Enrique Estrada

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.

Resultados oncológicos y funcionales del tratamiento no quirúrgico comparado con el quirúrgico en los carcinomas epidermoides de orofaringe

INTRODUCTION AND OBJECTIVES Squamous cell carcinomas of the oropharynx are aggressive tumours usually diagnosed at advanced stage. Their optimal treatment has not been established. The aim of this study was to compare the oncological and functional outcomes in patients with carcinomas of the oropharynx treated by radiotherapy (with chemotherapy in advanced stages) vs surgery (with radiotherapy in advanced stages). METHODS A retrospective study on 50 patients with squamous cell cancer of the oropharynx treated by radiotherapy (with or without chemotherapy) at our institution between 1998 and 2008 was carried out. The oncological and functional results were compared with patients with same cancer location and stage treated by surgery (with or without radiotherapy). In both groups, the patients were classified as follows: 10% Stage I, 12% Stage II, 16% Stage III, 48% Stage IVa and 14% Stage IVb. RESULTS The 5-year disease-specific survival was 33% in the radiotherapy group and 52% in the surgical group (P=.17). Five-year disease-specific survival for Stage I and II patients was 82% in the radiotherapy group and 70% in the surgical group. In Stage III and IV disease, 5-year disease-specific survival was higher in the surgical group (47% vs 17%). The functional results were similar; anatomical and functional preservation of the larynx was higher in the radiotherapy group but the successful return to oral food intake was higher in the surgical group. CONCLUSIONS The prognosis of squamous cell carcinoma of the oropharynx is poor. Oncological results in Stages I and II were similar for radiotherapy and surgical treatments. In advanced stages, the prognosis was better in patients treated by surgery with or without radiotherapy. Functional results were similar in both treatment modalities.

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).

Impact of the incorporation of tyrosine kinase inhibitor agents on the treatment of patients with a diagnosis of advanced renal cell carcinoma: study based on experience at the Hospital Universitario Central de Asturias.

IntroductionFor nearly the past two decades, cytokines (CKs) have been the only systemic treatment option available for advanced renal cell carcinoma (RCC). In recent years, tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity on this tumour. Our purpose is to describe one centre’s experience with the use of CKs and TKIs in the treatment of patients with advanced RCC.Materials and methodsThis study was designed as a retrospective chart review of RCC patients who were treated with CKs and/or TKIs in our department between July 1996 and June 2008. Efficacy and toxicity were assessed using World Health Organization (WHO) criteria. The Kaplan-Meier method was used to estimate progression-free (PFS) and overall (OS) survival.ResultsNinety-four patients were classified into three groups depending on the modality of treatment administered: 46 were treated with CKs alone and/or chemotherapy (27 with immunotherapy, one with chemotherapy and 18 with both), 28 with TKIs alone (25 with sunitinib and 13 with sorafenib) and 20 with TKIs in second-line treatment following failure with CKs (17 with sunitinib, eight with sorafenib, four with bevacizumab and one with lapatinib). The median age was 60 years in the CK group and 65 and 62, respectively, in TKI in first and second-line treatment groups. Eighty-five percent of patients treated with CKs and 75% in the TKI group in first-line treatment and 80% in second-line treatment were men. Overall, 89% of patients had favourable risk, and 11% had intermediate risk. All patients were considered evaluable for toxicity. The main grade 3–4 (%) toxicity was asthenia for both groups, (ten in TKIs and 15 in CKs). Other grade 1–2 toxicities were mucositis (39), bleeding (8), hypertension (19), skin toxicity (33) and hypothyroidism (12.5) associated with TKIs; and anaemia (33), cough (29), asthenia (39) and emesis (14) associated with CKs. The objective response rate among 80 patients evaluable for activity was 10.6% with CKs and 46.5% and 35%, respectively, with TKIs in first- and second-line treatments. Disease stabilisation with CKs was recorded at 59% of patients and with TKIs 25% and 50% in first- and second-line treatment groups, respectively. The median progression-free survival (PFS) with CKs was 122 days [95% confidence interval (CI) 82–162] and with TKIs 201 days (65–337) in the firstand 346 days (256–436) in second-line treatment groups. The median overall survival (OS) was 229 days (142–316) and 2,074 days (1,152–2,996) for patients treated with CKs and TKIs.ConclusionsOur results are in line with the activity and survival rates previously reported in the literature regarding the use of TKIs for patients with advanced RCC in first- and second-line treatment, which has demonstrated an acceptable toxicity level.

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.

Tratamiento adyuvante en pacientes diagnosticados de carcinoma no microcítico de pulmón: estado de la evidencia científica

Surgery is the current treatment of choice in patients with early-stage non-small cell lung cancer. Based on the high rates of recurrence, additional local and systemic treatments have been developed, aimed at improving the cure rates. The comparative studies about the benefits of post-operative adjuvant chemotherapy and/or radiotherapy, and the meta-analysis studies made during the last decades, reviewed in some articles appeared in 95 and 97, did not confirm a significant improvement of the overall survival. Since then, new comparative trials carried out with a higher number of patients and with more active and standard chemotherapy seem to show a benefit of the administration of platinum-based chemotherapy, although it has not gained general acceptance. More recently, a new meta-analysis, that included the previous studies, has confirmed an overall increase of 4 % in survival of patients treated by surgery and adjuvant chemotherapy, especially in stages II-III patients receiving schedules of cisplatin and vinorelbine. Further studies are needed to determine the real therapeutic value of other agents, as uracil-tegafur and radiotherapy.

Neo-Adjuvant chemotherapy in locally advanced invasive thymomas

Postoperative mediastinal irradiation has been the classical treatment for patients with residual invasive thymomas,but less than 50% of these patients are free from disease after 5 years [1–2]. In many short reports, chemotherapy has shown activity both in local and metastatic disease [3–5]. Some authors conclude that combination chemotherapy is effective in the first-line post-surgical treatment of incompletely resected thymoma [5]. Considering that Prednisone (P), Adriamycin (A), Iphosphamide (I) and Cisplatin (D) are anticancer drugs proven effective as single agents, we began a study with a combination of these 4 drugs in patients with locally advanced thymomas as neo-adjuvant chemotherapy trying to improve the results.