Maria Lina Tirrito

Pegylated liposomal doxorubicin with vinorelbine in metastatic breast carcinoma : A phase I-II clinical investigation

A multicenter phase I-II trial was carried out with the aim of identifying the dose-limiting toxicity and the maximum tolerated dose of vinorelbine (VNR) in combination with pegylated liposomal doxorubicin at a dose of 20 mg/m2 every 15 days in patients with metastatic breast carcinoma. In the phase I part of the trial, VNR was given at a dose of 20 mg/m2 every 15 days to a group of 3 patients. In absence of unacceptable toxicity, VNR was escalated to 25, 30, and 35 mg/m2 for subsequent groups of 3 patients, until the dose-limiting toxicity was reached. No case of palmar-plantar erythrodysesthesia was recorded in these patients. Grade 4 neutropenia, grade 3 thrombocytopenia, and grade 3 mucositis were the dose-limiting toxicities recorded in patients treated with VNR 35 mg/m2. These side effects caused a substantial decrease in programmed dose intensity. Therefore 30 mg/m2 was considered the maximum tolerated dose of VNR in combination with pegylated liposomal doxorubicin 20 mg/m2, both given every 15 days. These dosages were employed for the treatment of further 18 patients included in phase II of the study. The overall response rate, calculated according to an intention to treat analysis, was 63% (95% CI: 44–80%), with 2 patients achieving a complete response. The median time to progression was 7.0 months or more (range 2–14 months). Median duration of objective responses was 8.4 months or more. The duration of the 2 complete responses was 9 and 14 months, respectively. Median duration of survival was 16.0 months or more (range from 4.0 to ≧24.0). Toxicity was generally mild and easily manageable. Neutropenia and mucositis were the most frequently recorded side effects. A case of palmar-plantar erythrodysesthesia was recorded in phase II of the study. In conclusion, the maximum tolerated dose of VNR in association with pegylated liposomal doxorubicin is 30 mg/m2 on a bimonthly schedule. Moreover, the combination of VNR and pegylated liposomal doxorubicin is active against metastatic breast carcinoma and is associated with a good toxicity profile. Further studies with this combination regimen are warranted.

Oral granisetron with or without methylprednisolone versus metoclopramide plus methylprednisolone in the management of delayed nausea and vomiting induced by cisplatin‐based chemotherapy. A prospective randomized trial

Background. A single‐institution, randomized open trial was prospectively performed to compare orally administered granisetron with or without intramuscularly administered methylprednisolone to metoclopramide plus methylprednisolone in the prevention of delayed nausea and vomiting induced by cisplatin‐based chemotherapy. The effects of antiemetic treatments were evaluated from days 2 to 5 of the first cycle after cisplatin administration among patients who had never before received chemotherapy.

Cisplatin and vinorelbine in advanced and/or metastatic adenocarcinoma of the endometrium: A new highly active chemotherapeutic regimen

PURPOSE To date the systemic treatment of recurrent and/or metastatic adenocarcinoma of the endometrium (EAC), using both chemotherapy and hormonotherapy (HT), is far from satisfactory. The significant activity of vinorelbine (VNR), a relatively new semisynthetic vinca alkaloid, demonstrated in advanced breast cancer, bronchial adenocarcinoma, and in head and neck cancer, prompted us to carry out a phase II trial employing the combination of cisplatin and VNR in a pluri-institutional series of patients with recurrent and/or metastatic EAC. PATIENTS AND METHODS Thirty-five patients affected by recurrent and/or metastatic EAC have been treated with CDDP 80 mg/m2 on day 1 plus VNR 25 mg/m2 i.v. bolus on days 1 + 8. This cycle was repeated every 21 days. After three cycles patients were restaged for objective response. Analysis of response rate and duration, overall survival, and toxicity pattern were the main aims of the study. RESULTS Twenty out of thirty-five patients achieved a major objective response for an overall response rate of 57% (95% confidence limits (CL): 39%-74%). Four patients had a complete response (11%; 95% CL: 3%-27%) with a median progression-free survival (PFS) of eight hundred fourteen days, while sixteen patients had a partial response (46%; 95% CL: 29%-63%) with a median PFS of one hundred eighty-four days. Six patients had stable disease and nine progressed. All patients who achieved a clinical complete response had only a single site of disease at entry, but no association was noted between number of involved sites and likehood of achieving PR. Median overall survival was 240 days, while that of patients with complete and partial response was 855 and 300 days, respectively. Treatment was quite well tolerated with few cases of grade 3-4 myelosuppression. Alopecia was virtually absent and neurotoxicity was mild. One patient complained of an acute pain syndrome at the tumor site. CONCLUSIONS The CDDP + VNR regimen is quite active against recurrent and/or metastatic endometrial adenocarcinoma, at least in terms of objective response rate which is among the highest ever reported in medical literature. However. duration of objective response and median overall survival are in the disappointing range reported for other regimens. In our opinion the CDDP plus VNR regimen is good enough to be compared to the anthracycline-based regimens and may represent the basis for future development of newer active polychemotherapeutic schedules.

Phase I–II Parallel Study of Docetaxel on a Bimonthly Schedule in Refractory Metastatic Breast Carcinoma

AbstractBackground. The 3-week schedule with docetaxel (DTC) 75–100 mg/m2 is associated with severe neutropenia, gastro-intestinal side-effects and fluid retention in a significant proportion of patients, which may be of concern in more elderly or poor performance status patients. A phase I–II trial was carried out to test the feasibility and the activity of a new bimonthly schedule of DCT. Patients and methods. The trial included a phase I study which aimed at the identification of dose-limiting toxicity (DLT) and maximal tolerated dose (MTD) of DCT on a bimonthly schedule. The first group of three patients received DCT 40 mg/m2, and in absence of DLT, DCT dosage was escalated by 10 mg/m2/cycle until DLT was reached. In the phase II study, patients were randomized to receive: (a) standard 3-weekly DCT at the dose of 75 mg/m2 (calibration arm); or (b) bimonthly schedule with DCT at the dose recommended in the phase I study. All patients were pretreated with chemotherapy, mostly anthracycline-based regimens, for advanced/metastatic disease. Analysis of response rates, toxicity, and dose-intensity were the main aims of the study. Results. The DLT was represented by severe myelosuppression which was recorded in all patients treated at 70 mg/m2 dose level. Therefore, the MTD was 60 mg/m2 on a bimonthly schedule. However, the dose recommended for the phase II trial was 50 mg/m2, because no difference in delivered dose-intesity was seen between the 50 and 60 mg/m2 dose levels, and the latter dosage was still associated with grade 3 neutropenia in most patients. The parallel phase II study showed that the bimonthly schedule of DCT (50 mg/m2) allows to deliver the same dose-intensity of DCT 75 mg/m2 every 3 weeks. Grade 3–4 side-effects were rather infrequent in patients treated with the bimonthly schedule. Overall response rate (ORR) was 41 and 44% for the DCT 50 mg/m2 bimonthly and the DCT 75 mg/m2 every 3 weeks, respectively. Conclusions. Data achieved in the phase I part of the study showed that DCT 50 mg/m2 every 15 days is the recommended dose for phase II studies, while results achieved in the phase II trial suggest that DCT 50 mg/m2 in a bimonthly schedule is active as second-line chemotherapy for MBC being able to induce an ORR in the range reported for DCT 75–100 mg/m2 every 3 weeks. The bimonthly schedule is, however, associated with relatively low toxicity. This characteristic may render the bimonthly schedule particularly attractive for future phase II trials of DCT in combination with other antineoplastic agents.

Subcutaneous low-dose interleukin-2 and intravenous 5-fluorouracil plus high-dose levofolinic acid as salvage treatment for metastatic colorectal carcinoma

Thirty-three consecutive patients with recurrent and/or metastatic colorectal carcinoma (CRC) refractory to previous chemotherapy have been treated with levofolinic acid (1-FA) 100 mg/m2 i.v. over 1 h infusion followed by 5-fluorouracil (5-FU) 600 mg/m2 i.v. bolus every week for 6 weeks followed by a 2 week interval. Patients also received rIL-2 s.c. at 3 MU daily from day 1 to day 5 of each week for at least four consecutive weeks per cycle. Enrolled patients were divided in two groups: (i) group 1 including patients with progressive tumor refractory to chemotherapy with 1-FA + 5-FU given for metastatic disease and (ii) group 2 consisting of patients with diagnosis of metastatic disease within 3 months from the completion of adjuvant chemotherapy with 5-FU + levamisole (LEV) after primary surgery. No objective response was observed in the group of 11 patients with CRC resistant to previous 1-FA + 5-FU, thus no further patient with progressive disease after 1-FA + 5-FU was included in the trial. In the group of patients pretreated with 5-FU + LEV, four patients experienced a PR with a mean duration of 7.3 months (range ≥4.0–8.6) for an overall response rate of 18% (95% CI 12–26%). A stabilization of disease was observed in five cases (23%) with a mean duration of ≥5.6 months (range ≥2.0–7.0). The remaining 13 patients progressed. No complete responses were achieved. The mean overall survival was ≥9.5 months (range ≥2.0–14.0). Toxicity was generally mild. This study demonstrates that the combination of s.c. rIL-2 and intravenous 5-FU + 1-FA on a weekly schedule may be safely given to patients with metastatic CRC on an outpatients basis. The addition of low-dose rIL-2 does not modify the toxicity profile of 5-FU + 1-FA, even if IL-2-related side-effects such as systemic symptoms or cardiac abnormalities are to be expected. The clinical activity of the combination is not good, at least in terms of response rate, even if the duration of partial responses may suggest to test rIL-2 in a prospective study with response duration and overall survival as the final endpoints