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Background: There is a lack of published data on real-world cabozantinib use in patients with advanced renal cell carcinoma after prior vascular endothelial growth factor (VEGF)-targeted therapy., Methods: CASSIOPE was a real-world, prospective, multicenter, non-interventional postauthorization safety study of cabozantinib in adult patients with advanced renal cell carcinoma in Europe following prior VEGF-targeted treatment (NCT03419572). Endpoints included cabozantinib utilization (dose modifications due to adverse events [AEs; primary endpoint], dose, dose modifications, and treatment duration), safety, effectiveness (progression-free survival [PFS], overall survival [OS], best overall response [BOR]), and healthcare resource utilization., Findings: Full analysis set (FAS)/safety population comprised 679 patients; 433 of these initiated cabozantinib at 60 mg/day (recommended dose) (primary safety population). Median age (FAS) was 67 (range, 29-93) years; most were male (73·0%), had clear-cell histology (85·7%), metastatic disease at cabozantinib initiation (97·8%), and prior nephrectomy (80·3%). In the primary safety population, 77·1% experienced dose modification owing to an AE. In the safety population, the median daily dose was 40·0 (range, 7·8-60·0) mg/day and the median treatment duration was 7·8 (< 0·1-15·2) months. Treatment-emergent and treatment-related AEs were experienced by 95·9% and 90·4% of patients, respectively. Median PFS (FAS) assessed by the local investigator using any method was 8·3 months, and 1-year OS rate was 74%. Approximately one-third of all patients had a BOR of partial response and 6 had a complete response., Interpretation: Second- or later-line cabozantinib was effective and manageable in a real-world setting and had a safety profile consistent with previous studies., Competing Interests: Disclosure MS: Consulting or advisory role—Apogepha, Bristol-Myers Squibb, Eisai, EMD Serono, EUSA Pharma, Exelixis, Ipsen, Merck Sharp & Dohme, Novartis, Oncorena, Pfizer; Speakers’ bureau—Bristol-Myers Squibb, Eisai, EUSA Pharma, Ipsen, Novartis, Pfizer; Travel, accommodations, expenses—Bristol-Myers Squibb, Eisai, EMD Serono, EUSA Pharma, Ipsen, MSD Oncology, Novartis, Pfizer; Honoraria—Astellas Pharma, Bayer, Bristol-Myers Squibb, Incyte, EMD Serono, EUSA Pharma, Exelixis, Ipsen, MDS Oncology, Novartis, Pfizer, Roche; Research funding—Bayer, Bristol-Myers Squibb, Eisai, Exelixis, Novartis, Pfizer, Roche/Genentech. UB: Consulting or advisory role—AAA Novartis, AstraZeneca, Bristol-Myers Squibb, Pfizer; Research funding—Ipsen; Travel, accommodations, expenses—Astellas Pharma, Bayer, Bristol-Myers Squibb, Janssen Oncology, Ipsen, Merck/Pfizer, MSD Oncology; Other relationship—Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen Oncology, Ipsen, Merck/Pfizer, MSD. J-CE: Honoraria—Bristol-Myers Squibb, Ipsen, Pfizer; Consulting or advisory role—Bayer, Pfizer; Travel, accommodations, expenses—Janssen, Pfizer. PhB: Consulting or advisory role—AAA/Endocyte/Novartis, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Gilead Sciences, Ipsen, Janssen-Cilag, Merck KGaA, MSD Oncology, Pfizer; Travel, accommodations, expenses—Bristol-Myers Squibb, Ipsen, Janssen-Cilag, Merck/Pfizer, MSD, Pfizer; Honoraria—Astellas Pharma, Bayer, Bristol-Myers Squibb, Gilead Sciences, Ipsen, Janssen-Cilag, Merck KGaA, MSD, Novartis, Pfizer, Seattle Genetics. PiB: Honoraria—MSD; Consultancy or advisory role—Bristol-Myers Squibb, Ipsen, MSD. ML: Consulting or advisory role—Amgen, AstraZeneca, Bristol-Myers Squibb, Ipsen, MSD, Novartis, Pfizer; Speakers’ bureau—AstraZeneca, Ipsen; Travel, accommodations, expenses—Ipsen, MSD, Pfizer. MR: Consulting or advisory role—AstraZeneca, Bayer Healthcare, Bristol-Myers Squibb, Ipsen Pharma, MSD, Novartis, Pfizer, Roche; Honoraria—AstraZeneca, Bayer Healthcare, Bristol-Myers Squibb, Ipsen Pharma, MSD, Novartis, Pfizer, Roche; Speakers’ bureau—Bayer Healthcare, Bristol-Myers Squibb, EUSA Pharma, Ipsen Pharma, Novartis, Olympus, Pfizer, Roche. CS: Consulting or advisory role—Astellas Pharma, Bristol-Myers Squibb, Eisai, EUSA Pharma, Ipsen, Merck Sharp & Dohme, Pfizer, Roche/Genentech; Speakers’ bureau—Bristol-Myers Squibb, Eisai, Ipsen, Merck Sharp & Dohme, Pfizer, Roche/Genentech; Travel, accommodations, expenses—Bristol-Myers Squibb, Ipsen, Roche; Research funding—AB Science, Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, Exelixis, GlaxoSmithKline, Novartis, Pfizer, Roche/Genentech, Sanofi Aventis GMbH. AG: Nothing to disclose. JB: Consulting or advisory role—Apogepha, Astellas, AstraZeneca, BMS, Eisai, Ipsen, Janssen, Merck Serono, MSD, Pfizer, Roche; Speakers’ bureau—Astellas, BMS, Ipsen, Merck Serono, MSD, Pfizer, Roche, Seagen; Research funding—Astellas, AstraZeneca, BMS, Eisai, Ipsen, MSD, Nektar, Novartis, Pfizer, Roche, Seagen; Travel, accommodations, expenses—Merck. PH: Consulting or advisory role—Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Ipsen, MDS, Pfizer. RDV: Honoraria—AstraZeneca, Bayer, Ipsen, Janssen, MDS, Pfizer; Travel, accommodations, expenses—AAA Novartis. PG: Consulting or advisory role—Astellas, Bristol-Myers Squibb, Ipsen, Merck, MSD, Pfizer, Roche; Speakers’ bureau—Astellas, Bristol-Myers Squibb, Ipsen, Merck, MSD, Pfizer, Roche; Travel, accommodations, expenses—Ipsen, Merck, Pfizer. ML-Q: Consulting or advisory role—Astellas, AstraZeneca, Bayer, MSD, Pfizer; Speakers’ bureau—Astellas, AstraZeneca, BMS, Eisai, Ipsen, MSD, Pfizer; Research funding—AstraZeneca, BMS, Gilead, Ipsen, MSD, Roche; Travel, accommodations, expenses—Ipsen, MSD, Pfizer. PR: Employment—Ipsen. VP: Employment—Ipsen; Stockholder—Ipsen; Travel, accommodations, expenses—Ipsen. BQ: Employment—Ipsen; Stockholder—Ipsen; Honoraria—Ipsen; Travel, accommodations, expenses—Ipsen. PD: Employment—Ipsen. EV: Consulting or advisory role: AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Ipsen, Janssen, Merck Sharp & Dohme, MSD Oncology, Novartis, Pfizer. GP: Consulting or advisory role—Accord, Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, EUSA Pharma, Ipsen, Janssen, Lilly, Merck Sharp & Dohme, MSD Oncology, Novartis, Pfizer, Roche Genentech; Research funding—Astellas Pharma, Gilead, Ipsen, Janssen Oncology, MSD; Travel, accommodations, expenses—AAA/Novartis, Ipsen, Janssen, Recordati., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cisplatin-based chemotherapy is the most recommended treatment for metastatic urothelial cancer (mUC). However, about 50% of patients are considered to be cisplatin ineligible. Anti-programmed cell death protein 1/programmed death-ligand 1 (PD-L1) therapies have, nevertheless, increased the options available to clinicians and are especially valuable for treating these patients. This study therefore tested the activity and safety of avelumab as first-line therapy for mUC., Patients and Methods: Patients with mUC who were ineligible for cisplatin-based chemotherapy were screened centrally for PD-L1 expression and only those with a tumour proportion score ≥ 5% were enrolled in the trial. The primary endpoint was 1-year overall survival (OS), and the secondary endpoints were median OS, median progression-free survival, overall response rate, duration of the response, safety and tolerability. All the survival rates were estimated with the Kaplan-Meier product-limit methodology and compared across groups using the log-rank test., Results: A total of 198 patients were screened, with 71 (35.9%) whose PD-L1 expression was ≥5% enrolled in the study. The median age was 75 years, bladder cancer was the primary tumour in 73.2% of cases and 25.3% had liver metastases. The main reasons for the cisplatin ineligibility were a low rate of creatinine clearance (<60 ml/min), present in 70.4% of patients, and an Eastern Cooperative Oncology Group performance status of 2, which affected 31%. The median OS was 10.0 months (95% confidence interval 5.5-14.5 months) and 43% of patients were alive at 1 year. A complete response was achieved in 8.5% of cases, and 15.5% had a partial response. Adverse any-grade and high-grade events occurred in 49.3% and 8.5% of patients, respectively. A grade 3 infusion reaction was the only high-grade treatment-related adverse event. No treatment-related deaths were reported., Conclusions: This ARIES trial confirmed the activity and safety of avelumab for treating mUC, adding a new therapy option to the armamentarium of checkpoint inhibitors already approved for platinum-ineligible, locally advanced/mUC., Competing Interests: Disclosure RI served as an advisory board member or consultant for Astellas, Pfizer, Janssen, Sanofi, IPSEN, MSD, BMS, Novartis and EISAI; received institutional support for research project from Pfizer and BMS. SB received honoraria as a speaker at scientific events and advisory role by Bristol-Myers Squibb (BMS), Pfizer; MSD, Ipsen, Roche, Eli-Lilly, AstraZeneca and Novartis; he also received research funding from Novartis. CM reported honoraria for advisory boards or speaker fees for Merck Serono, Pfizer, BMS, MSD, Astellas, Ipsen and Janssen. MR acted as a paid consultant and/or speaker for Pfizer, Novartis, MSD, AstraZeneca and BMS. DS reported honoraria for advisory boards for BMS, Janssen, MSD, Merck, EISAI, Bayer, Novartis, Lilly, Astellas and AstraZeneca. GT served as an advisory board member for BMS and Novartis. All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Radium 223 was introduced for metastatic castration-resistant prostate cancer based on the results of a randomized controlled trial showing risk reduction for death and skeletal events. Our aim was to evaluate the outcome of patients receiving radium 223 in a real-world setting., Patients and Methods: We conducted a multicenter retrospective analysis in the Triveneto region of Italy., Results: One hundred fifty-eight patients received radium 223 in our region. After a median follow-up of 9.5 months, 75 patients died. The median overall survival (OS) was 14.2 months, and the median progression-free survival (PFS) was 6.2 months. Seventy-one (45%) patients achieved progression as best response. Thirty-seven (23%) patients stopped the treatment early because of progression. Eastern Cooperative Oncology Group performance status was prognostic for OS (18.4 vs. 12.3 vs. 7.5 months; 0 vs. 1, P = .0062; 0 vs. 2, P = .0002), whereas previous prostatectomy or docetaxel exposure were not. A neutrophil to lymphocytes ratio ≥ 3 significantly impacted OS (18.1 vs. 9.7 months; P < .001) and slightly impacted PFS (6.6 vs. 5.6 months; P = .05). Patients with a baseline alkaline phosphatase (ALP) value ≥ 220 U/L had worse OS and PFS (24.1 vs. 10.5 months; 7.2 vs. 5.5 months; P < .001). Patients with changes in ALP value achieved better OS (P = .029) and PFS (P = .002). There was no difference according to the line of therapy (0 vs. ≥ 1; P = .490). The main grade 3/4 toxicities were anemia, asthenia, and thrombocytopenia., Conclusion: This large real-world report confirms comparable OS and PFS data when compared with the pivotal study, as well as the predictive role of ALP and neutrophil to lymphocytes ratio. The definition of the optimal position of radium 223 in the treatment of metastatic castration-resistant prostate cancer has still to be defined., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Despite the amelioration of systemic therapy, overall survival (OS) of metastatic gastric cancer (GC) patients remains poor. Liver is a common metastatic site and retrospective series suggest a potential OS benefit from hepatectomy, with interesting 5-year (5 y) and 10-year (10 y) OS rates in selected patients. We aim to evaluate the impact of liver resection and related prognostic factors on long-term outcome in this setting., Methods: We searched Pubmed, EMBASE, and Abstracts/posters from international meetings since 1990. Data were extracted from publish papers. Random effects models meta-analyses and meta-regression models were built to assess 5yOS and the impact of different prognostic factor. Heterogeneity was assessed using between study variance, I 2 and Cochran's Q. Funnel plot were used to assess small study bias., Results: Thirty-three observational studies (for a total of 1304 patients) were included. Our analysis demonstrates a 5yOS rate of 22% (95%CI: 18-26%) and 10yOS rate of 11% (95%CI: 7-18%) among patients undergoing radical hepatectomy. A favorable effect on OS was shown by several factors linked to primary cancer (lower T and N stage, no lympho-vascular or serosal invasion) and burden of hepatic disease (≤3 metastases, unilobar involvement, greatest lesion < 5 cm, negative resection margins). Moreover, lower CEA and CA19.9 levels and post-resection chemotherapy were associated with improved OS., Conclusions: Surgical resection of liver metastases from GC seems associated with a significant chance of 5yOS and 10yOS and compares favourably with results of medical treatment alone. Prospective evaluation of this approach and validation of adequate selection criteria are needed., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Actual tolerability of sunitinib is still poorly documented in elderly patients with metastatic renal cell carcinoma (mRCC)., Patients and Methods: Charts of elderly patients treated with sunitinib for mRCC were reviewed in six Italian centers to assess safety (primary objective), efficacy and correlation of toxicity with comprehensive geriatric assessment (CGA) (secondary objectives)., Results: Sixty-eight patients were eligible, and the median age was 74 years. CGA was carried out in 34 patients (41% fit, 41% vulnerable and 18.5% frail). The dose reduction to 37.5 mg was made upfront or soon after the first cycle in 69.1%. More frequent toxic effects were fatigue (80.9%), mucositis (61.8%) and hypertension (58.8%). Cardiac events occurred in nine patients. In 10 patients, therapy was interrupted early due to rapidly progressive disease (10.3%) or severe toxicity (4.4%: 1 cardiac failure, 1 fatigue, 1 febrile neutropenia). At a median follow-up of 27.1 months, the median OS was 18.3 months and the median PFS was 13.6 months. Correlation was not found between frailty at CGA with severe toxicity nor with response., Conclusions: Treatment with sunitinib is effective in elderly patients; yet early interruptions were frequent. Starting treatment at reduced dose and escalating in the absence of severe toxicity could be suggested.

Background: Gemcitabine is active in patients with otherwise resistant or refractory ovarian cancer. As the drug is well tolerated, studies using gemcitabine combined with other antineoplastic agents are needed. The aim of the study was to determine the maximum tolerated dose (MTD) of epirubicin combined with gemcitabine, with and without support of G-CSF., Patients and Methods: Patients with platinum-resistant or refractory ovarian cancer were eligible. Gemcitabine (G) (starting dose 800 mg/m2 day 1 and 8; 200 mg/m2 escalation per level) and epirubicin (E) (starting dose 60 mg/m2 day 1; 15 mg/m2 escalation per level) were given every 21 days for four to six cycles. G-CSF (filgrastim 5 microg/kg/die) was given in case of grade 4 neutropenia (levels without support) or from day 9 up to leukocyte count > 10.000/mm3 after nadir (levels with support). Cohorts of three patients were enrolled at each level, and another three patients were planned, if one dose-limiting toxicity (DLT) was registered. MTD was determined first without and then with G-CSF., Results: Four levels were studied (G 800 + E 60; G 1000 + E 60; G 1000 + E 75; G 1000 + E 75 + G-CSF) with four, four, three and three patients enrolled, respectively. DLT (grade 4 febrile neutropenia) was observed in two patients at level 3. Thus, G1000 + E 60 mg/m2 was the MTD without G-CSF. The addition of prophylactic G-CSF did not allow a further increase of the dose and grade 4 thrombocytopenia was the DLT at level 4. Non-hematological toxicity was mild. Grade 2 mucositis was reported in four patients. Among the 13 patients with measurable or evaluable disease, 3 partial responses were observed for an overall response rate of 23.1%., Conclusions: The combination of gemcitabine 1000 mg/m2 (day 1, 8) and epirubicin at 60 mg/m2 (day 1) is a feasible therapy. Grade 4 neutropenia is frequent and G-CSF support is often required. With prophylactic support of G-CSF, the DLT is thrombocytopenia.

Background: Cisplatin and paclitaxel are active in cervical cancer and both are able to potentiate the effects of radiotherapy. In this study we evaluated the maximum-tolerated dose (MTD) of paclitaxel in combination with a fixed dose of cisplatin when given weekly concurrently with pelvic radiotherapy to patients with carcinoma of the cervix uteri., Patients and Methods: Eighteen patients with cervical cancer were enrolled in this study. Cisplatin (30 mg/m2) and paclitaxel (starting dose 40 mg/m2; 5 mg/m2 escalation per level) were given on day 1 of radiotherapy and then weekly for six times. Radiotherapy was given to the pelvis with a four-field box technique for five days each week. Patients received 65 Gy in 1.8 Gy fractions. Cohorts of three patients were enrolled at each level and three further patients were included if one or two dose-limiting severe adverse events (SAE) were recorded. SAE was defined as grade 3 or 4 nonhematologic toxicity, excluding nausea or vomiting and alopecia, grade 4 neutropenia or thrombocytopenia, and prolonged (> 1 week) neutropenia or thrombocytopenia., Results: Four levels were studied (paclitaxel 40, 45, 50, 55 mg/m2) with three, five, four and six patients enrolled, respectively. The MTD of paclitaxel was found at 50 mg/m2/wk and cisplatin 30 mg/m2/wk. Diarrhea was the dose-limiting toxicity. Thirteen patients were evaluable for response: seven complete and five partial responses were obtained with an overall response rate of 92.3%., Conclusions: The MTD of paclitaxel is 50 mg/m2/wk when associated to cisplatin 30 mg/m2/wk and concurrent pelvic radiotherapy. Diarrhea is the dose limiting side effect. Preliminary data suggest that concurrent chemoradiotherapy with paclitaxel and cisplatin could be a very active treatment for patients with locally advanced carcinoma of the cervix.