E. Esteban

Phase I clinical trial of fixed-dose rate infusional gemcitabine and dacarbazine in the treatment of advanced soft tissue sarcoma, with assessment of gemcitabine triphosphate accumulation

In the current study, the authors set out to determine the dose‐limiting toxicity (DLT) and maximum tolerated dose (MTD) associated with a combination of gemcitabine and dacarbazine (DTIC) in patients with advanced soft tissue sarcoma (ASTS), to obtain preliminary information on the activity of this combination, and to explore possible pharmacodynamic interactions between gemcitabine and DTIC.

Phase I/II Study of Gemcitabine plus Vinorelbine in Non-Small Cell Lung Cancer

AbstractBackground: Because gemcitabine andvinorelbine have demonstrated single-agentactivity in non-small cell lung cancer(NSCLC), we conducted this phase I/II studyto determine the maximum tolerated dose(MTD) and activity of these drugs combined. Patients and methods: Patients withinoperable or advanced NSCLC and no priorchemotherapy were treated with gemcitabineplus vinorelbine on days 1 and 8 every 21days. The initial doses of gemcitabine1,000 mg/m2 and vinorelbine25 mg/m2 were escalated by250 mg/m2 and 5 mg/m2,respectively, in separate patient cohortsuntil the MTD was established. Results: In phase I, 32 patientsreceived a total of 115 cycles. Dose-limiting toxicities were neutropeniaand hepatotoxicity, occurring at the doselevel of 1,500 mg/m2 and30 mg/m2. Thus, the MTD used forphase II was 1,250 mg/m2 and30 mg/m2. Of 41 patients in phase II,16 (39%) achieved objective responses(95% confidence interval [CI] 24% to54%), with a median time to progression of4.2 months. Overall survival was 9 months(95% CI 5.7 to 12.7 months) and the 1-yearsurvival rate was 31%. World HealthOrganization (WHO) ≥grade 3neutropenia and reversible thrombocytosisoccurred in 15% and 65% of patients,respectively. Non-hematologic toxicity wasmild at all dose levels. Grades 3 and 4hepatotoxicity were reported in one patienteach. Conclusion: The combination of1,250 mg/m2 gemcitabine and30 mg/m2 vinorelbine on days 1 and 8every 21 days is well tolerated and activein patients with NSCLC. These resultsshould be confirmed in comparativestudies.

Phase III trial of cyclophosphamide, epirubicin, fluorouracil (CEF) versus cyclophosphamide, mitoxantrone, fluorouracil (CNF) in women with metastatic breast cancer.

Background: The mitoxantrone combination CNF and the epirubicin combination CEF have shown similar activity and less toxicity than the standard CAF combination in metastatic breast cancer (MBC). A prospective randomised study was started to compare safety and activity between CEF and CNF administered using a classical chemotherapeutic schedule in MBC.Patients and methods: From December 1987 to June 1993, 151 patients were randomised to receive cyclophosphamide (C) 100 mg m−2 p.o. days 1–14, fluorouracil (F) 500 mg m−2 i.v. days 1 and 8, and epirubicin (E) 30 mg m−2 i.v. days 1 and 8, or mitoxantrone (N) 6 mg m−2 i.v. days 1 and 8, every 4 weeks. Seventy‐three patients were eligible for CEF and 72 for CNF.Results: Objective responses were observed in 61.6 of the CEF group and 44.4 in CNF group (p=0.004). The median duration of response was 64 weeks in CEF and 50 weeks in CNF group (p=0.02) and median time to progression was 51 and 33 weeks, respectively (p=0.0004). At the time of analysis, all except six patients (one in CNF and five in CEF) had died and the median survival time in the CEF group was longer than in CNF (74.4 weeks vs 51.4 weeks; log-rank χ2 test p=0.015). CNF produced more hematologic toxicity than CEF (WHO scale; grades 2–4): leucopenia 84% vs 68% (p=0.03) and trombocytopenia 17% vs 4.5% (p=0.01); CEF caused more grade 2 and 3 alopecia: 93% vs 70% (p=0.00 1).Conclusion: The combination CEF using this schedule and dosage in metastatic breast cancer is more effective with less toxicity than CNF, except for alopecia, and was associated with longer survival.

Activity of weekly irinotecan (CPT-11) in patients with advanced non-small cell lung cancer pretreated with platinum and taxanes

Irinotecan (CPT-11), a semisynthetic derivative of camptothecin, is active in the treatment of non-small cell lung cancer (NSCLC). In this report we describe our experience with this drug when used as a single agent in patients with advanced NSCLC refractory to chemotherapy with platinum and taxanes. Nineteen NSCLC patients (thirteen males and six females; 53% adenocarcinoma and 26% squamous cell carcinoma) with a median age of 52 years (range 34–71) and a Karnofsky performance status of 60% (60–80%) were included in the study. At baseline, the patients had a median of two disease sites and had been treated with a median of two prior regimens. Irinotecan was given at a dose of 100 mg/m2 i.v.) weekly for 4 weeks followed by 1 week of rest. A total of 123 weekly infusions were administered, and each patient received a median of 4 weeks of treatment (range 1–32). All patients were evaluated by intention-to-treat analysis for efficacy and safety. Main toxicities reported were grade 3 neutropenia (10% of patients), diarrhea (10% of patients), and grade 4 thrombocytopenia (5% of patients). The overall clinical response rate was 16% (95% CI: 8–24) with three partial responses and 9 (47%) patients with stable disease. The median time to progression and the median survival time were 7 and 15 weeks, respectively. In conclusion, weekly irinotecan showed antitumoral activity and minimum toxicity in NSCLC patients refractory to platinum and taxanes.

Irinotecan in the treatment of advanced colorectal cancer in patients pretreated with Fluorouracil-based chemotherapy: a study to determine recommendable therapeutic dosage.

&NA; Because no consensus exists regarding recommendable dose levels for irinotecan, an intrapatient dose escalation phase I‐II study was initiated in previously treated patients with colorectal cancer. Survival was a secondary endpoint. Thirty‐five consecutive patients with progressive disease after 5‐fluorouracilbased chemotherapy were enrolled to receive irinotecan starting from 250 mg/m2/3 weeks and rising to currently used therapeutic doses. In total, 162 cycles were administered. The median tolerable dose was 250 mg/m2. Twelve patients (34%) were unable to tolerate doses greater than 250 mg/m2, 10 patients (28%) presented toxicity at 250 mg/m2 and 2 patients tolerated only 200 mg/m2. Three patients (9%) had partial response. The major adverse reactions were grade III‐IV diarrhea, grade II‐III nausea/vomiting, grade II‐III neutropenia, and grade II‐III anaemia in 28%, 48%, 11%, and 17% of the patients, respectively. Median survival time and time to progression were 8 and 3 months, respectively. The current irinotecan dose of 350 mg/m2/3 weeks appears unacceptably toxic and, hence, a lower dose needs to be considered. The response rates obtained are similar to the results observed in phase III studies, and its activity appears not to be adversely affected with this treatment scheme.

Phase I/II Study of Gemcitabine and Vinorelbine Plus Cisplatin in Non-Small Cell Lung Cancer

AbstractPurpose. We determine the maximum tolerated dose (MTD) and efficacy ofgemcitabine plus vinorelbine combined withcisplatin in patients with non-small celllung cancer (NSCLC). Patients and methods. Chemo naive patientswith stage IIIA to IV non-small cell lungcancer received outpatient administrationof gemcitabine 1000 mg/m2 andvinorelbine 25 mg/m2 intravenously ondays 1 and 8 every 21 days. Doses ofgemcitabine and vinorelbine were escalatedby 250 mg/m2 and 5 mg/m2,respectively, at each dose level. Cisplatin was administered at a fixed doseof 50 mg/m2 on days 2 and 9. Afterthe MTD was reached, the study wascontinued as a phase II trial. Results. From January 1998 to March 1999, sixty-five patients were enrolled. Thefirst 38 patients participated in the phaseI evaluation. After 130 cycles, thedose-limiting toxicities were neutropenia,stomatitis, asthenia, and hepatotoxicityoccurring at the third and fourth doselevels (doses of gemcitabine/vinorelbine of1500/25 and 1000/30 mg/m2).For the subsequent phase II evaluation, 27additional patients, out of a total of 53,receiving the MTD of gemcitabine andvinorelbine (1000–1250/25 mg/m2)followed (24 hours later) by cisplatin50 mg/m2. Thirty one (58%) of 53 assessable patients responded. Objectiveresponse for patients with stages III andIV disease, respectively, were 65% and47%. The median time to progression andthe overall survival time were 9 months(95% CI: 5–12) and 11 months (95 % CI:9–13), respectively. World HealthOrganization toxicity ≥ grade 3neutropenia was registered in 28 (54%) of52 assessable patients (2% with febrileneutropenia), and ≥ grade 3thrombocytopenia in 15 (29%) patients (4%with bleeding). Nausea/vomiting(≥ grade 2) and asthenia (moderate tosevere) occurred in 24 (46%) and 14 (27%)patients, respectively. Conclusion. Gemcitabine1000–1250 mg/m plus vinorelbine25 mg/m2 on days 1 and 8, followed bycisplatin 50 mg/m2 24 hours later, issafe for outpatient administration andactive in patients with NSCLC.

Negative phase II study with carboplatin and 5-fluorouracil in advanced breast cancer

THOSE PATIENTS with advanced breast cancer progressing to first-line chemotherapy have a poor prognosis and there is no accepted second-line standard treatment [l]. Since cisplatin has signa and S-FU, 1 g/m2 per day was delivered in continuous infusion over 120 h. The schedule was repeated every 4 weeks. In the absence of progressive disease, patients had to receive at least two cycles of treatment to be considered evaluable for activity. WHO criteria were used for response and toxicity. From October 1986 to December 1990, 21 patients were entered. 1 patient was not evaluable because of inadequate therapy, and one other due to protocol violation. The characteristics of the 19 evaluable patients are presented in Table 1. All patients had received S-FU before. There was 1 partial response, 5 patients had stable disease, and 13 progressed, for an overall activity of 5% (95% confidence interval 7.5-30.0%). The partial remission occurred in a patient with liver metastases and lasted 8 weeks. The median time to progression was 2 months (range 1-9). 1 patient is still on treatment with stable disease. Toxicity (grade 2 or more) was: leucocytes (6 patients), platelets (4), nausea/vomiting (7), stoma&is (7), diarrhoea (3) and alopecia (1).

Combination of Docetaxel, Epirubicin and Vinorelbine Administered Every 2 Weeks as First-line Therapy in Patients with Metastatic Breast Cancer: A Dose-finding Study

AbstractAims. To assess efficacy and optimum combination dosage of intravenous docetaxel (T), epirubicin (E) and vinorelbine (N) administered every 2 weeks and without colony stimulating factor (CSF) support in patients with metastatic breast cancer (MBC). Patients and method. Patients (n = 51) with MBC were consecutively assigned to four different dose levels (DL) to receive (in mg/m2): Level I = T35 + E30 + N25; Level II = T30 + E30 + N25; Level III = T30 + E25 + N25; and Level IV = T25 + E25 + N25. Consecutive cycles were delayed if absolute neutrophil and/or platelet counts fell below 1.5 × 109 and 100 × 109l−1, respectively. Treatment at a given dose level was suspended if 33% or more of patients included in a given cohort had unacceptable toxicity. Results. The patients evaluable for toxicity (n = 48) received 448 cycles (median 9; range 1–23). There was neutropenia G 3–4 in 30 patients (63%) with fever in 3 (6%). The G 2–3 non-hematological toxicities were alopecia in 39 patients (81%), mucositis in 11 (23%), and nausea/vomiting in 8 (17%). There were no toxic deaths. Treatment delay or dose reduction after first cycle occurred in ≥30% of patients treated in all DLs, except the fourth. Objective response was achieved in 29 of the 47 evaluable patients (58%; 95% CI: 50–66). The median duration of response, time-to-progression and overall survival were 13, 11 (range 8–14) and 20 (range 16–24) months, respectively. Conclusion. The combination of docetaxel, epirubicin and vinorelbine without CSF support ought not to exceed 25 mg/m2 every 2 weeks. The efficacy is no greater than other existing regimens for first-line treatment of MBC.

New molecular risk factors in germ cell tumors.

e21142 Background: Tumor histologic risk factors are inaccurate to predict risk of relapse in 25-30% of patients with clinical stage I germ cell tumors of the testis (CSIGCT), with important consequences in therapeutic strategies. The goal of this study is to identify new molecular criteria to improve the classic risk models of this cancer. METHODS From March 1976 to August 2010, sixty-nine patients with CSIGCT, independent of known risk factor or histology, were included in a surveillance program following orchidectomy. Paraffin-embedded GCT biopsies were reviewed for traditional histopathological features. Further, the samples were assessed for epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC) and for mutations on exons 19, 20, and 21 by PCR. Univariate and multivariate analyses were performed to evaluate the role of these parameters as prognostic factors. RESULTS EGFR was expressed in 23.2% of tumors, but no EGFR mutations were detected in any of the exons studied. In the univariate analysis, EGFR expression showed significant relation with risk of relapse (p=0.04), while in the multivariate analysis, epididymis invasion was the only independent prognostic factor (p=0.02). In the subgroup nonseminoma germ cell tumors (NSGCT), the presence of embryonal carcinoma (EC) and vascular invasion (VI) were confirmed as prognostic factors. A risk model built on EC and VI yielded a 73.7% accuracy to predict relapse, whereas the addition of EGFR expression and epididymis invasion to the existing model increased accuracy to 91.6% in NSGCT. CONCLUSIONS EGFR expression showed prognostic significance for prediction of relapse in CSIGCT. This additional molecular marker deserves further study to improve current models to manage this disease.

Prognostic factors in patients with advanced renal cell carcinoma.

e15011 Background: A retrospective cohort of 135 patients with advanced RCC treated with biological agents and/or cytokines (CK) was analysed between July 1996 and February 2010. METHODS The expression of several biomarkers by immunohistochemistry and 2 analytical variables were analysed and were correlated with prognosis. RESULTS 67 patients were treated only with biological agents and 68 with CK (23 received also biological agents). The univariate statistical analysis showed that the enhanced expression of HIF1α correlated with a poor prognosis in patients treated with biological agents (PFS 5,4 vs 13,5 months with low expression p=0,033) including sunitinib (PFS 5,4 vs 13,4 p=0,001) and CK (PFS 3,3 vs 5,7 p=0,003). The overexpression of CAIX was associated to a better prognosis in patients that received biological agents (PFS 18,3 vs 5,2 months with decreased expression p<0,001; OS 32,1 vs 7,8 p<0,001) including sunitinib (PFS 16,8 vs 5,5 p<0,001), sorafenib (PFS 8 vs 3,5 p<0,001) and CK (PFS 6,3 vs 2,7 p=0,003; OS 32,9 vs 5,9 p=0,001). Positive PTEN was related to a good prognosis in patients treated with sunitinib (PFS 15,1 vs 6,5 months with negative PTEN p=0,003) and CK (PFS 7,5 vs 3,8 p=0,037; OS 13,7 vs 7,9 p=0,039). The increased expression of p21 was related to a poor prognosis in patients that received biological agents (PFS 5,9 vs 16,8 months with high expression p=0,024) including sunitinib (PFS 6,2 vs 18,9 p<0,001), sorafenib (PFS 4 vs 9 p=0,013) and CK (PFS 3,9 vs 7,5 p<0,001). Thrombocytosis was related to a poor prognosis in patients treated with biological agents (OS 15,9 vs 26,7 months without thrombocytosis p=0,007) and CK (PFS 2,6 vs 5,1 p=0,017; OS 5,9 vs 14,3 p=0,010). Neutrophilia was related to a poor prognosis in patients that received biological agents (OS 17,6 vs 25,4 months without neutrophilia p=0,063) and CK (PFS 2,6 vs 5,7 p=0,019; OS 5,9 vs 12,8 p=0,035). In the multivariate analysis the overexpression of CAIX was a favourable prognostic factor independent of PFS with HR of 0,107 (p<0,001) and OS with HR of 0,055 (p<0,001). CONCLUSIONS Our experience suggests the utility of de HIF1α, CAIX, PTEN, p21, thrombocytosis and neutrophilia as prognostic factors in patients with advanced RCC. CAIX has shown to be an independent prognostic factor.