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Lordick F.,University of Leipzig | Kang Y.-K.,Asan Medical Center | Chung H.-C.,Yonsei University | Salman P.,Fundacion Arturo Lopez Perez | And 12 more authors.
The Lancet Oncology | Year: 2013

Background: Patients with advanced gastric cancer have a poor prognosis and few efficacious treatment options. We aimed to assess the addition of cetuximab to capecitabine-cisplatin chemotherapy in patients with advanced gastric or gastro-oesophageal junction cancer. Methods: In our open-label, randomised phase 3 trial (EXPAND), we enrolled adults aged 18 years or older with histologically confirmed locally advanced unresectable (M0) or metastatic (M1) adenocarcinoma of the stomach or gastro-oesophageal junction. We enrolled patients at 164 sites (teaching hospitals and clinics) in 25 countries, and randomly assigned eligible participants (1:1) to receive first-line chemotherapy with or without cetuximab. Randomisation was done with a permuted block randomisation procedure (variable block size), stratified by disease stage (M0 vs M1), previous oesophagectomy or gastrectomy (yes vs no), and previous (neo)adjuvant (radio)chemotherapy (yes vs no). Treatment consisted of 3-week cycles of twice-daily capecitabine 1000 mg/m2 (on days 1-14) and intravenous cisplatin 80 mg/m2 (on day 1), with or without weekly cetuximab (400 mg/m2 initial infusion on day 1 followed by 250 mg/m2 per week thereafter). The primary endpoint was progression-free survival (PFS), assessed by a masked independent review committee in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. This study is registered at EudraCT, number 2007-004219-75. Findings: Between June 30, 2008, and Dec 15, 2010, we enrolled 904 patients. Median PFS for 455 patients allocated capecitabine-cisplatin plus cetuximab was 4·4 months (95% CI 4·2-5·5) compared with 5·6 months (5·1-5·7) for 449 patients who were allocated to receive capecitabine-cisplatin alone (hazard ratio 1·09, 95% CI 0·92-1·29; p=0·32). 369 (83%) of 446 patients in the chemotherapy plus cetuximab group and 337 (77%) of 436 patients in the chemotherapy group had grade 3-4 adverse events, including grade 3-4 diarrhoea, hypokalaemia, hypomagnesaemia, rash, and hand-foot syndrome. Grade 3-4 neutropenia was more common in controls than in patients who received cetuximab. Incidence of grade 3-4 skin reactions and acne-like rash was substantially higher in the cetuximab-containing regimen than in the control regimen. 239 (54%) of 446 in the cetuximab group and 194 (44%) of 436 in the control group had any grade of serious adverse event. Interpretation: Addition of cetuximab to capecitabine-cisplatin provided no additional benefit to chemotherapy alone in the first-line treatment of advanced gastric cancer in our trial. Funding: Merck KGaA. © 2013 Elsevier Ltd.


PubMed | Manipal Hospital, University of Lyon, Netherlands Cancer Institute, Sanjay Gandhi Post Graduate Institute of Medical Sciences and 15 more.
Type: Comparative Study | Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine | Year: 2015

We aimed to assess the additional value of SPECT/CT over planar lymphoscintigraphy (PI) in sentinel node (SN) detection in malignancies with different lymphatic drainage such as breast cancer, melanoma, and pelvic tumors.From 2010 to 2013, 1,508 patients were recruited in a multicenter study: 1,182 breast cancer, 262 melanoma, and 64 pelvic malignancies (prostate, cervix, penis, vulva). PI was followed by SPECT/CT 1-3 h after injection of (99m)Tc-colloid particles. Surgery was performed the same or next day.Significantly more SNs were detected by SPECT/CT for breast cancer (2,165 vs. 1,892), melanoma (602 vs. 532), and pelvic cancer (195 vs. 138), all P < 0.001. The drainage basin mismatch between PI and SPECT/CT was 16.5% for breast cancer, 11.1% for melanoma, and 51.6% for pelvic cancers. Surgical adjustment was 17% for breast cancer, 37% for melanoma, and 65.6% for pelvic cancer.SPECT/CT detected more SNs and changed the drainage territory, leading to surgical adjustments in a considerable number of patients in all malignancies studied but especially in the pelvic cancer group because of this groups deep lymphatic drainage. We recommend SPECT/CT in all breast cancer patients with no SN visualized on PI, all patients with melanoma of the head and neck or trunk, all patients with pelvic malignancies, and those breast cancer and melanoma patients with unexpected drainage on PI.


PubMed | San Sebastián University, Fundacion Arturo Lopez Perez, University for Development and University of Sao Paulo
Type: | Journal: Stem cell research & therapy | Year: 2015

Chemotherapy has made an essential contribution to cancer treatment in recent decades despite its adverse effects. As cancer survivors have increased, concern about ex-patient lifespan has become more important too. Doxorubicin is an effective anti-neoplastic drug that produces a cardiotoxic effect. Cancer survivors who received doxorubicin became more vulnerable to cardiac disease than the normal population did. Many efforts have been made to prevent cardiac toxicity in patients with cancer. However, current therapies cannot guarantee permanent cardiac protection. One of their main limitations is that they do not promote myocardium regeneration. In this review, we summarize and discuss the promising use of mesenchymal stem cells for cardio-protection or cardio-regeneration therapies and consider their regenerative potential without leaving aside their controversial effects on tumor progression.


PubMed | Fundacion Arturo Lopez Perez, University of Sfax, University of Santiago de Chile, University of Chile and 2 more.
Type: | Journal: BMC cancer | Year: 2015

An increase in circulating platelets, or thrombocytosis, is recognized as an independent risk factor of bad prognosis and metastasis in patients with ovarian cancer; however the complex role of platelets in tumor progression has not been fully elucidated. Platelet activation has been associated with an epithelial to mesenchymal transition (EMT), while Tissue Factor (TF) protein expression by cancer cells has been shown to correlate with hypercoagulable state and metastasis. The aim of this work was to determine the effect of platelet-cancer cell interaction on TF and Metastasis Initiating Cell (MIC) marker levels and migration in ovarian cancer cell lines and cancer cells isolated from the ascetic fluid of ovarian cancer patients.With informed patient consent, ascitic fluid isolated ovarian cancer cells, cell lines and ovarian cancer spheres were co-cultivated with human platelets. TF, EMT and stem cell marker levels were determined by Western blotting, flow cytometry and RT-PCR. Cancer cell migration was determined by Boyden chambers and the scratch assay.The co-culture of patient-derived ovarian cancer cells with platelets causes: 1) a phenotypic change in cancer cells, 2) chemoattraction and cancer cell migration, 3) induced MIC markers (EMT/stemness), 3) increased sphere formation and 4) increased TF protein levels and activity.We present the first evidence that platelets act as chemoattractants to cancer cells. Furthermore, platelets promote the formation of ovarian cancer spheres that express MIC markers and the metastatic protein TF. Our results suggest that platelet-cancer cell interaction plays a role in the formation of metastatic foci.


Janni W.,Universitatsklinikum Ulm | Sarosiek T.,NZOZ Magodent | Karaszewska B.,Przychodnia Lekarska NZOZ KOMED | Pikiel J.,Wojewodzkie Centrum Onkologii | And 9 more authors.
Breast Cancer Research and Treatment | Year: 2014

Lapatinib is approved in combination with capecitabine for treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who have progressed on prior trastuzumab in the metastatic setting. Vinorelbine is an important chemotherapy option for MBC. We evaluated efficacy and safety of lapatinib plus vinorelbine, compared with lapatinib plus capecitabine, in women with HER2-positive MBC. In this open-label, multicenter, phase II study, eligible patients (N = 112) were randomized 2:1 to lapatinib plus vinorelbine [(N = 75) 1,250 mg orally once daily (QD) continuously plus 20 mg/m2/day intravenously] or lapatinib plus capecitabine [(N = 37) 1,250 mg orally QD continuously plus 2,000 mg/m2/day orally, 2 doses]. The primary endpoint was progression-free survival (PFS). Other endpoints included overall survival (OS) and safety. Patients progressing within the study were given the option of crossover to the other treatment arm; time to second progression was an exploratory endpoint. Patient demographics, stratification, and prognostic factors were well balanced between treatments. Median PFS in both arms was 6.2 months [95 % confidence interval (CI) 4.2, 8.8 (lapatinib plus vinorelbine); 4.4, 8.3 (lapatinib plus capecitabine)]. Median OS on lapatinib plus vinorelbine was 24.3 months (95 % CI 16.4, NE) and 19.4 months (95 % CI 16.4, 27.2) on lapatinib plus capecitabine. In total, 42 patients opted to cross over; median PFS was 3.2 months (95 % CI 1.7, 5.1) on lapatinib plus vinorelbine and 4.0 months (95 % CI 2.1, 5.8) on lapatinib plus capecitabine. Lapatinib plus vinorelbine offers an effective treatment option for patients with HER2-overexpressing MBC, having displayed comparable efficacy and tolerability rates to lapatinib plus capecitabine. © 2014 The Author(s).


PubMed | Hopital Rene Huguenin Institute Curie, Fundacion Arturo Lopez Perez, Medical University of Lódz, Przychodnia Lekarska NZOZ KOMED and 7 more.
Type: Clinical Trial, Phase II | Journal: Breast (Edinburgh, Scotland) | Year: 2015

Lapatinib plus capecitabine (lap+cap) is approved as treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), who have progressed on prior trastuzumab in the metastatic setting. We previously reported progression-free survival (PFS), overall survival (OS) and safety results from this open-label, multicentre, phase II study (VITAL; NCT01013740) conducted in women with HER2 positive MBC, to evaluate the efficacy and safety of lap plus vinorelbine (lap+vin), an important chemotherapy option for MBC, compared with lap+cap. In total, 112 patients were randomised 2:1 to treatment with lap+vin (N = 75) or lap+cap (N = 37). Results showed that the median PFS (primary endpoint) and OS (secondary endpoint) post-randomisation were comparable between treatment arms, with no new safety signals detected. Here, we assessed the final OS in this study at 40 months post-randomisation. At the time of final analyses, 24 (32%) patients were ongoing in the lap+vin arm, compared with 14 (38%) patients in the lap+cap arm (92% in both arms had discontinued treatment). Median OS in the lap+vin arm was 23.3 months (95% confidence intervals [CI]: 18.5, 31.1), compared with 20.3 months (95% CI: 16.4, 31.8) in the lap+cap arm. The median follow-up in the lap+vin arm was 18.86 months (95% CI: 10.68, 26.02), compared with 19.38 (95% CI: 25.56) months in the lap+cap arm. Similar rates of death (56-57%) were observed in both arms. The final OS was consistent with the previously reported data and suggest that lap+vin offers an effective treatment option for women with HER2-positive MBC.


Sternberg C.N.,San Camillo and Forlanini Hospitals | Hawkins R.E.,University of Manchester | Wagstaff J.,Singleton Hospital | Salman P.,Fundacion Arturo Lopez Perez | And 10 more authors.
European Journal of Cancer | Year: 2013

Background: In this randomised phase III study (VEG105192; NCT00334282), pazopanib previously demonstrated statistically and clinically meaningful improvement of progression-free survival versus placebo in patients with advanced/metastatic renal cell carcinoma (mRCC). Final overall survival (OS) and updated safety results are now reported. Methods: Treatment-naive or cytokine-pretreated mRCC patients (n = 435) stratified and randomised (2:1) to pazopanib 800 mg daily or placebo, were treated until disease progression, death or unacceptable toxicity. Upon progression, placebo patients could receive pazopanib through an open-label study. Final OS in the intent-to-treat population was analysed using a stratified log-rank test. Rank-preserving structural failure time (RPSFT) and inverse probability of censoring weighted (IPCW) analyses were performed post-hoc to adjust for crossover. Findings: The difference in final OS between pazopanib- and placebo-treated patients was not statistically significant (22.9 versus 20.5 months, respectively; hazard ratio [HR] = 0.91; 95% confidence interval [CI], 0.71-1.16; one-sided P =.224). Early and frequent crossover from placebo to pazopanib and prolonged duration of crossover treatment confounded the OS analysis. In IPCW analyses, pazopanib decreased mortality (HR = 0.504; 95% CI, 0.315-0.762; two-sided P =.002). Similar, albeit non-significant, results were obtained in RPSFT analyses (HR = 0.43; 95% CI, 0.215-1.388; two-sided P =.172). Since the last cutoff, cumulative exposure to pazopanib increased by 30%. The pazopanib safety profile showed no new safety signals or changes in the type, frequency and severity of adverse events. Interpretation: Although no significant difference in OS was observed in this study, extensive crossover from placebo to pazopanib confounded final OS analysis. Post-hoc analyses adjusting for crossover suggest OS benefit with pazopanib treatment for mRCC patients. © 2013 Elsevier Ltd. All rights reserved.


PubMed | Fundacion Arturo Lopez Perez, Florida Atlantic University, University of Turin, University of Navarra and 3 more.
Type: | Journal: Critical reviews in oncology/hematology | Year: 2016

B-Raf mutations occur in about 1-2% of non-small cell lung cancers (NSCLC). These mutations generate a permanent activation of the mitogen activated protein kinase (MAPK) pathway, which promotes tumor growth and proliferation. In the present review, we discuss B-Raf mutation epidemiology, diagnostic methods to detect B-Raf mutations, the role of B-Raf as a driver mutation and a potential therapeutic target in NSCLC. The results of clinical trials involving B-Raf or MAPK pathway inhibitors for the treatment of NSCLC are also discussed. Clinical trials evaluating B-Raf inhibitors in BRAF mutated NSCLC patients have shown promising results, and larger prospective studies are warranted to validate these findings. Enrollment of these patients in clinical trials is an interesting strategy to offer a potentially more effective and less toxic targeted therapy.


PubMed | Fundacion Arturo Lopez Perez, VU University Amsterdam, University of Antwerp, University of Palermo and 2 more.
Type: Journal Article | Journal: Expert opinion on investigational drugs | Year: 2016

Molecular alterations in neurotrophic tyrosine kinase (NTRK) genes have been identified in several solid tumors including lung cancer. Pre-clinical and clinical evidence suggested their potential role as oncogenic drivers and predictive biomarkers for targeted inhibition, leading to the clinical development of a new class of compounds blocking the NTRK molecular pathway, which are currently undner early clinical investigation.This review describes the biology of the NTRK pathway and its molecular alterations in lung cancer. It focuses on the pre-clinical and clinical development of emerging NTRK inhibitors, which have shown very promising activity in early phase I studies.Among the several NTRK-inhibitors, entrectinib and LOXO-101 are those in more advanced stage of clinical development. Both agents have shown encouraging activity along with a tolerable safety profile in patients with different solid tumors harboring NTRK-fusions, emerging as new promising therapeutic options for molecularly selected patients with advanced Trk-driven lung cancers. Results from ongoing phase II basket trials are eagerly awaited.


PubMed | Nanjing Yanggongjing Hospital, International Drug Development Institute, Instytut im. Marii Sklodowskiej Curie, Cancer International Research Group and 13 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

LBA4001 Background: HER2 amplification is common in upper GI tract (UGIT) adenocarcinomas and inhibition improves clinical outcomes. Lapatinib ditosylate (L), a dual anti EGFR and anti HER2 tyrosine kinase inhibitor with preclinical activity against these cancers, was investigated in a phase III, randomized, double blind trial evaluating efficacy and safety in combination with CapeOx as first-line treatment of advanced or metastatic HER2+ UGIT ACs.Subjects had measurable and/or non-measurable disease with overexpression or amplification of HER2 (IHC2+ and FISH amplified, or IHC 3+, or FISH, CISH, or SISH amplified). HER2 status was reviewed by the central lab. Subjects were randomized 1:1 to CapeOx q3w (oxaliplatin 130mg/m545 pts were randomized and 487 had HER2+ centrally confirmed. The primary endpoint was not reached with a hazard ratio (HR) for OS of CapeOx+L compared to CapeOx+P of 0.91 (95% CI 0.73, 1.12, p=0.35); median 12.2 vs. 10.5 months, respectively. HR for uncensored PFS was 0.86 (95% CI 0.71 - 1.04, p=0.10); median 6.0 vs. 5.4 months. The analysis of PFS censored by the time of subsequent anticancer therapy as per protocol showed a HR of 0.82 (95% CI 0.68, 1.00, p=0.04). ORR was 53% in the CapeOx+L arm and 40% in the CapeOx+P arm. Pre-specified subgroup analyses showed significant improvements in OS in Asian pts (HR= 0.68) and those under 60 years (HR=0.69). There was no association between IHC and OS. Toxicity profiles were similar except for increased overall diarrhea, and skin toxicity and grade 3+ diarrhea (12 vs 3%) with CapeOx+L.The addition of L to CapeOx did not reach its primary endpoint, though certain subgroups showed improvement. Further clinical and molecular analyses will be presented.NCT00680901.

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