Gemcitabine and vinorelbine in advanced nonsmall cell lung carcinoma: a phase II study.

BACKGROUND: The authors conducted a Phase II study to evaluate the activity of the combination of gemcitabine and vinorelbine in patients with advanced nonsmall cell lung carcinoma (NSCLC). METHODS: Patients were eligible if they had Stage IIIB (malignant pleural effusion) or Stage IV NSCLC, no prior chemotherapy, and Cancer and Leukemia Group B performance status (PS) 0-2. Patients with brain metastases were eligible if they were neurologically stable after brain irradiation. Thirty-three patients from participating institutions were enrolled. One patient was ineligible due to untreated brain metastases. Patients were treated with gemcitabine 1250 mg/m(2) over 30 minutes (1000 mg/m(2) for the first 6 patients) and vinorelbine 25 mg/m(2) over 6 minutes, both administered intravenously on Days 1 and 8 every 21 days. Treatment was planned for a total of six cycles or more if the patient had persistent benefit. Growth factors were not allowed. RESULTS: Among all 32 eligible patients, there were 8 partial responses, for an overall response rate of 25% (95% confidence interval [CI], 11.5-43. 4%). The median survival time was 8.3 months and the 1-year survival rate was 38% (95% CI, 24-59%). Patients with PS 0-1 had a median survival of 11.7 months and a 1-year survival rate of 48%. Grade 3 and 4 neutropenia was observed in 13% and 25% of the 148 treatment cycles, respectively. One patient died of neutropenic sepsis. Only 2 episodes of Grade 3 and 4 thrombocytopenia were observed. Nonhematologic toxicity was minimal. CONCLUSIONS: Gemcitabine and vinorelbine is an active and well-tolerated regimen in patients with advanced NSCLC, with response and survival rates at least comparable to those achieved with standard platinum-based regimens. This combination may be particularly suitable for the elderly or for patients who cannot tolerate more toxic platinum-based regimens.

Second malignancies after treatment for laparotomy staged IA-IIIB Hodgkin's disease: long-term analysis of risk factors and outcome.

The survival of patients with Hodgkin's disease has dramatically improved over the past 30 years because of advances in treatment. However, concern for the risk of long-term complications has resulted in a number of trials to evaluate reduction of therapy. The consequences of these trials on recurrence, development of long-term complications, and survival remain unknown. One major consequence of successful treatment of Hodgkin's disease is the development of second malignant neoplasms. We sought to determine the factors most important for development of second tumors in pathologically staged and treated Hodgkin's disease patients followed for long intervals to provide background information for future clinical trials and guidelines for routine patient follow-up. Between April 1969 and December 1988, 794 patients with laparotomy staged (PS) IA-IIIB Hodgkin's disease were treated with radiation therapy (RT) alone or combined radiation therapy and chemotherapy (CT). There were 8,500 person-years of follow-up (average of 10.7 person-years per patient). Age and gender-specific incidence rates were multiplied by corresponding person-years of observation to obtain expected numbers of events. Observed to expected results were calculated by type of treatment, age at treatment, sex, and time after Hodgkin's disease. Absolute (excess) risk was expressed as number of excess cases per 10,000 person-years. Seventy-two patients have developed a second malignant neoplasm. Eight patients developed acute leukemia, 10 had non-Hodgkin's lymphoma (NHL), and 53 patients developed solid tumors at a median time of 5 years, 7.25 years, and 12.2 years, respectively, after Hodgkin's disease. One patient developed multiple myeloma 16.5 years after Hodgkin's disease. The relative risk (RR) of developing a second malignancy was 5.6. The absolute excess risk per 10,000 person-years (AR) of developing a second malignancy was 69.6 (7.0% excess risk per person per decade of follow-up). The highest RR occurred for the development of leukemia (RR = 66.2), however because of the low expected risk, the AR was only 9.3. The RR of solid tumors after Hodgkin's disease was lower (4.7); however, the AR was greater (49) than for acute leukemia. Among the solid tumors, breast, gastrointestinal, lung, and soft tissue cancers had the highest absolute excess risks. The risk for developing breast cancer after Hodgkin's disease was greatest in women who were under the age of 25 at treatment. The most significant risk factor for the development of both leukemia and solid tumors was the combined use of radiation therapy and chemotherapy. The RR following RT alone was 4.1 (AR = 51.1); for RT + CT (initially or at relapse) the RR was 9.75 (P < 0.05, nonoverlapping confidence limits, AR = 123.9). Survival following development of a second malignancy was poor in patients with leukemia, gastrointestinal tumors, lung cancer, and sarcoma. Survival from other malignancies including NHL and breast cancer was more encouraging. Second malignant neoplasms are a major cause of late morbidity and mortality following treatment for Hodgkin's disease. The most significant risk factor for the development of second tumors is the extent of treatment for Hodgkin's disease. Recommendations are presented for both prevention and early detection of these tumors.

Long-term survival in Hodgkin's disease relative impact of mortality, second tumors, infection, and cardiovascular disease.

PURPOSE: Despite dramatic improvements in the survival of patients with Hodgkin's disease attributable to advances in treatment over the past 30 years, concern for the risk of treatment-related deaths has led to a number of trials to evaluate reduction of therapy. The consequences of these trials on recurrence, development of long-term complications, and survival remain unknown. We determined the causes of death in a group of patients with pathologically staged and intensively treated Hodgkin's disease who were followed for long intervals. MATERIALS AND METHODS: Between April 1969 and December 1988, 794 patients with laparotomy-staged IA to IIIB Hodgkin's disease were treated with radiation therapy alone or combined radiation therapy and chemotherapy. There were 8700 person-years of follow-up (average, 10.95 person-years/ patient). Causes of mortality were grouped into the categories Hodgkin's disease, second malignant tumors, cardiovascular, infection, and miscellaneous. Age- and gender-specific incidence rates were multiplied by corresponding person-years of observation to obtain expected numbers of events. Observed-to-expected results were calculated by type of treatment, age at treatment, sex, and time after Hodgkin's disease. Absolute (excess) risk was expressed as number of excess cases per 10,000 person-years. RESULTS: Of 124 patients who died, 56 died of Hodgkin's disease, 36 of second malignant neoplasms, 15 of cardiac causes, 9 of infection, and 8 of miscellaneous causes. The 20-year actuarial survival rate for all patients in this study is 73%. Age 40 years or older, mixed cellularity/lymphocyte-depleted histologic type, and stage-III disease were adverse independent predictors of survival. The largest differences were seen by age. The 20-year actuarial rates of survival were 78%, 78%, and 46%, respectively, for patients aged 16 or less, 17 to 39, and 40 years or older at diagnosis. Hodgkin's disease diagnosed at age 40 or older was a significant risk factor for all causes of death. The use of combined chemotherapy/ radiotherapy was a significant risk factor for second tumor and infection-related mortality. The excess risk of death from all causes, including Hodgkin's disease, remained constant with time from treatment and was approximately 1.2% per year over the first 20 years. Deaths from Hodgkin's disease decreased with time from treatment, with no patients dying after 15 years. This decrease, combined with an increased excess mortality risk with time from other causes, especially second tumors, accounted for the constant excess mortality with time after Hodgkin's disease. CONCLUSIONS: Hodgkin's disease followed by second tumors, cardiac events, and infections remain the major causes of death after treatment of Hodgkin's disease. Our findings suggest the importance of both maintaining a high disease-free survival and reducing long-term complications in designing treatments of Hodgkin's disease.

Alternate putrescine metabolites: quantitative analysis of delta'-pyrroline oxidation to 2-pyrrolidone in tissue homogenates by high-pressure liquid chromatography.

A sensitive analytical procedure for following the oxidation of delta'-pyrroline to 2-pyrrolidone in tissue homogenates is described. Homogenates are extracted with chloroform/acetonitrile and fractionated by high-performance liquid chromatography, and 2-pyrrolidone is quantitated by monitoring the column effluent at 200 nm. The lower limit of 2-pyrrolidone that can be accurately (+/- 5%) quantitated is approximately 100 pmol. Phenazine methosulfate significantly enhances the rate of 2-pyrrolidone biosynthesis from delta'-pyrroline. Phenazine methosulfate and reduced glutathione are required to obtain proportionality between 2-pyrrolidone formation and incubation time. Formation of 2-pyrrolidone as a function of protein concentration is linear and 2-pyrrolidone biosynthesis as a function of delta'-pyrroline concentration is characterized by hyperbolic kinetics. Based on analysis of enzyme activity in different tissues, liver appears to play the dominant role in 2-pyrrolidone biosynthesis. The metabolic step from delta'-pyrroline to 2-pyrrolidone was localized in the cellular cytosol. These results demonstrate that the oxidation of delta'-pyrroline to 2-pyrrolidone is enzyme mediated and provide a useful method for further characterization of this metabolic step.