Biweekly regimen of cisplatin, gemcitabine and vinorelbine for advanced non-small-cell lung cancer.

PURPOSE: Improving chemotherapeutic efficacy in non-small cell lung cancer (NSCLC) will require the development of new strategies to better use currently available agents. To assess the efficacy and safety of a biweekly regimen of cisplatin, gemcitabine and vinorelbine for advanced non-small-cell lung cancer. METHODS: Patients with selected stage IIIb (pleural effusion)/stage IV NSCLC, performance status of 0-2 and normal organ function were eligible. Treatment consisted of cisplatin 100 mg/m(2) on day 1 plus gemcitabine, 1,000 mg/m(2) and vinorelbine 25 mg/m(2) on days 1 and 15 every 28 days. RESULTS: Of the 40 patients enrolled and assessable for response, there were five (12.5%) with confirmed complete response and 14 (35%) with a confirmed partial response for an overall response rate of 47.5%. Nine patients had stable disease while 12 (30%) progressed. Median progression-free survival and overall survival for all patients were 6.3 and 11.1 months, respectively. Toxicity was principally hematologic, with grade 3-4 neutropenia in 30%, and grade 3-4 nausea/vomiting in 22.5%. There were no treatment-related deaths. CONCLUSIONS: The biweekly regimen of cisplatin, gemcitabine and vinorelbine is associated with a high rate of response, lesser toxicity than other three-drug regimens and no benefit of survival. Therefore, the regimen under study may be an appealing alternative when considering other treatment modalities for advanced lung cancer, such as neoadjuvant therapy.

Evaluation of the antitumor activity of interleukin-12 in an experimental murine model of colorectal cancer induced by 1,2 dimethyl-hydrazine (DMH).

OBJECTIVE: Interleukin 12 (IL-12) is a cytokine that may enhance the proliferation and cytotoxic activity of T lymphocytes and natural killer (NK) cells. A relationship between extensive intratumoral infiltration of NK cells and longer survival rates in colorectal cancer (CRC) patients was previously noted. Preliminary evidence suggests that the combined administration of IL-12 and IL-2 may produce additive immunomodulatory activity. The purpose of this study was to determine whether the systemic administration of IL-12 (+/- IL-2) may induce an immune response against CRC as induced by 1,2-dimethylhydrazine (DMH). METHODS: Sixty-five 6-week-old Wistar rats were treated with weekly subcutaneous injections of DMH for 26 weeks at a dose of 20 mg/kg of body weight. Once tumoral induction was over, the animals were randomly allocated to one of three groups: I, control; II, intraperitoneal injections of IL-12; III, intraperitoneal injections of IL-12 combined with IL-2. At 30 weeks, all surviving animals were sacrificed. We studied the following parameters in each rat--number of tumors, size of tumors, and total tumoral volume. Tumor samples were studied using the monoclonal antibody CD 57 for the detection of NK cells. The extent of NK infiltration was classified as small, less than 50 NK cells/50 high-power field (HPF); moderate, 50 to 150 NK cells/50 HPF, and extensive, more than 150 NK cells/50 HPF. RESULTS: Thirty-five rats died before completion of the carcinogen exposure, and 30 rats were randomized (10 each group). In group II, 2 animals died during treatment. All rats in groups I and III developed tumors, while in group II two rats (25%) were tumor-free. Moreover, only one rat in group II developed multiple neoplasms, in contrast with group I and group III, where six rats (60%) and seven rats (70%), respectively, had more than one tumor. We found statistically significant differences in the mean number of tumors found in group II when compared to group I (p = 0.028) and group III (p = 0.019). Other parameters measured, such as biggest tumor size and total tumoral volume were found to be lower in group II, although no statistical differences were found between groups. Only 10% of rats in group I showed moderated/extensive NK cell infiltration, vs. 60% of rats in group II (p = 0.077) and 70% in group III (p = 0.02). CONCLUSION: The administration of DMH to rodents provides a reliable and consistent means of inducing CRC that may be suitable for the evaluation of anti-cancer therapies. Our findings suggest that IL-12 is effective against the development of experimental CRC. Its antineoplastic effect could be attributed to the stimulus of this cytokine on the intratumoral infiltration of NK cells.

Estudio de la respuesta antitumoral de la interleucina- 12 en cáncer de colon inducido mediante 1, 2-dimetilhidracina (DMH) / Evaluation of the antitumor activity of interleukin-12 in an experimental murine model of colorectal cancer induced by 1, 2 dimethyl-hydrazine (DMH)

Objetivo: la interleucina (IL-12) es una citocina que estimulala proliferación y la actividad citotóxica de los linfocito T y las célulasnatural killer (NK). En trabajos previos se ha observado unarelación entre la infiltración intratumoral de células NK y una mayorsupervivencia en carcinomas colorrectales (CCR). Existen evidenciasde un efecto aditivo en la actividad inmunomoduladora dela asociación de IL-12 con IL-2. Así, nos hemos propuesto el estudiode la capacidad de respuesta inmune antitumoral, tras la administraciónsistémica de IL-12 sola o combinada con IL-2, en unmodelo experimental de CCR inducidos mediante la administraciónde 1,2-dimetilhidracina (DMH).Método: sesenta y cinco ratas Wistar de 6 semanas a las quese administró en inyección subcutánea una dosis semanal deDMH a razón de 20 mg/kg de peso durante 26 semanas. Finalizadoel periodo de inducción, los animales se distribuyeron aleatoriamenteen tres grupos. I: grupo control. Grupo II, se administróIL-12 recombinante murina. Grupo III: se administró IL-12, combinadacon IL-2. Las ratas se sacrificaron en la semana 30, estudiándoselos siguientes parámetros: número y localización de tumores,tamaño y carga tumoral. Se realizó inmunotinción paracélulas NK con anticuerpo monoclonal CD 57. Se establecierontres grupos según la cuantía del infiltrado: leve, menos 50 células/50 campos de gran aumento (CGA), moderado, entre 50 y150/células/50 CGA y elevado, más de 150 células/50 CGA.Resultados: durante la inducción tumoral fallecieron 35 ratas.Las 30 restantes fueron distribuidas aleatoriamente en 3 gruposde 10. Durante las 2 semanas de tratamiento fallecieron 2 ratas,del grupo II. Todas las ratas de los grupos I y III desarrollaronCCR. En el grupo II, dos animales (25%) no desarrollaron tumor.Sólo una rata del grupo II desarrolló neoplasias múltiples en contrastecon el grupo I en el que esto ocurrió en 6 ratas (60%) y siete(70%) en el grupo III. Se hallaron diferencias estadísticamentesignificativas en el número de tumores desarrollados entre el grupoII respecto al I (p = 0,028) y al grupo III (p = 0,019). El mayortamaño tumoral o el volumen tumoral total fueron menores en elgrupo II pero no se obtuvieron diferencias estadísticamente significativascon los restantes grupos. Un 10% de las ratas del grupo Ipresentó moderada o extensa infiltración, frente al 60% del grupoII (p = 0,077) y al 70% del grupo III (p = 0,02). Entre los grupos IIy III no se encontró ninguna diferencia estadística (p = 1).Conclusión: El modelo usado de inducción tumoral es un modeloútil para el estudio de la eficacia de distintos tratamientos antitumorales.Pensamos que la IL-12 tiene un efecto antineoplásicofrente al desarrollo de tumores experimentales, lo que puede seratribuido, al menos en parte, al estímulo ejercido por esta citocinasobre los infiltrados intratumorales de células NK

Objective: interlukin 12 (IL-12) is a cytokine that may enhancethe proliferation and cytotoxic activity of T lymphocytesand natural killer (NK) cells. A relationship between extensive intratumoralinfiltration of NK cells and longer survival rates in colorectalcancer (CRC) patients was previously noted. Preliminaryevidence suggests that the combined administration of IL-12 andIL-2 may produce additive immunomodulatory activity. The purposeof this study was to determine whether the systemic administrationof IL-12 (+/- IL-2) may induce an immune responseagainst CRC as induced by 1,2-dimethylhydrazine (DMH).Methods: sixty-five 6-week-old Wistar rats were treated withweekly subcutaneous injections of DMH for 26 weeks at a dose of20 mg/kg of body weight. Once tumoral induction was over, theanimals were randomly allocated to one of three groups: I, control;II, intraperitoneal injections of IL-12; III, intraperitoneal injectionsof IL-12 combined with IL-2. At 30 weeks, all surviving animalswere sacrificed. We studied the following parameters in eachrat – number of tumors, size of tumors, and total tumoral volume.Tumor samples were studied using the monoclonal antibodyCD 57 for the detection of NK cells. The extent of NK infiltrationwas classified as small, less than 50 NK cells/50 high-power field(HPF); moderate, 50 to 150 NK cells/50 HPF, and extensive,more than 150 NK cells/50 HPF.Results: thirty-five rats died before completion of the carcinogenexposure, and 30 rats were randomized (10 each group). Ingroup II, 2 animals died during treatment. All rats in groups I andIII developed tumors, while in group II two rats (25%) were tumorfree.Moreover, only one rat in group II developed multiple neoplasms,in contrast with group I and group III, where six rats(60%) and seven rats (70%), respectively, had more than one tumor.We found statistically significant differences in the meannumber of tumors found in group II when compared to group I(p=0.028) and group III (p = 0.019). Other parameters measured,such as biggest tumor size and total tumoral volume were found tobe lower in group II, although no statistical differences were foundbetween groups. Only 10% of rats in group I showed moderated/extensive NK cell infiltration, vs. 60% of rats in group II (p =0.077) and 70% in group III (p = 0.02).Conclusion: The administration of DMH to rodents provides areliable and consistent means of inducing CRC that may be suitablefor the evaluation of anti-cancer therapies. Our findings suggest thatIL-12 is effective against the development of experimental CRC. Itsantineoplastic effect could be attributed to the stimulus of this cytokineon the intratumoral infiltration of NK cells

Prognostic significance of the allelic loss of the BRCA1 gene in colorectal cancer.

BACKGROUND: Survival at the intermediate stage of colorectal cancer (CRC) is less predictable than in the early and advanced stages. Several genetic markers possibly involved in growth and progression of CRC can be used for prognosis. AIMS: This study investigated the proportion of allelic loss (loss of heterozygosity (LOH)) at the BRCA1 locus in sporadic CRC and its value in patient prognosis. PATIENTS AND METHODS: A total of 314 patients were investigated for LOH at the BRCA1 locus using polymerase chain reaction by means of three intragenic polymorphic microsatellite markers. Allelic losses were compared with clinicopathological characteristics of patients, recurrence rate, disease free survival (DFS), and overall survival. RESULTS: Twenty six patients were excluded because of microsatellite instability. Of the remaining 288 cases, 244 (84.7%) were informative, with 97 (39.8%) patients bearing BRCA1 LOH. Recurrence rate was higher in patients with LOH (p=0.0003), and DFS was 73.3% (SEM 5.7) at five years in patients without LOH, and 49.2% (7.1) in cases with positive allelic loss (p=0.0004). Retention of alleles at the BRCA1 locus was associated with a favourable DFS in stages I and II (p<0.05). The presence of LOH was also significantly associated with short overall survival (p=0.02). Multivariate analysis in the complete series showed that stage (p=0.006) and lymph node metastases (> or =4 nodes, p=0.0001; 1-3 nodes, p=0.038) were independent prognostic factors. However, multivariate study by stages revealed that BRCA1 LOH was an independent prognostic factor in stages I and II (p=0.001). CONCLUSIONS: BRCA1 LOH is a molecular alteration present in CRC, with unfavourable repercussions for overall survival, that could be considered as an outstanding independent prognostic factor in stages I and II.

The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma.

BACKGROUND: Natural killer (NK) cells have a spontaneous cytotoxic capacity-against tumor cells. These cells represent a small proportion of human colon carcinoma-infiltrating lymphocytes. Their prognostic significance in these tumors has yet to be determined. METHODS: One hundred and fifty-seven patients who each had a colectomy for large bowel adenocarcinoma were studied. No patient received adjuvant therapy. Immunohistochemical stains were performed for NK cells using the monoclonal antibody CD57. The number of NK cells was counted using a MICRON image analyzer. The total area studied for each tumor was 1 cm2. In this area, 50 intratumoral fields of 0.173 mm2 were selected. The degree of NK infiltration was classified as little (< 50 NK cells), moderate (50-150 NK cells), and extensive (> 150 NK cells). The Kaplan-Meier method was used to obtain survival figures. Multivariate analyses were performed using the Cox regression model. RESULTS: At 5 years, patients with little and moderate NK infiltration showed significantly shorter survival rates (overall and disease free survival) than those with extensive infiltration (P < 0.01). Three significant factors affecting survival were selected in a stepwise fashion in increasing order as follows: TNM stage, NK infiltration, and lymphocytic infiltration. Patients with TNM Stage III disease and extensive NK infiltration showed significantly longer survival rates than those with little or moderate infiltration (P < 0.001). In these patients, multivariate analysis using the Cox regression model identified two significant variables: number of involved lymph nodes and NK cells infiltration. CONCLUSIONS: In patients with colorectal carcinoma, an extensive intratumoral infiltration of NK cells is associated with a favorable tumor outcome. Intratumoral infiltration of NK cells can be used as a variable with prognostic value, especially in patients with TNM Stage III disease.

Uracil and tegafur modulated with leucovorin: an effective regimen with low toxicity for the treatment of colorectal carcinoma in the elderly. Oncopaz Cooperative Group.

BACKGROUND: In spite of the high prevalence of cancer in the elderly, little information is available about the efficacy and toxicity of chemotherapy in elderly patients. In a previous study, the authors demonstrated that the combination of uracil and tegafur (UFT) with leucovorin (LV) was active and well tolerated in patients with advanced colorectal carcinoma (ACC). The objective of the current study was to determine the efficacy and toxicity of this regimen in elderly patients with ACC. METHODS: Thirty-eight unselected patients older than 70 years (median age, 74 years) with measurable ACC were included. All patients were evaluable for toxicity and response. The regimen consisted of intravenous LV 500 mg/m2 on Day 1, oral LV 15 mg every 12 hours on Days 2-14, and oral UFT 390 mg/m2 on Days 1-14. Treatment was repeated every 28 days for a minimum of 4 courses per patient. RESULTS: Two hundred eighty-eight cycles of chemotherapy were delivered (median, 7 per patient). Two patients (5%) achieved a complete response and 9 (24%) a partial response, for an overall response rate of 29%. Toxicity was mild, without dose-limiting myelosuppression. Four patients (10%) experienced Grade 3-4 diarrhea, 1 patient had Grade 3-4 nausea/vomiting, and 1 had Grade 3-4 mucositis. Grade 3-4 toxicity was more frequent among women than men (38% vs. 4%, P < 0.05). CONCLUSIONS: Treatment with oral UFT modulated with LV is effective, well tolerated, and feasible on an outpatient basis for elderly patients with ACC. However, elderly women should be followed closely for the early detection of toxicity.

UFT modulated with leucovorin in advanced colorectal cancer: Oncopaz experience.

A phase II trial of UFT (Tegafur and Uracil) modulated by leucovorin was undertaken by the Oncopaz Cooperative Group to assess the efficacy and toxicity of this combination in patients with advanced colorectal cancer. A total of 75 patients were given 500 mg/m2 intravenous leucovorin and 195 mg/m2 of oral UFT on day 1, followed by oral leucovorin 15 mg/12 h and 195 mg/m2/12 h of oral UFT on days 2-14. An overall response rate of 39% was obtained, with seven complete responses (9%), and 22 partial responses (29%). The primary toxicity was gastrointestinal, with grade 1-2 diarrhea occurring in 8.5% of courses, and grade 3-4 in 3.5%. Hematologic toxicity was minimal, and there were no deaths due to toxicity. This regimen was active and well tolerated in patients with advanced colorectal cancer, including those 70 years of age or older.

Treatment of metastatic malignant melanoma with cisplatin plus tamoxifen.

A phase II study was performed to assess the efficacy and toxicity of the combination of cisplatin (CDDP) and tamoxifen (TAM) in patients with metastatic malignant melanoma (MM). A total of 31 consecutive previously untreated patients with unresectable measurable MM were given 100 mg/m2 CDDP every 21 days and 60 mg TAM every 12 h daily. All courses were given on an outpatient basis. A total of 119 courses of treatment were given. In all, 5 of the 31 patients (16%) had an objective response (95% confidence interval 5.3-34%) and 2 (6%) achieved a clinical complete response. The median duration of response was 7 months. The main side effect was gastrointestinal: 13% of the patients experienced grade 3/4 nausea/vomiting. Hematological or neurological toxicities were mild and rare. In conclusion, the combination CDDP-TAM has limited activity in MM, although its toxicity is tolerable. Our results do not allow us to recommend its use for the treatment of MM.

Efficacy of oral tegafur modulation by uracil and leucovorin in advanced colorectal cancer. A phase II study.

A phase II study was performed to assess the efficacy and toxicity of UFT (tegafur-uracil in the molar ratio 1:4) modulated with leucovorin (LV) in previously untreated patients with advanced colorectal carcinoma (CRC). 79 patients with measurable advanced colorectal cancer (CRC) and no prior chemotherapy were included. 75 patients were evaluable for toxicity and response. The regimen consisted of LV 500 mg/m2 administered intravenously on day 1, followed by oral UFT 390 mg/m2 on days 1-14. Patients received oral LV 15 mg every 12 h on days 2-14. Treatment was repeated every 28 days for a minimum of four courses per patient. Three hundred and ninety-eight cycles of chemotherapy were delivered (median five per patient). 7 patients (9%) had a complete response, and 22 a partial response for an overall response rate of 39%. Mild gastrointestinal toxicity was dose limiting: grade 3-4 diarrhoea appeared in 9% of patients. Other grade 3-4 toxicities were nausea/vomiting and mucositis in 4% of patients, gastric pain and leucopenia in 3%. Oral UFT modulated by oral LV is active in advanced CRC and can be administered on an outpatient basis with no significant toxicity requiring hospitalisation. Given its excellent tolerance profile and low toxicity, the regimen should be thoroughly studied and compared with 5-fluorouracil modulated by LV.

Treatment of advanced gastric cancer with the combination fluorouracil, leucovorin, etoposide, and cisplatin: a phase II study of the ONCOPAZ Cooperative Group.

A phase II study was performed to assess the efficacy and toxicity of the combination of 5-fluorouracil (5-FU), leucovorin (LV), etoposide, and cisplatin (FLEP) in patients with advanced gastric carcinoma. A total of 46 consecutive, previously untreated patients with unresectable, measurable gastric carcinoma were treated with 300 mg/m2 LV, 100 mg/m2 etoposide, 500 mg/m2 5-FU, and 30 mg/m2 cisplatin on days 1-3 every 28 days. All courses were given on an outpatient basis. A total of 169 courses of treatment were given. In all, 18 of the 46 patients (39%) had an objective response [95% confidence interval (CI), 25%-54%] and 2 (4%) patients experienced a clinical complete response. The median duration of response was 5 months. The main side effects were hematological and gastrointestinal. Grade 3-4 toxicity was encountered as follows: leukopenia, in 9.5% of the courses; anemia, in 3%; thrombocytopenia, in 3%; nausea/vomiting, in 4%; and diarrhea, in 5%. Hospitalization due to fever and granulocytopenia was required in 5 patients, 3 of whom died of sepsis. In conclusion, FLEP shows moderate activity in patients with advanced gastric carcinoma, albeit at the cost of a high degree of toxicity. For this reason we do not recommend its use.

Comparison of two chemotherapeutic regimens--mitomycin + vindesine + cisplatin (MVP) vs. mitomycin + ifosfamide + cisplatin (MIP)--in advanced non-small-cell lung cancer. ONCOPAZ Cooperative Group.

BACKGROUND: A prospectively randomized trial was performed to compare the efficacy and toxicity of two chemotherapeutic regimens widely used in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: From January 1989 to March 1992, 196 patients with measurable disease were included in the trial. Ninety-three patients received mitomycin-vindesine-cisplatin (MVP) and 94 mitomycin-ifosfamide-cisplatin (MIP). RESULTS: The objective response rate (complete plus partial remissions) was 28% (26/93 patients, 95% confidence interval 20%-40%) in the MVP arm and 30% (28/94 patients, 95% confidence interval 20.5%-40%) in the MIP arm. The median survival was 8.5 and 9 months, respectively. Neither the response rates nor the median survivals were significantly different. Grade III-IV leukopenia was more frequent with MVP (13% vs. 2% of the courses, p < 0.001), as well as grade I-II neurologic toxicity (30% vs. 6%, p < 0.001). In contrast, grade I-II anemia and grade I-II urologic toxicity were more frequent with MIP (7% vs. 25%, p < 0.001 and 1% vs. 11%, respectively). CONCLUSION: Given the low efficacy of both schemes in the treatment of advanced NSCLC, their use cannot be recommended outside of clinical trials.

Phase I study of UFT plus leucovorin in advanced colorectal cancer: a double modulation proposal.

Twenty-six patients with advanced colorectal cancer were treated with UFT and leucovorin (LV). On day 1, patients received LV 500 mg/m2 in IV infusion, followed by 15 mg/12 h for 13 days. On days 1 to 14, patients took oral UFT twice daily. Three cycles were given every 28 days, unless grade III-IV toxicity appeared. The initial dose of UFT (200 mg/day) was increased until 800 mg/day. Dose limiting toxicities were stomatitis, diarrhea and epigastralgia. The maximum tolerated dose of UFT was 390 +/- 10 mg/m2. Three out of 24 evaluable patients achieved a partial response and 1 a complete response with UFT doses of 260 to 390 mg/m2. These results warrant confirmation in phase II studies.