Margherita Ratti

Emerging combination therapies to overcome resistance in EGFR-driven tumors.

The epidermal growth factor receptor (EGFR) is responsible for the growth and progression of tumor cells; its overexpression and deregulation of its downstream signaling pathway have been found in many different neoplasms. These characteristics make it an ideal target for cancer treatment. Two classes of EGFR inhibitors, which bind to different parts of this molecule, have been developed and studied: monoclonal antibodies, such as cetuximab and panitumumab and tyrosine kinase inhibitors, including erlotinib and gefitinib. The effectiveness of these new drugs is considerably reduced by a number of mechanisms of resistance developed by tumor cells. Hence, there is a clear need for better characterization of these processes and finding new therapeutic strategies to make the action of these drugs more incisive. Here, we describe some of the mechanisms of resistance to EGFR inhibitors and review the main innovations attempting to overcome these drawbacks.

Pituitary gland metastasis from rectal cancer: report of a case and literature review

Pituitary metastases are unusual complications of malignancies. In about only 2% of patients they origin from colorectal cancer (CRC), with breast and lung as the most common primary tumors. Nevertheless, some authors reported a recent increase of the incidence of metastases in infrequent sites, such as brain or bone, arising from gastrointestinal cancers, probably due to the expanded treatment options and the resulting improved survival. Here, we report the case of a 54-year old woman diagnosed with lung metastases from rectal cancer, who, after several cycles of radio- and chemotherapy, presented symptoms and signs of pituitary disfunction (i.e. diabetes insipidus, hypothyroidism and diplopy). The diagnosis of pituitary metastasis from rectal cancer was histologically confirmed after surgery.

Ramucirumab for metastatic gastric or gastroesophageal junction cancer: results and implications of the REGARD trial.

Gastric cancer is a highly aggressive disease. In metastatic setting, median overall survival, even with modern chemotherapy regimens, generally does not exceed 1 year and toxicity is a major concern. Angiogenesis plays a crucial role in cancer development and progression, and VEGF is one of the most important mediators of this process. Ramucirumab, an anti-VEGFR-2 antibody, has been recently evaluated in the large Phase III REGARD trial, demonstrating a significant survival benefit in second-line treatment of patients with advanced gastric or gastro-eosophageal junction adenocarcinoma. Unlike traditional chemotherapy, treatment with ramucirumab was associated with very few toxic effects. This article will review the main findings of the REGARD trial and discuss their potential impact on future treatment of metastatic gastric cancer.

Targeted therapies in gastric cancer treatment: where we are and where we are going.

SummaryGastric cancer (GC) is one of the most common malignancies and a major cause of cancer-related deaths worldwide. Its incidence has significantly declined over the last few decades, probably due to the identification of specific etiologic agents such as Helicobacter pylori and other dietary and environmental risk factors. Nevertheless, most of the cases are unfortunately diagnosed at an advanced stage justifying median overall survival rates frequently not exceeding one year. Palliative combination chemotherapy usually represented by a platinum-based doublet is the mainstay of treatment in the metastatic setting. Adding a third drug such as an anthracycline or a taxane has been shown to improve response rate and provide limited survival benefits in fit selected patients. Unlike other tumors, the introduction of molecularly targeted drugs in the medical armamentarium for GC is relatively recent with trastuzumab and ultimately ramucirumab constituting the only agents approved to date. Recent advances in the understanding of GC biology have led to the development of novel targeted therapies holding the promise to further improve treatment outcomes. The aim of this paper is to review the main available data coming from clinical trials of targeted drugs and to describe some of the most interesting molecules in clinical development in GC. These include drugs targeting EGFR, angiogenesis, c-MET, FGFR2, mTOR and immune checkpoints.

New developments in the treatment of chemotherapy-induced neutropenia: focus on balugrastim

Neutropenia and febrile neutropenia are two major complications of chemotherapy. Dose reductions, delays in treatment administration, and the use of granulocyte colony-stimulating factors are equally recommended options to preserve absolute neutrophil count in case of chemotherapy regimens bringing a risk of febrile neutropenia of 20% or higher. Recombinant granulocyte colony-stimulating factors, such as filgrastim and lenograstim, have a short elimination half-life (t1/2) and need to be used daily, while others, like pegfilgrastim and lipegfilgrastim, are characterized by a long t1/2 requiring only a single administration per cycle. Balugrastim is a novel long-acting recombinant granulocyte colony-stimulating factor obtained by means of a genetic fusion between recombinant human serum albumin and granulocyte colony-stimulating factor. Albumin binding increases the molecular weight and determines a high plasmatic stability leading to a t1/2 of ~19 days. Balugrastim’s efficacy, safety, and tolerability have been assessed in four different clinical trials involving breast cancer patients treated with doxorubicin and docetaxel. Pegfilgrastim was chosen as a comparator. Balugrastim was noninferior to pegfilgrastim with regard to the reduction of mean duration of severe neutropenia during cycle 1. Moreover, both treatments were comparable in terms of efficacy and safety profile. Balugrastim was well tolerated, with the only related adverse event being mild to moderate bone pain. The aim of this review is to summarize the currently available literature data on balugrastim.

Lipegfilgrastim for the prophylaxis and treatment of chemotherapy-induced neutropenia

Chemotherapy is frequently associated with hematologic toxicity. Neutropenia with or without fever is a relevant cause of morbidity, mortality and costs, compromising treatment administration and clinical outcomes. The development of granulocyte colony-stimulating factors has had a positive impact on the clinician’s approach to neutropenia. Such agents, currently used for primary and secondary prophylaxis of chemotherapy-induced neutropenia and febrile neutropenia (FN), are effective in limiting hematologic toxicities and consequently allow the administration of intensive dose-dense regimens. Several biosimilar products of filgrastim have been developed over the years, showing effects similar to the originator drug. Until now, pegfilgrastim has been the only available long-acting factor, requiring just a single administration per chemotherapy cycle. The recent approval of the novel granulocyte colony-stimulating factors, lipegfilgrastim, offers interesting therapeutic alternatives. In fact, similar to pegfilgrastim, it has been demonstrated to reduce the duration of neutropenia and the occurrence of FN during chemotherapy safely.

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

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.

Modified dose-dense taxotere cisplatin fluorouracil regimen (mTCF-dd) in a large cohort of patients (pts) with metastatic or locally advanced non-squamous gastroesophageal cancer (GEC).

e15552Background: TCF is one of the most effective first-line option in metastatic GEC. We previously reported on the promising and high activity of mTCF-dd (Tomasello G et al: Gastric Cancer 2014 ...

Optimizing chemotherapy in patients with metastatic transitional-cell carcinoma: High rate of complete response with two sequential dose-dense regimens of cisplatin, gemcitabine, paclitaxel, followed by MVAC.

303 Background: Currently, cisplatin, gemcitabine, paclitaxel (CGP) and MVAC are the most active regimens in transitional-cell carcinoma (TCC). We tested the hypothesis that two sequential non-cross-resistant, dose-dense (DD) regimens may target different cancer cells, avoid drug resistance, and improve response rate. Methods: This is a phase II, single institutional trial, including patients (pts) with bladder, renal pelvis, or ureteral TCC. Primary end point was the rate of complete response (CR) after two sequential DD regimens. Primary analysis was carried out in the intention to treat (ITT) population.Patients with histological diagnosis of TCC, PS 0–2 (ECOG), adequate organ function and no previous systemic regimens were treated with 4 cycles of CGP DD followed by 4 cycles of M-VAC DD. All received peg-filgrastim after chemotherapy. Pts were evaluated with CT scan at the baseline, after 4 cycles, at the end of chemotherapy and then every 3 months for 2 years and 6 months thereafter. Results: 44 cons...