Publications by authors named "Rodolfo Passalacqua"

77 Publications

MDM2 gene amplification as selection tool for innovative targeted approaches in PD-L1 positive or negative muscle-invasive urothelial bladder carcinoma.

J Clin Pathol 2020 Nov 3. Epub 2020 Nov 3.

Division of Urology, University and Hospital Trust of Verona, Verona, Italy.

Aims: According to The Cancer Genome Atlas (TCGA), around 9% of bladder carcinomas usually show abnormalities of the murine double minute 2 (MDM2) gene, but a few studies have been investigated them. We profiled MDM2 gene amplification in a series of urothelial carcinomas (UC) considering the molecular subtypes and expression of programmed death ligand 1 (PD-L1).

Methods: 117 patients with muscle-invasive UC (pT2-3) without (N0) or with (N+) lymph-node metastases were revised. Only cases with availability of in toto specimens and follow-up were studied. Tissue microarray was built. p53, ER, RB1, GATA-3, CK20, CK5/6, CD44 and PD-L1 (clone sp263) immunoexpression was evaluated. Fluorescent in situ hybridisation was assessed by using the HER-2/neu, FGFR-3, CDKN2A and MDM2 probes. True (ratio 12q/CEP12 >2) MDM2 gene amplification was distinguished from polyploidy/gains (ratio <2, absolute copy number of MDM-2 >2). MDM2 and PD-L1 values were correlated to the TCGA molecular phenotypes. Statistical analysis was performed.

Results: 6/50 (12%) cases (5 N0 and 1 N+) were amplified for MDM2 without matching to molecular phenotypes. Of 50, 14 (37%) cases expressed PD-L1 at 1% cut-off; 3/50 (9%) at >50% cut-off; of these, 2 cases on side of neoplasia among inflammatory cells. Only one out of six (17%) cases amplified for MDM2 showed expression (>50% cut-off) of PD-L1. MDM2 amplification was independent to all documented profiles (k test=0.3) and was prevalent in recurrent UC.

Conclusion: MDM2 amplification has been seen in both PD-L1 positive and negative muscle-invasive bladder UC independently from the TCGA molecular phenotypes. MDM2 and PD-L1 might be assessed in order to predict a better response to combo/single targeted therapies.
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http://dx.doi.org/10.1136/jclinpath-2020-207089DOI Listing
November 2020

Neratinib in patients with HER2-mutant, metastatic cervical cancer: Findings from the phase 2 SUMMIT basket trial.

Gynecol Oncol 2020 Oct 25;159(1):150-156. Epub 2020 Jul 25.

Arizona Oncology (US Oncology Network), University of Arizona College of Medicine, Creighton University School of Medicine, Phoenix, AZ, USA. Electronic address:

Objective: Somatic HER2 mutations occur in ~5% of cervical cancers and are considered oncogenic and associated with poor prognosis. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, is active in multiple HER2-mutant cancers. SUMMIT is a phase II basket trial investigating the efficacy and safety of neratinib in solid tumors.

Methods: Patients with HER2-mutant, persistent, metastatic/recurrent cervical cancer with disease progression after platinum-based treatment for advanced/recurrent disease received oral neratinib 240 mg/day with mandatory loperamide prophylaxis during cycle 1. The primary endpoint was confirmed objective response rate (ORR). Secondary endpoints included: response duration (DOR); clinical benefit rate (CBR); progression-free survival (PFS); overall survival (OS); safety.

Results: Sixteen eligible patients were enrolled; 10 (62.5%) had endocervical adenocarcinoma. The most common HER2 mutation was S310F (63% of patients). Three of 12 RECIST-measurable patients had confirmed partial responses (ORR 25%; 95%CI 5.5-57.2%); 3 had stable disease ≥16 weeks (CBR 50%; 95%CI 21.1-78.9%). DOR for responders were 5.6, 5.9, and 12.3 months. Median PFS was 7.0 months (95%CI 0.7-18.3 months); median OS was 16.8 months (95%CI 4.1-NE months). Diarrhea (75%), nausea (44%), and decreased appetite (38%) were the most common adverse events. One patient (6%) reported grade 3 diarrhea. There were no grade 4 events, and no diarrhea-related treatment discontinuations.

Conclusions: Neratinib monotherapy showed evidence of activity in heavily pretreated patients with HER2-mutant cervical cancer, with no new safety signals. Given the few effective options for cervical cancer after platinum-based therapy failure, neratinib warrants further investigation in this molecularly defined patient population.

Trial Registration Number: NCT01953926 (ClinicalTrials.gov), 2013-002872-42 (EudraCT).
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http://dx.doi.org/10.1016/j.ygyno.2020.07.025DOI Listing
October 2020

Epidemiology and unmet needs of bladder cancer in Italy: a critical review.

Minerva Urol Nefrol 2020 Feb 4;72(1):1-12. Epub 2019 Nov 4.

Janssen Cilag SpA, Cologno Monzese, Milan, Italy.

Bladder cancer is one of the most frequent cancers in high-income countries. Information on bladder cancer in Italy is scattered across scientific literature and institutional and educational resources and no attempt has been made yet to organize and summarize this information across various sources of available data. We, therefore, present herein a critical literature review of recent epidemiological and healthcare data, including patients' unmet needs. We undertook a critical review of the scientific and grey literature by exploring several different databases and search browsers. Available official statistics indicate a high burden of bladder cancer in Italy, where this neoplasm has one of the highest incidences worldwide and, in consideration of its relatively high survival, it ranks 4th in cancer prevalence. The limited therapeutic options for muscle-invasive and advanced/metastatic urothelial cancer are one of the major unmet needs for patients with this neoplasm, in Italy and worldwide. Advances in cancer immunotherapy and in understanding molecular biology of bladder cancer are, however, rapidly altering the therapeutic landscape for targeted subgroups of patients with advanced/metastatic disease. Other unmet needs include the low quality of life after radical cystectomy, the lack of widespread clinical pathway schemes to improve and standardize the quality of care and low Italian patients empowerment. Bladder cancer represents a health burden in Italy, with high incidence and prevalence rates, and important unmet needs for patients, including the limited therapeutic options for advanced/metastatic cancers, the low quality of life after radical cystectomy, the lack of widespread clinical pathway schemes, and the low patients empowerment.
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http://dx.doi.org/10.23736/S0393-2249.19.03498-2DOI Listing
February 2020

Management of kidney cancer patients: 2018 guidelines of the Italian Medical Oncology Association (AIOM).

Tumori 2019 07;105(4_suppl):3-12

Department of Medical Oncology, Azienda Ospedaliero di Rilievo Nazionale "A. Cardarelli", Napoli, Italy.

In the past two decades, the treatment landscape for patients with metastatic renal cell carcinoma has significantly changed thanks to the approval of several targeted molecular therapies (VEGF and mTOR inhibitors) and recently immune-checkpoint inhibitors. The Italian Association of Medical Oncology (AIOM) Renal Cell Cancer (RCC) Guidelines Panel has developed clinical guidelines to provide evidence-based information and recommendations to oncologists, urologists and all professionals involved in the management of patients with renal cell cancer.
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http://dx.doi.org/10.1177/0300891619853392DOI Listing
July 2019

Major innovations and clinical applications of disodium-levofolinate: a review of available preclinical and clinical data.

Ther Adv Med Oncol 2019 4;11:1758835919853954. Epub 2019 Jun 4.

Oncology Unit, Oncology Department, ASST of Cremona, Hospital of Cremona, Viale Concordia, 1, Cremona CR, 26100, Italy.

The association of folinate salts with 5-fluorouracil (5-FU) represents a gold standard in the treatment of many cancers. In several clinical trials, the simultaneous administration of calcium-folinic acid (Ca-FA) and the prolonged infusion of 5-FU resulted in a better clinical response compared with fluoropyrimidine alone and 5-FU bolus. However, the simultaneous infusion of 5-FU and Ca-FA mixed in the same infusion pump is hindered by the crystallization of calcium salts, which eventually leads to catheter obstruction and damage. The sodium salt of leucovorin-disodium levofolinate (Na-Lv) is a novel molecule with a pharmacological profile similar to Ca-FA. Owing to its higher solubility, it can be safely mixed with 5-FU in a single pump without the risk of precipitation and catheter occlusion. The efficacy and safety of Na-Lv have been widely examined in preclinical and clinical phase II studies in combination with various schedules of 5-FU and in several cancer types. PubMed, EMBASE, SCOPUS and Web of Science databases were searched from inception to November 2018 to retrieve available published phase I and II series, including Western patients. Compared with Ca-FA, Na-Lv shows a more favourable efficacy and toxicity profile in terms of overall response rate, progression-free survival, time to progression and occurrence of severe adverse events. Moreover, it allows treatment time to be shortened, decreasing the number of required human resources for drug administration and limiting the occurrence of catheter damage.
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http://dx.doi.org/10.1177/1758835919853954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552345PMC
June 2019

Risk of second primary tumors in GIST survivors: A systematic review and meta-analysis.

Surg Oncol 2019 Jun 6;29:64-70. Epub 2019 Mar 6.

OncologyDepartment, ASST Ospedale di Cremona, Cremona, Italy.

Introduction: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors arising in the gastrointestinal tract. Second primary tumors (SPTs) have been reported frequently, either synchronously or during follow-up, in patients diagnosed with GISTs.

Methods: We carried out an electronic search of PubMed, SCOPUS, Web of Science, EMBASE, and the Cochrane Library seeking articles investigating the incidence of SPTs in patients with concomitant GIST. All studies were evaluated for heterogeneity before meta-analysis and for publication bias. Pooled incidence rate was estimated using fixed- and random-effects models. Subsite of SPTs was also investigated.

Results: A total of 32 studies met the inclusion criteria, for a total of 19,627 patients with a diagnosis of GIST. The pooled prevalence of SPTs was 20%, with 14% and 3% being synchronous and metachronous tumors, respectively. We found a risk for several specific cancer sites, in particular gastrointestinal (5%) and genitourinary tract cancers (3%). The most frequently associated malignancies were: colorectal (17%), prostate (14%), gastric (9%), esophageal (5.5%), lung (5.4%), hepato-biliopancreatic (4.7%), breast (4.6%), lymphoma (4.4%), kidney (4.35%), and sarcomas (3.3%). Regression analyses revealed a significant positive association for all SPTs with follow-up and Miettinen risk.

Conclusions: Our results indicate that 20% of patients with GIST experienced a SPT, primarily synchronously with a diagnosis of GIST. In particular, we observed an excess of incident gastrointestinal tumors. These findings have important implications for both pathologists, who should perform extensive molecular analysis of surgical non-GIST specimens in resected patients, and for oncologists, who should continue to follow up GIST patients.
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http://dx.doi.org/10.1016/j.suronc.2019.03.001DOI Listing
June 2019

Vinflunine in the treatment of relapsed metastatic urothelial cancer: A systematic review and meta-analysis of real-world series.

Crit Rev Oncol Hematol 2019 Aug 21;140:80-87. Epub 2019 May 21.

Karolinska University Hospital, Eugeniavägen 3, PO Bäckencancer, Theme Cancer, Solna 17176, Sweden. Electronic address:

Background: Vinflunine (VFL) is approved in Europe as second-line treatment of metastatic urothelial cancer after failure of platinum-containing therapy. We performed a systematic review and meta-analysis of real-world data (RWD) to assess utilization, efficacy and safety of VFL.

Methods: We performed a MEDLINE search for the period of 1/1/2000-31/8/2017. Full-length articles providing post-marketing RWD on VFL in patients failing previous chemotherapy were eligible. Interventional clinical trials were excluded.

Results: Ten studies with 797 patients were identified. According to pooled REs analysis, overall response rate was 19%, most frequent, all-grade toxicities were fatigue (41%), constipation (39%), nausea/vomiting (25%), and most prevalent Grade 3-4 toxicities were neutropenia (13%), anaemia (9%), fatigue (8%). Median OS was comparable to results reported in recent randomized studies.

Conclusion: Our findings confirm the efficacy and safety of VFL in an unselected population and support the use of VFL in the changing treatment paradigm of relapsed mUC.
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http://dx.doi.org/10.1016/j.critrevonc.2019.05.006DOI Listing
August 2019

Outcome of head compared to body and tail pancreatic cancer: a systematic review and meta-analysis of 93 studies.

J Gastrointest Oncol 2019 Apr;10(2):259-269

Oncology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio (BG), Italy.

Background: Even when resectable pancreatic cancer (PC) is associated with a dismal prognosis. Initial presentation varies according with primary tumor location. Aim of this systematic review and meta-analysis was to evaluate the prognosis associated with site (head versus body/tail) in patients with PC.

Methods: We searched PubMed, Cochrane Library, SCOPUS, Web of Science, EMBASE, Google Scholar, LILACS, and CINAHL databases from inception to March 2018. Studies reporting information on the independent prognostic role of site in PC and comparing overall survival (OS) in head versus body/tail tumors were selected. Data were aggregated using hazard ratios (HRs) for OS of head versus body/tail PC according to fixed- or random-effect model.

Results: A total of 93 studies including 254,429 patients were identified. Long-term prognosis of head was better than body/tail cancers (HR =0.96, 95% CI: 0.92-0.99; P=0.02). A pooled HR of 0.95 (95% CI: 0.92-0.99, P=0.02) from multivariate analysis only (n=77 publications) showed that head site was an independent prognostic factor for survival.

Conclusions: Primary tumor location in the head of the pancreas at the time of diagnosis is a predictor of better survival. Such indicator should be acknowledged when designing future studies, in particular in the operable and neoadjuvant setting.
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http://dx.doi.org/10.21037/jgo.2018.12.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465486PMC
April 2019

Comparative Effectiveness of Gemcitabine plus Nab-Paclitaxel and FOLFIRINOX in the First-Line Setting of Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis.

Cancers (Basel) 2019 Apr 5;11(4). Epub 2019 Apr 5.

Medical Oncology and Hemato-Oncology Department, ASST Bergamo Ovest, 24047 Bergamo, Italy.

Gemcitabine and nab-paclitaxel (GEM-NAB) and the combination of 5-fluorouracil, oxaliplatin, and irinotecan (FOLFIRINOX) are valid first-line options for advanced or metastatic pancreatic cancer (mPC). However, no randomized trials comparing the two schemes have been performed. This meta-analysis aims to compare GEM-NAB and FOLFIRINOX in terms of safety and effectiveness, taking into account data from real-life studies on mPC. We systematically searched PubMed, EMBASE and Cochrane library up to November 2018 to identify retrospective or cohort studies on mPC comparing GEM-NAB and FOLFIRINOX. We included 16 retrospective studies, including 3813 patients (2123 treated with GEM-NAB and 1690 treated with FOLFIRINOX). Despite a median weighted overall survival (OS) difference in favor of FOLFIRINOX (mean difference: 1.15, 95% confidence interval CI 0.08⁻2.22, = 0.03), in whole population OS was similar (hazard ratio (HR = 0.99, 95% CI 0.84⁻1.16; = 0.9). PFS was also not different between the two arms (HR = 0.88, 95% CI 0.71⁻1.1; = 0.26). The overall response rate was similar (25 vs. 24% with GEM-NAB and FOLFIRINOX). Among grade 3⁻4 toxicities, neutropenia, febrile neutropenia, and nausea were lower with GEM-NAB, while neurotoxicity and anemia were lower with FOLFIRINOX. In conclusion, despite a numerically longer median OS with FOLFIRINOX as compared to GEM-NAB, the overall risk of death and progression were similar. Their toxicity was different with less nausea, neutropenia, and febrile neutropenia with GEM-NAB, as compared to less neurotoxicity and anemia with FOLFIRINOX. Therefore, analysis of non-randomized "real world" studies to date has not provided evidence of a major benefit of one regimen over the other.
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http://dx.doi.org/10.3390/cancers11040484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520876PMC
April 2019

Randomized phase II study evaluating weekly oral vinorelbine versus weekly paclitaxel in estrogen receptor-positive, HER2-negative patients with advanced breast cancer (NorBreast-231 trial).

Breast 2019 Jun 28;45:7-14. Epub 2019 Jan 28.

Pierre Fabre Médicament, 45 Place Abel Gance, 92654, Boulogne-Billancourt, France. Electronic address:

Background: Single-agent paclitaxel and vinorelbine are recommended treatments for advanced breast cancer (ABC) non-responsive to hormone therapy and without visceral crisis. This phase II trial compared first-line oral vinorelbine versus weekly paclitaxel for ABC.

Methods: Eligible female patients had measurable locally recurrent/metastatic estrogen receptor-positive HER2-negative breast cancer and had received prior endocrine therapy (any setting) but no chemotherapy for ABC. Patients were stratified by prior taxane and visceral metastases and randomized to either oral vinorelbine 80 mg/m (first cycle at 60 mg/m, escalated to 80 mg/m in the absence of grade 3/4 toxicity) or intravenous paclitaxel 80 mg/m on days 1, 8, and 15 every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR; confirmed complete or partial response, or stable disease for ≥6 weeks).

Results: The 131 randomized patients had received a median of 2 prior endocrine therapies; >70% had prior (neo)adjuvant chemotherapy and 79% visceral metastases. DCR was 75.8% (95% confidence interval: 63.6-85.5%) with vinorelbine and 75.4% (63.1-85.2%) with paclitaxel. The most common grade 3/4 adverse events were neutropenia (52%), fatigue (11%), and vomiting (5%) with vinorelbine, and neutropenia (17%), dyspnea (6%), hypertension (6%), and peripheral sensory neuropathy (5%) with paclitaxel. Grade 2 alopecia occurred in 2% of vinorelbine-treated and 34% of paclitaxel-treated patients. Neither arm showed relevant global health status changes.

Conclusion: Oral vinorelbine and paclitaxel demonstrated similar DCRs (∼75%). Safety profiles differed and, together with administration route and convenience, may influence treatment choice (EudraCT number, 2012-003530-16).
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http://dx.doi.org/10.1016/j.breast.2019.01.009DOI Listing
June 2019

Biliary tract cancer: current challenges and future prospects.

Cancer Manag Res 2019 28;11:379-388. Epub 2018 Dec 28.

Department of Oncology, Operative Unit of Oncology, Azienda Socio Sanitaria Territoriale of Bergamo Ovest, Treviglio, Bergamo, Italy,

Purpose: Incidence and mortality of biliary tract carcinoma (BTC) are increasing, especially in South America and Asia. Such a disease often bears a dismal prognosis because of diagnosis occurring at late stages and for the frequent relapses after surgery. The aims of this review were to summarize the state of the art of the treatment of BTC and give a view at possible future prospects linked with molecular profiling, immunotherapy, and targeted therapies.

Design: We conducted a systematic literature search using MEDLINE and the 2018 ASCO Meeting abstract databases to identify published clinical trials, translational series, and meeting abstracts. All significant papers and abstracts available to date were included.

Results: For resected BTC, thanks to the BILCAP study, adjuvant chemotherapy (CT) with capecitabine should be regarded as the new standard of care. For locally advanced inoperable and metastatic diseases, the use of chemoradiotherapy and radioembolization has not been supported by any randomized Phase III study. The standard of care remains the combination of CT with gemcitabine and cisplatin, as reported by the ABC-02 trial. All targeted therapies have failed to improve the survival outcomes, either in combination with CT or as single agents and are not recommended in the treatment of BTC. Whole-exome sequencing and molecular profiling have helped in identifying genetic signatures typical of different BTC subtypes. With this support, new trials with targeted agents and immunotherapy have been designed, and results are awaited.

Conclusion: BTC still remains a disease with very few treatment options. Different BTC subtypes own peculiar gene mutations and pathways alterations. Therefore, molecular profiling may be the only key to enable new tailored strategies with targeted agents and immunotherapy.
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http://dx.doi.org/10.2147/CMAR.S157156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314055PMC
December 2018

Neoadjuvant chemoradiotherapy or chemotherapy for gastroesophageal junction adenocarcinoma: A systematic review and meta-analysis.

Gastric Cancer 2019 03 27;22(2):245-254. Epub 2018 Nov 27.

Oncology Unit, Oncology Department, ASST Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy.

Objective: The preferred neoadjuvant treatment for gastroesophageal junction (GEJ) adenocarcinoma is still matter of debate. We conducted a meta-analysis to assess the different impact of neoadjuvant combined chemotherapy and radiotherapy (CTRT) versus chemotherapy (CT) alone.

Methods: A comprehensive search was performed in EMBASE, PubMed, and Cochrane Library databases from inception to 30th June 2018. Studies comparing survival of patients who underwent CTRT or CT alone before surgery for GEJ adenocarcinoma were included. Hazard ratio (HR) for overall survival (OS) was extracted, and a random-effects model was used for pooled analysis. Median OS, 5-year OS, complete pathologic response (pCR), locoregional and distant failure rates were also calculated.

Results: 22 studies including 18,260 patients were considered for the final analysis. The pooled results demonstrated that combined CTRT do not significantly reduce the risk of death (HR 0.95, 95% CI 0.84-1.07; P = 0.41) but has a positive impact on the risk of relapse (HR 0.85, 95% CI 0.75-0.97; P = 0.01) compared to CT alone. Addition of RT to CT alone significantly increased the odds of pCR by 2.8 (95% CI 2.27-3.47; P < 0.001) and reduced the risk of locoregional failure (OR 0.6, 95% CI 0.39-0.91; P = 0.01) but not the risk of distant metastases (OR 0.81, 95% CI 0.59-1.11; P = 0.19).

Conclusions: In this systematic review and meta-analysis comparing neoadjuvant CTRT with CT for adenocarcinoma of GEJ, we found no difference in terms of median OS, despite a higher pCR rate and a reduced risk of locoregional recurrences for the combined approach. Further studies, preferably large randomized clinical trials, are needed to confirm these results.
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http://dx.doi.org/10.1007/s10120-018-0901-3DOI Listing
March 2019

Microsatellite instability in gastric cancer: molecular bases, clinical perspectives, and new treatment approaches.

Cell Mol Life Sci 2018 Nov 1;75(22):4151-4162. Epub 2018 Sep 1.

Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

Gastric cancer is one of the most aggressive malignancies, with limited treatment options in both locally advanced and metastatic setting, resulting in poor prognosis. Based on genomic characterization, stomach tumour has recently been described as a heterogeneous disease composed by different subtypes, each of them with peculiar molecular aspects and specific clinical behaviour. With an incidence of 22% among all western gastric tumour cases, stomach cancer with microsatellite instability was identified as one of these subgroups. Retrospective studies and limited prospective trials reported differences between gastric cancers with microsatellite stability and those with instability, mainly concerning clinical and pathological features, but also in regard to immunological microenvironment, correlation with prognostic value, and responses to treatment. In particular, gastric cancer with microsatellite instability constitutes a small but relevant subgroup associated with older age, female sex, distal stomach location, and lower number of lymph-node metastases. Emerging data attribute to microsatellite instability status a favourable prognostic meaning, whereas the poor outcomes reported after perioperative chemotherapy administration suggest a detrimental role of cytotoxic drugs in this gastric cancer subgroup. The strong immunogenicity and the widespread expression of immune-checkpoint ligands make microsatellite instability subtype more vulnerable to immunotherapeutic approach, e.g., with anti-PD-L1 and anti-CTLA4 antibodies. Since gastric cancer with microsatellite instability shows specific features and clinical behaviour not overlapping with microsatellite stable disease, microsatellite instability test might be suitable for inclusion in a diagnostic setting for all tumour stages to guarantee the most targeted and effective treatment to every patient.
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http://dx.doi.org/10.1007/s00018-018-2906-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182336PMC
November 2018

MicroRNAs as Mediators of Resistance Mechanisms to Small-Molecule Tyrosine Kinase Inhibitors in Solid Tumours.

Target Oncol 2018 08;13(4):423-436

Centre for Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK.

Receptor tyrosine kinases (RTKs) are widely expressed transmembrane proteins that act as receptors for growth factors and other extracellular signalling molecules. Upon ligand binding, RTKs activate intracellular signalling cascades, and as such are involved in a broad variety of cellular functions including differentiation, proliferation, migration, invasion, angiogenesis, and survival under physiological as well as pathological conditions. Aberrant RTK activation can lead to benign proliferative conditions as well as to various forms of cancer. Indeed, more than 70% of the known oncogene and proto-oncogene transcripts involved in cancer code for RTKs. Consequently, these receptors are broadly studied as targets in the treatment of different tumours, and a large variety of small-molecule tyrosine kinase inhibitors (TKIs) are approved for therapy. In most cases, patients develop resistance to the TKIs within a short time. MicroRNAs are short (18-22 nucleotides) non-protein-coding RNAs that fine-tune cell homeostasis by controlling gene expression at the post-transcriptional level. Deregulation of microRNAs is common in many cancers, and increasing evidence exists for an important role of microRNAs in the development of resistance to therapies, including TKIs. In this review we focus on the role of microRNAs in mediating resistance to small-molecule TKIs in solid tumours.
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http://dx.doi.org/10.1007/s11523-018-0580-3DOI Listing
August 2018

Correction to: Feasibility, Safety, and Efficacy of an Alternative Schedule of Sunitinib for the Treatment of Patients with Metastatic Renal Cell Carcinoma: A Retrospective Study.

Drugs R D 2018 06;18(2):163

Oncology Unit, Oncology Department, ASST Ospedale di Cremona, Cremona, Italy.

In the Original Publication of the article, In Introduction part, 7th line, the value "5-100nM" has been published incorrectly. The correct value should read as "Plasma concentration of 50-100ng/ml". In the Original Publication of the article, page 591, Table 2 has been published incorrectly. The corrected table is shown in the following page.
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http://dx.doi.org/10.1007/s40268-018-0234-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995793PMC
June 2018

Clinical and Molecular Predictors of PD-L1 Expression in Non-Small-Cell Lung Cancer: Systematic Review and Meta-analysis.

Clin Lung Cancer 2018 07 21;19(4):315-322. Epub 2018 Feb 21.

Department of Oncology, Oncology Unit, ASST Ospedale di Cremona, Cremona, Italy.

Clinicopathologic and molecular characteristics of non-small-cell lung cancers (NSCLCs) associated with a strong expression of programmed death ligand 1 (PD-L1 in > 5% of cells) have not been well elucidated. Expression of PD-L1 is a poor prognostic factor, but NSCLCs with higher levels of PD-L1 have greater benefit when treated with immunotherapy. We have performed a systematic review to synthesize the available evidence regarding clinicopathologic and molecular variables associated with PD-L1 expression in NSCLC. PubMed, EMBASE, SCOPUS, Web of Science and Cochrane Library databases were searched for relevant articles assessing predictors of PD-L1 expression in > 5% cells. Data were reported as odds ratio (OR) of events. Fifty-two studies (for a total of 5066 PD-L1 out of 13,279 NSCLC patients) were included in this meta-analysis. Factors associated with PD-L1 expression were: smoking status (OR 5.48; 95% confidence interval (CI) 2.8-10.4; P < .001), male gender (OR 4.8; 95% CI 3.2-7.2; P < .001), adenocarcinoma histology (OR 2.75; 95% CI, 1.5-4.8; P < .001), Epidermal growth factor receptor (EGFR) wild type (OR 4.83; 95% CI, 2.1-11.1; P < .001), ALK mutation negative (OR 388.6; 95% CI, 222.5-678.7; P < .001), ROS mutation negative (OR 1904.8; 95% CI, 630-5757; P < .001), and KRAS wild type (OR 19.8; 95% CI, 7.6-51.6; P < .001). Conversely higher pT stages (OR 0.16; 95% CI, 0.04-0.7; P = .01), pN+ stages (OR 0.29; 95% CI, 0.17-0.5; P < .001) are inversely associated with PD-L1 expression in > 5% cells. Expression of PD-L1 is more common in male smokers, with adenocarcinoma histology and not carriers of EGFR/ALK/ROS/KRAS mutations. These data could be useful to screening of PD-L1 expression and to select patients for immunotherapy.
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http://dx.doi.org/10.1016/j.cllc.2018.02.006DOI Listing
July 2018

Association of CDX2 Expression With Survival in Early Colorectal Cancer: A Systematic Review and Meta-analysis.

Clin Colorectal Cancer 2018 06 15;17(2):97-103. Epub 2018 Feb 15.

Oncology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio, Bergamo, Italy. Electronic address:

CDX2 is a homeobox gene encoding transcriptional factors for intestinal organogenesis and represents a specific marker of colorectal adenocarcinoma (CRC) differentiation. We have evaluated if CDX2 expression is associated with better overall and disease-free survival (OS and DFS) in patients with CRC. PubMed, SCOPUS, EMBASE, The Cochrane Library, and Web of Science (from inception to July 2017) were systematically reviewed for relevant studies on adult patients with CRC where OS and DFS were calculated according to CDX2 expression in uni- or multivariate analysis were included. Hazard ratio (HR) for mortality and/or disease progression was calculated. The search produced 16 studies suitable for inclusion (6291 individual patients). The meta-analysis showed a reduced risk of death for patients with CDX2-positive CRC in 14 studies (HR, 0.5; 95% confidence interval [CI], 0.38-0.66; P < .001 according to random effect model). In 6 studies where only DFS data was available, CDX2 expression led to a 52% lower risk of relapse or death (HR, 0.48; 95% CI, 0.39-0.59; P < .001 according to random effect model). The results did not change as a function of ethnicity, type of study, CDX2 detection modality, or stage. Interestingly, in stages II to III, CDX2 expression was associated with a 70% lower risk of death (HR, 0.3; 95% CI, 0.12-0.77; P = .01). CDX2 expression confirms to be a strong prognostic factor in stage II and III CRC. In this setting, along with other clinical and pathologic factors, the lack of expression of CDX2 may be considered an important variable when deciding for adjuvant chemotherapy.
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http://dx.doi.org/10.1016/j.clcc.2018.02.001DOI Listing
June 2018

First-line dose-dense chemotherapy with docetaxel, cisplatin, folinic acid and 5-fluorouracil (DCF) plus panitumumab in patients with locally advanced or metastatic cancer of the stomach or gastroesophageal junction: final results and biomarker analysis from an Italian oncology group for clinical research (GOIRC) phase II study.

Oncotarget 2017 Dec 4;8(67):111795-111806. Epub 2017 Dec 4.

Oncology Division, ASST Ospedale di Cremona, Cremona, Italy.

Background: Survival for patients with advanced gastroesophageal cancer (AGC) using standard treatment regimens is poor. EGFR overexpression is common in AGC and associated with poor prognosis. We hypothesized that increasing the dose intensity of chemotherapy and adding panitumumab could improve efficacy.

Methods: HER2 negative, PS 0-1 patients, received up to 4 cycles of panitumumab 6 mg/kg d 1, docetaxel 60 mg/m2 d 1, cisplatin 50 mg/m2 d 1, l-folinic acid 100 mg/m2 d 1-2, followed by 5-FU 400 mg/m2 bolus d 1-2, and then 600 mg/m2 as a 22 h c.i. on d 1-2, q15 d, plus pegfilgrastim 6 mg on d 3. Patients with disease control after 4 cycles received panitumumab until progression.

Results: From 05/2010 to 01/2014, 52 patients (75% male; median age 64.5 y; metastatic 90%, locally advanced 10%; 96% adenocarcinoma; 25% GEJ) were recruited. Three CR, 29 PR, 10 SD and 8 PD were observed, for an ORR by ITT (primary endpoint) of 62% (95% CI, 48%-75%) and a DCR of 81%. Median TTP was 4.9 months (95% CI, 4.2-7.0) and mOS 10 months (95% CI, 8.2- 13.5). Most frequent G3-4 toxicities: leucopenia (29%), asthenia (27%), skin rash (25%), neutropenia (19%), anorexia (17%), febrile neutropenia (13%), and diarrhea (15%). EGFR expression tested both with dd-PCR and FISH was not associated with any significant clinical benefit from treatment.

Conclusions: Dose-dense DCF plus panitumumab is an active regimen. However, the toxicity profile of this limits further development. Further research on predictive biomarkers for treatment efficacy in AGC is required.Clinical trial information: 2009-016962-10.
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http://dx.doi.org/10.18632/oncotarget.22909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762360PMC
December 2017

Effectiveness of the HuCare Quality Improvement Strategy on health-related quality of life in patients with cancer: study protocol of a stepped-wedge cluster randomised controlled trial (HuCare2 study).

BMJ Open 2017 Oct 6;7(10):e016347. Epub 2017 Oct 6.

Division of Medical Oncology, Hospital of Cremona, Cremona, Italy.

Introduction: Our group previously demonstrated the feasibility of the HuCare Quality Improvement Strategy (HQIS), aimed at integrating into practice six psychosocial interventions recommended by international guidelines. This trial will assess whether the introduction of the strategy in oncology wards improves patient's health-related quality of life (HRQoL).

Methods And Analysis: Multicentre, incomplete stepped-wedge cluster randomised controlled trial, conducted in three clusters of five centres each, in three equally spaced time epochs. The study also includes an initial epoch when none of the centres are exposed to the intervention, and a final epoch when all centres will have implemented the strategy. The intervention is applied at a cluster level, and assessed at an individual level with cross-sectional model. A total of 720 patients who received a cancer diagnosis in the previous 2 months and about to start medical treatment will be enrolled. The primary aim is to evaluate the effectiveness of the HQIS versus standard care in terms of improvement of at least one of two domains (emotional and social functions) of HRQoL using the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items) questionnaire, at baseline and at 3 months. This outcome was chosen because patients with cancer generally exhibit low HRQoL, particularly at certain stages of care, and because it allows to assess the strategy's impact as perceived by patients themselves. The HQIS comprises three phases: (1) clinician training-to improve communication-relational skills and instruct on the project; (2) centre support-four on-site visits by experts of the project team, aimed to boost motivation, help with context analysis and identification of solutions; (3) implementation of Evidence-Based Medicine (EBM) recommendations at the centre.

Ethics And Dissemination: Ethics committee review approval has been obtained from the Ethics Committee of Parma. Results will be disseminated at conferences, and in peer-reviewed and professional journals intended for policymakers and managers.

Trial Registration Number: NCT03008993; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2017-016347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640062PMC
October 2017

Clinical development of mTor inhibitors for renal cancer.

Expert Opin Investig Drugs 2017 Nov 3;26(11):1229-1237. Epub 2017 Oct 3.

b Oncology Unit, Oncology Department , ASST Bergamo Ovest , Treviglio , Italy.

Introduction: Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. In the last 10 years, clinical trials have established multitargeted tyrosine kinase inhibitors (TKIs) as the standard first-line treatment in patients with metastatic disease. Multiple agents are now available for treatment in subsequent lines.The mammalian target of rapamycin (mTOR) inhibitors (e.g., everolimus alone or with lenvatinib) are among the most effective options. Areas covered: This paper provides a complete and updated overview on mTOR inhibitors for the treatment of advanced RCC. The authors revised the results of the most recent completed clinical trials and provided information about ongoing trials. Expert opinion: mTOR pathway still represents an important driver for RCC management. Combination of everolimus and lenvatinib is considered a category 1 choice with cabozantinib and nivolumab for subsequent therapy in metastatic RCC according to NCCN guidelines v2.2017. These three treatments (levantinib/everolimus, cabozantinib, and nivolumab) all resulted in a superior efficacy compared to everolimus alone. Moreover, mTOR inhibitors, and in particular temsirolimus for poor risk patients, are available choices for treatment in non-clear cell carcinomas together with TKIs.
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http://dx.doi.org/10.1080/13543784.2017.1384813DOI Listing
November 2017

Feasibility, Safety, and Efficacy of an Alternative Schedule of Sunitinib for the Treatment of Patients with Metastatic Renal Cell Carcinoma: A Retrospective Study.

Drugs R D 2017 Dec;17(4):585-596

Oncology Unit, Oncology Department, ASST Ospedale di Cremona, Cremona, Italy.

Background: Standard treatment with sunitinib for patients with metastatic renal cancer provides an 'on-off' schedule (daily administration of a 50-mg capsule for 4 weeks, followed by a 2-week break; consecutive 6-week cycles). We developed an alternative intermittent schedule to reduce the toxicity and symptoms of tumor regrowth during the rest period and to allow prolonged continuation of therapy, maintaining dose intensity.

Objective: The objective of this study was to provide a retrospective evaluation of the feasibility, safety, and efficacy of an alternative schedule of sunitinib in patients who did not tolerate classical treatment.

Methods: Patients treated with the classical schedule with at least grade 2 toxicity or recurrence of symptoms during the rest period were switched to an alternative schedule (the same daily dose 5 consecutive days per week for 5 weeks and then the same daily dose on days 1, 3, and 5 in the sixth week; consecutive 6-week cycles).

Results: Twenty-five patients were enrolled. The median time from sunitinib initiation to schedule switch was 2.9 months. After the switch, the median therapy duration was 9.2 months. Rate of delay, corrected by cycle number, was 10% for both schedules. After the switch, 48.7% of patients obtained a toxicity reduction (hypertension -82%, stomatitis -71%, cutaneous toxicity -69%). A reduction in 'on-off symptoms' (-86%) was achieved. Overall response rate was 40% and the disease control rate was 80%. Median progression-free survival was 16.4 months and median overall survival was 41.3 months.

Conclusions: Despite the small sample size and retrospective nature, we demonstrated the feasibility, safety, and efficacy of the alternative schedule, allowing prolonged treatment and better quality of life.
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http://dx.doi.org/10.1007/s40268-017-0209-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694422PMC
December 2017

Disease-free survival is not a surrogate endpoint for overall survival in adjuvant trials of pancreatic cancer: a systematic review of randomized trials.

HPB (Oxford) 2017 11 29;19(11):944-950. Epub 2017 Jul 29.

Oncology Unit, Oncology Department, ASST Bergamo Ovest, Piazzale Ospedale 1, 24047, Treviglio, BG, Italy.

Background: Adjuvant chemotherapy (CT) is the standard of care for patients with resected pancreatic cancer (PC). Overall survival (OS) has traditionally represented the primary endpoint in randomized trials assessing adjuvant therapies for PC. The aim of this study was to assess if disease-free survival (DFS) was an adequate surrogate endpoint for OS in randomized trials of adjuvant therapy in PC.

Methods: A systematic literature search was conducted in PubMed, Web of Science, SCOPUS and Embase, Cochrane Library and the World Health Organization International Clinical Trials Registry Platform up to February 2nd, 2017. Surrogacy of DFS with OS was assessed between endpoints and OS through the Spearman rank correlation coefficient, and between the treatment effects on the endpoints using the squared correlation R.

Results: A total of 12 eligible randomized trials that enrolled 4,888 patients where identified for the final analysis. Correlation of DFS with OS was weak at the individual level (Spearman rank correlation coefficient = 0.31) and moderate at the trial level (R = 0.44).

Conclusions: DFS does not represent an appropriate surrogate for OS in randomized trials of adjuvant therapy for resected PC. Hence, OS should remain the primary endpoint of future trials evaluating new agents in postsurgical setting.
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http://dx.doi.org/10.1016/j.hpb.2017.07.005DOI Listing
November 2017

Clinical and pathological characterization of HER2 mutations in human breast cancer: a systematic review of the literature.

Breast Cancer Res Treat 2017 Nov 31;166(2):339-349. Epub 2017 Jul 31.

Oncology Unit, Oncology Department, ASST Ospedale di Cremona, Viale Concordia 1, 26100, Cremona, Italy.

Purpose: HER2 gene is a member of the epidermal growth factor receptor (EGFR) family. Across different malignancies, aberrations of HER2 gene commonly correspond to gain-of-function alterations leading to increased receptor signaling.

Methods: We have reviewed the literature currently available on HER2 mutations in human breast cancer (BC) evaluating type and frequency of such mutations. The primary objective was to determine the frequency and the number of patients with HER2-mut in the series analyzed. The secondary objectives were to assess characteristics of mutated cases (ER and HER2 status and stage of disease, type of mutations, and finally the clinical outcome if reported).

Results: We retrieved 31 published papers, and the pooled rate of HER2 mutations across 12,905 BC patients was calculated. Overall, the frequency of HER2 mutations was 2.7% with most involving the intracellular domain. About 4% of patients were finally mutated. The predictive role was not described. Only 30% of these patients were simultaneously HER2 positive and 63% were ER positive.

Conclusion: We have found that the prevalence of HER2 mutations is about 3%. These genic alterations are independently associated with HER2 amplification status, occurring in both ER-positive/HER2-negative diseases or HER2-enriched cancers. Ongoing trials are investigating small molecules tyrosine kinase inhibitors in patients harboring these mutations.
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http://dx.doi.org/10.1007/s10549-017-4419-xDOI Listing
November 2017

Real-life clinical practice results with vinflunine in patients with relapsed platinum-treated metastatic urothelial carcinoma: an Italian multicenter study (MOVIE-GOIRC 01-2014).

BMC Cancer 2017 Jul 19;17(1):493. Epub 2017 Jul 19.

Ricerca e Innovazione, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.

Background: Vinflunine is the only chemotherapeutic agent shown to improve survival in platinum-refractory patients with metastatic transitional cell carcinoma of the urothelium (TCCU) in a phase III clinical trial, which led to product registration for this indication in Europe. The aim of this study was to assess the efficacy of vinflunine and to evaluate the prognostic significance of risk factors in a large, unselected cohort of patients with metastatic TCCU treated according to routine clinical practice.

Methods: This was a retrospective multicenter study. Italian cancer centers were selected if, according to the Registry of the Italian Medicines Agency (AIFA), at least four patients had been treated with vinflunine between February 2011 and June 2014, after first- or second-line platinum-based chemotherapy. The primary objective was to test whether the efficacy measured by overall survival (OS) in the registration study could be confirmed in routine clinical practice. Multivariate analysis was carried out using Cox proportional hazard model.

Results: A total of 217 patients were treated in 28 Italian centers. Median age was 69 years (IQR 62-76) and 84% were male; Eastern Cooperative Oncology Group performance status (ECOG PS) was ≥ 1 in 53% of patients. The median number of cycles was 4 (IQR 2-6); 29%, 35%, and 36% received an initial dose of 320 mg/m, 280 mg/m or a lower dose, respectively. Median progression-free survival (PFS) and OS for the entire population was 3.2 months (2.6-3.7) and 8.1 months (6.3-8.9). A complete response was observed in six patients, partial response in 21, stable disease in 60, progressive disease in 108, with a disease control rate of 40%. Multivariate analysis showed that ECOG PS, number of metastatic sites and liver involvement were unfavorable prognostic factors for OS. Toxicity was mild, and grade 3-4 adverse effects were mainly: neutropenia (9%), anemia (6%), asthenia/fatigue (7%) and constipation (5%).

Conclusions: In routine clinical practice the results obtained with VFL seem to be better than the results of the registration trial and reinforce evidence supporting its use after failure of a platinum-based chemotherapy.
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http://dx.doi.org/10.1186/s12885-017-3466-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517798PMC
July 2017

Adjuvant chemotherapy for resected biliary tract cancers: a systematic review and meta-analysis.

HPB (Oxford) 2017 09 3;19(9):741-748. Epub 2017 Jul 3.

Oncology Unit, Oncology Department, ASST Bergamo Ovest, Treviglio, BG, Italy. Electronic address:

Introduction: The use of adjuvant treatment (AT) in resected biliary tract cancers (BTC) is still controversial. No efficacy comparison has been performed between chemotherapy (CT) and chemoradiotherapy (CTRT). A systematic review of the available evidence regarding adjuvant chemotherapy (AC) in resected BTC was performed.

Methods: PubMed, EMBASE, Web of Science, SCOPUS and The Cochrane Library databases were searched for relevant articles published. Only studies including at least 50 patients affected by tumors of gallbladder, intrahepatic, perihilar, and distal bile ducts were considered. Data were pooled using a random-effects model. The primary endpoint of the study was overall survival (OS).

Results: Thirty studies were analyzed with a total of 22,499 patients, 3967 of whom received AC. Eleven cohorts included Western patients and 19 were Asiatic. Surgeries were classified as R0 with negative margins, R1 with positive microscopic and R2 with positive macroscopic margins. Weighted mean OS difference among experimental (AC) and control arm was 4.3 months (95% CI 0.88-7.79, P = 0.014). AC reduced the risk of death by 41% (Hazard ratio [HR] = 0.59, 95% CI 0.49-0.71; P < 0.001).

Conclusions: AC administration gives an OS benefit in resected BTC. The results of prospective randomized studies are awaited in order to define the standard AT in BTC.
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http://dx.doi.org/10.1016/j.hpb.2017.05.010DOI Listing
September 2017

Prognostic Factor Analysis of Overall Survival in Gastric Cancer from Two Phase III Studies of Second-line Ramucirumab (REGARD and RAINBOW) Using Pooled Patient Data.

J Gastric Cancer 2017 Jun 16;17(2):132-144. Epub 2017 Jun 16.

Departments of Oncology and Hematology with Integrated Palliative Care, Kliniken Essen-Mitte, Essen, Germany.

Purpose: To identify baseline prognostic factors for survival in patients with disease progression, during or after chemotherapy for the treatment of advanced gastric or gastroesophageal junction (GEJ) cancer.

Materials And Methods: We pooled data from patients randomized between 2009 and 2012 in 2 phase III, global double-blind studies of ramucirumab for the treatment of advanced gastric or GEJ adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing therapy (REGARD and RAINBOW). Forty-one key baseline clinical and laboratory factors common in both studies were examined. Model building started with covariate screening using univariate Cox models (significance level=0.05). A stepwise multivariable Cox model identified the final prognostic factors (entry+exit significance level=0.01). Cox models were stratified by treatment and geographic region. The process was repeated to identify baseline prognostic quality of life (QoL) parameters.

Results: Of 1,020 randomized patients, 953 (93%) patients without any missing covariates were included in the analysis. We identified 12 independent prognostic factors of poor survival: 1) peritoneal metastases; 2) Eastern Cooperative Oncology Group (ECOG) performance score 1; 3) the presence of a primary tumor; 4) time to progression since prior therapy <6 months; 5) poor/unknown tumor differentiation; abnormally low blood levels of 6) albumin, 7) sodium, and/or 8) lymphocytes; and abnormally high blood levels of 9) neutrophils, 10) aspartate aminotransferase (AST), 11) alkaline phosphatase (ALP), and/or 12) lactate dehydrogenase (LDH). Factors were used to devise a 4-tier prognostic index (median overall survival [OS] by risk [months]: high=3.4, moderate=6.4, medium=9.9, and low=14.5; Harrell's C-index=0.66; 95% confidence interval [CI], 0.64-0.68). Addition of QoL to the model identified patient-reported appetite loss as an independent prognostic factor.

Conclusions: The identified prognostic factors and the reported prognostic index may help clinical decision-making, patient stratification, and planning of future clinical studies.
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http://dx.doi.org/10.5230/jgc.2017.17.e16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489542PMC
June 2017

FOLFOXIRI Plus Bevacizumab as Conversion Therapy for Patients With Initially Unresectable Metastatic Colorectal Cancer: A Systematic Review and Pooled Analysis.

JAMA Oncol 2017 Jul 13;3(7):e170278. Epub 2017 Jul 13.

Oncology Unit, Oncology Department, Azienda Socio Sanitaria Territoriale di Bergamo Ovest, Treviglio (Bergamo), Italy.

Importance: The combination of fluorouracil, oxaliplatin, and irinotecan plus bevacizumab (FOLFOXIRI-Bev) is an established and effective first-line chemotherapy regimen for metastatic colorectal cancer. However, resection rates of metastases and overall survival with this schedule have never been systematically evaluated in published studies including, but not limited to, the TRIBE (TRIplet plus BEvacizumab) trial.

Objective: To assess the clinical efficacy of FOLFOXIRI-Bev, including outcomes and rates of surgical conversions.

Data Sources: A systematic review was conducted in October 2016 in concordance with the PRISMA guidelines of PubMed, the Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, Google Scholar, CINAHL, Ovid, and EMBASE using the terms FOLFOXIRI and bevacizumab and (colorectal cancer).

Study Selection: Clinical trials, retrospective case series, and prospective case series that used FOLFOXIRI-Bev for the treatment of initially unresectable metastatic colorectal cancer in humans were included. Individual case reports and retrospective case series with fewer than 10 patients were excluded.

Data Extraction And Synthesis: Data were extracted independently by 2 reviewers on a predesigned, standardized form. Ultimately, data were aggregated to obtain the pooled effect size of efficacy, according to the random-effects model and weighted for the number of patients included in each trial.

Main Outcomes And Measures: Median overall survival and progression-free survival, overall response rates, and rates of R0 surgical conversions and overall surgical conversions.

Results: Eleven FOLFOXIRI-Bev studies published between 2010 and 2016 met the inclusion criteria and were pooled for analysis. The studies included 889 patients, with 877 patients clinically evaluable for overall response rates. The objective response rate to FOLFOXIRI-Bev was 69% (95% CI, 65%-72%; I2 = 25%). The rate of overall surgical conversions was 39.1% (95% CI, 26.9%-52.8%), and the rate of R0 surgical conversions was 28.1% (95% CI, 18.1%-40.8%). Median pooled overall survival was 30.2 months (95% CI, 26.5-33.7 months) in 6 trials with data available, and progression-free survival was 12.4 months (95% CI, 10.0-14.3 months) in 9 trials with data available. In meta-regression analysis, variables significantly associated with conversion surgery were disease limited to the liver and a higher median number of cycles (close to 12).

Conclusions And Relevance: For patients with surgically unresectable metastatic colorectal cancer, FOLFOXIRI-Bev is associated with a significant overall response rate. Such an effective regimen leads to a probability of surgical conversion of distant metastases approaching 40%, with more than one-fourth of patients having an R0 resection.
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http://dx.doi.org/10.1001/jamaoncol.2017.0278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824228PMC
July 2017

Radical treatment of oligometastatic non-small cell lung cancer: Ready for prime time?

Eur J Cancer 2017 07 8;79:149-151. Epub 2017 May 8.

Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy.

Oligometastatic non-small cell lung cancer (NSCLC), defined as a disease with low metastatic burden and limited organ involvement, is conceived as an intermediate condition between a truly localised disease and a widely metastatic tumour. Traditionally, local ablative therapies (LATs), such as surgery and radiotherapy, have been limited to symptoms' palliation in advanced NSCLC. Several retrospective studies suggest that using local ablative therapy for oligometastatic disease could offer good local control of the disease and improvement in terms of progression-free survival. The first randomised study of local consolidative therapy versus maintenance therapy or observation in oligometastatic NSCLC has been recently published. The results of this phase II trial showed an impressive improvement in median progression-free survival with local therapy and a delay in the appearance of new lesions, suggesting a systemically extended benefit of consolidation therapies. Nevertheless, further confirmation of this evidence with additional future trials is needed to definitively consider the combination of local treatment techniques with novel systemic agents recently approved for NSCLC therapy, such as immune checkpoint inhibitors.
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http://dx.doi.org/10.1016/j.ejca.2017.04.008DOI Listing
July 2017

Overview of different available chemotherapy regimens combined with radiotherapy for the neoadjuvant and definitive treatment of esophageal cancer.

Expert Rev Clin Pharmacol 2017 Jun 10;10(6):649-660. Epub 2017 Apr 10.

b Oncology Unit, Oncology Department , ASST Bergamo Ovest , Treviglio (BG) , Italy.

Introduction: Neoadjuvant chemoradiotherapy (CTRT) is the current standard of care for treatment of locally advanced cancer of the esophagus or gastroesophageal junction. Many efforts have been made over the last years to identify the best chemotherapy and radiotherapy combination regimen, but specific randomized trials addressing this issue are still lacking. Areas covered: A systematic review of the literature was performed searching in PubMed all published studies of combinations CTRT regimens for operable or unresectable esophageal cancer to describe activity and toxicity. Studies considered were prospective series or clinical phase II-III trials including at least 40 patients and published in English language. Expert commentary: Long-term results of CROSS trial have established RT combined with carboplatin plus paclitaxel chemotherapy as the preferred neoadjuvant treatment option for both squamous and adenocarcinoma of the esophagus. More effective multimodal treatment strategies integrating novel biological agents including immunotherapy and based on an extensive molecular tumor characterization are eagerly awaited.
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http://dx.doi.org/10.1080/17512433.2017.1313112DOI Listing
June 2017