Sara Delfanti

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer: results and open issues

The medical treatment of non-small-cell lung cancer (NSCLC) has progressively changed since the introduction of “targeted therapy”. The development of one of these molecular drug categories, e. g., the epidermal growth factor receptor (EGFR) tyrosine-kinase (TK) selective inhibitors, such as the orally active gefitinib and erlotinib, offers an interesting new opportunity. The clinical response rates obtained with their employment in unselected patient populations only account for approximately 10%. Because of this, over the last two years numerous studies have been performed in order to identify the patient subsets that could better benefit from these agents. Not only patient characteristics and clinical-pathological features, such as never-smoking status, female gender, East Asian origin, adenocarcinoma histology, bronchioloalveolar subtype, but also molecular findings, such as somatic mutations in the EGFR gene, emerge as potentially useful prognostic and predictive factors in advanced NSCLC. Further, specifically designed clinical trials are still needed to completely clarify these and other open issues that are reviewed in this paper, in order to clarify all the interesting findings available in the clinical practice.

High-Dose Chemotherapy With Autologous Hematopoietic Stem Cell Transplantation for High-Risk Primary Breast Cancer

BACKGROUND The efficacy of high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation for breast cancer (BC) has been an area of intense controversy among the medical oncology community. Over the last decade, due to the presentation of negative results from early randomized studies, this approach has not longer been considered an option by the vast majority of medical oncologists. This article is aimed to clarify what happened and where we are now in this not exhausted field. METHODS We critically revised the published literature regarding HDC in the setting of high-risk BC, including a recent meta-analysis using individual patient data from 15 randomized studies. RESULTS A significant benefit by HDC in recurrence-free survival has been clearly documented in unselected patient populations. In HER2-negative population, particularly in the triple-negative disease, a positive effect of intensified therapy in overall survival is biologically plausible and supported by clinical evidence. Over the years HDC with support of adequate number of stem cells has become a safe treatment modality. CONCLUSIONS The administration of higher doses of chemotherapy with stem cell support may still represent a therapeutic option (and not a recommendation) in selected BC patients. This approach should be investigated further.

An eight-colour flow cytometric method for the detection of reference values of lymphocyte subsets in selected healthy donors

Determination of immunoregulatory cells in peripheral blood is important in the management of disease or in the therapeutic approaches that involve alterations in lymphocyte subpopulations. The aims of the present study were (1) to develop a standard multiparametric flow cytometric method for phenotypic detection and enumeration of lymphocyte subsets so as to reduce the variability in both sample preparation methodology and flow cytometric operations; (2) to furnish reference values of lymphocytes by using a selected healthy population; and (3) to examine the influence of age and sex on the distribution of lymphocytes expressing surface markers. Eighty healthy donors were analysed, and ten-parameter, eight-colour analytical procedure was performed. We furnished a panel to detect and to enumerate lymphocyte subpopulations by a multiparametric flow cytometric method to set the reference values to a selected healthy population. These values showed statistically but not clinically significant differences in T lymphocyte subsets and natural killer cells. Furthermore, significant age-related correlations in T lymphocyte and natural killer cells were observed. Lastly, males and females in relation to age showed a significant different trend in T and B lymphocyte subsets. We confirmed that this study provides a rapid and accurate method for the detection and quantification of lymphocyte subsets that could be utilized in the clinical settings. The definition of reference values in the healthy selected population could be helpful also to better define the disease status and to evaluate the treatment efficacy during clinical trials.

Tissue and Soluble Biomarkers in Breast Cancer and Their Applications: Ready to Use?

Breast cancer therapies are in continuous evolution: From surgery to hormonal therapy, from classical and new combined chemotherapies to emerging targeted agents of recent introduction to the clinic. The attempt to personalize the best treatment for each patient is driven by efficacy and safety parameters and tumor biology investigations of markers for aggressiveness and response to treatment. The plethora of targeted therapies has provided momentum for the quest to better understand not only target mechanisms of action, but also tumor behavior. Moreover, how to monitor response to these agents is crucial today to achieve better resource-sharing and to find cheaper, less invasive, and standardized detection techniques for clinically validated biomarkers. In this report, we briefly summarize data on the major tissue and soluble biomarkers focusing on their actual use in daily practice, as well as their emerging role and possible future applications in breast cancer treatment.

Lymphocyte subpopulation and dendritic cell phenotyping during antineoplastic therapy in human solid tumors

Patients with cancer show variable levels of immunosuppression at the time of the presentation, and cytotoxic antineoplastic therapy is the primary contributor to the clinical immunodeficiency often observed during the course of the disease. In both hematological and solid tumors, this phenomenon is primarily related to the T-cell depletion associated with inhibition of dendritic cell ability to induce both primary and secondary T- and B-cell responses. Complete restoration of immunocompetence following antineoplastic therapy implicates the progressive recovery of various cell subpopulations, and it is a complex process that also depends on the type, the dose, the scheduling, and the associations of the employed drugs. In the era of target therapies, several antiangiogenic drugs are increasingly used in combination with standard chemotherapy in the treatment of advanced solid tumors. Their clinical efficacy has been recently related not only to the specific antiangiogenic properties but also to an indirect hypothetical effect on the host immune system. In the present work, we have reviewed the most recent information regarding (1) the capacity of standard antineoplastic therapy to induce and maintain an immunodeficiency in patients with solid tumors and (2) the influence of the antiangiogenic treatment in association with standard chemotherapy on lymphocyte and dendritic cell subsets and the possible resulting additional antitumor mechanism.

In Vitro Killing of Colorectal Carcinoma Cells by Autologous Activated NK Cells is Boosted by Anti-Epidermal Growth Factor Receptor-induced ADCC Regardless of RAS Mutation Status

Treatment of advanced metastatic colorectal cancer (mCRC) patients is associated with a poor prognosis and significant morbidity. Moreover, targeted therapies such as anti-epidermal growth factor receptor (EGFR) have no effect in metastatic patients with tumors harboring a mutation in the RAS gene. The failure of conventional treatment to improve outcomes in mCRC patients has prompted the development of adoptive immunotherapy approaches including natural killer (NK)-based therapies. In this study, after confirmation that patients’ NK cells were not impaired in their cytotoxic activity, evaluated against long-term tumor cell lines, we evaluated their interactions with autologous mCRC cells. Molecular and phenotypical evaluation of mCRC cells, expanded in vitro from liver metastasis, showed that they expressed high levels of polio virus receptor and Nectin-2, whereas UL16-binding proteins were less expressed in all tumor samples evaluated. Two different patterns of MICA/B and HLA class I expression on the membrane of mCRC were documented; approximately half of mCRC patients expressed high levels of these molecules on the membrane surface, whereas, in the remaining, very low levels were documented. Resting NK cells were unable to display sizeable levels of cytotoxic activity against mCRC cells, whereas their cytotoxic activity was enhanced after overnight or 5-day incubation with IL-2 or IL-15. The susceptibility of NK-mediated mCRC lysis was further significantly enhanced after coating with cetuximab, irrespective of their RAS mutation and HLA class I expression. These data open perspectives for combined NK-based immunotherapy with anti-epidermal growth factor receptor antibodies in a cohort of mCRC patients with a poor prognosis refractory to conventional therapies.

Chemotherapy-induced anemia in breast cancer patients treated with pegfilgrastim-supported dose-dense regimens

The primary use of recombinant granulocyte colony-stimulating factors has reduced the incidence of febrile neutropenia during dose-dense adjuvant/neoadjuvant chemotherapy programs for breast cancer. Otherwise, in this population, filgrastim seems to worse chemotherapy-induced anemia, especially when administered with prolonged schedules that induced leukocytosis. No exhaustive data are available about the effect of long-lasting formulation of filgrastim (pegfilgrastim) on hemoglobin levels. We retrospectively analyzed the data regarding hemoglobin level and leukocyte count of 38 breast cancer patients treated with dose-dense anthacycline and/or taxane-based chemotherapy with pegfilgrastim support, both in adjuvant and in neoadjuvant settings. Mean hemoglobin levels progressively decreased throughout the treatment (without correlation with both the schedule of chemotherapy and the patient’s age) but only two patients developed mild anemia. No significant correlation was found between the degree of leukocytosis and the hemoglobin decrease. These data suggest that pegfilgrastim, per se, doesn’t seem to worse chemotherapy-induced anemia. This fact may be at least in part explains by its “balanced” impact on hematopoietic recovery during dose-dense chemotherapy.

The Prognosis of Patients with Liver Metastases from Colorectal Cancer still Depends on Anatomical Presentation more than on Treatments.

BACKGROUND The best management of liver metastases from colorectal cancer is still debated and little is known about the true impact of treatments on survival. MATERIALS AND METHODS The study involved 122 patients (77 males), aged 64.0 ± 11.0 years (range: 27.8-86.1) at diagnosis of liver metastatization (synchronous in 59). All underwent chemotherapy and at least one procedure of radiofrequency ablation; 53 also had partial hepatic resections. Demographics, tumor characteristics and survival outcomes from liver metastatization were analyzed with univariate and multivariate techniques. This analysis was performed also taking into account relative survival as the best estimate of specific survival. RESULTS The analysis with observed survival selected the categorized number of involved lymph nodes in the colorectal specimens as the only statistically significant predictor, while the analysis with relative survival also showed site of the primary tumor (above the sigmoid colon or otherwise) and number of liver metastases as significant factors. The standardized mortality ratio was 9.673 (95% CI: 7.668-11.663) and a total of 201.85 years of life were lost in comparison with the survival of the reference population. CONCLUSIONS The computation of relative survival – better than observed survival – selected a more adequate number of predictors, making investigation of even limited series of patients with confounding factors reliable. The finding that prognosis was mainly dependent on the anatomical presentation of the primary tumor and of liver metastases – instead of treatments – could explain the still contrasting opinions on the role of the available therapies in this field.

Management of patients with end-stage renal disease undergoing chemotherapy: recommendations of the Associazione Italiana di Oncologia Medica (AIOM) and the Società Italiana di Nefrologia (SIN)

Background The overall risk of some cancers is increased in patients receiving regular dialysis treatment due to chronic oxidative stress, a weakened immune system and enhanced genomic damage. These patients could benefit from the same antineoplastic treatment delivered to patients with normal renal function, but a better risk/benefit ratio could be achieved by establishing specific guidelines. Key considerations are which chemotherapeutic agent to use, adjustment of dosages and timing of dialysis in relation to the administration of chemotherapy. Methods We have reviewed available data present in the literature, including recommendations and expert opinions on cancer risk and use of chemotherapeutic agents in patients with end-stage renal disease. Experts selected by the boards of the societies provided additional information which helped greatly in clarifying some issues on which clear-cut information was missing or available data were conflicting. Results Data on the optimal use of chemotherapeutic agents or on credible schemes of polychemotherapy in haemodialysed patients are sparse and mainly derive from case reports or small case series. However, recommendations on dosing and timing of dialysis can be proposed for the most prescribed chemotherapeutic agents. Discussion The use of chemotherapeutic agents as single agents, or in combination, can be safely given in patients with end-stage renal disease. Appropriate dosage adjustments should be considered based on drug dialysability and pharmacokinetics. Coordinated care between oncologists, nephrologists and pharmacists is of pivotal importance to optimise drug delivery and timing of dialysis.