Publications by authors named "Ugo De Giorgi"

250 Publications

The prognostic significance of lactate dehydrogenase levels in seminoma patients with advanced disease: an analysis by the Global Germ Cell Tumor Collaborative Group (G3).

World J Urol 2021 Mar 8. Epub 2021 Mar 8.

Department of Oncology, Hematology and Bone Marrow Transplantation with Division of Pneumology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Purpose: The prognostic significance of lactate dehydrogenase (LDH) in patients with metastatic seminoma is not defined. We investigated the prognostic impact of LDH levels prior to first-line systemic treatment and other clinical characteristics in this subset of patients.

Methods: Files from two registry studies and one single-institution database were analyzed retrospectively. Uni- and multivariate analyses were conducted to identify patient characteristics associated with recurrence free survival (RFS), overall survival (OS), and complete response rate (CRR).

Results: The dataset included 351 metastatic seminoma patients with a median follow-up of 5.36 years. Five-year RFS, OS and CRR were 82%, 89% and 52%, respectively. Explorative analysis revealed a cut-off LDH level of < 2.5 upper limit of normal (ULN) (n = 228) vs. ≥ 2.5 ULN (n = 123) to be associated with a significant difference concerning OS associated with 5-years OS rates of 93% vs. 83% (p = 0.001) which was confirmed in multivariate analysis (HR 2.87; p = 0.004). Furthermore, the cut-off LDH < 2.5 ULN vs. ≥ 2.5 ULN correlated with RFS and CRR associated with a 5-years RFS rate and CRR of 76% vs. 86% (p = 0.012) and 32% vs. 59% (p  ≤  0.001), respectively.

Conclusions: LDH levels correlate with treatment response and survival in metastatic seminoma patients and should be considered for their prognostic stratification.
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http://dx.doi.org/10.1007/s00345-021-03635-3DOI Listing
March 2021

Immunotherapy and Its Development for Gynecological (Ovarian, Endometrial and Cervical) Tumors: From Immune Checkpoint Inhibitors to Chimeric Antigen Receptor (CAR)-T Cell Therapy.

Cancers (Basel) 2021 Feb 17;13(4). Epub 2021 Feb 17.

Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Via P. Maroncelli 40, 47014 Meldola, Italy.

Gynecological tumors are malignancies with both high morbidity and mortality. To date, only a few chemotherapeutic agents have shown efficacy against these cancer types (only ovarian cancer responds to several agents, especially platinum-based combinations). Within this context, the discovery of immune checkpoint inhibitors has led to numerous clinical studies being carried out that have also demonstrated their activity in these cancer types. More recently, following the development of chimeric antigen receptor (CAR)-T cell therapy in hematological malignancies, this strategy was also tested in solid tumors, including gynecological cancers. In this article, we focus on the molecular basis of gynecological tumors that makes them potential candidates for immunotherapy. We also provide an overview of the main immunotherapy studies divided by tumor type and report on CAR technology and the studies currently underway in the area of gynecological malignancies.
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http://dx.doi.org/10.3390/cancers13040840DOI Listing
February 2021

Clinical Outcomes of Metastatic Renal Carcinoma Following Disease Progression to Programmed Death (PD)-1 or PD-L1 Inhibitors (IO): A Meet-URO Group Real World Study (Meet-Uro 7).

Am J Clin Oncol 2021 Mar;44(3):121-125

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.

Objectives: The aim of our study was to collect data about of the outcome of metastatic renal cell carcinoma patients who progressed after immune checkpoint inhibitors in order to enhance data about efficacy and safety of treatment beyond immune-oncology (IO).

Materials And Methods: A total of 162 eligible patients, progressing to IO, were enrolled from 16 Italian referral centers adhering to the Meet-Uro association. Baseline characteristics, outcome data and toxicities were retrospectively collected. Descriptive analysis was made using median values and ranges. Kaplan-Meier method and Mantel-Haenszel log-rank test were performed to compare differences between groups.

Results: A total of 111 patients (68.5%) were treated after IO progression. In all, 51 patients (31.5%) did not receive further treatment for clinical deterioration. Median IO progression free survival (PFS) was 4 months (95% confidence interval [CI]: 3.1-4.8). IO-PFS tends to be longer in patients reporting adverse events (AE) of any grade (5.03 [95% CI: 3.8-6.1] vs. 2.99 [95% CI: 2.4-3.5] months P=0.004). Subsequent therapies included cabozantinib (n=79, 48%), everolimus (n=11, 6.7%), and others (n=21, 12.9%).Median PFS post-IO was 6.5 months (95% CI: 5.1-7.8). Cabozantinib showed longer PFS compared with everolimus (7.6 mo [95% CI: 5.2-10.1] vs. 3.2 mo [95% CI: 1.8-4.5]) (hazard ratio: 0.2; 95% CI: 0.1026-0.7968) and other drugs (4.3 mo [95% CI: 1.3-7.4]) (hazard ratio: 0.6; 95% CI: 0.35-1.23). All grade AE were reported in 83 patients (74%) and G3 to G4 AE in 39 patients (35%). Target therapies post-IO showed median overall survival of 14.7 months (95% CI: 0.3-21.4).

Conclusions: In our real world experience after progression to IO, vascular endotelial groth factor-tyrosine kinase inhibitors, given to patients, proved to be active and safe choices. Cabozantinib was associated with a better outcome in terms of median PFS.
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http://dx.doi.org/10.1097/COC.0000000000000791DOI Listing
March 2021

Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.

N Engl J Med 2021 Feb 13. Epub 2021 Feb 13.

From Memorial Sloan Kettering Cancer Center, New York (R.M.); P. Hertsen Moscow Oncology Research Institute, Moscow (B.A.), the State Institution of Health Care Regional Clinical Oncology Dispensary, Omsk (E.K.), the State Budgetary Health Care Institution Novosibirsk Regional Clinical Oncology Dispensary, Novosibirsk (V.K.), and Prevoljskiy Region Medical Center, Novgorod (A.A.) - all in Russia; Yonsei Cancer Center, Yonsei University Health System (S.Y.R.), Seoul St. Mary's Hospital, Catholic University of Korea (S.-H.H.), and Seoul National University Hospital (M.K.), Seoul, South Korea; San Matteo University Hospital Foundation, Pavia (C.P.), Istituto Nazionale dei Tumori IRCCS, Milan (G.P.), and Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola (U.D.G.) - all in Italy; Kyushu University, Fukuoka (M.E.), and Tokyo Women's Medical University, Tokyo (T.T.) - both in Japan; the Royal Free NHS Trust, London (T.P.), and Eisai, Hatfield (A.D.S.) - both in the United Kingdom; University Hospital Essen, Essen (V.G.), and the University of Tübingen, Tübingen (J.B.) - both in Germany; Texas Oncology, Dallas (T.E.H.); Maimonides Institute for Biomedical Research of Cordoba Hospital Universitario Reina Sofía, Medical Oncology Department, Córdoba (M.J.M.-V.), Hospital Universitario Ramón y Cajal, Madrid (T.A.G.), and Hospital de la Santa Creu i Sant Pau, Barcelona (P.M.) - all in Spain; McMaster University, Hamilton (A.K.), and Western University, London (E.W.) - both in Ontario, Canada; the University of Miami Sylvester Comprehensive Cancer Center, Miami (J.R.M.), and Florida Cancer Specialists, Gainesville (V.P.); ICON Research, South Brisbane, and University of Queensland, St. Lucia, QLD (J.C.G.), Macquarie University, Sydney (H.G.), and Western Health, Melbourne, VIC (S.W.) - all in Australia; Rambam Health Care Campus, Haifa, Israel (A.P.); Palacky University and University Hospital Olomouc, Olomouc, Czech Republic (B.M.); Centre René Gauducheau, Saint Herblain, France (F.R.); the Department of Urology, Medical University of Vienna, Vienna (M.S.); Eisai, Woodcliff Lake (C.E.D., L.D., K.M., D.X.), and Merck, Kenilworth (R.F.P.) - both in New Jersey; and Dana-Farber Cancer Institute, Boston (T.K.C.).

Background: Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear.

Methods: In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated.

Results: A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels.

Conclusions: Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).
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http://dx.doi.org/10.1056/NEJMoa2035716DOI Listing
February 2021

Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial.

Lancet Oncol 2021 02;22(2):267-276

Dipartimento di Ricerca Traslazionale, Istituto Nazionale per lo Studio e la Cura dei Tumori IRCCS Fondazione Pascale, Naples, Italy.

Background: Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug.

Methods: In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB-IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0-2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin-carboplatin, or 15 mg/kg every 21 days combined with gemcitabine-carboplatin or paclitaxel-carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17.

Findings: Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4-9·3) in the standard chemotherapy group and 11·8 months (10·8-12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41-0·65; log-rank p<0·0001). Most common grade 3-4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related.

Interpretation: Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice.

Funding: Hoffmann-La Roche and Associazione Italiana per la Ricerca sul Cancro.
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http://dx.doi.org/10.1016/S1470-2045(20)30637-9DOI Listing
February 2021

Immunosenescence in Testicular Cancer Survivors: Potential Implications of Cancer Therapies and Psychological Distress.

Front Oncol 2020 15;10:564346. Epub 2021 Jan 15.

Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Testicular cancer (TC) is the most frequent solid tumor diagnosed in young adult males. Although it is a curable tumor, it is frequently associated with considerable short-term and long-term morbidity. Both biological and psychological stress experienced during cancer therapy may be responsible for stimulating molecular processes that induce premature aging and deterioration of immune system (immunosenescence) in TC survivors, leading to an increased susceptibility to infections, cancer, and autoimmune diseases. Immunosenescence is a remodeling of immune cell populations with inversion of the CD4:CD8 ratio, accumulation of highly differentiated memory cells, shrinkage of telomeres, shift of T-cell response to Th2 type, and release of pro-inflammatory signals. TC survivors exposed to chemotherapy show features of immunological aging, including an increase in memory T-cells (CD4+ and CD8+) and high expression of the senescence biomarker p16INK4a in CD3+ lymphocytes. However, the plethora of factors involved in the premature aging of TC survivors make the situation more complex if we also take into account the psychological stress and hormonal changes experienced by patients, as well as the high-dose chemotherapy and hematopoietic stem cell transplantation that some individuals may be required to undergo. The relatively young age and the long life expectancy of TC patients bear witness to the importance of improving quality of life and of alleviating long-term side-effects of cancer treatments. Within this context, the present review takes an in-depth look at the molecular mechanisms of immunosenescence, describing experimental evidence of cancer survivor aging and highlighting the interconnected relationship between the many factors modulating the aging of the immune system of TC survivors.
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http://dx.doi.org/10.3389/fonc.2020.564346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844142PMC
January 2021

New Prognostic Biomarkers in Metastatic Castration-Resistant Prostate Cancer.

Cells 2021 Jan 19;10(1). Epub 2021 Jan 19.

Interdisciplinary Group for Translational Research and Clinical Trials, Urological Cancers (GIRT-Uro), Candiolo Cancer Institute, FPO-IRCCS, Candiolo, 10060 Turin, Italy.

Prostate cancer is one of the most frequent cancers in men and is a common cause of cancer-related death. Despite significant progress in the diagnosis and treatment of this tumor, patients who relapse after radical treatments inevitably develop metastatic disease. Patient stratification is therefore key in this type of cancer, and there is an urgent need for prognostic biomarkers that can define patients' risk of cancer-related death. In the last 10 years, multiple prognostic factors have been identified and studied. Here, we review the literature available and discuss the most common aberrant genomic pathways in metastatic castration-resistant prostate cancer shown to have a prognostic relevance in this setting.
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http://dx.doi.org/10.3390/cells10010193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835961PMC
January 2021

Body Mass Index in Patients Treated with Cabozantinib for Advanced Renal Cell Carcinoma: A New Prognostic Factor?

Diagnostics (Basel) 2021 Jan 18;11(1). Epub 2021 Jan 18.

Oncology Unit, Macerata Hospital, Via Santa Lucia 2, 62100 Macerata, Italy.

We analyzed the clinical and pathological features of renal cell carcinoma (RCC) patients treated with cabozantinib stratified by body mass index (BMI). We retrospectively collected data from 16 worldwide centers involved in the treatment of RCC. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan-Meier curves. Cox proportional models were used at univariate and multivariate analyses. We collected data from 224 patients with advanced RCC receiving cabozantinib as second- (113, 5%) or third-line (111, 5%) therapy. The median PFS was significantly higher in patients with BMI ≥ 25 (9.9 vs. 7.6 months, < 0.001). The median OS was higher in the BMI ≥ 25 subgroup (30.7 vs. 11.0 months, = 0.003). As third-line therapy, both median PFS (9.2 months vs. 3.9 months, = 0.029) and OS (39.4 months vs. 11.5 months, = 0.039) were longer in patients with BMI ≥ 25. BMI was a significant predictor for both PFS and OS at multivariate analysis. We showed that a BMI ≥ 25 correlates with longer survival in patients receiving cabozantinib. BMI can be easily assessed and should be included in current prognostic criteria for advanced RCC.
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http://dx.doi.org/10.3390/diagnostics11010138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831923PMC
January 2021

Circulating Androgen Receptor for Prognosis and Treatment Selection in Prostate Cancer.

Eur Urol Oncol 2021 Jan 9. Epub 2021 Jan 9.

UCL Cancer Institute, University College London, London, UK.

Analysis of androgen receptor (AR) status, particularly AR copy number, in plasma DNA is a minimally invasive method with the potential to identify treatment resistance in patients with castration-resistant prostate cancer (CRPC) starting enzalutamide or abiraterone. Patients with elevated plasma AR do not have worse outcomes than patients with normal plasma AR when treated with taxanes. Consequently, circulating AR may improve clinical decision-making between AR-directed therapies versus taxanes and probably also between adapted versus standard taxane regimens. The evidence indicates that circulating AR could have a role in overall CRPC management. Promising clinical implications of plasma AR testing are measurement in earlier stages of prostate cancer, disease monitoring, and within the context of a multiplex biomarker strategy to improve treatment selection for CRPC patients. PATIENT SUMMARY: Measurement of the copy number of androgen receptor genes in plasma is a promising tool for guiding personalised treatment in patients with castration-resistant prostate cancer. However, prospective trials to validate these findings are needed.
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http://dx.doi.org/10.1016/j.euo.2020.12.009DOI Listing
January 2021

Hydroxychloroquine as Prophylaxis for COVID-19: A Review.

Front Pharmacol 2020 3;11:605185. Epub 2020 Dec 3.

Istituto Scientifico Romagnolo per Lo Studio e La Cura Dei Tumori (IRST) IRCCS, Meldola, Italy.

The impact of the COVID-19 pandemic worldwide has led to a desperate search for effective drugs and vaccines. There are still no approved agents for disease prophylaxis. We thus decided to use a drug repositioning strategy to perform a state-of-the-art review of a promising but controversial drug, hydroxychloroquine (HCQ), in an effort to provide an objective, scientific and methodologically correct overview of its potential prophylactic role. The advantage of using known drugs is that their toxicity profile is well known and there are fewer commercial interests (e.g., expired patents), thus allowing the scientific community to be freer of constraints. The main disadvantage is that the economic resources are almost always insufficient to promote large multinational clinical trials. In the present study, we reviewed the literature and available data on the prophylactic use of HCQ. We also took an in-depth look at all the published clinical data on the drug and examined ongoing clinical trials (CTs) from the most important CT repositories to identify a supporting rationale for HCQ prophylactic use. Our search revealed a substantial amount of preclinical data but a lack of clinical data, highlighting the need to further assess the translational impact of data in a clinical setting. We identified 77 CTs using a multiplicity of HCQ schedules, which clearly indicates that we are still far from reaching a standard of care. The majority of the CTs (92%) are randomized and 53% are being conducted in a phase 3 or 2/3 setting. The comparator is placebo or control in 55 (77%) of the randomized studies. Forty-eight (62%) CTs expect to enroll up to 1,000 subjects and 50 (71%) plan to recruit healthcare workers (HCW). With regard to drug schedules, 45 (58.5%) CTs have planned a loading dose, while 18 (23.4%) have not; the loading dose is 800 mg in 19 trials (42.2%), 400 mg in 19 (42.2%), 600 mg in 4 (8.9%) and 1,200 mg in 1 (2.2%). Forty trials include at least one daily schedule, while 19 have at least one weekly schedule. Forty-one (53.2%) will have a treatment duration of more than 30 days. Awaiting further developments that can only derive from the results of these prospective randomized CTs, the take-home message of our review is that a correct methodological approach is the key to understanding whether prophylactic HCQ can really represent an effective strategy in preventing COVID-19.
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http://dx.doi.org/10.3389/fphar.2020.605185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744418PMC
December 2020

The cyclin-dependent kinases pathway as a target for prostate cancer treatment: rationale and future perspectives.

Crit Rev Oncol Hematol 2021 Jan 13;157:103199. Epub 2020 Dec 13.

Department of Medical Oncology, Istituto Scientifico Romagnolo Per Lo Studio Dei Tumori "Dino Amadori" (IRST) IRCCS, Meldola, Italy.

The rapidly expanding scenario of treatment options for patients affected by prostate cancer (PC) is leading to improved outcomes; however, PC still represents one of the most frequent causes of male mortality. Thus, while translational research is trying to unravel the molecular landscape underlying carcinogenesis, disease progression and treatment resistance, several clinical trials are evaluating novel options to further expand therapeutic options. The cyclin-dependent kinases (CDK)-pathway represents a promising therapeutic target for different cancer types; due to the pivotal role of this pathway in the regulation of PC cell cycle, three CDK4/6-inhibitors (abemaciclib, palbociclib and ribociclib) are currently being investigated in several clinical trials. In this paper, we review the current knowledge on CDK-pathway and the mechanism of action of CDK-inhibitors; we discuss the biological rationale for their use in PC and the state of the art of clinical trials focused on the demonstration of their potential role in early or advanced stage, in hormone-sensitive and castration-resistant state. Finally, the potential application of precision oncology for treatment selection in PC is discussed.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103199DOI Listing
January 2021

Treatment of Metastatic Urothelial Carcinoma After Previous Cisplatin-based Chemotherapy for Localized Disease: A Retrospective Comparison of Different Chemotherapy Regimens.

Clin Genitourin Cancer 2020 Nov 12. Epub 2020 Nov 12.

Division of Oncology, Department of Medicine, University of Washington, Seattle Cancer Care Alliance, Seattle, WA. Electronic address:

Background: Optimal chemotherapy for patients who received cisplatin for localized urothelial carcinoma (UC) and develop metastatic disease is unclear. We compared the efficacy of platinum-based (PBC) versus non-platinum-based (NPBC) first-line chemotherapy for metastasis.

Patients And Methods: Data were collected from the Retrospective International Study of Cancers of the Urothelial Tract (RISC), a database of 3024 patients from 28 international academic centers from 2005 to 2012. Patient inclusion criteria included: (1) predominant UC; (2) any primary tumor site; (3) cT2-4, cN0-N2, cM0; (4) prior receipt of perioperative/radiation cisplatin-containing chemotherapy; and (5) receipt of cytotoxic chemotherapy in the first-line metastatic setting. Multivariate Cox proportional hazards models were used to show progression-free survival (PFS) and overall survival (OS) from the first day of chemotherapy for metastatic disease to date of censor.

Results: Eligibility criteria was met by 132 patients (n = 74 PBC; n = 58 NPBC). The median OS was 8.13 months (interquartile range, 4.87-16.64 months) and 8.77 months (interquartile range, 4.01-13.49 months) for PBC and NPBC, respectively. Neither OS (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.64-1.69; P = .87) nor PFS (HR, 0.86; 95% CI, 0.56-1.31; P = .48) differed for PBC versus NPBC. However, for patients who received chemotherapy more than a year after perioperative/radiation chemotherapy, OS was superior for PBC over NPBC (HR, 0.31; 95% CI, 0.10-0.92; P = .03).

Conclusions: There is no significant outcome difference between PBC and NPBC in patients with metastatic UC who previously received cisplatin-based chemotherapy for localized disease. However, if over a year has elapsed, return to PBC is associated with superior OS.
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http://dx.doi.org/10.1016/j.clgc.2020.10.006DOI Listing
November 2020

Ga-PSMA-11 PET/CT-Guided Stereotactic Body Radiation Therapy Retreatment in Prostate Cancer Patients with PSA Failure after Salvage Radiotherapy.

Biomedicines 2020 Nov 25;8(12). Epub 2020 Nov 25.

Department of Radiotherapy, Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.

(1) Purpose: To investigate the role of Ga-PSMA-11 PET/CT in guiding retreatment stereotactic body radiation therapy (SBRT) in prostate cancer (PCa) patients in biochemical recurrence (BCR) after salvage radiotherapy (S-RT). (2) Methods: We retrospectively evaluated PCa patients previously treated with S-RT on the prostate bed and with proven serum prostate antigen (PSA) failure after S-RT. In all patients (pts), Ga-PSMA-11 PET/CT was positive in the prostate bed only and guided retreatment SBRT. All retreatments were performed by applying the same radiotherapy protocol (median dose of 18 Gy/3 fractions; IQR 18-21 Gy). The median follow-up was 27 months (range 4-35 months). (3) Results: 38 consecutive patients were considered in this analysis. The overall median PSA level before RT was 1.10 ng/mL (IQR 0.82-2.59). PSA decreased at 3 and 6 months after treatment, with a median value of 0.60 ng/mL (IQR 0.31-0.96; < 0.001) and 0.51 ng/mL (IQR 0.29-1.17; < 0.001), respectively. Overall, biochemical recurrence-free survival (b-RFS) was 15.0 months (95% CI 13-23). Grade-1 toxicity was reported in 31.6% of patients (12/38). (4) Conclusion: These results confirm that Ga-PSMA-11-PET/CT is able to identify the site of recurrence in patients who have failed S-RT, thus supporting the use of metastases-directed radiotherapy as a safe and effective treatment.
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http://dx.doi.org/10.3390/biomedicines8120536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761444PMC
November 2020

Symptomatic COVID-19 in advanced-cancer patients treated with immune-checkpoint inhibitors: prospective analysis from a multicentre observational trial by FICOG.

Ther Adv Med Oncol 2020 2;12:1758835920968463. Epub 2020 Nov 2.

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

Background: This prospective, multicentre, observational INVIDIa-2 study is investigating the clinical efficacy of influenza vaccination in advanced-cancer patients receiving immune-checkpoint inhibitors (ICIs), enrolled in 82 Italian centres, from October 2019 to January 2020. The primary endpoint was the incidence of influenza-like illness (ILI) until 30 April 2020. All the ILI episodes, laboratory tests, complications, hospitalizations and pneumonitis were recorded. Therefore, the study prospectively recorded all the COVID-19 ILI events.

Patients And Methods: Patients were included in this non-prespecified COVID-19 analysis, if alive on 31 January 2020, when the Italian government declared the national emergency. The prevalence of confirmed COVID-19 cases was detected as ILI episode with laboratory confirmation of SARS-CoV-2. Cases with clinical-radiological diagnosis of COVID-19 (COVID-like ILIs), were also reported.

Results: Out of 1257 enrolled patients, 955 matched the inclusion criteria for this unplanned analysis. From 31 January to 30 April 2020, 66 patients had ILI: 9 of 955 cases were confirmed COVID-19 ILIs, with prevalence of 0.9% [95% confidence interval (CI): 0.3-2.4], a hospitalization rate of 100% and a mortality rate of 77.8%. Including 5 COVID-like ILIs, the overall COVID-19 prevalence was 1.5% (95% CI: 0.5-3.1), with 100% hospitalization and 64% mortality. The presence of elderly, males and comorbidities was significantly higher among patients vaccinated against influenza unvaccinated (0.009, 0.0001, 0.0001). Overall COVID-19 prevalence was 1.2% for vaccinated (six of 482 cases, all confirmed) and 1.7% for unvaccinated (8 of 473, 3 confirmed COVID-19 and 5 COVID-like), 0.52. The difference remained non-significant, considering confirmed COVID-19 only (0.33).

Conclusion: COVID-19 has a meaningful clinical impact on the cancer-patient population receiving ICIs, with high prevalence, hospitalization and an alarming mortality rate among symptomatic cases. Influenza vaccination does not protect from SARS-CoV-2 infection.
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http://dx.doi.org/10.1177/1758835920968463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649863PMC
November 2020

An Italian, multicenter, real-world, retrospective study of first-line pazopanib in unselected metastatic renal-cell carcinoma patients: the 'Pamerit' study.

Jpn J Clin Oncol 2021 Mar;51(3):484-491

Department of Internal Medicine and Therapeutics, University of Pavia, and Division of Translational Oncology, IRCCS Istituti Clinici Scientifici Maugeri, Pavia, Italy.

Objective: Despite the current immunotherapy era, VEGFR inhibitors maintain effectiveness in metastatic renal cell cancer. Real-world data concerning pazopanib are limited. The aim of this study is to add information about efficacy and safety of pazopanib as first-line treatment in metastatic renal cell cancer patients not enrolled into clinical trials.

Methods: Retrospective analysis (the PAMERIT study) of first-line pazopanib in real-world metastatic renal cell cancer patients among 39 Centers in Italy. Outcomes were progression-free survival, overall survival, objective response rate and treatment-related adverse events. Kaplan-Meier curves, log-rank test and multivariable Cox's models were used and adjusted for age, histology, previous renal surgery, International Metastatic RCC Database Consortium score and pazopanib initial dose.

Results: Among 474 patients, 87.3% had clear cell metastatic renal cell cancer histology. Most of them (84.6%) had upfront renal surgery. Median progression-free survival and overall survival were 15.8 and 34.4 months, respectively, significantly correlating with International Metastatic RCC Database Consortium's good prognosis (P < 0.001), ECOG PS 0 (P < 0.001), age (<75 years, P = 0.005), surgery (P < 0.001) and response to pazopanib (P < 0.001). After 3 months of pazopanib, overall disease control rate have been observed in 76.6% patients. Among International Metastatic RCC Database Consortium's favorable group patients, 57/121 (47%) showed complete/partial response. No unexpected AEs emerged.

Conclusions: In this real-world study, metastatic renal cell cancer patients treated with first-line pazopanib reached greater progression-free survival and overall survival than in pivotal studies and had high response rates when belonging to International Metastatic RCC Database Consortium's favorable group, without new toxicities. Pazopanib has been confirmed a valid first-line option for International Metastatic RCC Database Consortium's good prognosis metastatic renal cell cancer patients who cannot be submitted to immunotherapy.
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http://dx.doi.org/10.1093/jjco/hyaa193DOI Listing
March 2021

Activity of Platinum-Based Chemotherapy in Patients With Advanced Prostate Cancer With and Without DNA Repair Gene Aberrations.

JAMA Netw Open 2020 10 1;3(10):e2021692. Epub 2020 Oct 1.

Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.

Importance: DNA repair gene aberrations occur in 20% to 30% of patients with castration-resistant prostate cancer (CRPC), and some of these aberrations have been associated with sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition platinum-based treatments. However, previous trials assessing platinum-based treatments in patients with CRPC have mostly included a biomarker-unselected population; therefore, efficacy in these patients is unknown.

Objective: To characterize the antitumor activity of platinum-based therapies in men with CRPC with or without DNA repair gene alterations.

Design, Setting, And Participants: In this case series, data from 508 patients with CRPC treated with platinum-based therapy were collected from 25 academic centers from 12 countries worldwide. Patients were grouped by status of DNA repair gene aberrations (ie, cohort 1, present; cohort 2, not detected; and cohort 3, not tested). Data were collected from January 1986 to December 2018. Data analysis was performed in 2019, with data closure in April 2019.

Exposure: Treatment with platinum-based compounds either as monotherapy or combination therapy.

Main Outcomes And Measures: The primary end points were as follows: (1) antitumor activity of platinum-based therapy, defined as a decrease in prostate-specific antigen (PSA) level of at least 50% and/or radiological soft tissue response in patients with measurable disease and (2) the association of response with the presence or absence of DNA repair gene aberrations.

Results: A total of 508 men with a median (range) age of 61 (27-88) years were included in this analysis. DNA repair gene aberrations were present in 80 patients (14.7%; cohort 1), absent in 98 (19.3%; cohort 2), and not tested in 330 (65.0%; cohort 3). Of 408 patients who received platinum-based combination therapy, 338 patients (82.8%) received docetaxel, paclitaxel, or etoposide, and 70 (17.2%) received platinum-based combination treatment with another partner. A PSA level decrease of at least 50% was seen in 33 patients (47.1%) in cohort 1 and 26 (36.1%) in cohort 2 (P = .20). In evaluable patients, soft tissue responses were documented in 28 of 58 patients (48.3%) in cohort 1 and 21 of 67 (31.3%) in cohort 2 (P = .07). In the subgroup of 44 patients with BRCA2 gene alterations, PSA level decreases of at least 50% were documented in 23 patients (63.9%) and soft tissue responses in 17 of 34 patients (50.0%) with evaluable disease. In cohort 3, PSA level decreases of at least 50% and soft tissue responses were documented in 81 of 284 patients (28.5%) and 38 of 185 patients (20.5%) with evaluable disease, respectively.

Conclusions And Relevance: In this study, platinum-based treatment was associated with relevant antitumor activity in a biomarker-positive population of patients with advanced prostate cancer with DNA repair gene aberrations. The findings of this study suggest that platinum-based treatment may be considered an option for these patients.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.21692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593810PMC
October 2020

Inflammatory indexes as predictive factors for platinum sensitivity and as prognostic factors in recurrent epithelial ovarian cancer patients: a MITO24 retrospective study.

Sci Rep 2020 10 23;10(1):18190. Epub 2020 Oct 23.

Medical Oncology Department, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Neutrophil-to-lymphocyte ratio (NLR) and systemic inflammatory index (SII) are prognostic factors in epithelial ovarian cancer (EOC). Their predictive value for platinum-sensitivity and their role in recurrent EOC are unknown. A total of 375 EOC patients were retrospectively analyzed. The correlation between baseline NLR and SII, and platinum-free interval (PFI) according to first line bevacizumab treatment were analyzed using logistic regression analyses adjusted for baseline patient characteristics. Subsequently NLR and SII calculated before second line treatment initiation were evaluated to identify a potential correlation with progression-free survival (PFS) and overall survival (OS) in platinum-sensitive and in platinum-resistant population. In multivariate analysis, NLR ≥ 3 is an independent predictive factor for PFI at 6 months in the chemotherapy group (OR = 2.77, 95% CI 1.38-5.56, p = 0.004), not in bevacizumab treated patients. After having adjusted for ECOG performance status, histology, ascites, bevacizumab treatment at second line and BRCA status, NLR ≥ 3 and SII ≥ 730 are significantly associated with worse OS in platinum-sensitive (HR = 2.69, 95% CI 1.60-4.53, p = 0.002; HR = 2.11, 95% CI 1.29-3.43, p = 0.003, respectively), not in platinum-resistant EOC patients. Low NLR is an independent predictive factor for platinum-sensitivity in patients treated without bevacizumab. NLR and SII are prognostic factors in recurrent platinum-sensitive EOC patients.
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http://dx.doi.org/10.1038/s41598-020-75316-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585431PMC
October 2020

Plasma Copy Number Changes and Outcome to Abiraterone and Enzalutamide.

Front Oncol 2020 24;10:567809. Epub 2020 Sep 24.

Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Plasma androgen receptor () copy number (CN) status identifies castration-resistant prostate cancer (CRPC) patients with worse outcome on abiraterone/enzalutamide. However, the impact of CN changes on clinical outcome in CRPC is unknown. Plasma samples from 73 patients treated with abiraterone or enzalutamide were collected at baseline and at the time of progression disease (PD). Droplet digital polymerase chain reaction was used to assess CN status. We showed that 11 patients (15.1%) changed CN status from baseline to PD (9 patients from normal to gain, 2 from gain to normal). Patients changing CN status from normal at baseline to gain at PD had intermediate median overall survival (OS) of 20.5 months (95% CI = 8.0-44.2) between those who remained CN normal from baseline to PD (27.3 months [95% CI = 21.9-34.4]) and those who remained CN gain from baseline to PD (9.1 months [95% CI = 3.8-14.5], < 0.0001). Patients changing CN from normal at baseline to gain at PD had a median progression-free survival (PFS) of 9.2 months (95% CI = 2.0-14.7), patients who remained CN normal had a median PFS of 9.1 months (95% CI = 7.2-10.1), and patients who remained CN gain had a median PFS of 5.4 (95% CI = 3.6-6.5, = 0.0005). Both OS and PFS were not significantly different between patients with CN that changes from normal to gain and patients with stable CN normal. We showed that CRPC patients changing CN status from baseline to progression time point had intermediate OS and we suggested that CN evaluation at baseline could be the most informative for clinical outcome of CRPC patients treated with abiraterone or enzalutamide. Larger prospective studies are warranted.
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http://dx.doi.org/10.3389/fonc.2020.567809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542981PMC
September 2020

Potential Application of Chimeric Antigen Receptor (CAR)-T Cell Therapy in Renal Cell Tumors.

Front Oncol 2020 23;10:565857. Epub 2020 Sep 23.

Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Istituto di Ricovero e Cura a Carattere Scientifico, Meldola, Italy.

Currently, renal cell carcinoma is characterized by encouraging benefits from immunotherapy that have led to significant results in treatment outcome. The approval of nivolumab primarily as second-line monotherapy and, more recently, the approval of new combination therapies as first-line treatment have confirmed the importance of immunotherapy in this type of tumor. In this context, the chimeric antigen receptor (CAR)-T represents a further step forward in the field of immunotherapy. Initially tested on hematological malignancies, this new therapeutic approach is also becoming a topic of great interest for solid tumors. Although the treatment has several advantages over previous T-cell receptor-dependent immunotherapy, it is facing some obstacles in solid tumors such as a hostile tumor microenvironment and on-tumor/off-tumor toxicities. Several strategies are under investigation to overcome these problems, but the approval of CAR-T cell therapy is still some way off. In renal cancer, the significant advantages obtained from immune checkpoint inhibitors represent a good starting point, but the potential nephrological toxicity of CAR-T cell therapy represents an important risk. In this review, we provide the rationale and preliminary results of CAR-T cell therapy in renal cell malignancies.
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http://dx.doi.org/10.3389/fonc.2020.565857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538692PMC
September 2020

Effect of Weekly Paclitaxel With or Without Bevacizumab on Progression-Free Rate Among Patients With Relapsed Ovarian Sex Cord-Stromal Tumors: The ALIENOR/ENGOT-ov7 Randomized Clinical Trial.

JAMA Oncol 2020 Oct 8. Epub 2020 Oct 8.

GINECO and Centre Léon Bérard, Lyon, France.

Importance: To our knowledge, this is the first randomized trial in sex cord-stromal tumors, and it establishes weekly paclitaxel as standard-of-care therapy after platinum-based therapy in this setting.

Objective: To determine the efficacy of weekly paclitaxel with or without bevacizumab as treatment for relapsed sex cord-stromal tumors and evaluate whether the addition of bevacizumab to weekly paclitaxel improves 6-month progression-free rate.

Design, Setting, And Participants: This open-label, academic, international, randomized phase 2 trial (ALIENOR) was conducted at 28 referral centers in France, Germany, Italy, Japan, and Belgium in collaboration with the Rare Tumor committee of the Gynecologic Cancer InterGroup and used an adaptive bayesian design. It included 60 women with sex cord-stromal tumors that had relapsed after at least 1 platinum-based chemotherapy. Enrollment occurred from 2013 to 2016, and the final analysis database lock was on March 27, 2020 (median follow-up, 38.9 months).

Interventions: Participants were randomized to receive either paclitaxel (80 mg/m2, days 1, 8, and 15 every 4 weeks) alone or paclitaxel with bevacizumab (10 mg/kg, every 2 weeks) for 6 cycles followed by maintenance bevacizumab (15 mg/kg, every 3 weeks) for up to 1 year or until progression or unacceptable toxicity. Crossover to bevacizumab was permitted after progression during or following paclitaxel alone.

Main Outcomes And Measures: Six-month progression-free rate.

Results: Sixty patients (predominantly with granulosa cell tumors) were randomized, 32 to receive single-agent paclitaxel (median [interquartile range] age at inclusion, 60 [53-64] years) and 28 to receive paclitaxel-bevacizumab (median [interquartile range] age at inclusion, 55 [47-61] years; 1 did not receive treatment). The estimated 6-month progression-free rate was 71% (95% credible interval, 55%-84%) with paclitaxel alone and 72% (95% credible interval, 55%-87%) with paclitaxel-bevacizumab. The bayesian estimate for the probability that the 6-month progression-free rate distribution was higher with the combination than with paclitaxel alone was 57%, less than the predefined superiority threshold. The objective response rate increased from 25% (95% CI, 12%-43%) to 44% (95% CI, 26%-65%) with the addition of bevacizumab. One patient discontinued combination therapy within 6 months because of toxicity.

Conclusions And Relevance: Weekly paclitaxel is a new option for relapsed sex cord-stromal tumors. In this international randomized clinical trial of patients with relapsed sex cord-stromal tumors unsuitable for surgery, adding bevacizumab to weekly paclitaxel does not improve clinical benefit.

Trial Registration: ClinicalTrials.gov Identifier: NCT01770301.
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http://dx.doi.org/10.1001/jamaoncol.2020.4574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545353PMC
October 2020

Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial.

Lancet Oncol 2020 12 21;21(12):1574-1588. Epub 2020 Sep 21.

Beth Israel Deaconess Medical Center and PSMAR-IMIM Research Lab, Harvard Medical School, Boston, MA, USA.

Background: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma.

Methods: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice-web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24.

Findings: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9-43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4-17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4-15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71-1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1-18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9-14·0) in the chemotherapy group (0·85, 95% CI 0·72-1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (<1%) patient in the chemotherapy group (acute kidney injury).

Interpretation: This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S1470-2045(20)30541-6DOI Listing
December 2020

Plasma Androgen Receptor Copy Number Status at Emergence of Metastatic Castration-Resistant Prostate Cancer: A Pooled Multicohort Analysis.

JCO Precis Oncol 2019 24;3. Epub 2019 Sep 24.

University College London Cancer Institute, London, United Kingdom.

Purpose: Increases in androgen receptor () copy number (CN) can be detected in plasma DNA when patients develop metastatic castration-resistant prostate cancer. We aim to evaluate the association between CN as a continuous variable and clinical outcome.

Patients And Methods: PCR2023 was an international, multi-institution, open-label, phase II study of abiraterone acetate plus prednisolone (AAP) or abiraterone acetate plus dexamethasone that included plasma assessment as a predefined exploratory secondary end point. Plasma CN data (ClinicalTrials.gov identifier: NCT01867710) from this study (n = 133) were pooled with data from the following three other cohorts: cohort A, which was treated with either AAP or enzalutamide (n = 73); the PREMIERE trial (ClinicalTrials.gov identifier: NCT02288936) of biomarkers for enzalutamide (n = 94); and a phase II trial from British Columbia (ClinicalTrials.gov identifier: NCT02125357) that randomly assigned men to either AAP or enzalutamide (n = 201). The primary outcome measures for the biomarker analysis were overall survival and progression-free survival.

Results: Using multivariable fractional polynomials analysis using Cox regression models, a nonlinear relationship between plasma CN and outcome was identified for overall survival, where initially for small incremental gains in CN there was a large added hazard ratio that plateaued at higher CN. The CN cut point associated with the highest local hazard ratio was 1.92. A similar nonlinear association was observed with progression-free survival. In an exploratory analysis of PCR2023, the time from start of long-term androgen-deprivation therapy to start of AAP or abiraterone acetate plus dexamethasone was significantly shorter in patients with plasma CN of 1.92 or greater than patients with plasma CN of less than 1.92 (43 130 weeks, respectively; = .005). This was confirmed in cohort A ( = .003), the PREMIERE cohort ( = .03), and the British Colombia cohort ( = .003).

Conclusion: Patients with metastatic castration-resistant prostate cancer can be dichotomized by a plasma CN cut point of 1.92. Plasma CN value of 1.92 or greater identifies aggressive disease that is poorly responsive to AR targeting and is associated with a prior short response to primary androgen-deprivation therapy.
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http://dx.doi.org/10.1200/PO.19.00123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446348PMC
September 2019

Prognostic Role of Systemic Inflammatory Indexes in Germ Cell Tumors Treated With High-Dose Chemotherapy.

Front Oncol 2020 14;10:1325. Epub 2020 Aug 14.

Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

High-dose chemotherapy (HDCT) has curative potential in relapsed/refractory germ cell tumors (GCT). Due to the complexity of this population and the toxicity of HDCT, we evaluated the association between blood-based systemic inflammatory indexes and the outcome of GCT patients undergoing salvage treatment with HDCT in order to define additional prognostic factors able to orient clinical decision. Baseline characteristics, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and the systemic immune-inflammation index (SII) of 62 patients undergoing HDCT for GCT were retrospectively collected. The aim is to evaluate the correlation between each inflammatory marker (NLR, PLR, and SII) and response to HDCT, overall survival (OS), and progression-free survival (PFS). Using the receiver operating curve to identify the best cutoff values, it was found that patients with GCT with NLR ≥3.3 and SII ≥844,000 had shorter PFS and inferior OS. In the multivariable analysis including inflammatory markers, the International Prognostic Factor Study Group (IPFSG) risk group, age, and previous line of treatment, NLR ≥3.3 and SII ≥844,000 were identified to be independently associated with shorter PFS and OS. Moreover, NLR, PLR, and SII significantly correlate with overall response to HDCT. Associating IPFSG prognostic score to inflammatory markers at baseline of HDCT may improve prognostic information and could help physicians to make more personalized treatment decisions.
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http://dx.doi.org/10.3389/fonc.2020.01325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457022PMC
August 2020

Hyperphosphatemia Secondary to the Selective Fibroblast Growth Factor Receptor 1-3 Inhibitor Infigratinib (BGJ398) Is Associated with Antitumor Efficacy in Fibroblast Growth Factor Receptor 3-altered Advanced/Metastatic Urothelial Carcinoma.

Eur Urol 2020 12 23;78(6):916-924. Epub 2020 Aug 23.

City of Hope Comprehensive Cancer Center, Duarte, CA, USA. Electronic address:

Background: Infigratinib (BGJ398) is a potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor with significant activity in metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations. It can cause hyperphosphatemia due to the "on-target" class effect of FGFR1 inhibition.

Objective: To investigate the relationship between hyperphosphatemia and treatment response in patients with mUC.

Intervention: Oral infigratinib 125 mg/d for 21 d every 28 d.

Design, Setting, And Participants: Data from patients treated with infigratinib in a phase I trial with platinum-refractory mUC and activating FGFR3 alterations were retrospectively analyzed for clinical efficacy in relation to serum hyperphosphatemia. The relationship between plasma infigratinib concentration and phosphorous levels was also assessed.

Outcome Measurements And Statistical Analysis: Clinical outcomes were compared in groups with/without hyperphosphatemia.

Results And Limitations: Of the 67 patients enrolled, 48 (71.6%) had hyperphosphatemia on one or more laboratory tests. Findings in patients with versus without hyperphosphatemia were the following: overall response rate 33.3% (95% confidence interval [CI] 20.4-48.4) versus 5.3% (95% CI 0.1-26.0); disease control rate 75.0% (95% CI 60.4-86.4) versus 36.8% (95% CI 16.3-61.6). This trend was maintained in a 1-mo landmark analysis. Pharmacokinetic/pharmacodynamic analysis showed that serum phosphorus levels and physiologic infigratinib concentrations were correlated positively. Key limitations include retrospective design, lack of comparator, and limited sample size.

Conclusions: This is the first published study to suggest that hyperphosphatemia caused by FGFR inhibitors, such as infigratinib, can be a surrogate biomarker for treatment response. These findings are consistent with other reported observations and will need to be validated further in a larger prospective trial.

Patient Summary: Targeted therapy is a new paradigm in treating bladder cancer. In a study using infigratinib, a drug that targets mutations in a gene called fibroblast growth factor receptor 3 (FGFR3), we found that elevated levels of phosphorous were associated with greater clinical benefit. In the future, these data may help inform treatment strategies.
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http://dx.doi.org/10.1016/j.eururo.2020.08.002DOI Listing
December 2020

Ki67 and PR in Patients Treated with CDK4/6 Inhibitors: A Real-World Experience.

Diagnostics (Basel) 2020 Aug 8;10(8). Epub 2020 Aug 8.

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.

CDK4/6 inhibitors (CDK4/6i) are recommended in patients with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer (ABC). Up to now, no prognostic biomarkers have been identified in this setting. We retrospectively analyzed the expression of progesterone receptor (PR) and Ki67, assessed by immunohistochemistry, in 71 ABC patients treated with CDK4/6i and analyzed the impact of these markers on progression-free survival (PFS). The majority of patients 63/71 (88.7%) received palbociclib, 4 (5.6%) received ribociclib, and 4 (5.6%) received abemaciclib. A higher median value of Ki67 was observed in cases undergoing second-line treatment ( = 0.047), whereas the luminal B subtype was more prevalent ( = 0.005). In the univariate analysis of the first-line setting, luminal A subtype showed a trend towards a correlation with a longer PFS ( = 0.053). A higher continuous Ki67 value led to a significantly shorter PFS. When the interaction between pathological characteristics and line of treatment was considered, luminal B subtype showed a significantly ( = 0.043) worse outcome (Hazard Ratio (HR) 2.84; 1.03-7.82 95% Confidence Interval (CI)). PFS in patients undergoing endocrine therapy plus CDK4/6i was inversely correlated with Ki67 expression but not with PR, suggesting that tumor proliferation has a greater impact on cell cycle inhibitors combined with endocrine therapy than PR expression.
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http://dx.doi.org/10.3390/diagnostics10080573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460222PMC
August 2020

Enzalutamide for the treatment of nonmetastatic castration-resistant prostate cancer.

Expert Opin Pharmacother 2020 Dec 12;21(17):2091-2099. Epub 2020 Aug 12.

Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS , Meldola, Italy.

Introduction: Enzalutamide is the first characterized second-generation nonsteroidal androgen receptor inhibitor (ARi). Its efficacy has been established in several clinical trials evaluating its role in different settings of prostate cancer. Recently, enzalutamide has been approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC).

Areas Covered: In this paper, the authors describe the chemical structure and pharmacologic characteristics of enzalutamide, providing a summary of clinical trials evaluating its efficacy and safety in prostate cancer patients.

Expert Opinion: Enzalutamide adds to the growing arsenal of ARi used in nmCRPC. An improvement in metastasis-free survival was observed with the use of these new treatment options; recently released preliminary data report also an OS benefit. These novel agents are generally well tolerated, but their safety profiles differ slightly. Since head-to-head comparisons between ARi in nmCRPC are lacking, the adverse events profile, as well as drug availability, costs, and considerations on treatment-sequencing, would most likely influence the selection of the individual agent in this setting. Further research is needed to improve treatment selection and clarify many unsolved issues. ARi: nonsteroidal androgen receptor inhibitor; nmCRPC: nonmetastatic castration resistant prostate cancer; ADT: androgen deprivation therapy; OS: overall survival; PSA: prostate specific antigen; FDA: Food and Drug Administration; AR: Androgen Receptor; MFS: metastasis free survival; PSA-DT: PSA doubling time; HR: hazard ratio; CI: confidence interval; AEs: adverse events; mCRPC: metastatic castration resistant prostate cancer; mHSPC: metastatic hormone-sensitive prostate cancer; rPFS: radiographic progression-free survival; OR: odds ratio.
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http://dx.doi.org/10.1080/14656566.2020.1803281DOI Listing
December 2020

Management of Germ Cell Tumors During the Outbreak of the Novel Coronavirus Disease-19 Pandemic: A Survey of International Expertise Centers.

Oncologist 2020 10 18;25(10):e1509-e1515. Epub 2020 Sep 18.

Department of Clinical Medicine and Surgery, University of Naples "Federico II,", Naples, Italy.

Background: The coronavirus disease 2019 (COVID-19) pandemic has become a public health emergency affecting frail populations, including patients with cancer. This poses the question of whether cancer treatments can be postponed or modified without compromising their efficacy, especially for highly curable cancers such as germ cell tumors (GCTs).

Materials And Methods: To depict the state-of-the-art management of GCTs during the COVID-19 pandemic, a survey including 26 questions was circulated by e-mail among the physicians belonging to three cooperative groups: (a) Italian Germ Cell Cancer Group; (b) European Reference Network-Rare Adult Solid Cancers, Domain G3 (rare male genitourinary cancers); and (c) Genitourinary Medical Oncologists of Canada. Percentages of agreement between Italian respondents (I) versus Canadian respondents (C), I versus European respondents (E), and E versus C were compared by using Fisher's exact tests for dichotomous answers and chi square test for trends for the questions with three or more options.

Results: Fifty-three GCT experts responded to the survey: 20 Italian, 6 in other European countries, and 27 from Canada. Telemedicine was broadly used; there was high consensus to interrupt chemotherapy in COVID-19-positive patients (I = 75%, C = 55%, and E = 83.3%) and for use of granulocyte colony-stimulating factor primary prophylaxis for neutropenia (I = 65%, C = 62.9%, and E = 50%). The main differences emerged regarding the management of stage I and stage IIA disease, likely because of cultural and geographical differences.

Conclusion: Our study highlights the common efforts of GCT experts in Europe and Canada to maintain high standards of treatment for patients with GCT with few changes in their management during the COVID-19 pandemic.

Implications For Practice: Despite the chaos, disruptions, and fears fomented by the COVID-19 illness, oncology care teams in Italy, other European countries, and Canada are delivering the enormous promise of curative management strategies for patients with testicular cancer and other germ cell tumors. At the same time, these teams are applying safe and innovative solutions and sharing best practices to minimize frequency and intensity of patient contacts with thinly stretched health care capacity.
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http://dx.doi.org/10.1634/theoncologist.2020-0420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543332PMC
October 2020

High-dose chemotherapy in a patient with coronavirus disease (COVID-19).

Eur J Cancer 2020 09 4;136:130-131. Epub 2020 Jul 4.

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy.

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http://dx.doi.org/10.1016/j.ejca.2020.06.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334969PMC
September 2020