Juan José López

Randomized trial of neoadjuvant cisplatin and fluorouracil versus carboplatin and fluorouracil in patients with stage IV-M0 head and neck cancer.

PURPOSE A randomized trial was designed to compare cisplatin (CDDP) and fluorouracil (FU) versus carboplatin (CBDCA) and FU as neoadjuvant treatment in stage IV-M0 head and neck cancer to assess whether CBDCA-FU is better than CDDP-FU with regard to response and toxicity. PATIENTS AND METHODS Patients were randomized to receive CDDP 100 mg/m2 intravenously on day 1 and FU 5,000 mg/m2 over a 120-hour continuous infusion, or CBDCA 400 mg/m2 over a 24-hour continuous infusion on day 1 and FU with the same schedule. Both regimens were repeated every 21 days. The patients received three courses of chemotherapy, excluding those who failed to achieve a partial response (PR) after the second course. Complete responders were treated with radiotherapy. The remaining patients underwent surgery if the tumor was resectable. RESULTS Interim analysis was performed when 95 patients were included. The trial was stopped due to significantly better results in the control arm. Differences in response (P = .04) were favorable to CDDP-FU. Hematologic toxicity predominated in the CBDCA-FU arm (P < .001). Mucositis and vomiting predominated in the CDDP-FU arm (P = .03, P < .001, respectively). Favorable outcomes (complete response [CR] plus any grade of toxicity and PR plus grade 0 to 3 toxicity) predominated in the CDDP-FU arm (P = .02). Only the treatment assigned was associated with response (P = .02) and favorable outcomes (P = .009) in the logistic regression analysis. In the CDDP-FU arm, disease-free and overall survival were significantly better. Cox regression analysis showed that only treatment association with disease-free survival remains significant. CONCLUSION Our results indicate that CDDP-FU is more effective than CBDCA-FU as neoadjuvant treatment in stage IV-M0 head and neck cancer.

A phase III randomized trial of cyclophosphamide, mitoxantrone, and 5-fluorouracil (CNF) versus cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) in patients with metastatic breast cancer

SummaryOne hundred patients with metastatic breast cancer were randomly selected to receive combined chemotherapy treatment with adriamycin (50 mg/m2) or mitoxantrone (12 mg/m2) associated with 5-fluorouracil (600 mg/m2) and cyclophosphamide (600 mg/m2) administered intravenously every 21 days with a maximum of ten cycles. All patients included in this study were under 75 years of age and had ECOG performance status of less than 4. They had not been treated previously with chemotherapy for metastatic disease. Patients treated with adjuvant chemotherapy, which could not have included anthracyclines, had to have relapsed at least 12 months after the completion of therapy. There were no statistically significant differences in pretreatment characteristics or metastatic disease location between the two groups. Ninety-four patients were assessable for response. No differences were observed in response rate or in survival between the groups. The response rate (complete response (CR) and partial response (PR)) was 68% (13% CR and 55% PR for CAF; 0% CR and 68% PR for CNF). Median survival for all patients was 19 months (18 months with CAF and 19 months with CNF). All patients were assessable for toxicity. There were no differences in gastrointestinal and cardiac toxicity. More grade I-II hematologic toxicity episodes (p < 0.001) and treatment delays (p = 0.05) due to leucopenia were observed with the CNF group, and more grade III alopecia (p < 0.001) was observed with the CAF group. Patients received further therapeutic manoeuvres after finishing the study with a sequential treatment consisting of hormonal therapy and chemotherapy with mitomycin (M) -vinblastine (Vbl) (M 10 mg/m2 day 1, Vbl 5 mg/m2 days 1, 15 and 29; maximum 5 cycles). This chemotherapy treatment was received by 32 patients, with a response rate of 34% and grade III-IV hematologic toxicity of 37%. Treatment with CNF can be considered a good alternative to CAF for first-line treatment of metastatic breast cancer. M-Vbl treatment is useful as second-line treatment in patients with prior adriamycin exposure.

Follow-up of breast cancer stages I and II. An analysis of some common methods

A retrospective analysis of the follow-up methodology was done in 343 cases of breast cancer Stages I and II, in order to ascertain the effectiveness of the explorations performed and the usefulness of the follow-up program. The actuarial probability of relapse at 6 years was 35% for the 237 patients with negative axillary nodes and 46% for the 106 patients with nodal involvement. Fifty-eight per cent of the relapses were detected by the patients themselves, 24% of relapses were found by physical examination and 9% of relapses were discovered in chest radiographs, leading to 91% of relapses diagnosed by combination of these explorations. The authors conclude that follow-up methodology for these patients could be limited to the above-mentioned methods, without significant reduction of curability or survival possibilities after relapse.

Progression of liver fibrosis in HIV/hepatitis C virus‐coinfected individuals on antiretroviral therapy with early stages of liver fibrosis at baseline

The aim of the study was to assess the progression of liver fibrosis in HIV/hepatitis C virus (HCV)‐coinfected patients with no or mild‐to‐moderate fibrosis (stages F0−F2).

CHOP chemotherapy of intermediate and high-grade non-Hodgkin's lymphoma.

The results of CHOP treatment in 63 patients with intermediate and high-grade non-Hodgkins lymphoma (Working Formulation D to I), Ann Arbor stage I to IV were analyzed. The response rate was 87%, 71% complete remission and 16% partial remission with a mean duration of 22 months. The 5-year actuarial survival was 61% (95% confidence interval, 51-70%). The treatment was well tolerated and no deaths due to acute toxicity were observed. Poor prognostic factors in univariate analysis were: high-grade histology, stages III and IV, B symptoms, > or = 4 affected lymph node regions, Karnofsky index < or = 70, erythrocyte sedimentation rate (ESR) > 60 mm, haemoglobin < 100 g/l and elevated lactic dehydrogenase (LDH). Poor prognostic factors in multivariate analysis were: high-grade histology, stages III and IV, haemoglobin < 100 g/l and elevated LDH. In summary, good results were obtained with CHOP chemotherapy, without severe toxicity.

A phase II trial of carboplatin in untreated patients with extensive stage small cell lung cancer

Twenty‐five untreated patients with extensive stage small cell lung cancer (ESSCLC) were treated with carboplatin (CBDCA) (500 mg/m2) given as a 24‐hour infusion every 21 days. Thirteen patients responded for an overall response rate of 52% (95% confidence limits, 32% to 72%) with 3 complete responses (CR) (12%; 95% confidence limits, 0% to 25%). The median duration of response was 4.5 months. The median survival time was 8 months with three long‐term survivors (12%) at 27, 33, and 43 months from the start of CBDCA treatment. Ninety‐two courses of CBDCA were administered and one treatment‐related death occurred. The main toxicity was myelosuppression. Grade 3 or 4 hematologic toxicity (hemoglobin level, < 8 g/dl; granulocyte count, < 1900/μl; and platelet count, < 49,000/μl) was observed as follows: neutropenia in 7 courses (8%) and in 7 patients (28%), decreased hemoglobin level in 13 courses (15%) and in 7 patients (28%), and decreased platelet count in 10 courses (11%) all Grade 3 and in 8 patients (32%). This study demonstrates that at this dose and schedule CBDCA is a highly active drug in ESSCLC and it has tolerable toxicity.

Descripción de una nueva mutación germinal en el gen TP53 en una familia con síndrome de Li-Fraumeni. Asesoramiento clínico a los portadores sanos

Fundamento El sindrome de Li-Fraumeni (SLF) es un trastorno familiar autosomico dominantecon predisposicion a la aparicion de sarcomas de partes blandas, osteosarcomas, cancer demama en mujeres premenopausicas, leucemia aguda, tumores adrenocorticales y del sistemanervioso central. En mas de la mitad de las familias afectadas se identifican mutaciones en lineagerminal en el gen TP 53. Pacientes y metodo Se realizo el analisis de mutaciones del gen TP 53 en linea germinal en 8familias con agregacion de sarcomas infantiles, tumores cerebrales, neoplasia de mama en mujerespremenopausicas y tumores renales. El estudio genetico se realizo mediante la tecnicaSSCP y secuenciacion posterior. Resultados Siete familias reunian los criterios del sindrome de Li-Fraumeni like y una los criteriosclinicos clasicos. Se identifico la mutacion C238S en el exon 7 del gen TP 53 en linea germinalen la familia con criterios clasicos. Dicha mutacion no ha sido descrita previamente. Conclusiones La heterogeneidad clinica, la complejidad molecular y las implicaciones del asesoramientogenetico de las familias con este sindrome hacen necesaria la elaboracion de protocolosy su posterior evaluacion. Deberia plantearse un enfoque multidisciplinario coordinadodesde unidades de consejo genetico en cancer familiar.

Optimal Use of Transient Elastography and Acoustic Radiation Force Impulse to Stage Liver Fibrosis in HIV/HCV‐Coinfected Patients in Clinical Practice

Liver fibrosis (LF) is crucial for the individualized management of patients with hepatitis C virus (HCV). We evaluated the concordance between two noninvasive methods for staging LF, transient elastography (TE) and acoustic radiation force impulse (ARFI), in patients coinfected with human immunodeficiency virus and HCV. We propose an algorithm for optimal use of both techniques in routine clinical practice.

Supervivencia a largo plazo con quimioterapia a altas dosis de rescate en pacientes con cáncer de células germinales metastásico. Análisis de los patrones de recidiva

ResumenObjectivoAnalizar los patrones de recidiva y supervivencia de 13 pacientes con tumores de células germinales (TCG) con refractariedad parcial a cisplatino o en segunda recidiva que recibieron quimioterapia a dosis altas (QDA) y soporte con células progenitoras hematopoyéticas periféricas.Material y métodosLa mediana de ciclos de quimioterapia (QT) convencional con cisplatino previa era de 9 (3–13). Tratamiento: a) inducción: QT tipo EPI (VP16 120 mg/m2, ifosfamida 1,3 g/m2, cisplatino 25 mg/m2×4 días); b) movilización de células progenitoras con factor estimulante de colonias de granulocitos (G-CSF) (10 ug/kg/día) en 2 pacientes o EPI+G-CSF, y c) QDA (carboplatino 350 mg/m2, ciclofosfamida 1.500 mg/m2, VP16 4.00 mg/m2×3 días). Se administró G-CSF (5 μg/kg) hasta el injerto hematopoyético (neutrófilos > 1×109/l). Edad media: 32 años (rango 20–52). Origen: mediastino 2, testicular 11 (1 seminoma). Criterio de inclusión: no respuesta completa (RC) con QT convencional en 5 pacientes, tumor mediastínico en 1, primera recidiva tras QT con cisplatino e ifosfamida en 2 casos y segunda y tercera recidivas en 5 pacientes. Nueve de trece pacientes estaban en RC al inicio de la QDA. Un paciente que se incluyó en el análisis de supervivencia no continuó a QDA por progresión precoz cerebral.ResultadosLa mediana de supervivencia libre de progresión fue de 19 m, global 40 m; 2 pacientes están libres de progresión a 36 y 80 m. Todos los pacientes transplantados en respuesta parcial (RP) progresaron en el primer año. Cinco de once pacientes en áreas afectas como única localización. Rescate: consistió de VP16 oral, EMA-CO o CBDCA/taxol, y proporcionó 6 de 10 respuestas, una de ellas mantenida a 4 años.ConclusionesLa QDA como rescate de pacientes no curables con QT convencional y no quirúrgicos proporcionó 20% de largos supervivientes. No observamos beneficio en el tratamiento con QDA cuando sólo se obtuvo RP con el tratamiento convencional. La mayoría de las recidivas tuvieron lugar en áreas previamente afectas y en la mayoría de los pacientes fueron aún quimiosensibles.AbstractObjectiveTo evaluate survival and relapse patterns in 13 patients with recurrent, or refractory, germ-cell tumours treated with high-dose chemotherapy (HDC) and with peripheral blood stem-cell support.Material and methodsAll patients were treated in a single centre and received a median of 9 cycles (range 3–13) of cisplatinum-based chemotherapy (CT). The protocol consisted of: a) induction with ifosfamide-based CT (EPI: VP16 120 mg/m2, ifosfamide 1.3 g/m2, cisplatinum 25 mg/m2×4 days); b) mobilisation of PBSC with of either G-CSF (10 ug/kg/day) in 2 patients or EPI plus G-CSF, and c) HDC (carboplatin 350 mg/m2, cyclophosphamide 1500 mg/m2, VP16 400 mg/m2×3 days). G-CSF (5 μg/kg) was administered until haematopoietic graft. Median age=32 years (range 20–52); tumours=10/11 testicular (1 seminoma), 2 mediastinal. HDC was administered 21 months (range 6–66) post-diagnosis. Inclusion criteria: failure to achieve CR with conventional CT (n=5 patients), poor-prognosis mediastinal tumour (n=1), first recurrence after cisplatinum and ifosfamide-based CT (n=2) and second or third relapse (n=5). At the conclusion of HDC, 9/13 patients were in CR, 1 patient did not receive HDC because CNS progression but was included for survival analysis.ResultsMedian times to graft were 9 and 13 days for leukocytes and platelets, respectively. Non-haematological toxicity was low and no therapy-related deaths occurred. Median disease free and overall survival were 19 and 30 months, respectively. Currently, 2 patients have not relapsed at 36 and 80 months. Previously-affected sites of disease were the unique sites of relapse in 5/11 (50%), concomitant distant relapse in 4/11 patients, CNS metastases in 1 patient. Rescue CT consisted of either oral VP16 or CBDCA/Taxol, which induced a new response in 6/10 patients.ConclusionsHDC achieves 20% improved survival in patients refractory to conventional chemotherapy and non-resectable tumours. No benefit was observed in HDC treatment in patients having only partial response to conventional chemotherapy. Relapse following HDC occurred mainly at previously affected sites.

Características clinicopatológicas y evolución clínica de pacientes con cáncer de mama y mutaciones en los genes BRCA1 o BRCA2

BACKGROUND: Clinico-pathological differences between BRCA1 or BRCA2 mutation-associated breast cancer (BC) and sporadic BC are little known. PATIENT AND METHODS: We analysed the clinico-pathological characteristics and clinical follow-up of 30 patients with BC. BRCA1 and BRCA2 mutations were detected by SSCP and PTT. RESULTS: There were no differences in age, size or nodal status at the time of diagnosis. Mammography features were more heterogeneous in BRCA2 than in BRCA1 BC. All BRCA1 mutation-associated BC corresponded to infiltrating ductal carcinomas (20% medullary carcinomas) with a more aggressive pathological behavior. The frequency of local recurrences was 14% in BRCA1 and 20% in BRCA2. Contralateral BC and ovarian cancer (OC) were observed in 27% and 20% of BRCA1 cases, respectively, and 6% and 6% of BRCA2 cases. The median follow-up in BRCA1 and BRCA2 BC was 131 and 54 months, respectively. CONCLUSIONS: There were no differences in age at diagnosis and stage between BRCA1 and BRCA2 breast cancer. The mammographic pattern in BRCA2 was more heterogeneous. BRCA1 mutations were associated with more aggressive histopathologic findings and a higher risk of a second BC and OC.