Search

Randomised controlled trials (RCTs) with systemic therapies for patients with pre-treated mesothelioma have reported equivocal efficacy results and generated a degree of clinical uncertainty about the choice of active treatment in this poor prognosis malignancy.To compare the effectiveness and safety and weigh the benefit of different systemic treatments in patients with pre-treated mesothelioma by systematic review, meta-analysis and network meta-analysis of RCTs. Full-text articles and abstracts were searched on PubMed, EMBASE, Cochrane Library and oncology conferences proceedings from 2005 through November 2021 for phase 2 and 3 RCTs. The protocol was submitted to the PROSPERO registry. Reporting followed the PRISMA guideline. Outcomes of interest were overall survival (OS) and progression-free (PFS), grade ≥3 treatment-related (Tr) adverse events (AEs), Tr-deaths and Tr-AEs leading to treatment discontinuation.Nine trials at low risk of bias by Cochrane Collaboration's methodology were included, encompassing 2789 patients. Five studies showed PFS benefit in the experimental treatment. In two studies, OS was prolonged by immunotherapy (versus placebo) or by adding an antiangiogenic agent to chemotherapy. Reported Tr-AE were lower with single-agent anti-PD1 compared with chemotherapy or placebo. The meta-analysis revealed a beneficial global effect on OS and PFS from experimental treatments (HR 0.86, 95% CI 0.77-0.96, p = 0.0083 and HR 0.79, 95% CI 0.72-0.86, p 0.001), that for the PFS significantly favoured the comparison with non-active treatments (HR 0.73, 95% CI 0.66-0.81, p 0.001). Younger patients (i.e. 65-70 years) appeared to benefit the most in OS (HR 0.71, 95% CI 0.55-0.92, p = 0.04). The risk of serious Tr-AEs and Tr-deaths was not significantly increased by experimental treatments (RR 1.38, 95% CI 0.81-2.35, p = 0.24 and RR 2.07, 95% CI 0.69-6.24, p = 0.19, respectively) that instead increased TrAEs leading to treatment discontinuation (RR 2.9, 95% CI 1.44-6.08, p = 0.003). The network meta-analysis did not identify any superior treatment in PFS.For patients with pre-treated MPM, single-agent anti-PD1 or chemotherapy ± the antiangiogenic agent can be considered active and safe systemic therapeutic options, particularly for younger patients.

Purpose: Knowledge of prognostic factors for advanced non-small-cell lung cancer (NSCLC) patients eligible for second-line treatment is scarce. The aim of this study was to assess the prognostic role of a number of routinely collected clinical variables and to provide a summary index to discriminate patients according to probability of survival.Methods: individual data from nine randomised trials of second-line treatment in advanced NSCLC were analysed. Primary end-point was overall survival (OS). Cox model, stratified by trial, was used for multivariate analyses, and a prognostic index was provided and validated according to an internal/external procedure.Results: Out of 1239 patients, 1197 patients (97%) had complete information. Median OS was 7.4 months. At multivariate analysis, prognosis was significantly influenced by gender (worse in males), performance status (PS), tumour histology (worse in squamous and other histology versus adenocarcinoma), stage (worse in IV versus IIIB), type of previous treatment (worse for patients pretreated with platinum) and response to first-line (worse for patients not obtaining objective response). Prognostic score values ranges from 0 to 14. When three categories were derived, median overall survival values were equal to 11.6, 7.5 and 3.0 months for best (9) category, respectively.Conclusion: Prognosis of patients eligible for second-line treatment of advanced NSCLC is significantly conditioned by gender, PS, histology, stage, previous use of platinum and response to first-line. A prognostic score was derived that discriminates well subjects with a relatively more favourable prognosis and those with very short life expectancy. (C) 2009 Elsevier Ltd. All rights reserved.

Various reports have documented the efficacy of the combination of etoposide, doxorubicin and cisplatin (EAP) in the treatment of advanced gastric cancer, although other studies have not confirmed such results. This multicentre phase II study was designed to try to define the efficacy and tolerability of the original EAP regimen. From January 1990 to May 1992, 96 patients with locally advanced or metastatic gastric cancer were treated every 3 weeks with etoposide (120 mg/m2) on days 4, 5 and 6, doxorubicin (20 mg/m2) on days 1 and 7, and cisplatin (40 mg/m2) on days 2 and 8. All of the patients had measurable lesions, and were to receive a maximum of six cycles. A total of 416 courses was given (median four/patient), 27% with a delay of > or = 2 weeks. Objective responses were achieved in 34 of the 91 evaluable patients (37%: confidence interval 27-47%), with complete response (CR) in 11 (12%) and partial response (PR) in 23 (25%). The median duration of response was 6 months (range 1-19), and the median survival of the 96 eligible patients was 9 months. Side-effects (WHO grade 3-4) were leucopenia (30%), thrombocytopenia (9%) and mucositis (10%). We conclude that the EAP regimen is active in inducing major objective responses (12% of CR), and that treatment is feasible in patients with good performance status.

IN THE MANAGEMENT of thyroid carcinoma, doxorubicin alone, or in combination with cisplatin , is considered the most active regimen, although it gives unsatisfactory response rates with significant side-effects [1-3]. Epirubicin is endowed with a spectrum of activity similar to doxorubicin and an equivalent response rate with less cardiotoxicity and acute myelosuppres­ sion [4, 5]. Carboplatin produces less nephrolOxicity, neurotox­ icity and vomiting than cisplatin [6 , 7]. In an attempt lO identify a well tolerated regimen which does not affect patients' quality of life, the association of epirubicin 75 mg/m2 given by i.v. (intravenous) bolus on day l, and carboplatin 100 mg/m2 by 30 min infusion on days 1-3, repeated every 28 days, was proposed as fust-line chemotherapy to pati­ ents aged ,,; 70 years, ECOG perfonnance status ,,; 2, affected by histologically proven thyroid carcinoma (except medullary) not suitable for surgery or radioactive iodine . Eight cycles were planned except for the cases showing progressive disease. Response and toxicity were evaluated according to WHO-UICC criteria [8] . 20 patients entered the study: all were suitable for the evalu­ ation of response and toxicity. lO patients were male and lO female, the median age was 64 years (range 35-70), ECOG perfonnance status was O in 8 patients and l in 12. Sites of disease were thyroid (8 patients), local relapse (7), regional nodes (12), distant nodes (3), lung (12) and bone (1 ). 12 patients were pretreated with locoregional surgery, 5 with radioactive iodine and 2 with radiotherapy. A total of 83 cycles of chemotherapy have been delivered, with a median of four cycles per patient (range 1-8). Treatment was well lOlerated. No cases of grade 4 toxicity occurred; grade 3 anaemia occurred in 15% of patients, leucopenia was observed 'in 5% and nausea/vomiting in 5%. Alopecia was complete in 7 patients . 2 male patients achieved complete responses both lasting 12+ months: they were 70 years old with disease limited to the regional nodes, and in one case, local relapse . In these cases, the time to the best response was 5 and 3 months, respectively. One patient achieved a partial response lasting 4 months; 7 patients had stable disease for a median duration of 9 months (range

To evaluate the possibility that a low modulating dose of IFN can enhance the anti-tumor effect of FA-FU combination therapy, patients (pts) with ACC were randomized to receive either FA (I-isomer form) 100 mg/m 2 iv just before FU 375 mg/m 2 iv for five consecutive days alone (A), or with IFN-alpha2b 3 MU for seven consecutive days, starting two days before FA-FU administration (B). Both regimens were repeated every three weeks. Two hundred-three pts were entered in the study. Actually, 156 (79 arm A, and 77 arm B) are evaluable for response, and 23 are early to evaluate. The main characteristics of the evaluable pts were: sex (M/F): A:48/31. B:46/31; median age (A/B): 64/62 yrs; primary tumor site (colon/rectum): A:43/36, B:51/26; metastatic sites (A/B): liver 61/62, lung 13/16, lymph node 15/14, multiple sites 39/35. Tumor response rates (CR + PR) were 23% in the FA-FU group (1 CR, 17 PR; 95% Cl: 17%–32%), and 30% in the FA-FU + IFN group (5 CR, 18 PR; 95% Cl: 20%–40%). No significant difference was found in overall response rate between the two arms. A total of 180 pts (A:88; B:92) are evaluable for toxicity; grade 3–4 toxicity (WHO criteria) were (A/B): leukopenia 2%/l%, diarrhea 8%/22%, mucositis 5%/12%, nausea and vomiting 2%/7%. Our preliminary results shown better response rate in FA-FU + IFN arm, but a more severe (grade 3–4) gastrointestinal toxicity.

In order to verify if an increased dose intensity is associated with higher response rate and improved survival, starting from September 1993 untreated patients (pts) with ABC were enrolled in a multicentric study of GOIM (prot. n 9304). Chemotherapy consisted (mg/mq) of L-FA 100 iv d 1–3, F 340 iv d 1–3, N 12 iv d 1 and C 600 iv d 1. G-CSF was admin-istered se at 0.5 μgr/kg from day 5 to 14. Mitoxantrone was escalated by one dose level (2 mg/mg) up to a maximum of 18 mg/mq according to nadir toxicities. Treatment was repeated every 3 weeks or was moved up in the presence of good hemometry values. To date fifty-three pts entered into the study and 32 are evaluable for response and toxicity. The main characteristics of the evaluable pts were: median age 50 yrs; median Karnofsky PS 90; dominant site of disease: viscera 21 (62%), bone 4 (12%), soft tissue 9 (26%) of which 2 pts with locally advanced breast cancer (LABC), multiple site of disease 22 (65%). Globally 4 CR and 19 PR were observed for an ORR of 68%; there were 8 SD and 3 PD. Both the LABC pts achieved a PR and underwent to the surgery. Median duration of response was 9 months (range 4+–17+). A total of 188 cycles were administered: in 107 cycles (57%) it was possible to increase the mitoxantrone dosage and in 28 cycles (15%) the maximal dosage of 18 mg/mq was reached. In 43 cycles (23%) the internal among cycles was reduced. Toxicity was mild and gastrointestinal and hematological toxicity of grade (G) 3–4 was not observed. At nadir the most important hematological toxicity was leucopenia (85%), followed by anemia (76%) and thrombocytopenia (53%). Alopecia of grade G3 was seen in only 3 cases. The study is ongoing, but preliminary data show the F-FNC combination as a well tolerated and effective form of palliative treatment in ABC.

The clinical use of IL 2 and anthracycline in MRCC is based on pre-clinical studies that have shown a synergistic antitumor activity, due to an increased specific antitumor immunity (Gautam, Cancer Res. 1991; 51:6133–7). Seventeen pts (6 females and 11 males) with MRCC have been treated in a multicenter phase II study to test the safety and efficacy of low dose subcutaneous IL 2 in combination with EPI. The cycle consisted of IL 2 at 9 million I.U. for the first two days of the first week followed by 4.5 million I. U. for the remaining three days of the first week and for five days/week for five weeks, plus EPI at 25 mg/mq the first day of each week. Median age was 56 years (46–71); median Karnofsky index was 90. Thirteen pts had prior nephrectomy. Three of these had syncronous metastases and were subjected to debulking surgery. Only two pts received prior chemotherapy or immunotherapy. The disease sites were: lung in 9 pts, lymph nodes in 7, kidney in 2, adrenal glands in 2, bone in 3 and renal bed in 2 pts. Fourteen pts are evaluable for response and toxicity, 3 are early to evaluate. We observed one CR and one PR lasting 14+ and 6 months, respectively. In the 8 pts with SD (57%) the median time to progression was 9 months (range 4+ to 12+). CR was obtained after two cycles in superficial lymph nodes and bone lesions while PR was noted in the lung. The toxicity was mild: only one pt had grade 3 hypotension; the most frequent toxicities (grade 1–2) were fever (9 pts) and malaise (5 pts). No pts required a decrease in IL 2 or EPI dosage. This study is ongoing and a larger number of patients are necessary to draw definitive conclusions concerning the efficacy of this chemo-immunotherapy combination in MRCC.

A two-centre prospective randomized open cross-over study to compare granisetron (Gra) vs ondansetron (Ond) vs tropisetron (Tro) in the prevention of high-dose cisplatin-induced nausea and vomiting was carried out. The notable characteristics of our study were: all patients were very homogeneous for tumor site (head and neck cancer), all were treated with high-dose (80 to 100 mg/sqm) cisplatin on day 1 and all were chemotherapy-naive. 141 patients for a total number of 541 chemotherapy cycles containing high-dose cisplatin were randomized to receive 24 mg of Ond intravenously (i.v.) or 3 mg of Gra i.v. or 5 mg of Tro i.v. for the control of acute nausea and emesis. In the Gra group in 138 out of 193 cycles (71.5%) the patients experienced a complete response (CR), in 34 cycles (17.6%) a major response (MR), in 9 cycles, (4.7%) a minor response (MiR) and in 12 cycles (6.2%) a failure (F). In the Ond group in 126 out of 176 cycles (71.6%) the patients experienced a CR, in 35 cycles (19.9%) an MR, in 5 cycles (2.8%) a MiR and in 10 cycles (5.7%) a F. In the Tro group in 115 out of 172 cycles (66.9%) the patients experienced a CR, in 30 cycles (17.4%) a MR, in 18 cycles (10.5%) a MiR and in 9 cycles (5.2%) a F. The major efficacy (CR + MR) was achieved in 172 out of 193 cycles (89.1%) for Gra, in 161 out of 176 cycles (91.5%) for Ond and in 145 out of 172 cycles (84.3%) for Tro. The statistical analysis could detect a significant difference as for major efficacy only between Ond and Tro (P Work supported by CNR, Rome, AP. ACRO, Contract No. 94.01157.PF39.

Doxifluridine (5-dFUR) is a fluoropyrimidine derivative with a better therapeutic index than FU (Bajetta, Eur J Cancer, 1993). This study independently evaluated the activity of two different schedules of oral or i.v. 5-dFUR plus levo-Ieucovorin. Between April 1993 and September 1994, a total of 130 untreated (in an adjuvant and metastatic setting) pts with measurable colorectal cancer were randomized to 5-dFUR 750 mg/m2 p.o. on days 1→4 and levo-leucovorin 25 mg/dose p.o. two hours before 5-dFUR, repeated every 12 days (Arm A); or 5-dFUR 3000 mg/m2 as a one hour i.v. infusion for 5 consecutive days combined with levo-leucovorin 25 mg/dose i.v. immediately before 5-dFUR every 21 days (Arm B). The first response evaluation was made after 2 mos of treatment. The two arms were well balanced in terms ofage (median 61 yrs, range 31–80), sex (M/F: 69/61) and disease extension. A preliminary intent-to-treat analysis was made of 126 adequately treated pts (4 too early to evaluate), of whom 67 were in Arm A and 59 in Arm B. The response rates were 15% in Arm A (2 CR, 8 PR, 29 SD, 28 PD) and 39% in Arm B (5 CR, 15 PR, 15 SD, 21 PD). Toxicity included WHO grade 3 and 4 diarrhea in respectively 16% and 7% of Arm A and 16% and 15% of Arm B respectively. Mucositis was mainly observed in Arm B (grade 3 in 13% and grade 4 in 1%). The preliminary data confirm the good tolerability profile of both the oral and the i.v. schedule. The oral route seems to be promising and is interesting, because it could be benefit for pts suitable for home treatment. Moreover, this study confirms the efficacy of i.v. doxifluridine as a fast line therapy in advanced colorectal cancer. Data management by I.T.M.O. (ltalian Trials in Medical Oncology) Scietific Service.