Cytokinetic-driven myeloprotection after cytotoxic chemotherapy: from an old idea to a new clinical approach.

Chemotherapy is the backbone of the treatment of several solid tumours and lymphomas. Myelotoxicity is often a dose-limiting toxicity and myeloprotection has always been investigated. In fact, over the years, several approaches have been studied in order to reduce the incidence of haematological toxicities and allow patients to receive effective, full-dose, chemotherapy. After the use of stimulating factors, such as granulocyte colony-stimulating factors and erythropoiesis-stimulating agents, in the very last years, a new approach has emerged. Trilaciclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, has been studied and it has been demonstrated in several clinical trials to reduce the incidence of myelotoxicity in small-cell lung cancer patients treated with chemotherapy or chemo-immunotherapy. Its potential role has not been fully studied yet, but it represents a highly effective tool to reduce myelotoxicity, widen the applicability of full-dose chemotherapy, even in frailer patients, and finally to increase the efficacy of chemotherapy in those tumours where relative dose intensity is a standard to achieve to get the best clinical results.

Supportive therapies in the prevention of chemotherapy-induced febrile neutropenia and appropriate use of granulocyte colony-stimulating factors: a Delphi consensus statement.

PURPOSE: Data indicate that the use of prophylactic granulocyte colony-stimulating factors (G-CSFs) for chemotherapy-induced febrile neutropenia (FN) in routine practice is not consistent with guideline recommendations. The initiative "supportive care for febrile neutropenia prevention and appropriateness of G-CFS use" was undertaken to address the issue of inappropriate prescription of G-CSFs and to improve guideline adherence in the treatment of FN. METHODS: In a two-round Delphi procedure, 36 medical oncologists reviewed clinically relevant recommendations on risk assessment, the appropriate use of G-CSFs, and the prevention of FN based on available literature and individual clinical expertise. RESULTS: The consensus was reached on 16 out of 38 recommendations, which are backed by evidence from randomised clinical trials and routine clinical practice. The medical oncologists agreed that the severity of neutropenia depends on patients' characteristics and chemotherapy intensity, and therefore, the risk of severe neutropenia or FN should be assessed at each chemotherapy cycle so as to initiate prophylaxis with G-CSFs if required. The use of biosimilar G-CSFs, with similar efficacy and safety profiles to the originator biologic, has improved the availability and sustainability of cancer care. The timing of supportive therapy is crucial; for example, long-acting G-CSF should be administered 24-72 h after chemotherapy administration. Each biological agent has a recommended administration dose and duration, and it is important to follow these recommendations to avoid complications associated with under-prophylaxis. CONCLUSION: It is hoped that these statements will help to increase adherence to guideline recommendations for appropriate G-CSF use and improve patient care.

Immunotherapy in Underrepresented Populations of Patients with Cancer: Do We Have Enough Evidence at Present? A Focus on Patients with Major Viral Infections and Autoimmune Disorders.

The safety and activity of immune checkpoint inhibitors have been characterized in interventional and observational studies. However, only small studies have specifically investigated these agents in patients who are excluded or underrepresented in clinical trials, frequently referred to as "special populations" or "underrepresented populations." These include older adults, those with dysregulated immune activation, patients with a compromised immune function, and those carrying major viral infections, lymphoproliferative diseases, and major organ dysfunctions. Therefore, there remains substantial uncertainty regarding the use of immune checkpoint inhibitors in these specific settings. The Network of Italian Supportive Care in Oncology has carried out a multidisciplinary project, with the contribution of oncologists and other specialists, to retrieve the existing evidence on the use of immunotherapy in patients with solid and hematological cancers with the final aim to provide an expert guidance. The results of this effort are presented in this article, which is focused on patients with major viral infections or those with immune dysregulation/autoimmune diseases, and could be useful to guide decisions in clinical practice and to design prospective clinical trials focusing on the use of immunotherapy in these populations. IMPLICATIONS FOR PRACTICE: Substantial uncertainty remains regarding the use of immune checkpoint inhibitors in "underrepresented" patients, such as older adults, those with dysregulated immune activation, and patients with a compromised immune function, major viral infections, lymphoproliferative diseases or major organ dysfunctions. The Network of Italian Supportive Care in Oncology has carried out a multidisciplinary project to retrieve the existing evidence on the use of immunotherapy in underrepresented patients with cancer in order provide an expert guidance. The results of this effort, with a focus on patients with major viral infections or those with immune dysregulation/autoimmune diseases, are presented in this article and could be useful to guide decisions both in clinical practice and to design clinical trials.

Recent advances in the management of chemotherapy-induced neutropenia: biosimilar granulocyte colony-stimulating factor use in Italy.

During the National Congress of the Italian Association of Medical Oncology, which was held in Rome, Italy, October 2019, experts met to discuss advantages of febrile neutropenia prevention based on biosimilar G-CSF. This issue is of paramount importance in oncology as recent biological products may be of great benefit, provided that costs are sustainable.

Refining the role of pegfilgrastim (a long-acting G-CSF) for prevention of chemotherapy-induced febrile neutropenia: consensus guidance recommendations.

PURPOSE: Chemotherapy-induced febrile neutropenia (FN) causes treatment delays and interruptions and can have fatal consequences. Current guidelines provide recommendations on granulocyte colony-stimulating factors (G-CSF) for prevention of FN, but guidance is unclear regarding use of short- vs long-acting G-CSF (e.g., filgrastim vs pegfilgrastim/lipegfilgrastim, respectively). An international panel of experts convened to develop guidance on appropriate use of pegfilgrastim for prevention of chemotherapy-induced FN. METHODS: Guidance recommendations were developed following a literature review, survey, evaluation of current practice, and an expert meeting. Consensus was established using an anonymous Delphi-based approach. RESULTS: Guidance recommendations for prevention of treatment-associated FN were as follows: for treatment with curative intent, maintenance of dose intensity using G-CSF to prevent dose delays/reduction should be standard of care; for treatment-associated FN risk ≥ 20%, short-acting G-CSF/pegfilgrastim should be given from cycle 1 onwards; and for treatment-associated FN risk < 20%, short-acting G-CSF/pegfilgrastim should be given if factors suggest overall risk (including treatment-related and patient-related risk factors) is ≥ 20%. It was agreed that pegfilgrastim and 11 days' filgrastim have similar efficacy and safety and that pegfilgrastim is preferred to < 11 days' filgrastim (and may be preferred to ≥ 11 days' filgrastim based on adherence and convenience); pegfilgrastim is not appropriate in weekly chemotherapy; in split-dose chemotherapy, pegfilgrastim is recommended 24 h after last chemotherapy dose; and during palliative chemotherapy, patient adherence and convenience may favor pegfilgrastim. CONCLUSION: In this era of targeted therapies, additional trials with G-CSF are still required. These recommendations should be used with existing guidelines to optimize pegfilgrastim use in clinical practice.

Use of procalcitonin in clinical oncology: a literature review.

The use of procalcitonin (PCT) as an early marker of infectious episodes in cancer patients is still controversial. We performed a MEDLINE search of peer-reviewed articles published between January 1990 and December 2015, and finally we analysed 15 articles. PCT seems to have a good diagnostic value of infectious episodes in cancer patients and its accuracy seems greater if we consider major events, such as bloodstream infections and sepsis. Serial evaluations of this protein seem to be more accurate in the diagnostic phase and useful to predict outcome and response to antibacterial treatment. On the other hand, some issues have yet to be solved, such as the use of a validated method of determination, the definition of a standard cut-off, and the heterogeneity among different settings of patients (e.g. early versus advanced-stage cancer, or haematological versus solid tumours). However, it is credible to think that PCT use in everyday clinical practice, preferably in combination with other clinical or laboratory tests, might be of help in finding and detecting early infectious complications in cancer patients.

Neutrophil CD64 expression: a reliable diagnostic marker of infection in advanced cancer patients?

Infection and sepsis are major health problems in cancer patients. There is a need for the identification and validation of biomarkers to improve their early diagnosis and treatment. Emerging evidence showed that neutrophil CD64 is a highly sensitive and specific marker for systemic infection and sepsis in critically ill patients with various diseases but data on patients bearing solid tumors are still lacking. Using a dedicated flow cytometric assay we evaluated neutrophil CD64 expression in patients with advanced cancer without active infections to verify if it could be utilized as a reliable biomarker of early infections also in oncologic patients.

Histochemistry in Advanced Cytometry: From Fluorochromes to Mass Probes.

For over half a century, fluorescence has been the milestone of most of the quantitative approaches in various fields from chemistry and biochemistry to microscopy. This latter also evolved into cytometry, thanks to the development of fluorescence techniques. The dyes of classical cytochemistry were replaced by fluorochromes, and the pioneer microphotometry was replaced by microfluorometry. The latter has great advantages in terms of simplicity, sensitivity, and accuracy. The extensive research and availability of new fluorochromes as well as the technological evolution contributed to the success of microfluorometry. The development of flow cytometry in the 1960s gave a giant boost to cell analysis and in particular to the clinical diagnostics. The synergy between flow cytometry and the subsequent development of monoclonal antibodies allowed the setup of multiparametric analytical panels that are today popular and irreplaceable in many clinical and research laboratories. Multiparametric analysis has required the application of an increasing number of fluorochromes, but their simultaneous use creates problems of mutual contamination, hence the need to develop new fluorescent probes. Semiconductor and nanotechnology research enabled the development of new probes called nanocrystals or quantum dots, which offered great advantages to the multiparametric analysis: in fact, thanks to their spectrofluorometric peculiarities, dozens of quantum dots may be simultaneously used without appreciable crosstalk between them. New analytical horizons in cytometry seem to be associated with a new concept of analysis that replaces fluorescence toward new markers with (non-radiative) isotopes of heavy metals. Thus, the mass flow cytometry was born, which seems to guarantee the simultaneous compensation-free analysis of up to 100 markers on a single sample aliquot.

Prognostic role of hematologic parameters of metastatic renal cell carcinoma treated with sunitinib.

BACKGROUND: Hemochrome parameters at the diagnosis of metastatic renal cell carcinoma (mRCC) and the development of macrocytosis during sunitinib therapy are considered prognostic. OBJECTIVE: To evaluate the prognostic role of hematologic parameters and macrocytosis in mRCC treated with sunitinib. METHODS: We analyzed clinical data of 100 patients with mRCC treated with sunitinib as first-line therapy in a retrospective multicenter study. We calculated neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) at baseline and erythrocyte mean corpuscular volume (MCV) during therapy. We considered the following cutoffs: NLR >3, PLR >150, LMR <3, and MCV >100 fl. Clinical data histology, prior nephrectomy, Fuhrman grading, metastatic sites, Memorial Sloan-Kettering Cancer Center score, and Heng score were collected. Overall survival (OS) and progression-free survival (PFS) were calculated. Univariate and multivariate analysis using Cox regression model with time-dependent (macrocytosis) covariate were applied. RESULTS: At the univariate analysis, low LMR was associated with shorter PFS and OS (p = 0.02 and p = 0.06, respectively). High PLR was associated with worse PFS (p = 0.005); median OS was 23 vs 28 months (p = 0.13). At the multivariate analysis, poor risk (Heng score), low LMR, and high PLR were associated with shorter PFS (hazard ratio 7.1, 1.5, and 2, respectively); poor PS and poor risk (Heng score) were related to worst OS. Macrocytosis was observed in 26 patients and was not prognostic of survival. CONCLUSIONS: In our cohort of patients with mRCC treated with sunitinib, low LMR (>3) and high PLR (>150) were associated with shorter PFS. Macrocytosis was not prognostic.

Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer.

BACKGROUND: Molecular predictors of bevacizumab efficacy in colorectal cancer have not been identified yet. Specific VEGF polymorphisms may affect gene transcription and therefore indirectly influence the efficacy of bevacizumab. METHODS: Genomic DNA of 111 consecutive metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab was obtained from blood samples. VEGF -2578 C/A, -1498 C/T, + 405 C/G, + 936 C/T polymorphisms were analyzed by means of PCR-RFLP. DNA samples from 107 patients treated with FOLFIRI alone served as historical control group. The relation of VEGF polymorphisms with PFS, evaluated through Kaplan-Meier method and log-rank test, was the primary end-point. An interaction test with a Cox model has been performed in order to demonstrate the heterogeneity of the effect of VEGF -1498 C/T polymorphism between bevacizumab-and control group. RESULTS: In the bevacizumab-group median PFS and OS of patients carrying VEGF -1498 C/C, C/T and T/T allelic variants were, respectively, 12.8, 10.5, 7.5 months (p = 0.0046, log-rank test) and 27.3, 20.5, 18.6 months (p = 0.038, log-rank test). VEGF -1498 T/T genotype was associated with shorter PFS (HR = 2.13, [1.41-5.10], p = 0.0027). In the control group no significant association of VEGF -1498 C/T allelic variants and PFS or OS was found. Interaction between VEGF -1498 C/T variants and treatment effect suggested that the relation of VEGF -1498 T/T genotype with shorter PFS was caused by the effect of bevacizumab (p = 0.011). Other investigated polymorphisms did not affect the outcome. CONCLUSIONS: These data suggest a possible role for VEGF -1498 C/T variants in predicting the efficacy of bevacizumab in the up-front treatment of metastatic colorectal cancer patients. A molecular tool for selecting subjects candidate to benefit from the anti-VEGF could be important for clinical practice. The retrospective and exploratory design of the present study, coupled with the non-randomized nature of the comparison between treated and untreated patients, imply that these results should be considered as hypothesis generators. A prospective validating trial is currently ongoing.

Single-dose palonosetron and dexamethasone in preventing nausea and vomiting induced by moderately emetogenic chemotherapy in breast and colorectal cancer patients.

AIMS AND BACKGROUND: Palonosetron, a unique second-generation 5-HT3 receptor antagonist, has been demonstrated to control emesis related to chemotherapy-induced nausea and vomiting (CINV). The aim of this study was to evaluate the efficacy and tolerability of palonosetron followed by a single dose of dexamethasone in patients with breast cancer (BC) or colorectal cancer (CRC) receiving moderate emetogenic chemotherapy (MEC). METHODS AND STUDY DESIGN: Chemotherapy-naive BC and CRC patients were given MEC as adjuvant or first-line treatment. Palonosetron (0.25 mg IV) and dexamethasone (8 mg IV) were administered before chemotherapy on day 1. The primary endpoint was complete response (CR; no vomiting and no use of rescue medication) during the overall study period (days 1-5). The antiemetic response was evaluated during the acute (day 1) and delayed (days 2-5) phases. RESULTS: Sixty-eight patients were enrolled (median age 61 years, 56 females; BC = 40, CRC = 28). CR was observed in 46 of 68 patients (67.6%), while CR during the acute and delayed phases was 75.0% in each cancer group. The antiemetic regimen was well tolerated. CONCLUSIONS: A single administration of palonosetron and dexamethasone on day 1 in BC and CRC patients adequately controls CINV during the entire period of emetic risk.

Anti-Cancer Treatment Strategies in the Older Population: Time to Test More?

Aging is a well-recognized risk factor for the development of cancer. The incidence of new cancer diagnoses has increased globally given the rising senior population. Many hypotheses for this increased risk have been postulated over decades, including increased genetic and epigenetic mutations and the concept of immunosenescence. The optimal treatment strategies for this population with cancer are unclear. Older cancer patients are traditionally under-represented in clinical trials developed to set the standard of care, leading to undertreatment or increased toxicity. With this background, it is crucial to investigate new opportunities that belong to the most recent findings of an anti-cancer agent, such as immune-checkpoint inhibitors, to manage these daily clinical issues and eventually combine them with alternative administration strategies of antiblastic drugs such as metronomic chemotherapy.

Baseline Characteristics and Outcomes of Cancer Patients Infected with SARS-CoV-2 in the Lombardy Region, Italy (AIOM-L CORONA): A Multicenter, Observational, Ambispective, Cohort Study.

Cancer patients may be at high risk of infection and poor outcomes related to SARS-CoV-2. Analyzing their prognosis, examining the effects of baseline characteristics and systemic anti-cancer active therapy (SACT) are critical to their management through the evolving COVID-19 pandemic. The AIOM-L CORONA was a multicenter, observational, ambispective, cohort study, with the intended participation of 26 centers in the Lombardy region (Italy). A total of 231 cases were included between March and September 2020. The median age was 68 years; 151 patients (62.2%) were receiving SACT, mostly chemotherapy. During a median follow-up of 138 days (range 12-218), 93 events occurred. Age ≥60 years, metastatic dissemination, dyspnea, desaturation, and interstitial pneumonia were all independent mortality predictors. Overall SACT had a neutral effect (Odds Ratio [OR] 0.83, 95%Confidence Interval [95%CI] 0.32-2.15); however, metastatic patients receiving SACT were less likely to die as compared to untreated counterparts, after adjusting for other confounding variables (OR 0.23, 95%CI 0.11-0.51, p < 0.001). Among cancer patients infected by SARS-CoV-2, those with metastases were most at risk of death, especially in the absence of SACT. During the ongoing pandemic, these vulnerable patients should avoid exposure to SARS-CoV-2, while treatment adjustments and prioritizing vaccination are being considered according to international recommendations.

Granulocyte colony-stimulating factors (G-CSF) and Covid-19: a double-edged sword?

Not available.

Biosimilar pegfilgrastim and adherence to guidelines for chemotherapy-induced neutropenia and infections in cancer patients.

Not available.

Management of anemia in patients with cancer: 2019 Italian Association of Medical Oncology (AIOM) guidelines.

This article summarizes the latest Italian Medical Oncology Association (AIOM) guidelines on the management of cancer-related and chemotherapy-related anemia with a particular attention to the use of erythropoiesis-stimulating agents and iron supplementation.

Management of chemotherapy-induced neutropenia in patients with cancer: 2019 guidelines of the Italian Medical Oncology Association (AIOM).

Neutropenia is the most frequent side effect of commercially available myelosuppressive drugs and its most significant complication is febrile neutropenia. It is associated with increased hospital admissions and higher probability of death. Prophylaxis with the administration of granulocyte colony-stimulating factor can prevent neutropenia caused by anticancer drugs. The correct administration of these drugs and the management of febrile neutropenia are extremely important in the treatment of patients with cancer.

Clinical and economic effect of administration of red blood product transfusions in an outpatient supportive care cancer service.

Patients with cancer may develop disease- or treatment-associated anemia, requiring red blood product transfusions. In Italy, transfusions are usually administered in a day hospital service or in inpatient wards. Since 2013, a dedicated supportive care service for outpatients has been implemented in Pisa, where red blood product transfusions are administered. The present study evaluated the patients that received red blood product transfusions at the dedicated supportive care service for outpatients in 2016. The clinical features of patients were analyzed, and the procedural cost was evaluated by comparing its administration with a hypothetical scenario in which transfusions were provided via day hospital services or inpatient wards. The results revealed that the dedicated supportive care service for outpatients avoided the hospitalization of patients, allowing them to receive prompt and timely transfusions, with a rapid resolution of symptoms. Avoiding hospitalization was also estimated to decrease transfusion-associated costs by €48,805-177,805.

Health technology assessment-based approach to flow cytometric immunophenotyping of acute leukemias: a literature classification.

OBJECTIVE: Acute leukemia (AL) is a broad, heterogeneous group of malignant diseases. The diagnostic workup of AL is based on several clinical and laboratory findings, including flow cytometric immunophenotyping. However, the role of this assay in the diagnosis of AL has not been systematically investigated. The aim of this study was to determine the accuracy and utility of flow cytometric immunophenotyping in the identification, characterization, and staging of AL. METHODS: We performed a systematic selection and classification of the literature since 1980, focused on flow cytometric immunophenotyping of AL. We applied a 6-variables model to cover both the technical capabilities and the clinical value of flow cytometric immunophenotyping in the diagnosis of AL. RESULTS: Using 3 key words (acute leukemia, immunophenotyping, flow cytometry), we screened the literature from January 1985 to April 2015 in PubMed and Embase databases and found 1010 articles. A total of 363 were selected and submitted to the expert panel, which selected a final data set of 248 articles to be analyzed. Of these, 160 were focused on clinical and biological issues, 55 were technical articles, and 31 were reviews. These 248 articles were then analyzed according to the 6-variables model and definitively classified. CONCLUSIONS: We assessed the literature on flow cytometric immunophenotyping of AL over 3 decades as the first step toward an evidence-based analysis of the impact of this technology on the clinical management of patients with AL.

On-target Toxicities Predictive of Survival in Metastatic Renal Cell Carcinoma (mRCC) Treated With Sunitinib: A Multicenter Retrospective Study.

BACKGROUND: Preliminary studies suggested that selected drug-related toxicities of sunitinib may correlate with a better prognosis. PATIENTS AND METHODS: From January 2006 through December 2015, we retrospectively analyzed data of 145 patients with metastatic renal cell carcinoma treated with sunitinib as a first-line therapy in 7 different Italian oncology departments. Hypertension, hypothyroidism, thrombocytopenia, neutropenia, and anemia were evaluated. Overall survival (OS) and progression-free survival (PFS) were calculated. OS and PFS were compared in patients who developed and who did not develop a drug-related toxicity. A multivariate analysis using the Cox regression model was performed. RESULTS: We evaluated 145 patients (92 males; median age, 70 years); 105 (62.4%) patients experienced at least 1 toxicity: 66 (45.5%) patients developed hypothyroidism, 41 (28.3%) thrombocytopenia, 39 (26.9%) hypertension that required medical therapy, 22 (15.2%) anemia, and 11 (7.6%) neutropenia. The median PFS of patients who developed hypertension was 12 months (95% confidence interval [CI], 9-21 months) versus 9 months (95% CI, 7-12 months) in patients who did not develop toxicity; the median OS was 36 months (95% CI, 22 months to not reached) versus 26 months (95% CI, 18-34 months). For neutropenia, the median PFS was 17.5 months (95% CI, 9-65 months) versus 10 months (95% CI, 8-12 months); the median OS was 23 months (95% CI, 13 months to not reached) versus 28 months (95% CI, 22-35 months). At univariate and multivariate analysis, we observed a protective effect of hypertension and neutropenia on tumor progression (hazard ratio, 0.47; 95% CI, 0.28-0.78 and hazard ratio, 0.26; 95% CI, 0.09-0.76, respectively). CONCLUSIONS: Many patients developed toxicities during treatment with sunitinib; hypertension and neutropenia were related to longer PFS in our cohort.