Sara Donati

Cardiotoxicity of Epirubicin/Paclitaxel–Containing Regimens: Role of Cardiac Risk Factors

PURPOSE To evaluate the incidence of clinically relevant cardiac toxicity after treatment with epirubicin/paclitaxel-containing regimens in patients with metastatic breast cancer and to identify high-risk patients in whom the benefit of chemotherapy may be negated by the occurrence of congestive heart failure (CHF). PATIENTS AND METHODS A total of 105 patients who were referred for epirubicin/paclitaxel treatment were included in this study. Treatment regimens were as follows: (1) epirubicin 90 mg/m(2) plus paclitaxel 135 to 225 mg/m(2) over 3 hours (n = 76); and (2) gemcitabine 1,000 mg/m(2) on days 1 and 4 plus epirubicin/paclitaxel (n = 29). The occurrence of CHF was detected by physical examination, and left ventricular function was evaluated by bidimensional echocardiography to support the diagnosis. Cardiac risk factors examined in this study included age, prior radiotherapy to the chest, hypertension, and diabetes. RESULTS No patient experienced CHF while on treatment. Nine patients (9%) developed CHF after cumulative epirubicin doses of 1,080 mg/m(2) (n = 4), 720 mg/m(2) (n = 2), 630 mg/m(2) (n = 1), and 540 mg/m(2) (n = 2). One of the two patients who developed CHF after a cumulative epirubicin dose of 540 mg/m(2) had received consolidation with high-dose chemotherapy. Median time to appearance of cardiologic symptoms was 3 months after the end of treatment (range, 3 to 6 months). Overall, the incidence of CHF was 13% and 4% in patients with or without cardiac risk factors, respectively. The cumulative risk of developing CHF was estimated as 7.7% at a cumulative doses of 720 mg/m(2) and 48.7% at a cumulative dose of 1,080 mg/m(2). CONCLUSION This study shows that the incidence of CHF after an epirubicin/paclitaxel regimen is low up to cumulative epirubicin doses of 990 mg/m(2), thus allowing the safe administration of this regimen even in patients who received epirubicin in the adjuvant setting. However, the risk of developing CHF increases when a cumulative dose exceeding 990 mg/m(2) is reached, concomitantly with the presence of an additional cardiac risk factor.

Gemcitabine plus epirubicin plus taxol (GET) in advanced breast cancer: a phase II study*

AbstractPurpose. To investigate the activity of the combination of gemcitabine (G) plus epirubicin (E) and taxol (T), (GET), in metastatic breast cancer, to evaluate the feasibility of this regimen as induction before high dose chemotherapy and to study the pharmacokinetic interactions of these three drugs. Patients and methods. Metastatic breast cancer patients, with bidimensionally measurable disease were eligible. Treatment consisted of G 1000mg/sqm days 1 and 4 plus E 90 mg/sqm day 1 plus T 175mg/sqm/3h day 1, every 21 days. After six courses of GET, patients aged less than 60 years, in complete or partial remission or stable disease entered a programme of high dose chemotherapy (HDCT), as consolidation treatment. Results. Thirtysix patients were included in this study. Grade 4 neutropenia was observed in 64% of the patients, with four episodes of febrile neutropenia; 39% of the patients experienced mild to moderate peripheral neuropathy; grade 2 and 3 mucositis occurred respectively in 9 (25%) and 6 (17%) patients. The overall response rate to GET was 92% (95% CI, 77.53%–98.25%); CR 31% and PR 61%. After six courses of GET, 25 patients received HDCT, leading to an overall response rate of 96% with 58% CR. At a median follow up of 25 months (range 8–39), 13 out of 36 patients are progression free and 26 alive. Median progression free survival is 21 months, while median overall survival has not yet been reached. The pharmacokinetic data show that G does not influence the interactions between E and T, while gemcitabine kinetics remains unchanged. Conclusions. The results of the present study indicate that the addition of G to E plus T as front line treatment for advanced breast cancer is well tolerated with an ORR of 92%. On the basis of the high activity and interesting progression free and overall survival rates, the GET combination deserves further evaluation in randomized trials.

Metronomic oral vinorelbine as first-line treatment in elderly patients with advanced non-small cell lung cancer: results of a phase II trial (MOVE trial)

BackgroundMetronomic oral vinorelbine could be a safe option for elderly patients with advanced non small cell lung cancer (NSCLC). Metronomic administration of chemotherapy leads to a cytostatic action shifting treatment target from cancer cell to tumor angiogenesis.Methods43 chemotherapy naive elderly (≥70 yrs) PS 0-2 patients with stage IIIB-IV NSCLC were prospectively recruited. Median age was 80 yrs (M/F 36/7) with predominantly squamous histology. PS distribution was 0-1(16)/2(27) with a median of 3 serious co-morbid illnesses. Study treatment consisted of oral vinorelbine 50mg three times weekly (Monday-Wednesday-Friday) continuously until disease progression, unacceptable toxicity or patient refusal. Primary endpoints were overall response rate (ORR), clinical benefit (CB – disease response plus disease stabilization >12 weeks) and safety. Health-related QoL (HRQoL) was also assessed with FACT-L V4 scoring questionnaire. We conducted an exploratory time-course analysis of VEGF and thrombospondin-1 (TSP1) serum levels in a subgroup of patients.ResultsPatients received a median of 5 (range 1-21) cycles with a total of 272 cycles delivered. ORR was 18.6% with 7 partial and 1 complete responses; 17/43 experienced stable disease lasting more than 12 weeks leading to an overall CB of 58.1%. Median time to progression was 5 (range 2-21) and median overall survival 9 (range 3-29) months. Treatment was well tolerated with rare serious toxicity. Regardless of severity main toxicities observed were anemia in 44%, fatigue in 32.4%, and diarrhoea 10.5%. FACT-L v4 scores did not significantly vary during treatment. Baseline VEGF levels were lower and showed a rapid increase during treatment in non-responders pts only while TSP1 levels did not change.ConclusionsMetronomic oral vinorelbine is safe in elderly patients with advanced NSCLC with an interesting activity mainly consisting in long-term disease stabilization coupled with an optimal patient compliance (Eudra-CT 2010-018762-23, AIFA OSS on 26 February 2010).

Phase II trial of single-agent oral vinorelbine in elderly (≥70 years) patients with advanced non-small-cell lung cancer and poor performance status

BACKGROUND Elderly patients with advanced non-small-cell lung cancer (NSCLC) with poor performance status (PS) are a special population requiring particular attention. Single-agent oral vinorelbine could be an attractive option. PATIENTS AND METHODS A total of 43 patients with stage IIIB-IV NSCLC and Eastern Cooperative Oncology Group (ECOG) PS of two or more with good functional status were prospectively recruited. Oral vinorelbine was administered at the dose of 60 mg/m(2) on days 1-8 every 3 weeks. Primary end points were response rate and safety. RESULTS Overall response rate was 18.6% with 8 partial responses; 18 of 43 (41.8%) experienced stable disease lasting >12 weeks and 17 of 43 (39.6%) disease progression for an overall clinical benefit of 60.4%. Median time to progression was 4.0 (range 2-22) months and median overall survival 8.0 (range 3-35) months. Treatment was well tolerated. Of 187 cycles, we did not observe any grade 3/4 toxicity with the exception of a single not-febrile G3 neutropenia. Regardless of severity, main toxic effects observed were nausea in 48.1% and vomiting in 22.9% of patients, anemia in 43.2%, fatigue in 32.6% and leukopenia in 23.2%. CONCLUSION Single-agent oral vinorelbine is extremely safe in elderly patients with advanced NSCLC and ECOG PS of two or more and may represent a valid option in this very special population.

Gemcitabine, epirubicin, and paclitaxel combinations in advanced breast cancer.

Strategies to improve outcome in metastatic breast cancer include the first-line use of combinations of optimal doses of active agents, with the goal being to improve complete response rates and thus long-term survival. Although prior studies of anthracycline/taxane combinations generally have shown improved response rates and progression-free survival in comparison with single-agent regimens or anthracycline/cyclophosphamide-containing combinations, the data have not consistently demonstrated improved overall survival; indeed, they have yielded generally disappointing complete response rates. We evaluated the combination of gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN), epirubicin, and paclitaxel (GET) based on the hypothesis that epirubicin/paclitaxel is best suited for achieving delivery of optimal doses, and the addition of gemcitabine (which exhibits good single-agent activity with a favorable toxicity profile) will increase activity. In a phase II trial of 36 patients, the GET regimen produced reasonable toxicity and was associated with a 92% response rate, including complete responses in 31% of patients. The overall response rate increased to 97%, including complete responses in 41% of patients, with high-dose consolidation chemotherapy in 25 patients. A trial comparing GET with epirubicin/paclitaxel as first-line treatment in more than 600 patients with metastatic breast cancer has been initiated, with survival as the primary end point. Another large-scale trial is being planned to compare the GET regimen with an anthracycline/cyclophosphamide/paclitaxel combination in patients with early stage high-risk breast cancer. Semin Oncol 28 (suppl 7):15-17.

Pharmacogenetic interaction analysis of VEGFR-2 and IL-8 polymorphisms in advanced breast cancer patients treated with paclitaxel and bevacizumab

AIM To investigate pharmacogenetic interactions among VEGF-A, VEGFR-2, IL-8, HIF-1α, EPAS-1 and TSP-1 SNPs and their role on progression-free survival in a population of metastatic breast cancer patients treated with bevacizumab in combination with first-line paclitaxel. PATIENTS & METHODS Analyses were performed on germline DNA obtained from blood samples and SNPs were investigated by real-time polymerase chain reaction technique. The multifactor dimensionality reduction methodology was applied to investigate the interaction between SNPs. RESULTS One hundred and thirteen patients were enrolled from eight Italian Oncology Units ( clinicaltrial.gov : NCT01935102). The multifactor dimensionality reduction software provided two pharmacogenetic interaction profiles consisting of the combination between specific VEGFR-2 rs11133360 and IL-8 rs4073 genotypes. The median progression-free survival was 14.1 months (95% CI: 11.4-16.8) and 10.2 months (95% CI: 8.8-11.5) for the favorable and the unfavorable genetic profile, respectively (HR: 0.44, 95% CI: 0.29-0.66, p < 0.0001). CONCLUSION The pharmacogenetic statistical interaction between VEGFR-2 rs11133360 and IL-8 rs4073 genotypes may identify a population of patients with a better outcome.

A DOSE-FINDING STUDY OF IFOSFAMIDE BY THREE-DAY CONTINUOUS INFUSION IN PRETREATED, ADVANCED BREAST CANCER PATIENTS

The purpose of the study was to establish the maximum tolerated dose of ifosfamide, administered over 72 hr, in metastatic breast cancer patients, pretreated with chemotherapy. Ifosfamide and mesna were given at the same dose, in the same solution, using a portable Pharmacia CADD-1 pump connected to a central venous access, at three dose levels: 7.5 g/m2 (6 patients), 9 g/m2 (8 patients), 10.5 g/m2 (3 patients); the courses were repeated every 3 weeks. Seventeen patients with a median age of 55 years (range, 34-68) and median performance status of 0 (range, 0-2) were treated. The patients were pretreated with a median of 2 (range, 1-3) prior regimens including anthracyclines in 14 patients and paclitaxel in 9. Dose-limiting toxicity was defined as the occurrence of any of the following events in ≥ 2/6 patients: absolute neutrophil count <500/ml for >7 days or <100/ml for >3 days; febrile neutropenia; grade 4 thrombocytopenia; any grade ≥ 3 nonhematologic toxicity. The dose-limiting toxicities were febrile neutropenia and grade 4 thrombocytopenia in 2/3 patients treated at 10.5 g/m2. Seven patients achieved an objective response (response rate 41%; 95% CI, 18% to 67%). We conclude that 72-hr infusion of ifosfamide is feasible in ambulatory patients. The recommended dose for phase II studies is 9 g/m2, with courses repeated every 21 days.

First-line treatment of NSCLC with bevacizumab: real world data from an Italian regional based survey

Background: We aimed to explore the use of platinum plus bevacizumab in a real world NSCLC population. Patients and methods: We retrospectively collected data from patients affected by NS-NSCLC treated with platinum plus bevacizumab across Tuscany. Results: We evaluated 62 (median age: 63.5 [30–77] years) pts. All but one presented with adenocarcinoma and the majority had ECOG PS of 0/1. 17.7% presented with central lesion, 11.3% with brain metastasis, 38.7% with hypertension and 4.8% with mild haemoptysis. We observed a median time to progression (TTP) of 6.5 [2–37] and a median overall survival (OS) of 10.5 [2–39] months. Overall response rate (ORR) was 59.6% with a disease control rate (DCR) of 80.6%. Safety profile was acceptable. We observed five cardiovascular events and two major bleedings with no toxic deaths. Conclusion: Safety and efficacy real world data are consistent with those from clinical trials even in a less selected population.

1259PPHASE II TRIAL OF METRONOMIC ORAL VINORELBINE AS FIRST-LINE TREATMENT IN ELDERLY PATIENTS WITH ADVANCED NON-SMALL CELL LUNG CANCER (MOVE TRIAL)

ABSTRACT Aim: Metronomic oral vinorelbine could be a safe option for elderly patient with advanced non small cell lung cancer (NSCLC). Metronomic administration of chemotherapy leads to a cytostatic action shifting treatment target from cancer cell to tumor angiogenesis. Methods: 43 chemotherapy naive elderly (≥70 yrs) PS 0-2 patients with stage IIIB-IV NSCLC were prospectively recruited. Median age was 80 yrs (M/F 36/7) with predominantly squamous histology. PS distribution was 0-1(16)/2(27) with a median of 3 serious co-morbid illnesses. Study treatment consisted of oral vinorelbine 50mg three times weekly (Monday-Wednesday-Friday) continuously. Primary endpoints were overall response rate (ORR), clinical benefit (CB – disease response + stabilization >12 weeks) and safety. Health-related QoL (HRQoL) was also assessed. We conducted an exploratory time-course analysis of VEGF and thrombospondin-1 (TSP1) serum levels in a subgroup of patients. Results: Patients received a median of 5 (range 1-21) cycles with a total of 272 cycles delivered. ORR was 18.6% with 7 partial and 1 complete responses; 17/43 experienced stable disease lasting more than 12 weeks leading to an overall CB of 58.1%. Median time to progression was 5 (range 2-21) and median overall survival 9 (range 3-29) months. Treatment was well tolerated with rare G3/4 toxicity. Regardless of severity main toxicities observed were anemia in 44%, fatigue in 32.4%, and diarrhoea 10.5%. HRQoL scores did not significantly vary. Baseline VEGF levels were lower and showed a rapid increase during treatment in non-responders pts only while TSP1 levels did not change. Conclusions: Metronomic oral vinorelbine is safe in elderly patients with advanced NSCLC with an interesting activity mainly consisting in long-term disease stabilization coupled with an optimal patient compliance. Disclosure: All authors have declared no conflicts of interest.