression under CDK4/6is, there is currently no standard treatment recommended at the category 1 level in international guidelines. The purpose of this article is to review the cellular mechanisms underlying the resistance to CDK4/6is, as well as treatment strategies and the clinical data about the efficacy of subsequent treatments after CDK4/6is-based therapy. In the first part, this review mainly discusses cell-cycle-specific and cell-cycle-non-specific resistance to CDK4/6is, with a focus on early and late progression. In the second part, this review analyzes potential therapeutic approaches and the available clinical data on them: switching to other CDK4/6is, to another single hormonal therapy, to other target therapies (PI3K, mTOR and AKT) and to chemotherapy.

Tas-102 for Refractory Metastatic Colorectal Cancer: A Multicenter Retrospective Cohort Study.

Trifluridine/tipiracil (TAS-102) is an oral chemotherapy approved for the treatment of metastatic colorectal cancer. The efficacy and tolerability of TAS-102 were shown in phase II-III clinical trials and in several real-life studies. The elderly and other special subgroups are underrepresented in published literature. We conducted a retrospective multicenter study to assess the effectiveness and safety of TAS-102 in consecutive patients with pretreated mCRC. In particular, we estimated the effectiveness and safety of TAS-102 in elderly patients (aged ≥70, ≥75 and ≥80 years) and in special subgroups, e.g., patients with concomitant heart disease. One hundred and sixty patients were enrolled. In particular, 71 patients (44%) were 70 years of age or older, 50 (31%) were 75 years of age or older, and 23 (14%) were 80 years of age or older. 19 patients (12%) had a concomitant chronic heart disease, three (2%) patients were HIV positive, and one (<1%) patient had a DPYD gene polymorphism. In 115 (72%) cases TAS-102 was administered as a third-line treatment. The median overall survival (OS) in the overall population was 8 months (95% confidence interval [CI], 6-9), while the median progression-free survival (PFS) was 3 months (95% CI, 3-4). No significant age-related reduction in effectiveness was observed in the subpopulations of elderly patients included. The toxicity profile was acceptable in both the whole and subgroups' population. Our study confirms the effectiveness and safety of TAS-102 in patients with pretreated mCRC, suggesting a similar risk-benefit profile in the elderly.

First-line treatment of metastatic castration-resistant prostate cancer: the real-world Italian cohort of the Prostate Cancer Registry.

BACKGROUND: With the availability of multiple treatment options for metastatic castration-resistant prostate cancer (mCRPC), new real-world data on disease management and drugs' performance are needed. METHODS: We described characteristics, management and clinical outcomes of patients receiving first-line mCRPC treatment within the Italian cohort of the real-world, prospective, international Prostate Cancer Registry. Patients were enrolled consecutively (2013-2016) in 32 Italian sites and followed for 3 years. RESULTS: 238 patients were included: 157 received first-line abiraterone acetate plus prednisone ("abiraterone" thereafter) and 70 first-line docetaxel; 11 patients receiving other treatments were not considered. Compared with docetaxel-treated patients, those receiving abiraterone were significantly older (age ⩾75: 63.7% vs 38.6%), less frequently had a Gleason score >8 (48.2% vs 67.6%, p<0.005) at initial diagnosis, and more frequently an ECOG score ⩾1 (52.7% vs 36.2%, p<0.05) and comorbidities (76.4% vs 57.1%, p<0.05) at baseline; they reported a lower analgesic use (15.3% vs 30%, p<0.005). In the abiraterone group (median follow-up 22.1 months), median time to progression (TTP) and progression-free survival (PFS) were, respectively, 14.4 months (95% confidence interval, CI, 10.6-18.0) and 13.0 months (95% CI, 9.1-16.8); median overall survival (OS) was not reached, and 3-year OS was 59.1%. In the docetaxel treatment group (median follow-up 25.3 months), median TTP, PFS and OS were, respectively, 8.2 months (95% CI, 6.1-10.3), 8.2 months (95% CI, 5.8-10.3) and 33.2 months (95% CI, 19.2-not estimable). CONCLUSION: This investigation provided valuable information on the overall mCRPC treatment pattern and the effectiveness of first-line abiraterone and docetaxel in a population representative of everyday practice.

Response to Chemotherapy and Clinical Outcome of Patients With Recurrent Epithelial Ovarian Cancer After PARP Inhibitor Maintenance Treatment: A Multicenter Retrospective Italian Study.

BACKGROUND/AIM: To assess response rates and survival in patients with recurrent platinum-sensitive epithelial ovarian cancer (EOC) who received PARP inhibitor (PARP-i) maintenance and who subsequently underwent salvage chemotherapy for disease progression after PARPi. PATIENTS AND METHODS: This retrospective investigation analyzed 103 patients who were treated in five Italian Gynecologic centers. The PARPi used was olaparib in 46 patients, niraparib in 55, and rucaparib in 2. The interval time between the last cycle of pre- PARPi platinum-based chemotherapy and the diagnosis of progression during PARPi maintenance was defined as platinum-free interval (PFI). RESULTS: Of the 28 patients with PFI <6 months, 23 received chemotherapy (non-platinum single agent, 20; trabectedin + pegylated liposomal doxorubicin (PLD), 3). Forty-two of the 43 patients with PFI 6-12 months underwent chemotherapy (platinum-based chemotherapy,11; trabectedin + PLD, 10; non platinum-single agent, 21). Thirty-one of the 32 patients with PFI >12 months received chemotherapy (platinum-based chemotherapy, 23; trabectedin + PLD, 3; non platinum - single agent, 5). An objective response was found in 13.0%, 26.2% and 41.9 % of the patients with PFI <6 months, 6-12 months, and >12 months (p= 0.03), respectively, and the corresponding median survivals after PARPi were 8.9 months, 17.5 months and 24.1 months (p= 0.002), respectively. CONCLUSION: Before the PARPi era, some randomized trials on platinum rechallenge in patients with recurrent EOC after more than 6 months from the last platinum cycle have shown response rates ranging from 47.2% to 66%. Response rates to chemotherapy for progression after PARPi appear to be lower than those expected according to PFI.

Neoadjuvant radiotherapy dose escalation for locally advanced rectal cancers in the new era of radiotherapy: A review of literature.

BACKGROUND: The standard treatment of locally advanced rectal cancers (LARC) consists on neoadjuvant chemoradiotherapy followed by total mesorectal excision. Different data in literature showed a benefit on tumor downstaging and pathological complete response (pCR) rate using radiotherapy dose escalation, however there is shortage of studies regarding dose escalation using the innovative techniques for LARC (T3-4 or N1-2). AIM: To analyze the role of neoadjuvant radiotherapy dose escalation for LARC using innovative radiotherapy techniques. METHODS: In December 2020, we conducted a comprehensive literature search of the following electronic databases: PubMed, Web of Science, Scopus and Cochrane library. The limit period of research included articles published from January 2009 to December 2020. Screening by title and abstract was carried out to identify only studies using radiation doses equivalent dose 2 Gy fraction (EQD2) ≥ 54 Gy and Volumetric Modulated Arc Therapy (VMAT), intensity-modulated radiotherapy or image-guided radiotherapy (IGRT) techniques. The authors' searches generated a total of 2287 results and, according to PRISMA Group (2009) screening process, 21 publications fulfil selection criteria and were included for the review. RESULTS: The main radiotherapy technique used consisted in VMAT and IGRT modality. The mainly dose prescription was 55 Gy to high risk volume and 45 Gy as prophylactic volume in 25 fractions given with simultaneous integrated boosts technique (42.85%). The mean pCR was 28.2% with no correlation between dose prescribed and response rates (P value ≥ 0.5). The R0 margins and sphincter preservation rates were 98.88% and 76.03%, respectively. After a mean follow-up of 35 months local control was 92.29%. G3 or higher toxicity was 11.06% with no correlation between dose prescription and toxicities. Patients receiving EQD2 dose > 58.9 Gy and BED > 70.7 Gy had higher surgical complications rates compared to other group (P value = 0.047). CONCLUSION: Dose escalation neoadjuvant radiotherapy using innovative techniques is safe for LARC achieving higher rates of pCR. EQD2 doses > 58.9 Gy is associated with higher rate of surgical complications.

Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial.

BACKGROUND: Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. METHODS: In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB-IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0-2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin-carboplatin, or 15 mg/kg every 21 days combined with gemcitabine-carboplatin or paclitaxel-carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. FINDINGS: Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4-9·3) in the standard chemotherapy group and 11·8 months (10·8-12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41-0·65; log-rank p<0·0001). Most common grade 3-4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. INTERPRETATION: Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. FUNDING: Hoffmann-La Roche and Associazione Italiana per la Ricerca sul Cancro.

High-dose-rate brachytherapy as monotherapy for localized prostate cancer using three different doses - 14 years of single-centre experience.

PURPOSE: To evaluate clinical outcomes in patients with localized prostate cancer (LPC) treated with 3D conformal high-dose-rate (HDR) brachytherapy (BT) as monotherapy. MATERIAL AND METHODS: From March 2004 to November 2017, 277 men with LPC underwent 3D conformal HDR-BT as monotherapy, with a temporary implant. The dose prescription was: 38 Gy in 4 fractions (149 patients), 27 Gy in 2 fractions (41 patients), and 19-20 Gy in a single fraction (87 patients). Biochemical progression-free survival (bPFS), progression-free survival (PFS), and cancer-specific survival (CSS) were calculated. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicity assessment were performed using Common Terminology Criteria for Adverse Events v5.0. RESULTS: The mean age was 67 (range, 47-81) years. Overall, 145 patients were low-risk, 116 intermediate-risk, and 16 high-risk prostate cancer. After a median follow-up of six years (range, 6-160 months), bPFS, PFS, and CSS were 81%, 96%, and 97%, respectively. Dose prescription, initial prostate specific antigen (iPSA) ≥ 9,5 ng/ml, and high-risk disease resulted in prognostic factors regarding bPFS. Only G2-G3 acute or late GI and GU toxicities were observed. CONCLUSIONS: HDR-BT as monotherapy is a valid and safe treatment modality for localized prostate cancer. After a long follow-up, patients receiving 19-20 Gy in a single fraction had a lower biochemical control rate compared to patients receiving 38 Gy in 4 fractions or 27 Gy in 2 fractions. Randomized prospective trials with a longer follow-up are necessary to confirm our results, and define total doses and dose per fraction for HDR-BT in patients with LPC.

Multisite analysis of high-grade serous epithelial ovarian cancers identifies genomic regions of focal and recurrent copy number alteration in 3q26.2 and 8q24.3.

High-grade serous epithelial ovarian cancer (HGS-EOC) is a systemic disease, with marked intra and interpatient tumor heterogeneity. The issue of spatial and temporal heterogeneity has long been overlooked, hampering the possibility to identify those genomic alterations that persist, before and after therapy, in the genome of all tumor cells across the different anatomical districts. This knowledge is the first step to clarify those molecular determinants that characterize the tumor biology of HGS-EOC and their route toward malignancy. In our study, -omics data were generated from 79 snap frozen matched tumor biopsies, withdrawn before and after chemotherapy from 24 HGS-EOC patients, gathered together from independent cohorts. The landscape of somatic copy number alterations depicts a more homogenous and stable genomic portrait than the single nucleotide variant profile. Genomic identification of significant targets in cancer analysis identified two focal and minimal common regions (FMCRs) of amplification in the cytoband 3q26.2 (region α, 193 kb long) and 8q24.3 (region ß, 495 kb long). Analysis in two external databases confirmed regions α and ß are features of HGS-EOC. The MECOM gene is located in region α, and 15 genes are in region ß. No functional data are yet available for the genes in the ß region. In conclusion, we have identified for the first time two FMCRs of amplification in HGS-EOC, opening up a potential biological role in its etiopathogenesis.

Specific Expression of a New Bruton Tyrosine Kinase Isoform (p65BTK) in the Glioblastoma Gemistocytic Histotype.

Bruton's tyrosine-kinase (BTK) is a non-receptor tyrosine kinase recently associated with glioma tumorigenesis and a novel prognostic marker for poor survival in patients with glioma. The p65BTK is a novel BTK isoform involved in different pathways of drug resistance of solid tumors, thus we aimed to investigate the expression and the putative role of p65BTK in tumors of the central nervous system (CNS). We selected a large cohort of patients with glial tumors (n = 71) and analyzed the expression of p65BTK in different histotypes and correlation with clinical parameters. Sections were stained with glial fibrillary acidic protein (GFAP), p53, epidermal growth factor receptor (EGFR), S100, vimentin, and epithelial membrane antigen (EMA) antibodies. Glioma stem cell (GSC) lines, isolated from glioblastoma multiforme (GBM), were treated with different concentrations of ibrutinib, a specific inhibitor of BTK, in order to evaluate their metabolic activity, mitotic index and mortality. Moreover, an orthotopic xenotransplant of GSC from human GBM was used to evaluate the expression of p65BTK in the brain of immunodeficient mice. p65BTK was expressed in GSC and in gemistocytes in human gliomas at different histological grade. We found a significant correlation between BTK expression and low-grade (LG) tumors (p ≤ 0.05) and overall survival (OS) of patients with grade III gliomas (p ≤ 0.05), suggestive of worst prognosis. Interestingly, the expression of p65BTK remained restricted exclusively to gemistocytic cells in the xenograft mouse model. Ibrutinib administration significantly reduced metabolic activity and mitotic index and increased mortality in GSC, highlighting the specific role of p65BTK in cell proliferation and survival. In conclusion, our data demonstrated that p65BTK is expressed in glioma tumors, restricted to gemistocytic cells, has a key role in GSC and has a bad prognostic value, thus highlighting the importance of future research for targeted therapy of human gliomas.

Incidence of nausea and vomiting in breast cancer patients treated with anthracycline plus cyclophosphamide-based chemotherapy regimens in Italy: NAVY observational study.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is a common adverse event with cancer chemotherapy, despite the availability of effective antiemetic agents. This is a prospective observational study of Italian breast cancer patients treated with anthracycline plus cyclophosphamide (AC), assessed CINV incidence, adherence to national antiemetic guidelines (AIOM 2012), and the relationship with CINV outcomes. METHODS: Patients with breast cancer scheduled to receive their first cycle of an AC-based regimen were enrolled at 12 Italian centers and their clinical data prospectively recorded. CINV incidence was assessed from patient diaries after the first chemotherapy cycle. The relationship between guideline adherence and CINV outcomes was examined using multiple logistic regression. RESULTS: The overall incidence rates of nausea and vomiting among 246 evaluable patients were 63.0 and 25.4%, respectively. Most patients received a 5-HT3-RA agent and dexamethasone for acute phase CINV prophylaxis, whereas a triple combination including aprepitant (NK1-RA), consistent with national guidelines, was used in only 45.5% of cases. In the delayed phase, the guideline adherence was 48.8%, while the overall adherence was 43.5%. After adjusting for confounding factors, adherence to antiemetic prophylaxis guidelines was associated with a significant reduction in the odds of three endpoints, namely any nausea, "significant nausea," and vomiting (OR = 0.49, OR = 0.54, and OR = 0.48, respectively), and a 90% increase in the odds of overall complete protection (OR = 1.90). CONCLUSIONS: CINV is still a critical issue in AC-treated patients, despite antiemetic treatment. Non-adherence to antiemetic guidelines may lead to poorer outcomes and indicates the need for strategies to enhance the use of guidelines in clinical practice.

Pomalidomide Plus Low-Dose Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma and Renal Impairment: Results From a Phase II Trial.

Purpose Renal impairment (RI) limits treatment options in patients with relapsed/refractory multiple myeloma (RRMM). Here, we prospectively studied pomalidomide plus low-dose dexamethasone (LoDEX) in patients with RRMM and moderate or severe RI, including those receiving hemodialysis. Patients and Methods MM-013, a noncomparative, European phase II trial, enrolled three patient cohorts: moderate RI (cohort A; estimated glomerular filtration rate, 30 to < 45 mL/min/1.73 m2); severe RI (cohort B; estimated glomerular filtration rate, < 30 mL/min/1.73 m2); and severe RI that requires hemodialysis (cohort C). Patients received pomalidomide 4 mg/d on days 1 to 21 and LoDEX 20 or 40 mg once per week in 28-day cycles. The primary end point was overall response rate. Results Of 81 enrolled patients (33, 34, and 14 patients in cohorts A, B, and C, respectively), 13 were still receiving treatment at data cutoff (January 28, 2017). Overall response rates were 39.4%, 32.4%, and 14.3%, with a median duration of response of 14.7 months, 4.6 months, and not estimable, respectively. Of importance, 100%, 79.4%, and 78.6% of patients, respectively, achieved disease control. With a median follow-up of 8.6 months, median overall survival was 16.4 months, 11.8 months, and 5.2 months, respectively. Complete renal responses were observed only in cohort A (18.2%), and no patients in cohort C became hemodialysis independent. Grade 3 and 4 hematologic treatment-emergent adverse events and pomalidomide discontinuations as a result of treatment-emergent adverse events occurred more frequently in cohort C. Pomalidomide pharmacokinetics were comparable among the three renal cohorts. Conclusion Pomalidomide 4 mg/d plus LoDEX is efficacious in patients with RRMM with moderate or severe RI, including those who had more advanced disease and required hemodialysis. The safety profile was acceptable among the three groups, and no new safety signals were observed.

Outcomes of First-Generation EGFR-TKIs Against Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Post Hoc Analysis of the BE-POSITIVE Study.

BACKGROUND: Beyond progression after tyrosine kinase inhibitor in EGFR-positive non-small-cell lung cancer patients (BE-POSITIVE) was the first Italian multicenter observational study that reported the outcomes of first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in a "real-life" Caucasian EGFR-mutated non-small-cell lung cancer (NSCLC) population. The sharing of multi-institutional experiences represents a crucial strategy to enrich knowledge about uncommon EGFR mutations. Therefore, we performed a post hoc analysis of the BE-POSITIVE study. PATIENTS AND METHODS: Data of advanced NSCLC patients with uncommon EGFR mutations who received first-line first-generation EGFR-TKIs in 24 Italian Hospitals were collected. In this analysis we aimed to evaluate overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) of EGFR-TKIs in NSCLC patients harboring uncommon EGFR mutations. RESULTS: Thirty-five patients harboring uncommon EGFR mutations (any mutation other than deletion 19 or substitution of leucine by arginine at codon 858) were included of the original 312 EGFR-mutated cases. Most of them were female (n = 20, 57.1%), former smokers (n = 23, 65.7%), with adenocarcinoma (n = 31, 88.6%). The most frequent EGFR mutations were G719X (n = 6, 17.2%) and L861Q (n = 5, 14.2%). The population presented an ORR of 25.7%, a median PFS of 5.19 months, and a median OS of 14.49 months. When stratified according to type of EGFR mutation, median OS ranged from 3.65 months for unspecified mutations to 21.29 for double EGFR mutations. Median PFS ranged from 1.77 months for unspecified mutations to 20.83 months for concomitant EGFR-anaplastic lymphoma kinase alteration. ORR varied from 0% in exon 18, 20 and double gene alteration to 66.6% in exon 19. CONCLUSION: Our study supports the existence of a strong outcome heterogeneity within patients harboring uncommon EGFR mutations, which needs to be clarified to achieve a real personalized treatment strategy.

Single-Agent Oral Vinorelbine as First-Line Chemotherapy for Endocrine-Pretreated Breast Cancer With Bone Metastases and No Visceral Involvement: NORBREAST-228 Phase II Study.

PURPOSE: Single-agent oral chemotherapy is widely used in patients with bone metastases without visceral involvement, especially in hormone receptor-positive metastatic breast cancer (mBC). However, this option has been poorly evaluated in clinical trials. METHODS: Eligible patients had mBC with predominantly bone but not visceral metastases, were receiving bisphosphonate therapy, and had previously received endocrine therapy (any setting) but not chemotherapy for mBC. Patients received oral vinorelbine 60 mg/m2 on days 1, 8, 15, and 22 every 4 weeks (escalating to 80 mg/m2 from cycle 2 in the absence of grade 3/4 toxicity) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included clinical benefit rate (complete/partial response or ≥24 weeks' stable disease), overall survival, and safety. RESULTS: Seventy patients were treated for a median of 6 cycles (range 1-18). Most (73%) continued treatment until disease progression. After 43 months' median follow-up, median PFS was 8.2 months (95% confidence interval [CI], 5.5-9.8). The clinical benefit rate was 56% (95% CI, 43%-68%). Median overall survival was 35.2 months (95% CI, 26.8-47.1). The most common grade 3/4 adverse event was neutropenia (38% of patients); febrile neutropenia was absent. The most common grade 1/2 adverse events were bone pain, fatigue, and gastrointestinal toxicities. Alopecia was infrequent. CONCLUSIONS: In patients with hormone receptor-positive mBC, bone disease, and prior endocrine therapy, first-line oral vinorelbine chemotherapy demonstrated long PFS and good tolerability. In this setting, it could be considered as an active oral alternative to intravenous chemotherapy.

Pattern of care and outcome in elderly patients with glioblastoma: Data in 151 patients from 3 Lombardia Hospitals.

The appropriate treatment approach for elderly patients with glioblastoma multiforme (GBM) is unclear, although different studies suggest survival benefit in fit patients treated with radiotherapy and chemiotherapy after surgery. We performed a retrospective analysis of 151 patients older than 65years with GBM treated in 3 Lombardia Hospitals. In univariate regression analysis higher KPS (p=0.02), macroscopical total resection (p<0.003), radiotherapy (p<0.0001), chemotherapy (p<0.0001) and second line chemotheraphy (p=0.02) were of positive prognostic value. On the contrary older age (>70years), presence of seizure at onset and additional resection after tumor recurrence did not influence OS. Multivariate analysis revealed radiotherapy (HR 0.2 p<0.0001) and extent of surgery (HR 0.3, p=0,0063) as positive independent prognostic factors. Patients receiving radio-chemiotherapy displayed more treatment-related toxicities with a slightly prolonged OS versus those receiving hypofractionated radiotherapy. With the limits of a retrospective study, our data suggest that in elderly fit patients extensive surgery should be considered, moreover adjuvant treatments led to an increase in OS. Randomized controlled study are needed to develop treatment guidelines for elderly GBM patients and to assess whether the combination of post-surgical radio and chemiotherapy may be superior to hypofractionated radiotherapy and chemiotherapy in fit patients.

BE-POSITIVE: Beyond progression after tyrosine kinase inhibitor in EGFR- positive non small cell lung cancer patients: Results from a multicenter Italian observational study.

OBJECTIVES: Non-small-cell-lung-cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations develop drug resistance after 9-12 months of EGFR tyrosine kinase inhibitors (TKIs) therapy pointing out the issue of the second-line treatment choice. MATERIALS AND METHODS: From June 2009 until May 2013 patients affected by advanced NSCLC harbouring EGFR mutations receiving first-line TKI were collected mainly retrospectively in 24 Italian Centers. Primary objective was to describe the percentage of EGFR mutated patients receiving second-line therapy after progression to first-line EGFR-TKIs assessing the type, the activity in terms of objective response rate (ORR), efficacy in terms of progression free survival (PFS) and overall survival (OS), and safety of second-line treatment. Secondary objective was to describe the efficacy of first-line EGFR-TKIs. RESULTS: 312 patients were included. Most of them were females (203, 65.1%), never smokers (200, 64.1%), with adenocarcinoma histology (290, 92.9%). The most common mutations were EGFR exon 19 deletion and L858R, detected in 186 and 97 cases (59.6% and 31.1%), respectively. At data cut-off, 274 patients (95.1%) received any second-line treatment (including best supportive care or local treatments only). A total of 163 patients received second-line systemic therapy with an ORR of 20.9% (95% CI:14.62-27.10), a median PFS and OS of 4.7 (95% CI:3.81-5.26) and 24.5 (95% CI:21.65-27.37) months, respectively. Grade 3-4 hematological and non-hematological toxicities were reported in 9% and 6.3% of 144 patients treated with chemotherapy while non-hematological toxicity was reported in 4 cases of the 17 patients receiving second-line target agents. CONCLUSIONS: BE-Positive is the first multicenter observational study reporting outcomes of therapies in a "real-life Caucasian EGFR-mutated population", highlighting the need of further researches about new treatment strategies in this setting.

Improved 5-year survival of patients with immunochemical faecal blood test-screen-detected colorectal cancer versus non-screening cancers in northern Italy.

BACKGROUND: Colorectal cancer screening may reduce disease-related mortality by early-stage detection of cancers. AIMS: To study the effect of a single immunochemical faecal occult blood test (i-FOBt) screening round on reduction in colorectal cancer-related-mortality among average risk subjects. METHODS: Comparison of 5-year mortality rates in 3 cohorts from a Northern Italian province: (1) colorectal cancers detected at the 1st biennial round of a mass-screening programme targeting 50-69 years old subjects, (2) non-screening cancers symptomatically diagnosed during the same time period, and (3) cancers detected in the pre-screening biennium. Multivariate analyses were performed with the Cox regression model including tumour node metastasis (TNM) stage at diagnosis, anatomical distribution of cancers, age at diagnosis, gender and patient group. Kaplan-Meyer survival estimates and log-rank test for equality of survivor functions were calculated. RESULTS: Stage distribution significantly differed between screening and non-screening colorectal cancers: 73% of screen-detected colorectal cancers were stages I and II versus 43% and 40% of non-screening and pre-screening colorectal cancers. Cumulative 5-year mortality rate was significantly lower in screening compared to non-screening or pre-screening colorectal cancers patients (19% versus 37% and 41%, p < 0.001). CONCLUSIONS: Colorectal cancers were detected at earlier stages in i-FOBT-positive subjects in comparison with non-screening patients; colorectal cancers found at screening had a significantly improved 5-year survival.

A combination of faecal tests for the detection of colon cancer: a new strategy for an appropriate selection of referrals to colonoscopy? A prospective multicentre Italian study.

INTRODUCTION: Colonoscopy workload for endoscopy services in Western countries is increasing markedly because of the implementation of faecal occult blood-based mass screening programmes against colorectal cancer (CRC). We therefore explored the possibility of using a combination of faecal tests to prioritize the access to colonoscopy with criteria other than symptoms and/or time of referral. AIMS AND METHODS: We tested a combination of faecal tests [immunochemical faecal occult blood test (i-FOBT), M2-PK, calprotectin] as markers for advanced neoplasia in a selected series of patients requiring colonoscopy for the suspicion of CRC. All the tests were performed in a 1-day stool sample of patients aged 50-80 years, without any dietary restriction, before colonoscopy. RESULTS: A total of 280 patients' stool single samples were analysed. Forty-seven patients had CRC and 85 patients had one or more advanced adenoma(s) at colonoscopy/histology. CRCs were associated with a highly significant increase (P<0.001) in faecal tumour M2-PK (mean 24.2 kU/l), which correlated with Dukes' staging. For CRC detection, i-FOBT was the test with the highest specificity and positive predictive value (0.89 and 0.53), whereas M2-PK had the highest sensitivity and negative predictive value (0.87 and 0.96). Calprotectin showed performance similar to M2-PK in terms of sensitivity and negative predictive value (0.93), but had lower specificity (0.39). The best combination of tests to predict the risk of CRC in this series was i-FOBT+M2-PK, as in patients showing positivity to both markers, the risk of cancer was as high as 79%. CONCLUSION: The combination of i-FOBT and M2-PK is a sensitive tool in clinical practice for the appropriate management of waiting lists for colonoscopy, as it allows the classification of patients into different degrees of priority for investigation, according to their foreseeable risk of CRC.

Impact of a population-based colorectal cancer screening program on local health services demand in Italy: a 7-year survey in a northern province.

OBJECTIVES: In 2005, the National Health Service recommended a population-based colorectal cancer (CRC) screening program using biennial fecal occult blood testing (FOBT), followed by total colonoscopy in positive patients. So far, no studies have been performed to evaluate the impact of a mass-screening CRC campaign on the health system services at the community level in Italy. We have therefore assessed the workload generated by the first two biennial rounds of screening program on the activity of hospital services involved in CRC diagnosis in the Lecco province. METHODS: Routine data from all hospital services of our province were collected on activity levels related to CRC diagnosis from January 2003 to December 2009. This time span covered the 2 years prior to, as well as the two biennial rounds of the CRC screening program. In particular, we focused on the volume of outpatient FOBTs and colonoscopies (both diagnostic and interventional) performed among subjects outside the screening program. Joinpoint models were used to test whether an apparent change in trend of examination over time was statistically significant in different age cohorts of the population (<50 years, 50-69 years, and ≥70 years). RESULTS: The volume of "extra-screening" per-patient/FOBTs and colonoscopies increased significantly over the evaluated periods in all ages, until year 2008, when a steady trend was beginning; the AAPCs (average of the annual percent changes) values were 5.7, 3.1, and 8.4 for FOBT and 14.6, 13.4, and 16.7 for colonoscopy in the three age cohorts, respectively. However, the increase in both FOBT and colonoscopy demand was maximal in the cohort ≥70 years, where three statistically significant annual percent changes (APCs) were identified (in 2003-2005, 2005-2006, and 2006-2007 APCs were 12.3, 14.9, and 15.9 for FOBT, and 18.7, 36.8, and 25.4 for colonoscopy, respectively). CONCLUSIONS: After the implementation of a FOBT-based mass-screening program for CRC, careful consideration must be given to the significant increase in the workload of hospital services involved in CRC diagnosis, outside the screening campaign. The extra-work mainly involves gastroenterologists performing colonoscopy, whose activity increased over the 5-year period by 118%, as well as laboratory services, where the demand of FOBTs rose by 40%. This phenomenon, mainly attributable to a profound change in the attitude toward CRC screening by those age cohorts outside the program, covers a time span of two full rounds of screening, whereupon a steady trend for colonoscopy is apparent.

Rationale for treatment and study design of tailor: a randomized phase III trial of second-line erlotinib versus docetaxel in the treatment of patients affected by advanced non-small-cell lung cancer with the absence of epidermal growth factor receptor mutations.

We present the rationale and study design of the Tarceva Italian Lung Optimization trial phase III, multicenter, open-label, randomized trial on efficacy of second-line therapies in different subgroups of non-small-cell lung cancer (NSCLC) patients identified using molecular and clinical evaluations. To date, we can assume that advanced NSCLC epidermal growth factor receptor (EGFR)-mutated patients benefit from EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, whereas their role in the treatment of patients who do not have EGFR mutations is controversial. The aim of this study is to assess whether it is possible to optimize second-line treatment in NSCLC patients with absence of EGFR mutations. Moreover, the predictive value of the K-ras mutation, EGFR protein expression, and EGFR gene copy number, as well as a smoking habit and histotype for determining a different effect of erlotinib compared with chemotherapy will be assessed in patients who do not have EGFR mutations. The primary endpoint is overall survival; the secondary endpoints are progression-free survival, response rate, quality of life, and toxicity. We have planned to collect blood samples to identify different prognosis-related polymorphisms and to assess their sensitivity and specificity in the detection of EGFR and K-ras mutations with respect to histologic samples.