Search

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 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.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.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.

Background: Carboplatin/paclitaxel every 3 weeks is the standard for patients with ovarian cancer, but elderly patients frequently receive modified schedules or single agent chemotherapy to avoid toxicity. A phase II study was conducted to describe tolerability of a weekly schedule of both drugs in elderly patients. Methods: Patients aged ≥70 years with stage IC-IV ovarian cancer, performance status ≤2, were eligible. Treatment was carboplatin (AUC 2) + paclitaxel (60 mg/m2) on days 1, 8, 15 every 4 weeks, up to six cycles. A two-stage design was applied with lack of unacceptable toxicity as primary endpoint; 26 patients were required at the final stage, with at least 23 of them without unacceptable toxicity to conclude for a positive result. Geriatric assessment was performed by activity daily living (ADL) and instrumental ADL (IADL) scales. Results: Twenty-six patients were analysed (median age 77 years, range 70–84). Performance status was 0 in 10 and 1 in 16 patients; 14 patients had two or more comorbidities; 8 and 18 patients had some dependency in ADL or IADL. Twenty-three patients (88.5%) were treated without suffering unacceptable toxicity. Unacceptable toxic events were grade 3 heart rhythm, grade 3 increase of liver transaminases and prolonged haematological toxicity. Grade 1 neuropathy was reported in four cases. Out of 13 patients evaluable by RECIST, 5 partial responses were observed (response rate 38.5%). Two complete responses were observed among six patients with non-target lesions. Eight patients eligible for CA-125 response assessment had a response after six cycles. Median estimated progression-free survival was 13.6 months, and median overall survival was 32.0 months. Conclusions: In a series of elderly ovarian cancer patients, characterized by a high incidence of comorbidities and functional impairment, weekly carboplatin and paclitaxel demonstrated a favourable toxicity profile.

The aim of this study was to compare survival of resected and unresected patients in a large cohort of patients with metastases to the pancreas from renal cell carcinoma (PM-RCC). Data from 16 Italian centers involved in the treatment of metastatic RCC were retrospectively collected. The Kaplan–Meier and log-rank test methods were used to evaluate overall survival (OS). Clinical variables considered were sex, age, concomitant metastasis to other sites, surgical resection of PM-RCC, and time to PM-RCC occurrence. Overall, 103 consecutive patients with radically resected primary tumors were enrolled in the analysis. PM-RCCs were synchronous in only three patients (3 %). In 56 patients (54 %), the pancreas was the only metastatic site, whereas in the other 47 patients, lung (57 %), lymph nodes (28 %), and liver (21 %) were the most common concomitant metastatic sites. Median time for PM-RCC occurrence was 9.6 years (range 0–24 years) after nephrectomy. Surgical resection of PM-RCC was performed in 44 patients (median OS 103 months), while 59 patients were treated with tyrosine kinase inhibitors (TKIs; median OS 86 months) (p = 0.201). At multivariate analysis, Memorial Sloan Kettering Cancer Center risk group was the only independent prognostic factor. None of the other clinical variables, such as age, sex, pancreatic surgery, or the presence of concomitant metastases, were significantly associated with outcome in PM-RCC patients. The presence of PM-RCC is associated with a long survival, and surgical resection does not improve survival in comparison with TKI therapy. However, surgical resection leads to a percentage of disease-free PM-RCC patients.

Background The MITO-2 (Multicentre Italian Trials in Ovarian cancer) study is a randomized phase III trial comparing carboplatin plus paclitaxel to carboplatin plus pegylated liposomal doxorubicin in first-line chemotherapy of patients with ovarian cancer. Due to the paucity of published phase I data on the 3-weekly experimental schedule used, an early safety analysis was planned. Methods Patients with ovarian cancer (stage Ic-IV), aged < 75 years, ECOG performance status ≤ 2, were randomized to carboplatin AUC 5 plus paclitaxel 175 mg/m2, every 3 weeks or to carboplatin AUC 5 plus pegylated liposomal doxorubicin 30 mg/m2, every 3 weeks. Treatment was planned for 6 cycles. Toxicity was coded according to the NCI-CTC version 2.0. Results The pre-planned safety analysis was performed in July 2004. Data from the first 50 patients treated with carboplatin plus pegylated liposomal doxorubicin were evaluated. Median age was 60 years (range 34–75). Forty-three patients (86%) completed 6 cycles. Two thirds of the patients had at least one cycle delayed due to toxicity, but 63% of the cycles were administered on time. In most cases the reason for chemotherapy delay was neutropenia or other hematological toxicity. No delay due to palmar-plantar erythrodysesthesia (PPE) was recorded. No toxic death was recorded. Reported hematological toxicities were: grade (G) 3 anemia 16%, G3/G4 neutropenia 36% and 10% respectively, G3/4 thrombocytopenia 22% and 4% respectively. Non-haematological toxicity was infrequent: pulmonary G1 6%, heart rhythm G1 4%, liver toxicity G1 6%, G2 4% and G3 2%. Complete hair loss was reported in 6% of patients, and G1 neuropathy in 2%. PPE was recorded in 14% of the cases (G1 10%, G2 2%, G3 2%). Conclusion This safety analysis shows that the adopted schedule of carboplatin plus pegylated liposomal doxorubicin given every 3 weeks is feasible as first line treatment in ovarian cancer patients, although 37% of the cycles were delayed due to haematological toxicity. Toxicities that are common with standard combination of carboplatin plus paclitaxel (neurotoxicity and hair loss) are infrequent with this experimental schedule, and skin toxicity appears manageable.

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 anti-neoplastic 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 ug/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/m (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 This multi-institutional retrospective real life study was conducted in 22 Italian Oncology Centers and evaluated the role of Axitinib in second line treatment in not selected mRCC patients. Methods 148 mRCC patients were evaluated. According to Heng score 15.5%, 60.1% and 24.4% of patients were at poor risk, intermediate and favorable risk, respectively. Results PFS, OS, DCR and ORR were 7.14 months, 15.5 months, 70.6% and 16.6%, respectively. The duration of prior sunitinib treatment correlated with a longer significant mPFS, 8.8 vs 6.3 months, respectively. Axitinib therapy was safe, without grade 4 adverse events. The most frequent toxicities of all grades were: fatigue (50%), hypertension (26%), and hypothyroidism (18%). G3 blood pressure elevation significantly correlated with longer mPFS and mOS compared to G1-G2 or no toxicity. Dose titration (DT) to 7 mg and 10 mg bid was feasible in 24% with no statistically significant differences in mPFS and mOS. The sunitinib-axitinib sequence was safe and effective, the mOS was 41.15 months. At multivariate analysis, gender, DCR to axitinib and to previous sunitinib correlated significantly with PFS; whereas DCR to axitinib, nephrectomy and Heng score independently affected overall survival. Conclusions Axitinib was effective and safe in a not selected real life mRCC population. Trial registration INT – Napoli – 11/16 oss. Registered 20 April 2016. http://www.istitutotumori.na.it

Olaparib is the first poly(ADP-ribose) polymerase inhibitor approved as maintenance therapy of recurrent ovarian cancer (OC) patients with a BRCA mutation. To achieve the maximum clinical benefit, adherence to olaparib must be persistent. However, in clinical practice, this is challenged by the frequent suboptimal management of toxicities. In view of the expanding use of olaparib also in Italy, physicians must learn how to adequately and promptly manage drug toxicities not to unnecessarily interrupt or reduce the dose. The experts agreed that nausea,vomiting, anemia, and fatigue are the most frequent events experienced by OC patients on olaparib, and that these toxicities usually develop early during treatment, are mainly of grade 1-2 and transient and can be managed with simple non-pharmacological interventions. By sharing their real-world experiences, the panel prepared, for each toxicity, an algorithm organized by grade and besides the procedures indicated in the local label, included supportive care interventions based also on nutritional and lifestyle modifications and psycho-oncology consultation. Moreover, in view of the tablet entry into the Italian market, the full and reduced dosages of capsules and tablets were compared. This practical guidance is intended to be a tool to support especially less-experienced physicians in the management of these complex patients, with the aim to help preventing the worsening of patients' conditions and the unnecessary interruption/reduction of olaparib dosage, which may jeopardize treatment efficacy.

Axitinib is an oral angiogenesis inhibitor, currently approved for treatment of metastatic renal cell carcinoma (mRCC) after failure of prior treatment with Sunitinib or cytokine. The present study is an Italian Multi-Institutional Retrospective Analysis that evaluated the outcomes of Axitinib, in second-line treatment of mRCC. The medical records of 62 patients treated with Axitinib, were retrospectively reviewed. The Progression Free Survival (PFS), the Overall Survival (OS), the Objective Response Rate (ORR), the Disease Control Rate (DCR), and the safety profile of axitinib and sunitinib–axitinib sequence, were the primary endpoint. The mPFS was 5.83 months (95% CI 3.93–7.73 months). When patients was stratified by Heng score, mPFS was 5.73, 5.83, 10.03 months according to poor, intermediate, and favorable risk group, respectively. The mOS from the start of axitinib was 13.3 months (95% CI 8.6–17.9 months); the observed ORR and DCR were 25 and 71%, respectively. When stratified patients by subgroups defined by duration of prior therapy with Sunitinib (≤ vs. >median duration), there was a statistically significant difference in mPFS with 8.9 (95% CI 4.39–13.40 months) vs. 5.46 months (95% CI 4.04–6.88 months) for patients with a median duration of Sunitinib >13.2 months. DCR and ORR to previous Sunitinib treatment was associated with longer statistically mPFS, 7.23 (95% CI 3.95–10.51 months, p = 0.01) and 8.67 (95% CI 4.0–13.33 months, p = 0.008) vs. 2.97 (95% CI 0.65–5.27 months, p = 0.01) and 2.97 months (95% CI 0.66–5.28 months, p = 0.01), respectively. Overall Axitinib at standard schedule of 5 mg bid, was well-tolerated. The most common adverse events of all grades were fatig (25.6%), hypertension (22.6%), gastro-intestinal disorders (25.9%), and hypothyroidism (16.1%). The sequence Sunitinib–Axitinib was well-tolerated without worsening in side effects, with a median OS of 34.7 months (95% CI 18.4–51.0 months). Our results are consistent with the available literature; this retrospective analysis confirms that Axitinib is effective and safe in routine clinical practice.

The study gives an analysis of the ideal types of «conflict» and «selection» in Max Weber???s interpretive sociology. The author shows that Weber???s sociology distinguishes sharply the conflict from the selection (understood both as «social selection» than as «biological selection»). But the author also highlights the interest of Weber for the actual connection that exists between the two phenomena and that influences the socio-historical processes.

I discuss three passages of Heliodorus' novel Aithiopika in the light of their connections with some classical tragic antecedents. The wording of 8.17.4 is reminiscent of Soph. Oed. Col. 770-774. The allusion to Eur. Hel. 1285-1286 in 8.7.4 recalls not only the form and the content of the Euripidean passage, but also its context. The explicit quotation of Eur. Med. 1317 in 1.8.7 points to the paratragic overtones of the following digression and lays the cornerstone on which Heliodorus builds a whole part of his novel.

La produzione letteraria di Plutarco costituisce un momento importante nel processo di evoluzione della lingua greca nelle due direzioni della koinè e dei rapporti col latino, le quali caratterizzano anche nell???età bizantina la storia del greco. Plutarco si regola con la lingua latina così come fa con la koinè: adegua il lessico e la sintassi, lì dove ritiene necessario, alla contaminazione linguistica che caratterizzava il greco. Di fronte alla necessità di rappresentare ad un pubblico ellenofono un mondo concreto ed astratto a lui estraneo Plutarco ricorre a tutte le risorse linguistiche a sua disposizione, quelle già istituzionalizzate e quelle che gli offre la sua conoscenza della lingua e della società romana. Senza essere un purista contrario ad ogni parola straniera, attento alla corrispondenza degli antichi termini greci con quelli latini, talora forzati nel loro significato originario o coniati da lui stesso; lo storico di Cheronea si apre alle novità, pur conservando una forte aderenza alla lingua ed al mondo ideologico dell???antica Grecia.

In a famous passage of Calgacus??? speech in the Agricola (30.4), Tacitus borrows some expressions from Seneca???s vocabulary, especially from the de clementia and the de beneficiis. Starting from the syntagm mare scrutantur, the main evidence of the paradigmatic rôle Seneca plays in this crucial moment in the narrative of Tacitus??? monograph, the paper focuses on the dense web of texts and auctores ??? mostly belonging to the historiographic genre ??? with which Tacitus founds a dialogue to shape his original representation of the words of an enemy of Rome. Together whith the need to reconsider Seneca???s presence in Tacitus??? Agricola, the analysis carried out in the paper also points out how some verbal and thematic references to Alexander the Great could be interpreted as allusions to Trajan???s propaganda.