Multicentre risk-adapted management for stage I non-seminomatous germ cell tumours.

BACKGROUND: The Spanish Germ Cell Group is composed of 60 centres. Our challenge was to define a surveillance protocol that would be safe and suitable regardless of population size or geographic coverage. METHODS: From January 1994 to January 2004, 589 patients with stage I non-seminomatous germ cell tumours entered a risk-adapted surveillance protocol after orchiectomy. Patients with vascular or local invasion of adjacent structures (231/589; 39%) received two cycles of BE400P (bleomycin 30 U/week, etoposide 100 mg/m2 x4, cisplatinum 25 mg/m2 x4). Other patients (358/589; 61%) were kept on close follow-up (chest X-ray; serum tumour markers: first year every 2 months, second year every 3 months, third year every 4 months; abdominal computed tomography scans at every other outpatient control). The outcomes selected for the study were feasibility, relapse rate and number of patients lost to follow-up and mortality. RESULTS: Median follow-up was 40 months. In the surveillance group, 21 patients were lost to follow-up. In the chemotherapy group, two patients relapsed at 12 and 14.5 months and they are presently free of disease. In the surveillance group, 71 (19%) patients relapsed, of which 55 (71%) relapsed within the first year. Five (1.4%) patients died of their cancer. Factors associated with relapse were embryonal carcinoma and vascular invasion in patients who refused chemotherapy. CONCLUSIONS: Our risk-adapted surveillance protocol provided a low rate of recurrences.

Phase II study of a fixed dose-rate infusion of gemcitabine associated with docetaxel in advanced non-small-cell lung carcinoma.

PURPOSE: To evaluate the efficacy and toxicity profile of the combination of docetaxel and prolonged gemcitabine infusion in front-line chemonaive patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 50 chemonaive patients diagnosed with advanced NSCLC according to the AJCC/TNM classification system were included in the present study. Treatment consisted of 1000 mg/m(2) gemcitabine given as a 100-min continuous infusion (10 mg/m(2) per min) on days 1 and 8 of each course and 75 mg/m(2) docetaxel as a 60-min infusion on day 8, repeating each course every 21 days. RESULTS: The ECOG performance status of the patients were as follows: 0 (10%), 1 (60%), and 2 (30%). All patients had two-dimensionally measurable disease. Their median age was 63 years (range 41-75 years). Of the 50 patients, 28 (56%) had squamous cell carcinoma, 14 adenocarcinoma (28%), and 8 (16%) large-cell carcinoma, and 40% and 60% of patients presented with stage IIIB and IV disease, respectively. Of those with stage IV disease, 33% had more than one metastatic site. A total of 220 courses were administered with a median of five courses per patient. Of 46 patients assessed for response, 12 (26%) had a partial remission (95% CI 13-39%). In 19 patients (41%) the disease remained stable, while disease progression was observed in 15 (33%). The median time to disease progression was 4 months, and median survival time was 7 months. At 1 year, 25% of patients remained alive, and the main grade 3/4 toxicity (according to the WHO scale) consisted of neutropenia ( n=6, 12%), asthenia ( n=4, 8%), peripheral edema ( n=3, 6%), dyspnea ( n=3, 6%), and diarrhea ( n=2, 4%). CONCLUSIONS: Prolonged gemcitabine infusion combined with docetaxel is well tolerated and its efficacy is similar to that of other chemotherapeutic schemes used for NSCLC treatment. However, the prolonged infusion of gemcitabine did not appear to result in any improvement in outcome or toxicity versus the standard dose rate.

Phase II study of weekly irinotecan (CPT-11) as second-line treatment of patients with advanced colorectal cancer.

This phase II trial studied the antitumor effect and toxicity of weekly irinotecan (CPT-11, 125 mg/m(2) 60 min iv infusion, weekly for 4 wk plus 2 wk rest) as second-line chemotherapy in patients with advanced colorectal cancer (CRC) resistant or refractory to prior 5-fluorouracil (5-FU) therapy. Sixty-nine patients with adenocarcinoma (57% in the colon and 43% in the rectum) were enrolled. The median number of treatment cycles received per patient was 4 (range, 1-6). Overall response rate was 18% (95% CI, 9-26), with 4 complete responses (6%) and 8 partial responses (12%), and a median duration of response of 8.1 mo (95% CI, 4.2-12.1). Stable disease was observed in 19 patients (28%). The median time to disease progression was 5.2 mo (95% CI, 4.3-6.1), and the median overall survival was 13.3 mo (95% CI, 9.8-16.8 months). The toxicity profile was favorable: grade 3/4 delayed diarrhea was observed in 10 patients (14.5%) in one cycle each, and grade 3/4 neutropenia in 6 patients (8.7%) and 6 cycles (3.3%). No febrile neutropenia or infection was documented. Grade 3/4 nausea and vomiting were reported in 1 (1.4%) and 7 patients (10.1%), respectively. In conclusion, this phase II trial showed a response rate and a toxicity profile of weekly CPT-11 in line with the results of prior phase II studies.

Phase II study of carboplatin and 1-h intravenous etoposide and paclitaxel in a novel sequence as first-line treatment of patients with small-cell lung cancer.

PURPOSE: To evaluate the efficacy and tolerability of paclitaxel, carboplatin and etoposide when administered in combination to previously-untreated small-cell lung cancer (SCLC) patients. PATIENTS AND METHODS: Patients (n=95) with limited-stage disease (LSD; n=45) or extensive-stage disease (ESD; n=50) from 14 Spanish hospitals were entered into the study. Etoposide was administered 80 mg/m(2)/day intravenous (i.v.) on days 1, 2 and 3, paclitaxel 175 mg/m(2) i.v. on day 3 and carboplatin area-under-the-concentration-time-curve=6; i.v. on day 3, of a 3-week cycle, and repeated for up to 6 cycles. RESULTS: The overall response (OR) rate was 74% (n=70; 32 complete, 38 partial). Although the OR in LSD and ESD patients was similar (73 vs 74%, respectively), the percentage complete response was significantly higher among the former (49 vs 20%). The main toxicities were grade 3-4 neutropenia and febrile neutropenia (62 and 18%, respectively) and there were 3 toxic deaths. Other toxicities were rare or easily manageable. Disease-free survival and overall survival rates at 1 year were 53 and 70% in LSD and 18 and 39% in ESD patients, respectively. CONCLUSION: The results indicate that the combination of paclitaxel, etoposide and carboplatin has an anti-tumour activity in SCLC that is comparable to other combination regimens, and is well tolerated.

Phase II study of a fixed dose-rate infusion of gemcitabine associated with uracil/tegafur in advanced carcinoma of the pancreas.

BACKGROUND: The objectives of this study were to evaluate the efficacy and toxicity of a fixed dose-rate infusion of gemcitabine associated with uracil/tegafur (UFT) in patients with advanced adenocarcinoma of the pancreas. PATIENTS AND METHODS: Forty-three chemotherapy-naïve patients with adenocarcinoma of the pancreas were included in this phase II study. All of whom had a Karnofsky performance status >or=50 and bi-dimensionally measurable disease (either advanced non-resectable or metastatic); median age 59 years (range 39-77); male:female ratio 29:14. Eight patients (19%) had locally advanced disease and 35 (81%) distant metastases. Treatment consisted of gemcitabine 1200 mg/m(2) given as a 120-min infusion weekly for 3 consecutive weeks, plus oral UFT 400 mg/m(2)/day (in 2-3 doses per day) on days 1-21, cycles were given every 28 days. Measurements of efficacy included response rate, clinical benefit response, time to disease progression and overall survival. RESULTS: A total of 192 cycles of chemotherapy were delivered with a median of four per patient. There were two complete responses (5%) and 12 partial responses (28%), producing an overall response rate of 33% [95% confidence interval (CI) 16% to 49%]. Thirteen patients (30%) had stable disease, whereas 16 (37%) had a progression. The median time to progression was 6 months and the median overall survival was 11 months. Twenty-five patients (64%, 95% CI 47% to 78%) experienced a clinical benefit response. Grade 3-4 WHO toxicities were: neutropenia in nine patients (21%); thrombocytopenia in four (9%); anaemia in five (12%); diarrhoea in four (9%); and asthenia in one (2%). CONCLUSIONS: A fixed dose-rate infusion of gemcitabine associated with UFT was well tolerated and showed promising activity in patients with locally advanced or metastatic carcinoma of the pancreas. This is an appropriate palliative treatment in this setting.

Estudio fase II de doxorubicina liposomal pegilada (Caelyx®) en carcinoma de ovario avanzado: análisis de eficacia y toxicidad / Phase II study of pegylated liposomal doxorubicin (Caelix®) in advanced ovarian cancer: analysis of efficacy and toxocity

La doxorubicina liposomal pegilada (Caelyx®) es una nueva formulación con un perfil diferente de toxicidad y actividad demostrada en cáncer de ovario avanzado. Nuestro grupo diseñó un estudio fase II de la administración de Caelyx® en pacientes con carcinoma de ovario avanzado recidivadas a platino/paclitaxel. Se administró Caelyx® 50 mg/m2 IV (1 hs.) en ciclos repetidos cada 4 semanas. Fueron incluidas 53 pacientes con adecuada función hematológica, renal y hepática. La mediana de edad fue 60 años (rango 40-78 años), Karnosfky 100 por ciento= 15, 90 por ciento= 29, 80 por ciento= 9 y 76 por ciento de las pacientes habían recibido 2 o más líneas de quimioterapia previa. La mediana de ciclos administradas fue 5 (rango: 1-17) con una intensidad del 87 por ciento de la dosis teórica. En un total de 223 ciclos administrados fueron necesarios 8 por ciento de reducciones y 16 por ciento de retrasos de tratamiento. La principal toxicidad fue no hematológica con eritrodisestesia palmo-plantar grado 1-2: 23 por ciento y grado 3-4: 6 por ciento; mucositis grado 3-4: 3 por ciento y 2 episodios de reacción de hipersensibilidad a la infusión. La toxicidad hematológica fue moderada con neutropenia grado 3-4 en 18 ciclos (8 por ciento) y 3 episodios de neutropenia febril (2 con sepsis a Gram -). La tasa de respuesta global fue 23,5 por ciento con 2 RC y 9 RP. Después de una mediana de seguimiento de 15 meses, la mediana de intervalo libre de progresión y de supervivencia global fueron 5,8 meses (95 por ciento CI: 4,5-7,3) y 14,7 meses (95 por ciento CI: 11,2-18,3), respectivamente. Estos resultados confirman la actividad de Caelyx® en cancer de ovario altamente pretratado y progresadas a la combinación platino-paclitaxel, con una buena tolerancia y excelente manejo terapéutico. (AU)

Sequential therapy in advanced non-small-cell lung cancer with weekly paclitaxel followed by cisplatin-gemcitabine-vinorelbine. A phase II study.

OBJECTIVES: New effective therapies are needed to improve the outcome of patients with advanced non-small-cell lung cancer (NSCLC). The aim of this study was to assess the response rate and survival obtained with a sequential regimen of chemotherapy. PATIENTS AND METHODS: Patients with newly diagnosed stage IIIb-IV NSCLC were included. They all had measurable disease and a good performance status (0-2 in the Eastern Cooperative Oncology Group scale). Chemotherapy consisted of weekly paclitaxel 150 mg/m2 x 6, followed two weeks later by cisplatin 100 mg/m2 on day 1, gemcitabine 1,000 mg/m2 on days 1 and 14, and vinorelbine 25 mg/m2 on days 1 and 14 (CGV). CGV was administered every 28 days for a maximum of six courses. RESULTS: Fifty-two patients were included, 19 (37%) with stage IIIb and 33 (63%) with stage IV disease. After therapy with weekly paclitaxel. 29 partial responses were obtained (56%, 95% confidence interval (95% CI): 38%-67%), whereas 15 patients had stable disease (29%) and eight had a progression (15%). After CGV, there were four complete remissions (8%) and 24 partial responses (46%), for an overall response rate of 54% (95% CI: 37%-65%). Eight patients had stable disease (15%) and 16 had a progression (31%). No patient progressing after paclitaxel responded to CGV, whereas 5 out of 15 patients with stable disease reached a partial response with CGV (33%). On the contrary, 5 out of 29 patients with a partial response to paclitaxel progressed after CGV (17%). Median survival has not been reached after a median follow-up of 14 months. Median time to progression was nine months. Fifty-six percent of patients remain alive at one year. Two hundred eighty-nine courses of paclitaxel and 170 of CGV were given, with a median of 5.5 and 3.4 per patient, respectively (ranges 2-6 and 0-6. respectively). WHO grade 3-4 toxicities for paclitaxel were: neutropenia in two patients (4/) and peripheral neuropathy in five (10%). Two patients had allergic reactions requiring paclitaxel withdrawal, whereas four (8%) had hyperglycemia >250 mg/ml. Grade 3-4 toxicities for CGV were: neutropenia in ten patients (20%), peripheral neuropathy in six (12%), anemia in four (8%), nausea/vomiting in five (10%). thrombocytopenia in two (4%), and fatigue in four (8%). CONCLUSION: Our results suggest that sequential chemotherapy with weekly paclitaxel followed by CGV is highly active in patients with advanced NSCLC and has an acceptable toxicity. This schedule deserves further evaluation in a phase III study.

Phase II trial of gemcitabine and UFT modulated by leucovorin in patients with advanced pancreatic carcinoma. The ONCOPAZ Cooperative Group.

BACKGROUND: Use of chemotherapy for advanced pancreatic carcinoma (APC) pursues a palliative objective. Gemcitabine is active against this tumor and shows in vitro synergism with 5-fluorouracil. UFT is a combination of tegafur (a prodrug of 5-flouorouracil) and uracil that can be given orally. The administration of UFT for several weeks may simulate the effects of a continuous infusion of 5-fluorouracil. The objective of the current study was to assess the efficacy and toxicity of the combination gemcitabine-UFT-leucovorin in the treatment of APC. METHODS: Forty-two patients with bidimensionally measurable APC were included. The study regimen consisted of gemcitabine 1000 mg/m(2) once weekly for 3 consecutive weeks, followed by a 1-week rest, intravenous 6S-steroisomer of leucovorin (6SLV) 250 mg/m(2) in 2 hours on Day 1, oral 6SLV 7.5 mg/12 hours on Days 2-14, and oral UFT 390 mg/m(2)/day (in 2 doses) on Days 1-14. Cycles were repeated every 4 weeks for a minimum of 3 per patient unless progressive disease was detected. RESULTS: One hundred eighty-three courses were given, with a median of 4 per patient. World Health Organization Grade 3-4 toxicity was: diarrhea in 7 patients (17%), leucopenia in 2 (5%), nausea/vomiting in 2 (5%), and anemia in 1 (4%). Among 38 patients evaluable for response, 6 achieved a partial response (16%; 95% confidence interval (CI), 6-31. 4), 15 had stable disease (39%), and 17 had progression (45%). Improvement in performance status and symptoms (pain, analgesic consumption, and weight) was present in 11 (29%) and 17 (45%) patients, respectively. Eighteen patients (47%; 95% CI, 31.5-54.5) experienced a clinical benefit response. CONCLUSIONS: The combination of gemcitabine-UFT-6SLV is convenient and moderately active and shows a low toxicity for the palliative treatment of patients with APC.

Treatment of catheter-induced thrombotic superior vena cava syndrome: a single institution's experience.

Thrombosis is the most frequent benign etiology of superior vena cava syndrome among cancer patients who have a long-term central venous catheter. In this paper, six cases of thrombotic superior vena cava syndrome are discussed. There were four women and two men. One patient was treated with streptokinase and five with urokinase. The mean age was 46 years (range 22-69), and the mean time for thrombosis development after catheter insertion was 125 days (range: 53-211 days). The mean time for resolution of thrombosis was 7 days (range 2-11) in five patients. One patient had no response to fibrinolysis.

Seventy-two hour epirubicin infusion plus quinidine in unresectable and metastatic adenocarcinoma of the pancreas: a phase II trial.

Twenty-two previously untreated patients who had unresectable and metastatic pancreatic cancer were treated in a prospective phase II trial with high-dose continuous infusion epirubicin (45 mg/m2 once every 24 hours continuous infusion days 4 through 6) plus quinidine (495 mg once every 24 hours on days 1-6). There were no objective responses (0 of 18 evaluable patients). Subjective responses were achieved in 2 of 21 evaluable patients (9%), all of whom had good performance status (Eastern Cooperative Oncology Group: 0-1). Median survival was 5.7 months for the overall population. Two patients who exhibited symptomatic improvement achieved responses lasting 7 and 13 months, respectively. Toxicity was generally mild and tolerable. Little benefit regarding survival and quality of life was observed with the use of this regimen. The role in chemoresistance of mdrl, p53, and the mismatch repair system was examined.

Superior vena cava thrombosis secondary to hickman catheter and complete resolution after fibrinolytic therapy.

We present a case of acute-onset vena cava syndrome produced by thrombosis of the vena cava superior in a patient receiving adjuvant chemotherapy through a Hickman catheter. After angiographic diagnosis fibrinolytic therapy was administered, which brought about complete resolution. We also present a brief review of the literature.

A phase II trial of weekly high dose continuous infusion 5-fluorouracil plus oral leucovorin in patients with advanced colorectal cancer. The Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD).

BACKGROUND: In a previous Phase II trial, the authors showed that a weekly continuous infusion of 5-fluorouracil (5-FU) at a dose of 3.5 g/m2 for 48 hours is an active treatment for advanced colorectal cancer. The overall response rate was 38.5%, and the median survival was 12 months. These data were comparable to those achieved by biochemical modulation of 5-FU with leucovorin. To study the modulation of this weekly, high dose, continuous infusion 5-FU with oral leucovorin, a new Phase II trial was planned. METHODS: From December 1991 to July 1992, 43 previously untreated patients with measurable advanced colorectal cancer were included in a multicenter study. They received on an outpatient basis 5-FU at a weekly dose of 3 g/m2 by continuous infusion for 48 hours until progression or toxicity. Oral leucovorin (60 mg every 6 hours) also was given during the infusion of 5-FU. RESULTS: Patients received a median dose intensity of 5-FU of 2.2 g/m2/week (range, 0.76-3 g/m2/week). One complete response and 11 partial responses were observed. The overall response rate was 29% (95% confidence interval [CI], 16-45%). Median time to progression was 7 months, and the median survival was 15 months. World Health Organization Grades 3 and 4 diarrhea were observed in 19 (45%) and 6 (14%) patients, respectively. Grade 3 mucositis also was observed in 10 (24%) patients, and Grade 4 mucositis was observed in 1. Grade 3 nausea and vomiting were reported in seven (17%) patients. Grade 3 hand-foot syndrome was detected in only two (2.5%) patients. No leukopenia or thrombocytopenia was observed. CONCLUSIONS: Oral leucovorin modulation of a weekly 48-hour infusion of 5-FU at a dose of 3 g/m2 of leucovorin is a toxic regimen, always requiring dose reduction, with diarrhea and mucositis as the main limiting toxicities. Its antitumor activity does not seem superior to that observed with a weekly 48-hour infusion of 5-FU alone at a dose of 3.5 g/m2.

Percutaneous insertion of Hickman catheters while the patient is in bed: a simplification of the technique.

Central-venous long-term catheters are an important tool for patients undergoing anticancer chemotherapy. To circumvent dependence on the surgical department and their waiting lists, catheters were placed while the patient was in bed in the ward of a general oncology unit. A total of 84 single-lumen Hickman catheters were inserted with aseptic technique, percutaneously in this setting. The complication rate after the insertion was low, with only 1 case of pneumothorax (1.2%) and 7.1% of patients suffering arterial puncture. The placement of Hickman catheters while the patient is in bed is a safe procedure that can save hospitalization costs and permits the insertion at the optimum time in the care of the patient.

Use of acute peritoneal dialysis catheters for intraperitoneal chemotherapy instead of the semipermanent/permanent Tenkhoff catheters.

Intraperitoneal chemotherapy was administered to 13 patients with peritoneal carcinomatosis, using acute peritoneal dialysis catheters immediately before the administration of the chemotherapy. A total of 59 cycles were administered, with insertion of the corresponding catheter. There were no inflow or outflow problems and no insertion-related complications. With the removal of the catheter after its use, there is no risk of abdominal infections.

5-Fluorouracil, folinic acid, epidoxorubicin and cisplatin (FLEP) combination chemotherapy in advanced measurable gastric cancer. A phase II trial of the Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD).

BACKGROUND: Metastatic disease is a common problem in gastric cancer and the development of better chemotherapeutic regimens is a clear priority in gastrointestinal oncology. PATIENTS AND METHODS: Ninety consecutive, previously untreated patients with unresectable or measurable metastatic gastric cancer were included in a multicenter phase II trial with a combination of folinic acid (200 mg/m2) and 5-fluorouracil (400 mg/m2) days 1-3, with epidoxorubicin (60 mg/m2) and cisplatin (100 mg/m2) on day 2. RESULTS: A total of 376 courses of FLEP were given, with a median of four courses per patient. Objective responses were observed in 32 (35%) patients (CI at 95%: 25.7%-46.3%). Eight (9%) patients experienced clinical complete remissions. Median time to progression was 25 weeks for the entire group of patients and 38 weeks for responders. Myelosuppression was the primary toxicity. WHO grade 3 leukopenia appeared in 26 patients (29%). Ten presented episodes of febrile neutropenia requiring hospitalization, but no toxic deaths were observed. Grades 3 and 4 thrombocytopenia were seen in 8 and 1 patients, respectively. Median survival time was 8 months for all treated patients and 11 months for responders. CONCLUSIONS: The FLEP regimen is an active combination in advanced gastric cancer with moderate toxicity that warrants further testing in a phase III trial.

Etoposide (E) + epirubicin (E) + cisplatin (P) combination chemotherapy (EEP) in advanced gastric cancer: negative impact on clinical outcome. Spanish Cooperative Group for GI Tumor Therapy (T.T.D.).

One hundred nineteen patients with advanced gastric cancer were included in a study comparing EEP vs. FEM chemotherapy. The response rate was higher (30%) in patients on EEP than in those treated with FEM (p = 0.05). Severe leukopenia, anemia, alopecia and infection were significantly more frequent on EEP. In addition, because of its intrinsic toxicity, EEP chemotherapy has a negative impact on the performance status of patients treated with this regimen, more than half of whom presented at least one episode of severe symptomatic toxicity while on EEP chemotherapy. The median time to progression and median survival for EEP-FEM were 2.08-3.4 and 4.2-7.9 months, respectively. Our data do not support the use of EEP chemotherapy in patients with AGC.