Phase II randomized trial comparing metronomic anthracycline-containing chemotherapy versus standard schedule in untreated HER2 negative advanced breast cancer: activity and quality of life results of the GOIM 21003 trial.

BACKGROUND: Optimizing chemotherapy to achieve disease and symptoms control is a noteworthy purpose in advanced breast cancer (ABC). We reported the activity and quality of life of a phase II study, comparing metronomic regimen with standard schedule as first line chemotherapy for ABC. METHODS: Patients with HER2 negative ABC were randomized to non-pegylated liposomal doxorubicin (NPLD, 60 mg/m2 every 3 weeks) and cyclophosphamide (CTX, 600 mg/m2 every 3 weeks) (Arm A) or NPLD (20 mg/m2 day, on day 1, 8 and 15 every 4 weeks) and metronomic daily oral CTX 50 mg (ARM B). Primary end-points were overall response rate (ORR) and quality of life, secondary progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: From August 2012 to December 2017, 121 patients were enrolled, 105 evaluable. Median follow-up was 21.3 months. Most patients had hormone receptor positive. ORR was 43 % in arm A and 50 % in arm B. Median PFS was 8.9 months in arm A and 6,4 months in arm B. There was no difference in OS. Total score was not clinically different between the two arms. Grade 4 neutropenia was observed in 12 patients and 16 patients respectively; alopecia G2 in 41 % (77 %) vs 14 (27 %) in arm A and in arm B respectively. One cardiac toxicity was observed (arm A). CONCLUSIONS: First line metronomic chemotherapy for HER2 negative ABC had similar clinical activity and quite better tolerability than standard schedule and could be considered a further treatment option when chemotherapy is indicated.

APOLLO 11 Project, Consortium in Advanced Lung Cancer Patients Treated With Innovative Therapies: Integration of Real-World Data and Translational Research.

INTRODUCTION: Despite several therapeutic efforts, lung cancer remains a highly lethal disease. Novel therapeutic approaches encompass immune-checkpoint inhibitors, targeted therapeutics and antibody-drug conjugates, with different results. Several studies have been aimed at identifying biomarkers able to predict benefit from these therapies and create a prediction model of response, despite this there is a lack of information to help clinicians in the choice of therapy for lung cancer patients with advanced disease. This is primarily due to the complexity of lung cancer biology, where a single or few biomarkers are not sufficient to provide enough predictive capability to explain biologic differences; other reasons include the paucity of data collected by single studies performed in heterogeneous unmatched cohorts and the methodology of analysis. In fact, classical statistical methods are unable to analyze and integrate the magnitude of information from multiple biological and clinical sources (eg, genomics, transcriptomics, and radiomics). METHODS AND OBJECTIVES: APOLLO11 is an Italian multicentre, observational study involving patients with a diagnosis of advanced lung cancer (NSCLC and SCLC) treated with innovative therapies. Retrospective and prospective collection of multiomic data, such as tissue- (eg, for genomic, transcriptomic analysis) and blood-based biologic material (eg, ctDNA, PBMC), in addition to clinical and radiological data (eg, for radiomic analysis) will be collected. The overall aim of the project is to build a consortium integrating different datasets and a virtual biobank from participating Italian lung cancer centers. To face with the large amount of data provided, AI and ML techniques will be applied will be applied to manage this large dataset in an effort to build an R-Model, integrating retrospective and prospective population-based data. The ultimate goal is to create a tool able to help physicians and patients to make treatment decisions. CONCLUSION: APOLLO11 aims to propose a breakthrough approach in lung cancer research, replacing the old, monocentric viewpoint towards a multicomprehensive, multiomic, multicenter model. Multicenter cancer datasets incorporating common virtual biobank and new methodologic approaches including artificial intelligence, machine learning up to deep learning is the road to the future in oncology launched by this project.

Nine-Week Versus One-Year Trastuzumab for Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: 10-Year Update of the ShortHER Phase III Randomized Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present the final analysis of the phase III noninferiority, randomized ShortHER trial comparing 9 weeks versus 1 year of adjuvant trastuzumab with chemotherapy in patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (BC). Women with HER2+ BC were randomly assigned to anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or 9-week trastuzumab (arm B, short). Here, we report the second coprimary end point overall survival (OS), updated disease-free survival (DFS), and outcomes according to hormone receptor status, age, and nodal status. At a median follow-up of 9 years, 10-year DFS is 77% versus 78% in the long versus short arm, respectively. Ten-year OS is 89% versus 88% in the long versus short arm, respectively. 10-year DFS rates in the long versus short arm according to nodal status are N0 81% versus 85%; N1-3 77% versus 79%; and N4+ 63% versus 53%. Ten-year OS rates in long versus short arm according to nodal status are N0 89% versus 95%%; N1-3 92% versus 89%; and N4+ 84% versus 64%. The updated analysis of the ShortHER trial shows that 1-year trastuzumab is the standard treatment for patients with HER2+ early BC as noninferiority cannot be claimed. However, numerically, the differences for the patients at low or intermediate risk (N0/N1-3) is negligible, while patients with N4+ have a clear benefit with 1-year trastuzumab.

Role of IL-6/STAT3 Axis in Resistance to Cisplatin in Gastric Cancers.

Gastric cancer, the second most common cause of death worldwide, is characterized by poor prognosis and low responsiveness to chemotherapy. Indeed, multidrug resistance, based mainly on cellular and molecular factors, remains one of the most limiting factors of the current approach to gastric cancer (GC) therapy. We employed a comprehensive gene expression analysis through data mining of publicly available databases to assess the role of the signal transducer and activator of transcription 3 (STAT3) in gastric cancer drug efficiency. It has been proposed that gastric cancer cells are less sensitive to these drugs because they develop resistance to these agents through activating alternative signalling pathways responsible for overcoming pharmacological inhibition. Our study evaluated the hypothesis that activating STAT3 signalling in response to cisplatin reduces the reaction to the drug. Consistent with this hypothesis, inhibition of interleukin 6 (IL-6)/STAT3 in combination therapy with cisplatin prevented both STAT3 activation and more lethality than induction by a single agent. The data suggest that the IL-6/STAT3 axis block associated with cisplatin treatment may represent a strategy to overcome resistance.

First-line treatment of metastatic castration-resistant prostate cancer: the real-world Italian cohort of the Prostate Cancer Registry.

BACKGROUND: With the availability of multiple treatment options for metastatic castration-resistant prostate cancer (mCRPC), new real-world data on disease management and drugs' performance are needed. METHODS: We described characteristics, management and clinical outcomes of patients receiving first-line mCRPC treatment within the Italian cohort of the real-world, prospective, international Prostate Cancer Registry. Patients were enrolled consecutively (2013-2016) in 32 Italian sites and followed for 3 years. RESULTS: 238 patients were included: 157 received first-line abiraterone acetate plus prednisone ("abiraterone" thereafter) and 70 first-line docetaxel; 11 patients receiving other treatments were not considered. Compared with docetaxel-treated patients, those receiving abiraterone were significantly older (age ⩾75: 63.7% vs 38.6%), less frequently had a Gleason score >8 (48.2% vs 67.6%, p<0.005) at initial diagnosis, and more frequently an ECOG score ⩾1 (52.7% vs 36.2%, p<0.05) and comorbidities (76.4% vs 57.1%, p<0.05) at baseline; they reported a lower analgesic use (15.3% vs 30%, p<0.005). In the abiraterone group (median follow-up 22.1 months), median time to progression (TTP) and progression-free survival (PFS) were, respectively, 14.4 months (95% confidence interval, CI, 10.6-18.0) and 13.0 months (95% CI, 9.1-16.8); median overall survival (OS) was not reached, and 3-year OS was 59.1%. In the docetaxel treatment group (median follow-up 25.3 months), median TTP, PFS and OS were, respectively, 8.2 months (95% CI, 6.1-10.3), 8.2 months (95% CI, 5.8-10.3) and 33.2 months (95% CI, 19.2-not estimable). CONCLUSION: This investigation provided valuable information on the overall mCRPC treatment pattern and the effectiveness of first-line abiraterone and docetaxel in a population representative of everyday practice.

Addition of Niraparib to Best Supportive Care as Maintenance Treatment in Patients with Advanced Urothelial Carcinoma Whose Disease Did Not Progress After First-line Platinum-based Chemotherapy: The Meet-URO12 Randomized Phase 2 Trial.

BACKGROUND: Platinum-based chemotherapy (PBCT) is the standard first-line treatment for advanced urothelial carcinoma (UC). Potential cross-sensitivity can be hypothesized between platinum drugs and poly-ADP ribose-polymerase (PARP) inhibitors. OBJECTIVE: To compare maintenance treatment with the PARP inhibitor niraparib plus best supportive care (BSC) versus BSC alone in patients with advanced UC without disease progression after first-line PBCT. DESIGN, SETTING, AND PARTICIPANTS: Meet-URO12 is a randomized, multicenter, open-label phase 2 trial. Patients with advanced UC, without disease progression after four to six cycles of PBCT, with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, were enrolled between August 2019 and March 2021. Randomization was stratified by ECOG performance status (0/1) and response to PBCT (objective response/stable disease). INTERVENTION: Patients were randomized (2:1) to experimental arm A (niraparib 300 or 200 mg daily according to body weight and baseline platelets, plus BSC) or control arm B (BSC alone). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was progression-free survival (PFS). The analysis was performed on an intention-to-treat basis. The secondary endpoints reported in this primary analysis are progression-free rate at 6 mo and safety (adverse event rate). RESULTS AND LIMITATIONS: Fifty-eight patients were randomized (39 in arm A and 19 in arm B). The median age was 69 yr, ECOG performance status was 0 in 66% and 1 in 34%; and the best response with chemotherapy was objective response in 55% and stable disease in 45%. The median PFS was 2.1 mo in arm A and 2.4 mo in arm B (hazard ratio 0.92; 95% confidence interval 0.49-1.75, p = 0.81). The 6-mo progression-free rates were 28.2% and 26.3%, respectively. The most common adverse events with niraparib were anemia (50%, grade [G]3 11%), thrombocytopenia (37%, G3-4 16%), neutropenia (21%, G3 5%), fatigue (32%, G3 16%), constipation (32%, G3 3%), mucositis (13%, G3 3%), and nausea (13%, G3 3%). The main limitation of the study is the small sample size: in March 2021, approval of maintenance avelumab for the same setting rendered randomization of patients in the control arm to BSC alone unethical, and accrual was stopped prematurely. CONCLUSIONS: Addition of maintenance niraparib to BSC after first-line PBCT did not demonstrate a significant improvement in PFS in patients with UC. These results do not support the conduction of a phase 3 trial with single agent niraparib in this population. PATIENT SUMMARY: In this trial, we tested the efficacy of niraparib as maintenance treatment in patients affected by advanced urothelial cancer after the completion of first-line chemotherapy. We could not demonstrate a significant improvement in progression-free survival with maintenance niraparib.

Potential Role of Tumor-Derived Exosomes in Non-Small-Cell Lung Cancer in the Era of Immunotherapy.

Lung cancer, of which non-small-cell lung cancer (NSCLC) represents about 80% of all cases, is the second most common cancer diagnosed in the general population and one of the major causes of cancer-related deaths worldwide. Overall, the outcomes of patients with advanced NSCLC are still disappointing despite advances in diagnosis and treatment. In recent years immune-checkpoint inhibitors (ICIs), administered alone or in combination with chemotherapy, have revolutionized the treatment landscape of patients with advanced non-small-cell lung cancer. However, until now, tissue expression of PD-L1 and tumor mutation burden represent the only available biomarkers for NSCLC patients treated with ICIs. A growing body of evidence showed that tumor-derived exosomes (TDEs) have the PD-L1 protein on their surface and that they are involved in angiogenesis, tumor growth, invasion, metastasis and immune escape. This review focused on the potential clinical applications of TDEs in NSCLC, including their possible role as a biomarker for prognosis and disease monitoring in patients undergoing immunotherapy.

Therapeutic management of a symptomatic Kaposi's sarcoma patient with renal failure undergoing haemodialysis: A case report.

Kaposi's sarcoma (KS) is a rare inflammation- based vascular cancer involving the skin. The viral aetiology of KS is the Human Herpesvirus 8. KS may be frequently diagnosed in immunosuppressed kidneytransplanted patients, while is less common in patients with dialysis. It is known that various immunological abnormalities can lead to impaired immune status in uremic patients. It is noteworthy that despite the incidence of KS in patients with renal impairment, only few cases have reported efficacy and safety profile of KS targeting anti-cancer drugs in this kidney disease population. Herein, we report the first case of a symptomatic KS patient with renal disease in haemodialysis and focus on its therapeutic management. We also review the main data available from literature regarding the safety of KS therapy in dialysis patients.

CHIR99021, trough GSK-3ß Targeting, Reduces Epithelioid Sarcoma Cell Proliferation by Activating Mitotic Catastrophe and Autophagy.

Epithelioid sarcoma (ES) is a rare disease representing <1% of soft tissue sarcomas. Current therapies are based on anthracycline alone or in combination with ifosfamide or other cytotoxic drugs. ES is still characterized by a poor prognosis with high rates of recurrence. Indeed, for years, ES survival rates have remained stagnant, suggesting that conventional treatments should be revised and improved. New therapeutic approaches are focused to target the key regulators of signaling pathways, the causative markers of tumor pathophysiology. To this end, we selected, among the drugs to which an ES cell line is highly sensitive, those that target signaling pathways known to be dysregulated in ES. In particular, we found a key role for GSK-3ß, which results in up-regulation in tumor versus normal tissue samples and associated to poor prognosis in sarcoma patients. Following this evidence, we evaluated CHIR99021, a GSK-3 inhibitor, as a potential drug for use in ES therapy. Our data highlight that, in ES cells, CHIR99021 induces cell cycle arrest, mitotic catastrophe (MC) and autophagic response, resulting in reduced cell proliferation. Our results support the potential efficacy of CHIR99021 in ES treatment and encourage further preclinical and clinical studies.

Docetaxel and prednisone with or without enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer: CHEIRON, a randomised phase II trial.

BACKGROUND: Pre-clinical data suggest that docetaxel and enzalutamide interfere with androgen receptor translocation and signalling. The aim of this study is to assess the efficacy of their concurrent administration in the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC). METHODS: In this open-label, randomised, phase II trial, previously untreated mCRPC patients were randomised 1:1 to receive eight 21-d courses of docetaxel 75 mg/m2, oral prednisone 5 mg twice daily and oral enzalutamide 160 mg/d (arm DE), or the same treatment without enzalutamide (arm D). The primary end-point was the percentage of patients without investigator-assessed disease progression 6 months after the first docetaxel administration. RESULTS: The 246 eligible patients were randomly assigned to receive docetaxel, prednisone and enzalutamide (n = 120) or docetaxel and prednisone (n = 126). The 6-month progression rate was 12.5% (95% confidence interval [CI] 8.1-20.6) in arm DE and 27.8% (95% CI 22.8-39.4) in arm D (chi-squared test 10.01; P = 0.002). The most frequent grade III-IV adverse events were fatigue (12.5% in arm DE versus 5.6% in arm D), febrile neutropenia (9.3% versus 4.0%) and neutropenia (7.6% versus 5.6%). CONCLUSIONS: The combination of enzalutamide and docetaxel appears to be more clinically beneficial than docetaxel alone in previously untreated mCRPC patients, although serious adverse events were more frequent. Our findings suggest that first-line treatment with this combination could lead to an additional clinical benefit when prompt and prolonged disease control is simultaneously required. Clearly, these results should be considered cautiously because of the study's phase II design and the absence of an overall survival benefit. TRIAL REGISTRATION NUMBERS: EudraCT 2014-000175-43 - NCT02453009.

Prognostic Role of Circulating Tumor Cells in Metastatic Renal Cell Carcinoma: A Large, Multicenter, Prospective Trial.

BACKGROUND: Circulating tumor cells (CTCs) correlate with adverse prognosis in patients with breast, colorectal, lung, and prostate cancer. Little data are available for renal cell carcinoma (RCC). MATERIALS AND METHODS: We designed a multicenter prospective observational study to assess the correlation between CTC counts and progression-free survival (PFS) in patients with metastatic RCC treated with an antiangiogenic tyrosine kinase inhibitor as a first-line regimen; overall survival (OS) and response were secondary objectives. CTC counts were enumerated by the CellSearch system at four time points: day 0 of treatment, day 28, day 56 and then at progression, or at 12 months in the absence of progression. RESULTS: One hundred ninety-five eligible patients with a median age of 69 years were treated with sunitinib (77.5%) or pazopanib (21%). At baseline, 46.7% of patients had one or more CTCs per milliliter (range, 1 to 263). Thirty patients had at least three CTCs, with a median PFS of 5.8 versus 15 months in the remaining patients (p = .002; hazard ratio [HR], 1.99), independently of the International Metastatic RCC Database Consortium score at multivariate analysis (HR, 1.91; 95% confidence interval [CI], 1.16-3.14). Patients with at least three CTCs had a shorter estimated OS of 13.8 months versus 52.8 months in those with fewer than three CTCs (p = .003; HR, 1.99; multivariate analysis HR, 1.67; 95% CI, 0.95-2.93). Baseline CTC counts did not correlate with response; neither did having CTC sequencing counts greater than or equal to one, two, three, four, or five. CONCLUSION: We provide prospective evidence that the presence of three or more CTCs at baseline is associated with a significantly shorter PFS and OS in patients with metastatic RCC. IMPLICATIONS FOR PRACTICE: This prospective study evaluated whether the presence of circulating tumor cells (CTCs) in the peripheral blood correlates with activity of first-line tyrosine kinase inhibitors in metastatic renal cell carcinoma (RCC). This study demonstrated that almost half of patients with metastatic RCC have at least one CTC in their blood and that those patients with at least three CTCs are at increased risk of early progressive disease and early death due to RCC. Studies incorporating CTC counts in the prognostic algorithms of metastatic RCC are warranted.

A fully automated assay to detect the expression of pan-cytokeratins and of EML4-ALK fusion protein in circulating tumour cells (CTCs) predicts outcome of non-small cell lung cancer (NSCLC) patients.

BACKGROUND: In advanced non-small cell lung cancer (NSCLC) a recent meta-analysis confirms circulating tumour cells (CTCs) as an independent prognostic indicator of progression-free survival (PFS) and overall survival (OS). However, further investigations are necessary to predict and dynamically monitor the therapy in NSCLC patients using CTCs. To this aim, we combined the classical standard assay (SA) with an expanded cytokeratins profile (EA) and quantified the expression of EML4-ALK fusion protein in CTCs. METHODS: The CellSearch (CS) platform-first marked in vitro diagnostic use (IVD) from Food and Drug Administration (FDA), and "gold standard" for quantifying CTCs - detects EpCAM and cytokeratins (CKs) 8, 18, and 19. Since NSCLC shows different CKs profile, we customized the SA, to recognize CK 4, 5, 6, 7, 8, 10, 13, 14, 18, and 19 (EA). Using both assays we designed a prospective, multi-center study, primarily aimed to enumerate CTCs in advanced NSCLC. Secondarily, we developed an integration of the EA to quantify the expression of EML4-ALK fusion protein in CTCs, and correlated them with PFS and OS. RESULTS: EA identified a significantly much more number of CTC-positive patients (115 out of 180) than SA (103 out of 192; Chi-square =4.0179, with 1 degrees of freedom, P=0.04502). Similar to SA, EA levels were still associated with patient' outcomes. Furthermore, the expression of EML4-ALK on CTCs allowed stratifying NSCLC patients according to a statistically significant difference in PFS. CONCLUSIONS: We proposed here two novel automated tests, to characterize the expression of specific molecules on CTCs. We demonstrated that these integrated assays are robust and actionable in prospective clinical studies, and in the future could allow clinicians to improve both choice and length of treatment in individual NSCLC patient.

Novel Epigenetic Eight-Gene Signature Predictive of Poor Prognosis and MSI-Like Phenotype in Human Metastatic Colorectal Carcinomas.

Epigenetics is involved in tumor progression and drug resistance in human colorectal carcinoma (CRC). This study addressed the hypothesis that the DNA methylation profiling may predict the clinical behavior of metastatic CRCs (mCRCs). The global methylation profile of two human mCRC subgroups with significantly different outcome was analyzed and compared with gene expression and methylation data from The Cancer Genome Atlas COlon ADenocarcinoma (TCGA COAD) and the NCBI GENE expression Omnibus repository (GEO) GSE48684 mCRCs datasets to identify a prognostic signature of functionally methylated genes. A novel epigenetic signature of eight hypermethylated genes was characterized that was able to identify mCRCs with poor prognosis, which had a CpG-island methylator phenotype (CIMP)-high and microsatellite instability (MSI)-like phenotype. Interestingly, methylation events were enriched in genes located on the q-arm of chromosomes 13 and 20, two chromosomal regions with gain/loss alterations associated with adenoma-to-carcinoma progression. Finally, the expression of the eight-genes signature and MSI-enriching genes was confirmed in oxaliplatin- and irinotecan-resistant CRC cell lines. These data reveal that the hypermethylation of specific genes may provide prognostic information that is able to identify a subgroup of mCRCs with poor prognosis.

A Vismodegib Experience in Elderly Patients with Basal Cell Carcinoma: Case Reports and Review of the Literature.

Cutaneous basal cell carcinoma (BCC) is the most common type of human tumor, and its incidence rate is increasing worldwide. Up until a few years ago, therapeutic options have been limited for patients with advanced BCC (including metastatic and locally-advanced BCC). Over the last few years, promising systemic therapies have been investigated for the treatment of advanced BCC. In particular, the Hedgehog signaling inhibition has shown remarkable results for this population. Hedgehog inhibitors, represented by vismodegib and sonidegib, have been approved by the Food and Drug Administration and the European Medicines Agency for the treatment of both locally advanced and metastatic BCC, with, generally, a good safety profile. Notwithstanding the late onset of BCC in the global population, associated with life expectancy increase, only a few clinical trials have evaluated the efficacy and safety profile of Hedgehog inhibitors in this complex and neglected population. Herein, we review the major mechanisms implicated in the pathogenesis of BCC focusing on the Hedgehog signaling pathway and its therapeutic role in the elderly population. Finally, we report two case reports of BCC elderly patients in order to demonstrate both efficacy and safety of the Hedgehog inhibitors.

Association between neutropenia and survival to nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer.

Neutropenia is a common side effect associated with nab-paclitaxel gemcitabine (Nab-Gem) therapy. We retrospectively investigated the association between neutropenia induced by first-line Nab-Gem and survival in metastatic pancreatic carcinoma patients. Metastatic pancreatic patients treated with first-line Nab-Gem were included in this retrospective analysis. Neutropenia was categorized using the National Cancer Institute Common Toxicity Criteria scale. Outcome measures were overall survival (OS), progression-free survival (PFS) and response rate. 115 patients were analyzed. Median PFS was 7 months (95% CI 5-8) for patients with grade ≥ 3 neutropenia and 6 months (95% CI 5-6) for patients with grade < 3 neutropenia [p = 0.08; hazard ratio (HR 0.68)]. Median OS was 13 months (95% CI 10-18) for patients with grade ≥ 3 neutropenia and 10 months (95% CI 8-13) for patients with grade < 3 neutropenia (p = 0.04; HR 0.44). In multivariate analysis, the occurrence of grade ≥ 3 neutropenia showed a statistically significant association with OS (HR 0.62; 95% CI 0.09-0.86; p = 0.05). Nab-Gem-induced neutropenia is associated with longer survival in metastatic pancreatic cancer patients.

Impact of COVID-19 outbreak on cancer immunotherapy in Italy: a survey of young oncologists.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has overwhelmed the health systems worldwide. Data regarding the impact of COVID-19 on cancer patients (CPs) undergoing or candidate for immune checkpoint inhibitors (ICIs) are lacking. We depicted the practice and adaptations in the management of patients with solid tumors eligible or receiving ICIs during the COVID-19 pandemic, with a special focus on Campania region. METHODS: This survey (25 questions), promoted by the young section of SCITO (Società Campana di ImmunoTerapia Oncologica) Group, was circulated among Italian young oncologists practicing in regions variously affected by the pandemic: high (group 1), medium (group 2) and low (group 3) prevalence of SARS-CoV-2-positive patients. For Campania region, the physician responders were split into those working in cancer centers (CC), university hospitals (UH) and general hospitals (GH). Percentages of agreement, among High (H) versus Medium (M) and versus Low (L) group for Italy and among CC, UH and GH for Campania region, were compared by using Fisher's exact tests for dichotomous answers and χ2 test for trends relative to the questions with 3 or more options. RESULTS: This is the first Italian study to investigate the COVID-19 impact on cancer immunotherapy, unique in its type and very clear in the results. The COVID-19 pandemic seemed not to affect the standard practice in the prescription and delivery of ICIs in Italy. Telemedicine was widely used. There was high consensus to interrupt immunotherapy in SARS-CoV-2-positive patients and to adopt ICIs with longer schedule interval. The majority of the responders tended not to delay the start of ICIs; there were no changes in supportive treatments, but some of the physicians opted for delaying surgeries (if part of patients' planned treatment approach). The results from responders in Campania did not differ significantly from the national ones. CONCLUSION: Our study highlights the efforts of Italian oncologists to maintain high standards of care for CPs treated with ICIs, regardless the regional prevalence of COVID-19, suggesting the adoption of similar solutions. Research on patients treated with ICIs and experiencing COVID-19 will clarify the safety profile to continue the treatments, thus informing on the most appropriate clinical conducts.

Focus on lung cancer screening.

Poor survival of lung cancer (LC) patients depends on several factors first of all the delay in the diagnosis, considering that the majority of patients have an advanced-stage disease at the time of diagnosis. In this context, use of screening to increase the percentage of early LC detection can play a crucial role. After the preliminary unsatisfactory experiences with chest X-rays and sputum cytology, low dose computed tomography (LDCT) has become the best method for LC screening. In particular, several randomized LDCT screening trials conducted in the last year showed significant reductions in LC mortality in high-risk subjects. This review focuses on both recent advances in LC screening and some open questions.

Targeting Immunometabolism Mediated by CD73 Pathway in EGFR-Mutated Non-small Cell Lung Cancer: A New Hope for Overcoming Immune Resistance.

Despite the relevant antitumor efficacy of immunotherapy in advanced non-small cell lung cancer (NSCLC), the results in patients whose cancer harbors activating epidermal growth factor receptor (EGFR) mutations are disappointing. The biological mechanisms underlying immune escape and both unresponsiveness and resistance to immunotherapy in EGFR-mutant NSCLC patients have been partially investigated. To this regard, lung cancer immune escape largely involves high amounts of adenosine within the tumor milieu with broad immunosuppressive effects. Indeed, besides immune checkpoint receptors and their ligands, other mechanisms inducing immunosuppression and including adenosine produced by ecto-nucleotidases CD39 and CD73 contribute to lung tumorigenesis and progression. Here, we review the clinical results of immune checkpoint inhibitors in EGFR-mutant NSCLC, focusing on the dynamic immune composition of EGFR-mutant tumor microenvironment. The adenosine pathway-mediated dysregulation of energy metabolism in tumor microenvironment is suggested as a potential mechanism involved in the immune escape process. Finally, we report the strong rationale for planning strategies of combination therapy with immune checkpoints blockade and adenosine signaling inhibition to overcome immune escape and immunotherapy resistance in EGFR-mutated NSCLC.

Metronomic oral chemotherapy with cyclophosphamide plus capecitabine combined with trastuzumab (HEX) as first line therapy of HER-2 positive advanced breast cancer: A phase II trial of the Gruppo Oncologico Italia Meridionale (GOIM).

BACKGROUND: The combination of chemotherapy plus anti HER-2 agents is the mainstay of HER-2 positive advanced breast cancer (ABC) therapy. We conducted a phase II trial testing activity and safety of trastuzumab and metronomic capecitabine/cyclophosphamide (HEX) as first-line therapy in HER-2 positive ABC.Methods. Patients at first relapse or with synchronous metastasis were treated with trastuzumab (4 mg/kg, biweekly) plus oral capecitabine (1500 mg/daily) and cyclophosphamide (50 mg/daily). Primary endpoint was objective response rate (ORR), secondary endpoints progression-free survival (PFS), clinical benefit rate (CBR; PR + CR + SD for ≥ 24 weeks) and tolerability. Optimal two-stage design was applied. RESULTS: Sixty patients with measurable ABC, tumors scored as +3 for HER-2 or FISH +, untreated for advanced disease were enrolled. Median age was 62.5 years, visceral metastases were present in most patients (57.9%). Median number of cycles was 16 (range 1-98). ORR was 56.7% (95% CI, 44.1-68.4%), with 5 CR (8.3%) and 29 PR (48.3%). Fifteen patients had SD (25%). The CBR was 78.2%. Nine progressions were observed (15%). Median PFS was 11 months. One year PFS was 47.7%. Median OS was 45.9 months. Worst toxicities were grade 3 hand-foot syndrome in 2 pts (3.3%), grade 3 anaemia in 2 pts (3.3%), grade 2 nausea in 2 pts (3.3%) and grade 3-4 diarrhea in 2 pts (3.3%). Cardiac toxicity grade 1 was reported in 1 pt. CONCLUSIONS: Combination of trastuzumab and metronomic oral chemotherapy has clinical activity. The tolerability was excellent and allowed the prolonged delivery of treatment.