21-day oral etoposide for metastatic breast cancer: a phase II study and review of the literature.

Previous studies of etoposide for metastatic breast cancer commonly used bolus regimens given over a short period of time and included heavily pretreated patients. Results were poor. Chronic oral regimens would be expected to be superior to bolus doses based on pharmacologic studies and patients with less previous chemotherapy would be expected to have higher response rates. We studied the efficacy of oral etoposide at a dose of 50 mg/m2/day for 21 days of a 28-day cycle in good-risk patients with metastatic breast cancer. Healthy patients (Eastern Cooperative Oncology Group performance status 0, 1, or 2) who had not received chemotherapy for at least 1 year before study entry were selected for therapy. Thirty-four patients were entered; three patients were ineligible and one was cancelled. Thirty patients were available for analysis of response. One complete response and eight partial responses were documented (response rate, 30%; 95% confidence interval, 15-49%). A higher response rate was observed in those patients who never received chemotherapy compared with those who had received prior chemotherapy (57 vs. 6%, p = 0.004). There were two treatment-related deaths, both owing to myelosuppression and infection. We found long-term administration of oral etoposide to have a reasonable response rate for metastatic breast cancer (30%). Our response rate was comparable to those of other published studies of long-term oral etoposide regimens for metastatic breast cancer. Response rates in single-arm studies have generally been higher for long-term oral regimens than those for bolus regimens. We also found the regimen to be significantly toxic, an observation that may be underemphasized in the earlier literature.

Aerosolized pentamidine as pneumocystis prophylaxis after bone marrow transplantation is inferior to other regimens and is associated with decreased survival and an increased risk of other infections.

Pneumocystis carinii pneumonia (PCP) is a life-threatening but preventable infection that may occur after bone marrow transplantation (BMT). Although various prophylactic regimens have been used in this setting to prevent active infection, their efficacy, toxicity profile, and impact on outcomes are poorly described in this patient group. We undertook a retrospective cohort study in which we reviewed the records of 451 adult patients who underwent BMT for hematologic malignancies, aplastic anemia, or myelodysplasia over a 7-year period at the Brigham and Women's Hospital. Post-BMT PCP prophylaxis consisted of aerosolized pentamidine (AP) 150 mg every 2 weeks or 300 mg per month, trimethoprim/sulfamethoxazole (TMP/SMX) 160/800 mg orally b.i.d. 3 times per week, or dapsone 100 mg orally each day. Prophylaxis was continued for 1 year post-BMT in all patients when clinically feasible. One hundred twenty-one patients were unevaluable because of death or relapse <60 days after BMT (n = 89), loss to follow-up upon hospital discharge (n = 20), or other reasons (n = 12). Three eligible patients did not receive any prophylaxis and were not further evaluated. Of the 327 patients analyzed, 133 underwent autologous BMT, 4 syngeneic BMT, 159 related allogeneic BMT, and 31 unrelated allogeneic BMT. Graft-versus-host disease prophylaxis in the 190 patients receiving allogeneic BMT consisted of T-cell depletion with anti-CD5 and complement in 58 patients and cyclosporine/methotrexate or FK506 with or without steroids in 132 patients. Eight of 327 (2.4%) documented PCP cases were identified, 0 of 105 in patients receiving only TMP/SMX. Four cases occurred in patients receiving only AP (4/44, 9.1%; odds ratio [OR] relative to TMP/SMX 23.4, 95% confidence interval [CI] 1.2, 445.2); 1 in patients receiving only dapsone (1/31, 3.2%; OR not significant); 2 in patients receiving more than 1 prophylactic regimen (2/147 1.4%; OR not significant); and 1 >1 year post-BMT in a patient who was off PCP prophylaxis. Although the patients receiving only AP had a significantly lower probability of treatment-related toxicity than those receiving TMP/SMX (OR 0.19 [95% CI 0.04, 0.851), the probability of their acquiring other serious non-PCP infections was increased (OR 2.2 [95% CI 1.0, 4.6]), and the probability of their dying by 1 year post-BMT was significantly higher (OR 5.2 [95% CI 2.4, 26.6]), even when adjusted for variables such as type of BMT (autologous versus allogeneic; high versus low risk) and sex. Although AP is associated with fewer toxicities, the data show that it is inferior to TMP/SMX in preventing PCP in the post-BMT setting and is associated with an increased risk of other infections and a higher mortality at 1 year after BMT.

Parametric cure models of relative and cause-specific survival for grouped survival times.

With parametric cure models, we can express survival parameters (e.g. cured fraction, location and scale parameters) as functions of covariates. These models can measure survival from a specific disease process, either by examining deaths due to the cause under study (cause-specific survival), or by comparing all deaths to those in a matched control population (relative survival). We present a binomial maximum likelihood algorithm to be used for actuarial data, where follow-up times are grouped into specific intervals. Our algorithm provides simultaneous maximum likelihood estimates for all the parameters of a cure model and can be used for cause-specific or relative survival analysis with a variety of survival distributions. Current software does not provide the flexibility of this unified approach.

Respiratory tract inflammation during the induction of chronic bronchitis in rats: role of C-fibres.

The hypothesis that chronic stimulation of C-fibres by inhaled irritants contributes to the inflammatory changes that occur during the development of chronic bronchitis was tested. The effect of neonatal capsaicin pretreatment on the development of respiratory tract inflammation was examined in a rat model of chronic bronchitis induced by SO2 exposure. Adult capsaicin- and vehicle-treated rats were exposed to SO2 (250 parts per million (ppm) 5 h x day(-1)) for one day, 2 weeks or 4 weeks. Nasal (NL), airway (AL) and bronchoalveolar (BAL) lavages were performed and the number and types of cells in the lavage fluids measured. SO2-induced changes in ventilation were also measured on day 1 of SO2 exposure and in the 3rd and 5th week of exposure. In the vehicle-treated rats, neutrophils became elevated in NL after just one day of SO2 exposure, in AL after 2 weeks, and in the BAL after 4 weeks. In comparison to vehicle animals, more neutrophils were recovered in the AL of capsaicin-treated rats after one day of SO2 (p=0.012), and in the BAL after 2 or 4 weeks (p=0.004 and p=0.01, respectively). On day 1, SO2 caused a transient increase in tidal volume and a sustained decrease in frequency that was not different in capsaicin- and vehicle-treated rats. With continued exposure, these ventilatory responses to SO2 were attenuated in both groups of rats. These data support the hypothesis that the presence of C-fibres limits or delays the inflammation that occurs during the development of chronic bronchitis induced by SO2 exposure. The protective effect of C-fibres is not the result of ventilatory responses to stimulation of these afferents.

Testing for trend with count data.

Among the tests that can be used to detect dose-related trends in count data from toxicological studies are nonparametric tests such as the Jonckheere-Terpstra and likelihood-based tests, for example, based on a Poisson model. This paper was motivated by a data set of tumor counts in which conflicting conclusions were obtained using these two tests. To define situations where one test may be preferable, we compared the small and large sample performance of these two tests as well as a robust and conditional version of the likelihood-based test in the absence and presence of a dose-related trend for both Poisson and overdispersed Poisson data. Based on our results, we suggest using the Poisson test when little overdispersion is present in the data. For more overdispersed data, we recommend using the robust Poisson test for highly discrete data (response rate lower than 2-3) and the robust Poisson test or the Jonckheere-Terpstra test for moderately discrete or continuous data (average responses larger than 2 or 3). We also studied the effects of dose metameter misspecification. A clear effect on efficiency was seen when the 'wrong' dose metameter was used to compute the test statistic. In general, unless there is strong reason to do otherwise, we recommend the use of equally spaced dose levels when applying the Poisson or robust Poisson test for trend.

Nonadditive developmental toxicity in mixtures of trichloroethylene, Di(2-ethylhexyl) phthalate, and heptachlor in a 5 x 5 x 5 design.

In order to identify nonadditive effects on development, three compounds were combined using five dosages of each agent (a 5 x 5 x 5 full-bacterial design). Trichloroethylene (TCE), di(2-ethylhexyl) phthalate (DEHP), and heptachlor (HEPT), in corn oil, were administered by gavage to Fischer-344 rats on Gestation Days 6-15. Dose levels were 0, 10.1, 32, 101, and 320 mg/kg/day for TCE; 0, 24.7, 78, 247, and 780 mg/kg/day for DEHP; and 0, 0.25, 0.8, 2.5, and 8 mg/kg/day for HEPT. The dams were allowed to deliver and their pups were weighed and examined postnatally. Maternal death showed no main effects but DEHP and HEPT were synergistic. For maternal weight gain on Gestational Days 6-8, main effects for all three agents were observed, as well as 6-8 main effects for all three agents were observed, as well as TCE-DEHP synergism, and DEHP-HEPT antagonism. Maternal weight gain on Gestational Days 6-20 adjusted for litter weight showed main effects for TCE and HEPT, but no interactions. Main effects for all three agents were evident for full-litter resorptions and prenatal loss. The HEPT main effects were unexpected and were interpreted as reflecting potentiation by HEPT of the other agents. For full-litter loss, the TCE-HEPT and DEHP-HEPT interactions were antagonistic, perhaps due to a "ceiling" effect. For prenatal loss, the TCE-DEHP interaction was synergistic. Postnatal loss showed DEHP and HEPT main effects but no interaction. Analysis of pup weights on Day 1 revealed TCE and DEHP main effects and DEHP-HEPT antagonism; on Day 6, DEHP and HEPT main effects, DEHP-HEPT antagonism, and TCE-DEHP synergism were evident. Microphthalmia and anophthalmia incidences revealed TCE and DEHP main effects but no interactions. This extensive examination of a full-factorial design elucidates the complexities of studying and interpreting mixture toxicity. The data are available for further analysis.