Antonio Brugarolas

Polymorphisms of the Repeated Sequences in the Enhancer Region of the Thymidylate Synthase Gene Promoter May Predict Downstaging After Preoperative Chemoradiation in Rectal Cancer

PURPOSE Thymidylate synthase (TS) is an important target enzyme for the fluoropyrimidines. TS gene promoter possesses regulatory tandemly repeated (TR) sequences that are polymorphic in humans, depending on ethnic factors. These polymorphisms have been reported to influence TS expression. TS expression levels affect tumor downstaging after preoperative fluoruracil (5-FU)-based chemoradiation. Tumor downstaging correlates with improved local control and disease-free survival. The aim of this study is to correlate TR polymorphisms with downstaging and disease-free survival. PATIENTS AND METHODS Sixty-five patients with rectal cancer underwent tumor resection after preoperative 5-FU-based chemoradiation. Tumor downstaging was evaluated by comparing the pretreatment T stage with the pathologic stage observed in the surgical specimen. TS polymorphism genotype was determined by polymerase chain reaction amplification of the corresponding TS promoter region, and products of amplification were electrophoresed, obtaining products of 220 bp (2/2), 248 bp (3/3), or both (2/3). The TS polymorphism genotype results were subsequently compared with the downstaging observed and with disease-free survival. RESULTS Patients who were homozygous for triple TR (3/3) had a lower probability of downstaging than patients who were homozygous with double TR or heterozygous patients (2/2 and 2/3): 22% versus 60% (P =.036; logistic regression). Furthermore, a trend toward improved 3-year disease-free survival was detected in the 2/2 and 2/3 groups, compared with that in the 3/3 group (81% v 41%; P =.17). CONCLUSION This preliminary study suggests that TS repetitive-sequence polymorphisms are predictive for tumor downstaging. TR sequences in TS promoter may be useful as a novel means of predicting response to preoperative 5-FU-based chemoradiation.

Urokinase combination chemotherapy in small cell lung cancer. A phase II study

Background and Methods. Fifty‐one patients with small cell lung cancer (SCLC) were treated with alternating urokinase (UK)‐cyclophosphamide‐doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH)‐vincristine and cisplatin‐etoposide‐vincristine. UK was given as a loading dose of 3000 μg/kg body weight, followed by 3000 μg/kg/h for 6 hours. Thoracic irradiation with split technique (46 Gy) and prophylactic cranial irradiation (25 Gy) were administered to responding patients. A second staging was performed in patients exhibiting a clinical complete response (CR) after 1 year.

Second-line chemotherapy with irinotecan and vinorelbine in stage IIIB and IV non-small-cell lung cancer: a phase II study.

The purpose of this study was to evaluate the efficacy and tolerance of combined irinotecan and vinorelbine in previously treated patients with stage IIIB and IV non–small-cell lung cancer (NSCLC). Thirty-three patients with NSCLC (7 stage IIIB and 26 stage IV) were enrolled. All had been previously treated with cisplatin, paclitaxel, and gemcitabine as first-line chemotherapy. In addition, 24 patients had received radiotherapy. Irinotecan (300 mg/m2) was administered on day 1 and vinorelbine (30 mg/m2) on days 1 and 14, every 4 weeks. Partial response was achieved in 3 patients (9%; 95% CI: 2–24%), stable disease (SD) in 13 (39%; 95% CI: 23–58%), whereas 17 patients progressed (51%; 95% CI: 33–69%). Median event-free survival was 10 weeks and median overall survival was 25 weeks. Three patients were event free at the end of the study with a follow-up of 40, 73, and 75 weeks. Toxicity was mild, with leukopenia grade III–IV in 8.6% of cycles. No episodes of diarrhea III-IV were observed. Three patients died early after administration of this combination, one of them in the context of severe leukopenia and thrombocytopenia. Approximately 50% of patients treated with CPT-11 and vinorelbine in combination show partial response or stable disease with minimal toxicity.

Paclitaxel, cisplatin, and gemcitabine combination chemotherapy within a multidisciplinary therapeutic approach in metastatic nonsmall cell lung carcinoma.

Cisplatin‐based chemotherapy combinations improve quality of life and survival in advanced nonsmall cell lung carcinoma (NSCLC). The emergence of new active drugs might translate into more effective regimens for the treatment of this disease.

Cisplatin, mitomycin, and vindesine followed by intraoperative and postoperative radiotherapy for stage III non-small cell lung cancer: final results of a phase II study.

Sixty-two patients with stage III non-small cell lung cancer (NSCLC) were treated with neoadjuvant chemotherapy consisting of cisplatin 120 mg/m2 day 1, mitomycin 8 mg/m2 day 1, and vindesine 3 mg/m2 days 1 and 14. Each cycle was repeated every 4 weeks for a total of 1 to 6 cycles (median, 3 cycles). Resection was attempted 4 to 5 weeks after the last course of chemotherapy. Intraoperative radiation therapy (IORT) (10-15 Gy) was delivered during surgery and postoperative external beam radiotherapy (EBRT) (46 Gy) was begun 4 weeks after surgery. Fifty-five patients (25 IIIA, 30 IIIB) were evaluable. Only partial responses occurred (64%), and 29 patients (53%) underwent resection. Complete resection rates were 85% (12/14) and 40% (6/15) in stage IIIA and IIIB, respectively (p = 0.01). In 3 of 29 patients (10%), no tumor was found in the resected specimen. There was one chemotherapy-related death and three postoperative-related deaths. The median survival time was 10 months, and the 5-year survival rate was 29 and 7% for stage IIIA and stage IIIB, respectively (p = 0.3). High complete resection rates and modest increase in 5-year survival have been observed in stage IIIA NSCLC. Although a number of stage IIIB patients can be made technically resectable, the low complete resectability rate reflects the lack of survival benefit in these patients.

Fixed higher dose schedule of suramin plus hydrocortisone in patients with hormone refractory prostate carcinoma

Using a fixed higher‐dose schedule, the efficacy and toxicity of suramin plus hydrocortisone were assessed in patients with metastatic hormone‐refractory prostate carcinoma (HRPC).

Photodynamic therapy (PDT) in the multidisciplinary treatment of brain tumors: A feasibility study.

2094 Background: Usual treatment of brain tumors includes surgery, radiotherapy and chemotherapy, but the general prognosis is bad, with local relapse as the main cause of death. PDT is a local anticancer treatment that has showed promising results in other tumors (GI, H&N, etc) and can be administered in addition to the classical modalities. METHODS Patients (pts) diagnosed of primary, relapsed or metastatic (mets) brain tumors received an endovenous photosensitizer agent (Photofrin or Foscan). After a 2-4 days period, the tumor was removed. The residual cavity was exposed to a special laser during a predetermined time, in order to achieve the optimal activation of the photosensitizer that, once activated, kills the residual tumor cells. Complementary treatment with radio and chemotherapy was also administered after surgical recovery. RESULTS From December 2000 to January 2011, 51 pts (34 M/ 17 F; age 13-73, median 51) were treated with a total of 61 procedures (22 Photofrin, 39 Foscan). Diagnoses were glioblastoma (20), gliosarcoma (1), anaplastic astrocitoma (9), grade 2 astrocitoma (7), oligodendroglioma (6, 2 anaplastic), malignant meningioma (1), lung ca. mets (4), breast ca. mets (3). 18/44 primary CNS tumor pts had PDT at the initial resection procedure and 32 procedures were performed at the time of relapse. In 10 cases a second procedure was performed after relapse. TOXICITY 2 pts with thalamic gliomas died in the first 24 h; 6 pts presented postoperative neurological alterations, recovering in 3 to 17 days, and 4 pts presented cutaneous ulcerations related to the PDT, one of them requiring plastic surgery. Median OS of the treated primary brain tumors was 13 m (0-120+) and 8 pts are alive at 1+, 71+, 92+, 93+, 96+, 98+, 104+, and 120+ m (1 GBM, 1 AA, 3 grade 2 A, 3 OD). CONCLUSIONS PDT can be safely used in the multidisciplinary treatment of brain tumors. In this group of heavily treated pts, it clearly benefits some of them, showing an improvement in OS over expected from historical data. Further studies are warranted.

Factors determining the actual received dose intensity in a program of multicyclic dose-intensive alternating chemotherapy with sequential stem cell support.

Dose intensity has been related to clinical outcome in several solid tumors. We studied the influence of clinical and cellular parameters on dose intensity received in a series of 53 patients with metastatic breast cancer or advanced ovarian cancer. They received courses of cisplatin 120 mg/m2 plus etoposide 600 mg/m2 alternating every 14 days with ifosfamide 8 g/m2 plus paclitaxel 200–350 mg/m2. Blood stem cell support was administered after every course except for the first one. Patients with excellent mobilization underwent immunomagnetic selection of CD34+ cells. We found a significant inverse correlation between the CD34+ cell dose infused and the delay for the administration of the next cycle. A CD34+ cell dose between 1.5 and 5 × 106/kg per cycle was found to be feasible and was followed by a median delay of 1day (not different from doses above 5 × 106/kg). Three factors independently predicted the actually received dose intensity in a multiple regression model (R2 = 0.4): previous autologous transplantation, eligibility for immunomagnetic selection (excellent response to mobilization) and median CD34+ cell dose received along the treatment.

Carcinoma de nasofaringe localmente avanzado: resultados finales del tratamiento de quimiorradioterapia seguido de quimioterapia complementaria

Resultados finales de tolerancia, control local y supervivencia de un estudio fase II con quimioterapia y radioterapia radical en el tratamiento del carcinoma nasofaríngeo localmente avanzado. Entre septiembre de 1986 y mayo de 1996 fueron tratados 45 pacientes. El tratamiento consistió en lomustina y ciclofosfamida simultánea con radioterapia sobre cavum y áreas ganglionares locorregionales (60-70 Gy) y posteriormente cada 4 semanas durante 1 año.Cuarenta y tres pacientes (95%) finalizaron radioterapia. La mediana de ciclos por paciente fue 7. Se obtuvieron 29 respuestas completas (64%), 7 parciales (16%) y 4 progresiones (9%). Desarrollaron leucopenia grado III-IV 26 pacientes (57%) y xerostomía crónica 30 pacientes (67%). El fallo fue: locorregional, 12 pacientes (30%); mixto, 2 (5%), y a distancia, 7 (17%). Con una mediana de seguimiento de 102 meses, la supervivencia actuarial a 5 y 10 años fue del 39% y 23%, respectivamente, y la supervivencia actuarial libre de eventos a 5 y 10 años fue del 39% y 22%, respectivamente. Al cierre del estudio, 14 pacientes (31%) viven sin enfermedad.Nuestros resultados reproducen los publicados en la literatura. La incidencia de recidivas locales y complicaciones tardías empleando técnicas convencionales es elevada. Se necesitan protocolos que disminuyan la morbilidad y mejoren la tasa de curación actual.AbstractThe final results of tolerance, local control and survival from a phase II study in patients with locoregio nally advanced carcinoma who received concurrent chemo-radiotherapy followed by adjuvant chemotherapy are shown.Between September 1986 and May 1996, 45 patients were enrolled in a trial of cyclophosphamide and lomustine concurrent with radiotherapy over the primary lesion and cervical-supraclavicular areas (60-70 Gy), followed by the same chemotherapy every four weeks during one year.Forty three patients (95%) completed the radiotherapy. The median number of chemotherapy cycles was 7. There were 29 (64%) complete responses, 7 (16%) partial responses and 3 (9%) progressions. Twentysix (57%) patients had grade III-IV leucopenia and 30 patients (67%) developed permanent xerostomia. Patterns of first failure were as follows: locoregional in 12 patients (30%), distant relapse in 7 patients (17%) and both locoregional and distant failure in 2 patients (5%). The median of follow-up was 102 months. The survival at 5 and 10 year was 39% and 23% respectively and the event-free-survival at 5 and 10 year was 39% and 22% respectively. At the end of the study, 14 patients (31%) are alive.Our results are acceptable, but the local relapses and the incidences of long-term complications using conventional techniques are important. Improved radiotherapeutic techniques coupled with effective systemic therapy should further improve the prognosis of patients with nasopharyngeal carcinoma and decrease the acute and long-term morbidity.