Publications by authors named "Sara Elena Rebuzzi"

26 Publications

  • Page 1 of 1

Immunotherapy retreatment: case report, review of the literature and proposal for the definition of different scenarios.

Immunotherapy 2021 Apr 7. Epub 2021 Apr 7.

Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino of Genova, Genova, 16132, Italy.

Immune checkpoint inhibitors have improved the treatment landscape of different tumors and one of the emerging issues is the reintroduction of immunotherapy after discontinuation. Scarce evidence is currently available and different definitions have been used. The case of a patient with pretreated advanced urothelial cancer, who responded to immunotherapy retreatment after long-term benefit from the previous course, is reported. Based on a review of the different clinical scenarios, a definition of immunotherapy retreatment was proposed, as rechallenge or reintroduction, based on the reasons of discontinuation of the previous course. Clinical factors potentially associated with clinical benefit from immunotherapy retreatment are discussed, even though studies are needed to assess the efficacy and safety of the different immunotherapy retreatment strategies.
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http://dx.doi.org/10.2217/imt-2021-0006DOI Listing
April 2021

Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer.

Int J Mol Sci 2021 Mar 5;22(5). Epub 2021 Mar 5.

Department of Internal Medicine and Medical Specialties (Di.M.I.), University of Genoa, 16132 Genoa, Italy.

In the scenario of systemic treatment for advanced non-small cell lung cancer (NSCLC) patients, one of the most relevant breakthroughs is represented by targeted therapies. Throughout the last years, inhibitors of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-Ros oncogene 1 (ROS1), and V-raf murine sarcoma viral oncogene homolog B (BRAF) have been approved and are currently used in clinical practice. However, other promising molecular drivers are rapidly emerging as therapeutic targets. This review aims to cover the molecular alterations with a potential clinical impact in NSCLC, including amplifications or mutations of the mesenchymal-epithelial transition factor (MET), fusions of rearranged during transfection (RET), rearrangements of the neurotrophic tyrosine kinase (NTRK) genes, mutations of the Kirsten rat sarcoma viral oncogene (KRAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), as well as amplifications or mutations of human epidermal growth factor receptor 2 (HER2). Additionally, we summarized the current status of targeted agents under investigation for such alterations. This revision of the current literature on emerging molecular targets is needed as the evolving knowledge on novel actionable oncogenic drivers and targeted agents is expected to increase the proportion of patients who will benefit from tailored therapeutic approaches.
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http://dx.doi.org/10.3390/ijms22052625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961376PMC
March 2021

Beyond First-Line Immunotherapy: Potential Therapeutic Strategies Based on Different Pattern Progressions: Oligo and Systemic Progression.

Cancers (Basel) 2021 Mar 15;13(6). Epub 2021 Mar 15.

Oncologia Medica 1, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy.

First-line immune-checkpoint inhibitor (ICI)-based therapy has deeply changed the treatment landscape and prognosis in advanced non-small cell lung cancer (aNSCLC) patients with no targetable alterations. Nonetheless, a percentage of patients progressed on ICI as monotherapy or combinations. Open questions remain on patients' selection, the identification of biomarkers of primary resistance to immunotherapy and the treatment strategies to overcome secondary resistance to first-line immunotherapy. Local ablative approaches are the main therapeutic strategies in oligoprogressive disease, and their role is emerging in patients treated with immunotherapy. Many therapeutic strategies can be adapted in aNSCLC patients with systemic progression to personalize the treatment approach according to re-characterization of the tumors, previous ICI response, and type of progression. This review's aim is to highlight and discuss the current and potential therapeutic approaches beyond first-line ICI-based therapy in aNSCLC patients based on the pattern of disease progression (oligoprogression versus systemic progression).
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http://dx.doi.org/10.3390/cancers13061300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999258PMC
March 2021

Neuroendocrine Differentiation of Prostate Cancer Is Not Systematically Associated with Increased 18F-FDG Uptake.

Diagnostics (Basel) 2021 Mar 8;11(3). Epub 2021 Mar 8.

Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy.

Neuroendocrine differentiation (NED) of prostate cancer represents an acknowledged predictor of resistant and more aggressive disease. NED can be functionally exploited in vivo using PET/CT imaging with somatostatin analogs radiolabeled with 68Ga. Many previous reports have shown that 18F-FDG PET/CT should also be used in cases such as guiding management, as NED is systematically associated with increased glycolysis. We hereby discuss the case of a metastatic prostate cancer patient in which 68Ga-Dotatoc PET/CT revealed the occurrence of NED with low FDG-avidity.
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http://dx.doi.org/10.3390/diagnostics11030468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998830PMC
March 2021

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

The Prognostic Role of Baseline Metabolic Tumor Burden and Systemic Inflammation Biomarkers in Metastatic Castration-Resistant Prostate Cancer Patients Treated with Radium-223: A Proof of Concept Study.

Cancers (Basel) 2020 Oct 31;12(11). Epub 2020 Oct 31.

Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy.

Over the last years has emerged the urgent need for the identification of reliable prognostic biomarkers able to potentially identify metastatic castration-resistant prostate cancer (mCRPC) patients most likely to benefit from Radium-223 (Ra-223) since baseline. In the present monocentric retrospective study, we analyzed the prognostic power of systemic inflammation biomarkers and 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET)-derived parameters and their potential interplay in this clinical setting. The following baseline laboratory parameters were collected in 59 mCRPC patients treated with Ra-223: neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelets-to-lymphocyte ratio (PLR), and systemic inflammation index (SII), while maximum Standardized Uptake Value, Metabolic Tumor Volume (MTV), and Total Lesion Glycolysis (TLG) were calculated in the 48 of them submitted to baseline FDG-PET. At the univariate analysis, NLR, dNLR, MTV, and TLG were able to predict the overall survival (OS). However, only NLR and MTV were independent predictors of OS at the multivariate analysis. Additionally, the occurrence of both increased NLR and MTV at baseline identified mCRPC patients at higher risk for lower long-term survival after treatment with Ra-223. In conclusion, the degree of systemic inflammation, the quantification of the metabolically active tumor burden and their combination might represent potentially valuable tools for identifying mCRPC patients who are most likely to benefit from Ra-223. However, further studies are needed to reproduce these findings in larger settings.
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http://dx.doi.org/10.3390/cancers12113213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693606PMC
October 2020

Clinical impact of COVID-19 in a single-center cohort of a prospective study in cancer patients receiving immunotherapy.

Immunotherapy 2020 10 15;12(15):1139-1148. Epub 2020 Sep 15.

Medical Oncology Unit, University of Parma, 43126, Parma, Italy.

Evaluating the incidence and course of COVID-19 in cancer patients treated with immunotherapy. We reported the influenza-like illness events with diagnosis of COVID-19 within the patient cohort enrolled in the prospective observational multicenter INVIDIa-2 study in the single center of Parma. Among 53 patients, eight experienced influenza-like illness during the influenza season 2019/2020, and three of them had diagnosis of COVID-19. They were males, elderly, with cardiovascular disease. Radiological features of COVID-19 pneumonitis were found in all of three cases, although the pharyngeal swab resulted positive in only two. Two of these three patients died due to respiratory failure. Cancer patients are at high risk of severe events from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
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http://dx.doi.org/10.2217/imt-2020-0211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493722PMC
October 2020

Adjuvant Chemotherapy for Stage II Colon Cancer.

Cancers (Basel) 2020 Sep 10;12(9). Epub 2020 Sep 10.

Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino of Genova, Largo Rosanna Benzi 10, 16132 Genova, Italy.

In stage II colon cancer management, surgery alone has shown a high cure rate (about 80%), and the role of adjuvant chemotherapy is still a matter of debate. Patients with high-risk features (T4, insufficient nodal sampling, grading, etc.) have a poorer prognosis and, usually, adjuvant chemotherapy is recommended. The purpose of the present study is to highlight and discuss what is still unclear and not completely defined from the previous trials regarding risk stratification and therapeutic benefit of adjuvant chemotherapy. With all the limitations of generalizing, we make the effort of trying to quantify the relative contribution of each prognostic factor and the benefit of adjuvant chemotherapy for stage II colon cancer. Finally, we propose a decision algorithm with the aim of summarizing the current evidence and translating it to clinical practice.
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http://dx.doi.org/10.3390/cancers12092584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565376PMC
September 2020

Abscopal effect after hypofractionated radiotherapy in metastatic renal cell carcinoma pretreated with pazopanib.

Immunotherapy 2020 Jul 28. Epub 2020 Jul 28.

Medical Oncology Unit, University Hospital of Parma, Parma, Italy.

The abscopal effect consists of distant metastases response after local treatment based on systemic immune stimulation. It is a rare event observed in many tumors, especially with radiotherapy and immunotherapy. We report the long-term abscopal effect in a metastatic renal cell carcinoma patient with lung metastasectomy, after hypofractionated radiotherapy on lymph node metastasis. The patient was pretreated with pazopanib, which was discontinued early owing to toxicity before radiotherapy. Immunohistological analyses of the primary tumor and metastases were performed. We supposed that radiotherapy, and maybe tyrosine kinase inhibitors, could act as immune-primers for abscopal effect modifying the immune tumor microenvironment. Future studies are needed to optimize the combination of radiotherapy with systemic therapy for better long-term tumor control in selected patients.
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http://dx.doi.org/10.2217/imt-2020-0072DOI Listing
July 2020

EPSILoN: A Prognostic Score Using Clinical and Blood Biomarkers in Advanced Non-Small-cell Lung Cancer Treated With Immunotherapy.

Clin Lung Cancer 2020 07 7;21(4):365-377.e5. Epub 2020 Mar 7.

Medical Thoracic Oncology Unit, Clinical Cancer Center "Giovanni Paolo II", Bari, Italy.

Background: Second-line immunotherapy (IO) has shown an overall survival benefit. However, only 18% to 20% of patients with advanced non-small-cell lung cancer (aNSCLC) will respond, with a median progression-free survival (PFS) of 2 to 4 months. Thus, biomarkers to select those patients most likely to benefit from IO are greatly needed.

Patients And Methods: We conducted a retrospective analysis of 154 patients with aNSCLC who had received anti-programmed cell death 1 therapy as second line or further treatment. We assessed the absolute neutrophil, lymphocyte, monocyte, and eosinophil counts at baseline (T0) and the second (T1) and third (T2) cycles. The neutrophil/lymphocyte ratio (NLR), derived-NLR (dNLR), lymphocyte/monocyte ratio (LMR), and their percentage of change at T1 and T2 compared with T0 were evaluated. The clinical characteristics and lactate dehydrogenase (LDH) level were also considered. Univariate and multivariate analyses were performed. Significant biomarkers for PFS on multivariate analysis were combined in a prognostic score.

Results: For overall survival, the negative prognostic biomarkers were Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, NLR at T0, and dNLR at T1; the LMR at T0, T1, and T2 was identified as a positive prognostic biomarker. For PFS, the negative prognostic biomarkers were ECOG PS 2, liver metastases, NLR at T0, dNLR at T1 and T2, and ≥ 30% increase of NLR from T0 to T1; the positive prognostic biomarkers were heavy smoking, LDH, and LMR at T2. The ≥ 30% increase of LMR from T0 to T1 and T0 to T2 correlated with the overall response rate. A prognostic score (EPSILoN score; smoking, ECOG PS, liver metastases, LDH, NLR) identified 3 prognostic groups (median PFS, 10.2, 4.9, and 1.7 months, respectively; P < .001).

Conclusions: The EPSILoN score combines 5 baseline clinical and blood biomarkers and can help to identify patients with aNSCLC who will most likely benefit from second-line IO. Further studies are warranted.
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http://dx.doi.org/10.1016/j.cllc.2019.11.017DOI Listing
July 2020

Impact of influenza syndrome and flu vaccine on survival of cancer patients during immunotherapy in the INVIDIa study.

Immunotherapy 2020 02;12(2):151-159

Biostatistical Unit, Regina Elena National Cancer Institute, IRCCS, Rome, Italy.

INVIDIa was a retrospective, multicenter study, exploring the clinical efficacy of influenza vaccine in 300 cancer patients undergoing immunotherapy. Overall survival (OS) was immature at the initial report. We reported the final OS analysis from the original study population and within subgroups. Both at the univariate and multivariate analysis, the occurrence of influenza syndrome (IS) was significantly related to better OS in the overall population (OR: 0.53 [95% CI: 0.32-0.88]; p = 0.01). In the lung cancer subgroup, receiving flu vaccine and/or developing IS was related to better OS (p = 0.04). Within elderly patients, the flu vaccine was the main variable for the relative OS advantage (p = 0.05). Receiving the flu vaccine and/or developing IS was related to better OS within the INVIDIa population.
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http://dx.doi.org/10.2217/imt-2019-0180DOI Listing
February 2020

EPSILoN: A Prognostic Score for Immunotherapy in Advanced Non-Small-Cell Lung Cancer: A Validation Cohort.

Cancers (Basel) 2019 12 5;11(12). Epub 2019 Dec 5.

Medical Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy.

Background: Beyond programmed death ligand 1 (PD-L1), no other biomarkers for immunotherapy are used in daily practice. We previously created EPSILoN (Eastern Cooperative Oncology Group performance status (ECOG PS), smoking, liver metastases, lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR)) score, a clinical/biochemical prognostic score, in 154 patients treated with second/further-line immunotherapy. This study's aim was to validate EPSILoN score in a different population group.

Methods: 193 patients were included at National Cancer Institute of Milan (second-line immunotherapy, 61%; further-line immunotherapy, 39%). Clinical/laboratory parameters such as neutrophil-to-lymphocyte ratio and lactate dehydrogenase levels were collected. Kaplan-Meier and Cox hazard methods were used for survival analysis.

Results: Overall median progression-free survival and median overall survival were 2.3 and 7.6 months, respectively. Multivariate analyses for Progression-Free Survival (PFS) identified heavy smokers (hazard ratio (HR) 0.71, = 0.036) and baseline LDH < 400 mg/dL (HR 0.66, = 0.026) as independent positive factors and liver metastases (HR 1.48, = 0.04) and NLR ≥ 4 (HR 1.49, = 0.029) as negative prognostic factors. These five factors were included in the EPSILoN score which was able to stratify patients in three different prognostic groups, high, intermediate and low, with PFS of 6.0, 3.8 and 1.9 months, respectively (HR 1.94, < 0.001); high, intermediate and low prognostic groups had overall survival (OS) of 24.5, 8.9 and 3.4 months, respectively (HR 2.40, < 0.001).

Conclusions: EPSILoN, combining five baseline clinical/blood parameters (ECOG PS, smoking, liver metastases, LDH, NLR), may help to identify advanced non-small-cell lung cancer (aNSCLC) patients who most likely benefit from immune checkpoint inhibitors (ICIs).
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http://dx.doi.org/10.3390/cancers11121954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966664PMC
December 2019

Combination of EGFR-TKIs and chemotherapy in advanced EGFR mutated NSCLC: Review of the literature and future perspectives.

Crit Rev Oncol Hematol 2020 Feb 31;146:102820. Epub 2019 Oct 31.

Medical Oncology, University Hospital of Parma, Via Gramsci 14, 43126, Parma, Italy; Department of Medicine and Surgery, University of Parma, Via Gramsci 14, 43126, Parma, Italy. Electronic address:

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improved clinical outcome compared to chemotherapy in EGFR mutated advanced non-small cell lung cancer (NSCLC) patients. Nonetheless, acquired resistance develops within 10-14 months and 20-30% of EGFR-mutated patients do not respond to EGFR-TKI. In order to delay or overcome acquired resistance to EGFR-TKIs, combination therapies of EGFR-TKIs with chemotherapy has been investigated with conflicting results. Early studies failed to show a survival benefit because of a lack of patient selection, but more recently clinical studies in EGFR mutated patients have shown promising results. This review summarizes preclinical and clinical studies of combination of EGFR-TKIs, including the third-generation TKI osimertinib, with chemotherapy in first- and second-line settings, using concurrent or intercalated treatment strategies. In the new era of third-generation EGFR-TKIs, new studies of this combination strategy are warranted.
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http://dx.doi.org/10.1016/j.critrevonc.2019.102820DOI Listing
February 2020

Prognostic and predictive molecular biomarkers in metastatic renal cell carcinoma patients treated with immune checkpoint inhibitors: a systematic review.

Expert Rev Mol Diagn 2020 02 24;20(2):169-185. Epub 2019 Oct 24.

Medical Oncology Unit, University Hospital of Parma, Parma, Italy.

: In recent years, the treatment landscape of metastatic renal cell carcinoma (mRCC) has been improved using immune-checkpoint inhibitors (ICI). Nevertheless, the number of patients experiencing clinical benefit from immunotherapy is still limited, while others obtain more benefit from tyrosine kinase inhibitors (TKI). The identification of prognostic and predictive factors would be crucial to better select patients most likely to benefit from immunotherapy among the other potentially available therapeutic options.: This systematic review summarizes the current knowledge (2010-2019) on molecular prognostic and predictive biomarkers, assessed in peripheral blood and/or from tumor tissue, in mRCC patients treated with ICI.: Among all the biomarkers analyzed, PD-L1 expression on tumor tissue is the most studied. It has an unfavorable prognostic role for patients treated with TKI, which seems to be overcome by ICI-based combinations. Nevertheless, no clear predictive role of immunotherapy efficacy has been observed for PD-L1 in mRCC. Emerging evidence regarding pro-angiogenic or pro-immunogenic genomic and transcriptomic signatures suggests a potential predictive role in patients treated with ICI-based combinations. The rationale for TKI-ICI combinations is based on tumor microenvironment and genomic background, which represent the target of these two main therapeutic options for mRCC.
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http://dx.doi.org/10.1080/14737159.2019.1680286DOI Listing
February 2020

Multiple systemic treatment options in a patient with malignant tenosynovial giant cell tumour.

Anticancer Drugs 2020 01;31(1):80-84

Medical Oncology 1, Ospedale Policlinico San Martino, University of Genova, Genova.

Tenosynovial giant cell tumour (TGCT) is a group of rare soft tissues neoplasia affecting synovial joints, bursae and tendon sheaths and is classified as localized type or diffuse type. The diffuse type (TGCT-D), also known as 'pigmented villonodular (teno)synovitis' is characterized by local aggressivity, with invasion and destruction of adjacent soft-tissue structures, and high local recurrence rate. Radical surgery remains the standard therapy while adjuvant radiotherapy may help to control local spread. Malignant TGCT is characterized by high rate of local recurrences and distant metastasis. Few cases of malignant TGCT and very few evidences on systemic therapies are described in the literature, so, to date, no systemic treatment is approved for this rare disease. We report the case of a malignant TGCT patient treated with many different systemic therapies, including chemotherapy and tyrosine-kinase inhibitors, and performed a review of the literature on the systemic treatment options of this rare tumour.
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http://dx.doi.org/10.1097/CAD.0000000000000844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903349PMC
January 2020

Advances in the prediction of long-term effectiveness of immune checkpoint blockers for non-small-cell lung cancer.

Immunotherapy 2019 08 19;11(12):993-1003. Epub 2019 Jul 19.

INSERM U981, Gustave Roussy Cancer Campus, Université Paris Saclay, 94800 Villejuif, France.

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http://dx.doi.org/10.2217/imt-2019-0107DOI Listing
August 2019

Cabozantinib-related cardiotoxicity: a prospective analysis in a real-world cohort of metastatic renal cell carcinoma patients.

Br J Clin Pharmacol 2019 06 31;85(6):1283-1289. Epub 2019 Mar 31.

Department of Medical Oncology, Azienda Ospedaliera Universitaria Integrata (AOUI), Verona, Italy.

Aims: Data regarding the cardiac toxicity of cabozantinib lacks. The aim of our study was to assess the risk of cabozantinib-related cardiotoxicity in mRCC patients.

Methods: We performed a multicentre prospective study on mRCC patients treated with cabozantinib between October 2016 and November 2017. Transthoracic echocardiogram and plasma biomarkers assay were assessed at baseline, 3 and 6 months after cabozantinib initiation.

Results: The study population included 22 mRCC patients. At baseline, 9.1% had a reduced left ventricular ejection fraction (LVEF), but none had a left ventricular systolic dysfunction. Patients with baseline reduced LVEF did not show further significant LVEF modification after 3 months. After 6 months, only 1 had an LVEF decline >10% compared to baseline, resulting in LV systolic dysfunction. At baseline, 64.7% and 27.3% of patients had elevated precursor brain natriuretic peptide (proBNP) and high-sensitivity troponin I (hsTnI), respectively. Among patients with basal normal proBNP and hsTnI, none had elevated values at 3 and 6 months. No correlation was found between basal elevated proBNP and basal reduced LVEF (P = .29), and between elevated proBNP and reduced LVEF after 6 months (P = .37). Similarly, we found no correlations between elevated hsTnI and reduced LVEF or elevated proBNP at baseline (P = .47; P = .38), at 3 (P = .059; P = .45) and after 6 months (P = .72; P = 1.0).

Conclusions: This prospective study revealed a modest risk of developing left ventricular systolic dysfunction related to cabozantinib. A lack of correlation between elevated cardiac biomarkers and reduced LVEF at different time-points was detected. Assessments of the cardiac function should be reserved at the occurrence of clinical symptoms.
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http://dx.doi.org/10.1111/bcp.13895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533423PMC
June 2019

The Optimal Duration of Adjuvant Therapy for Stage III Colon Cancer: the European Perspective.

Curr Treat Options Oncol 2019 01 26;20(1). Epub 2019 Jan 26.

Policlinico San Martino IRCCS, Largo R. Benzi 10, 16132, Genoa, Italy.

Opinion Statement: The International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration was created to pool data from different studies worldwide in order to assess whether a shorter duration of adjuvant treatment in colon cancer could maintain the expected benefit while reducing toxicity. The results of the IDEA trials were clinically relevant. They confirmed a two- to sixfold reduction in neurotoxicity for the shorter duration across trials. Overall, the 3-year disease-free survival was very similar: only 0.9% lower for the 3 months group. However, the results were partially unexpected, because they revealed a difference among chemotherapy regimens (CAPOX better than FOLFOX) and risk groups within stage III. The similar outcome between 3 and 6 months of CAPOX coupled with the substantial reduction in toxicity makes us use the CAPOX regimen for 3 months for most stage III patients. An exception to this general rule is the patient with very high risk, i.e., either T4N1b-T4anyN2 or anyTN2b where we use 6 months of CAPOX. Our take from the trial results is also that FOLFOX should never be given for 3 months and preferably not used at all in the adjuvant setting. The conduction of the IDEA enterprise was truly global. The European contribution was major with three fourths of patients enrolled in the four European trials. Herein, we review the results of the "3 versus 6" trials and the literature regarding the interpretation of the collected data in Europe and in the rest of the world.
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http://dx.doi.org/10.1007/s11864-019-0600-2DOI Listing
January 2019

Radium-223 in patients with metastatic castration-resistant prostate cancer: Efficacy and safety in clinical practice.

Oncol Lett 2019 Feb 30;17(2):1467-1476. Epub 2018 Nov 30.

Department of Radiological, Oncological and Anatomo-Pathological Sciences, 'Sapienza' University of Rome, Policlinico Umberto I, I-00161 Rome, Italy.

Radium-223 has improved overall survival (OS) and reduced symptomatic skeletal events (SSE) in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases (ALSYMPCA trial). Our aim was to assess clinical and biochemical factors related to survival, safety and survival outcomes of Radium-223 in a clinical practice setting. We retrospectively analysed 32 mCRPC patients treated with Radium-223, assessing bone scan, pain reduction, alkaline phosphatase (ALP) and prostate-specific antigen (PSA) response (≥30% reduction). At scintigraphic assessment, 41% had partial response with a disease control rate of 91%; 56% had ALP response and 25% had PSA response; 41% had pain reduction with pain control of 72%. Scintigraphic response and stability were correlated with longer median progression-free survival (mPFS) (13 and 12 vs. 6 months; P=0.002) and mOS (16 and 12 vs. 6 months; P=0.003). ALP response was associated with longer mPFS (13 vs. 12 months; P=0.2) and mOS (16 vs. 12 months; P=0.2). PSA response was associated with longer mPFS (13 vs. 12 months; P=0.02), whereas mOS could not be computed. Pain response and stability were associated with survival benefit according to mPFS (13 and 12 vs. 9 months) and mOS (both 16 vs. 12 months) without statistical significance. Baseline ALP <220 UI/l, Eastern Cooperative Oncology Group (ECOG) performance status 0 and absence of previous chemotherapy correlated with statistically significantly longer survival outcomes. Skeletal-related events (SRE) occurred in three patients and median time to first SRE was 9.5 months, mPFS was 12 months and mOS 14 months. G3-G4 toxicities developed in 16% of patients. Our results are in line with those reported in the pivotal trial and in other retrospective studies. In conclusion, Radium-223 was associated with high scintigraphic, biochemical and pain response rates and was tolerated well by most patients. Response to Radium-223 and better baseline factors correlated to longer survival in clinical practice experience as in the clinical trial setting.
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http://dx.doi.org/10.3892/ol.2018.9785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341517PMC
February 2019

Non-conventional fotemustine schedule as second-line treatment in recurrent malignant gliomas: Survival across disease and treatment subgroup analysis and review of the literature.

Mol Clin Oncol 2019 Jan 16;10(1):58-66. Epub 2018 Oct 16.

Department of Radiological, Oncological and Anatomo-Pathological Sciences, 'Sapienza' University of Rome, Policlinico Umberto I, I-00161 Rome, Italy.

Fotemustine (FTM) is a treatment option in recurrent malignant gliomas (MGs) after first-line Stupp treatment. The efficacy and the safety of fractionated FTM schedule proposed by Addeo was analysed in the present study in recurrent MGs patients. A retrospective analysis on 40 recurrent MGs patients and second-line fractionated FTM chemotherapy was performed. Response evaluation was assessed using RANO criteria and safety was assessed using CTCAE v.4.03. Subgroup analyses based on MGMT methylation, resurgery and reirradiation were performed. A review of the literature was also performed. The results revealed 5 partial responses (13%) and 19 stable diseases (47%) with a disease-control rate of 60%. Median progression-free survival (PFS) was 4 months, with a PFS of 33% at 6 months and 13% at 1 year. The median overall survival (OS) was 9 months and OS at 6 months was of 55% and at 1 year of 30%. Methylated patients experienced longer mPFS (6 vs. 3 months; p=0.004) and mOS (10 vs. 4 months; p<0.0001) compared with unmethylated patients. Patients treated with reirradiation experienced longer mPFS (5 vs. 3.5 months; p=0.48) and mOS (10 vs. 5 months; p=0.11). No survival benefit with resurgery was observed. Furthermore, the fractioned schedule was well tolerated, only 15% of patients developed severe myelotoxicities. Considering the present findings, fractionated FTM schedule is an efficient second-line option for MGs associated with an acceptable myelotoxicity profile. Additionally, MGMT methylation is associated with improved survival outcomes. However, this study highlights the requirement for further prospective randomized studies on resurgery and reirradiation.
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http://dx.doi.org/10.3892/mco.2018.1746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313958PMC
January 2019

Multimodal treatment for local recurrent malignant gliomas: Resurgery and/or reirradiation followed by chemotherapy.

Mol Clin Oncol 2019 Jan 16;10(1):49-57. Epub 2018 Oct 16.

Department of Medical Oncology Unit A, Policlinico Umberto I, 'Sapienza' University of Rome, I-00161 Rome, Italy.

The therapeutic management of recurrent malignant gliomas (MGs) is not determined. Therefore, the efficacy of a multimodal approach and a combination systemic therapy was investigated. A retrospective analysis of 26 MGs patients at first relapse treated with multimodal therapy (chemotherapy plus surgery and/or reirradiation) or chemotherapy alone was performed. Second-line chemotherapy consisted of fotemustine (FTM) in combination with bevacizumab (BEV) (cFTM/BEV) or followed by third-line BEV (sFTM/BEV). Subgroup analyses were performed. Multimodal therapy provided a higher overall response rate (ORR) (73 vs. 47%), disease control rate (DCR) (82 vs. 67%), median progression-free survival (mPFS) (11 vs. 7 months; P=0.08) and median overall survival (mOS) (13 vs. 8 months; P=0.04) compared with chemotherapy. Concomitant FTM/BEV resulted in higher ORR (84 vs. 36%), DCR (92 vs. 57%), mPFS (10 vs. 5 months; P=0.22) and mOS (11 vs. 5.2 months; P=0.15) compared with sFTM/BEV. Methylated patients did not experience additional survival benefits with multimodality treatment but had higher mPFS (10 vs 7.1 months; P=0.33) and mOS (11 vs. 8 months; P=0.33) with cFTM/BEV. Unmethylated patients experienced the greatest survival benefit with the multimodal approach (mPFS: 10 vs. 5 months; mOS 11 vs 6 months; both P=0.02) and cFTM/BEV (mPFS: 5 vs. 2 months; mOS 6 vs. 3.2 months; both P=0.01). In conclusion, in recurrent MGs, multimodal therapy and cFTM/BEV provide survival and response benefits. Methylated patients benefit from a cFTM/BEV but not from a multimodal approach. Notably, unmethylated patients had the highest survival benefit with the two strategies.
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http://dx.doi.org/10.3892/mco.2018.1745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313879PMC
January 2019

INfluenza Vaccine Indication During therapy with Immune checkpoint inhibitors: a transversal challenge. The INVIDIa study.

Immunotherapy 2018 10;10(14):1229-1239

Medical Oncology Unit, University Hospital of Parma, Parma, Italy.

Aim: Considering the unmet need for the counseling of cancer patients treated with immune checkpoint inhibitors (CKI) about influenza vaccination, an explorative study was planned to assess flu vaccine efficacy in this population.

Methods: INVIDIa was a retrospective, multicenter study, enrolling consecutive advanced cancer outpatients receiving CKI during the influenza season 2016-2017.

Results: Of 300 patients, 79 received flu vaccine. The incidence of influenza syndrome was 24.1% among vaccinated, versus 11.8% of controls; odds ratio: 2.4; 95% CI: 1.23-4.59; p = 0.009. The clinical ineffectiveness of vaccine was more pronounced among elderly: 37.8% among vaccinated patients, versus 6.1% of unvaccinated, odds ratio: 9.28; 95% CI: 2.77-31.14; p < 0.0001.

Conclusion: Although influenza vaccine may be clinically ineffective in advanced cancer patients receiving CKI, it seems not to negatively impact the efficacy of anticancer therapy.
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http://dx.doi.org/10.2217/imt-2018-0080DOI Listing
October 2018

Immunotherapy beyond progression in advanced renal cell carcinoma: a case report and review of the literature.

Immunotherapy 2018 09;10(13):1123-1132

Medical Oncology Unit 1, Ospedale Policlinico San Martino IST, University of Genova, Largo R. Benzi 10, 16143, Genova, Italy.

Immunotherapy is associated with different response patterns compared with chemotherapy and targeted therapy, including delayed response and stabilization after progression (pseudoprogression). According to new immuno-based response criteria, immunotherapy can be continued after radiological progression when a clinical benefit is observed. We report a case of an advanced renal cell carcinoma patient treated with nivolumab, who developed clinical benefit and delayed radiological response after initial progression. We performed a review of the literature on immunotherapy beyond progression in advanced solid tumors. 12 clinical trials were identified and showed that selected patients have subsequent response and survival benefit receiving immunotherapy beyond progression. Future studies are needed to optimize timing and duration of immunotherapy and to define patient selection criteria for treatment beyond progression.
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http://dx.doi.org/10.2217/imt-2018-0042DOI Listing
September 2018

Therapeutic approach in glioblastoma multiforme with primitive neuroectodermal tumor components: Case report and review of the literature.

Oncol Lett 2018 May 21;15(5):6641-6647. Epub 2018 Feb 21.

Department of Medical Oncology Unit A, Policlinico Umberto I, 'Sapienza' University of Rome, I-00161 Rome, Italy.

Glioblastoma multiforme (GBM) is the most common and aggressive malignant glioma that is treated with first-line therapy, using surgical resection followed by local radiotherapy and concomitant/adjuvant temozolomide (TMZ) treatment. GBM is characterised by a high local recurrence rate and a low response to therapy. Primitive neuroectodermal tumour (PNET) of the brain revealed a low local recurrence rate; however, it also exhibited a high risk of cerebrospinal fluid (CSF) dissemination. PNET is treated with surgery followed by craniospinal irradiation (CSI) and platinum-based chemotherapy in order to prevent CSF dissemination. GBM with PNET-like components (GBM/PNET) is an emerging variant of GBM, characterised by a PNET-like clinical behaviour with an increased risk of CSF dissemination; it also may benefit from platinum-based chemotherapy upfront or following failure of GBM therapy. The results presented regarding the management of GBM/PNET are based on case reports or case series, so a standard therapeutic approach for GBM/PNET is not defined, constituing a challenging diagnostic and therapeutic dilemma. In this report, a case of a recurrent GBM/PNET treated with surgical resection and radiochemotherapy as Stupp protocol, and successive platinum-based chemotherapy due to the development of leptomeningeal dissemintation and an extracranial metastasis, is discussed. A review of the main papers regarding this rare GBM variant and its therapeutic approach are also reported. In conclusion, GBM/PNET should be treated with a multimodal approach including surgery, chemoradiotherapy, and/or the early introduction of CSI and platinum-based chemotherapy upfront or at recurrence.
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http://dx.doi.org/10.3892/ol.2018.8102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5876436PMC
May 2018

Evaluation of the efficacy of cisplatin-etoposide and the role of thoracic radiotherapy and prophylactic cranial irradiation in LCNEC.

ERJ Open Res 2017 Jan 29;3(1). Epub 2017 Mar 29.

Dept of Medical Oncology Unit A, Policlinico Umberto I, "Sapienza" University of Rome, Rome, Italy.

In small-cell lung cancer (SCLC), the role of chemotherapy and radiotherapy is well established. Large-cell neuroendocrine carcinoma (LCNEC) shares several clinicopathological features with SCLC, but its optimal therapy is not defined. We evaluated clinical response and survival outcomes of advanced LCNEC treated in first-line therapy compared with SCLC. 72 patients with stage III-IV LCNEC (n=28) and extensive-stage SCLC (ES-SCLC) (n=44) received cisplatin-etoposide with/without thoracic radiotherapy (TRT) and prophylactic cranial irradiation (PCI). Comparing LCNEC with SCLC, we observed similar response rates (64.2% 59.1%), disease control rates (82.1% 88.6%), progression-free survival (mPFS) (7.4 6.1 months) and overall survival (mOS) (10.4 10.9 months). TRT and PCI in both histologies showed a benefit in mOS (34 7.8 months and 34 8.6 months, both p=0.0001). LCNEC patients receiving TRT showed an improvement in mPFS and mOS (12.5 5 months, p=0.02 and 28.3 5 months, p=0.004), similarly to ES-SCLC. PCI in LCNEC showed an increase in mPFS (20.5 6.4 months, p=0.09) and mOS (33.4 8.6 months, p=0.05), as in ES-SCLC. Advanced LCNEC treated with SCLC first-line therapy has a similar clinical response and survival outcomes to ES-SCLC.
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http://dx.doi.org/10.1183/23120541.00128-2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5370316PMC
January 2017

Neoadjuvant Chemotherapy in Neuroendocrine Bladder Cancer: A Case Report.

Am J Case Rep 2016 Apr 13;17:248-53. Epub 2016 Apr 13.

Department of Medical Oncology Unit A, Umberto I, ''Sapienza'' University of Rome, Rome, Italy.

Background: Small cell carcinoma of the urinary bladder is a rare and aggressive form of bladder cancer that mainly presents at an advanced stage. As a result of its rarity, it has been described in many case reports and reviews but few retrospective and prospective trials, showing there is no standard therapeutic approach. In the literature the best therapeutic strategy for limited disease is the multimodality treatment and most authors have extrapolated treatment algorithms from the therapy recommendations of small cell lung cancer.

Case Report: A 71-year-old male patient was referred to our hospital with gross hematuria and dysuria. Imaging and cystoscopy revealed a vegetative lesion of the bladder wall. A transurethral resection of the bladder was performed. Pathological examination revealed a pT2 high-grade urothelial carcinoma with widespread neuroendocrine differentiation. Multimodal treatment with neoadjuvant platinum-based chemotherapy was performed. A CT scan performed after chemotherapy demonstrated a radiological complete response. The patient underwent radical cystectomy and lymphadenectomy. The histopathological finding of bladder and node specimen confirmed a pathological complete response. A post-surgery CT scan showed no evidence of local or systemic disease. Six months after surgery, the patient is still alive and disease-free.

Conclusions: A standard treatment strategy of small cell cancer of the urinary bladder is not yet well established, but a multimodal treatment of this disease is the best option compared to surgical therapy alone. The authors confirm the use of neoadjuvant chemotherapy in limited disease of small cell carcinoma of the urinary bladder.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831333PMC
http://dx.doi.org/10.12659/ajcr.896989DOI Listing
April 2016