Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer.

PURPOSE: This randomized, controlled, multicenter, open-label, phase III study compared docetaxel versus paclitaxel in patients with advanced breast cancer that had progressed after an anthracycline-containing chemotherapy regimen. PATIENTS AND METHODS: Patients (n = 449) were randomly assigned to receive either docetaxel 100 mg/m2 (n = 225) or paclitaxel 175 mg/m2 (n = 224) on day 1, every 21 days until tumor progression, unacceptable toxicity, or withdrawal of consent. RESULTS: In the intent-to-treat population, both the median overall survival (OS, 15.4 v 12.7 months; hazard ratio [HR], 1.41; 95% CI, 1.15 to 1.73; P = .03) and the median time to progression (TTP, 5.7 months v 3.6 months; HR, 1.64; 95% CI, 1.33 to 2.02; P < .0001) for docetaxel were significantly longer than for paclitaxel, and the overall response rate (ORR, 32% v 25%; P = .10) was higher for docetaxel. These results were confirmed by multivariate analyses. The incidence of treatment-related hematologic and nonhematologic toxicities was greater for docetaxel than for paclitaxel; however, quality-of-life scores were not statistically different between treatment groups over time. CONCLUSION: Docetaxel was superior to paclitaxel in terms of OS and TTP. ORR was higher for docetaxel. Hematologic and nonhematologic toxicities occurred more frequently in the docetaxel group. The global quality-of-life scores were similar for both agents over time.

Hormone replacement therapy after breast cancer: a systematic review and quantitative assessment of risk.

PURPOSE: Hormone replacement therapy (HRT) is typically withheld from women with breast cancer because of concern that it might increase the risk of recurrence. The purpose of this study was to quantify the risk of recurrent breast cancer associated with HRT among breast cancer survivors. METHODS: We performed a systematic literature review through May 1999, calculating the relative risk (RR) of breast cancer recurrence in each study by comparing the number of recurrences in the HRT group to those in the control group. In studies that did not contain a control group, we constructed one by estimating the expected number of recurrences based on data from the Early Breast Cancer Trialists' Collaborative Group, adjusting for nodal status and disease-free interval. RRs across all studies were combined using random-effects models. RESULTS: Of the 11 eligible studies, four had control groups and included 214 breast cancer survivors who began HRT after a mean disease-free interval of 52 months. Over a mean follow-up of 30 months, 17 of 214 HRT users experienced recurrence (4.2% per year), compared with 66 of 623 controls (5.4% per year). HRT did not seem to affect breast cancer recurrence risk (RR = 0.64, 95% confidence interval [CI], 0.36 to 1.15). Including all 11 studies in the analyses (669 HRT users), using estimated control groups for the seven uncontrolled trials, the combined RR was 0.82 (95% CI, 0.58 to 1.15). CONCLUSION: Although our analyses suggest that HRT has no significant effect on breast cancer recurrence, these findings were based on observational data subject to a variety of biases.

Phase I/II study of cyclophosphamide, carboplatin, and etoposide and autologous hematopoietic stem-cell transplantation with posttransplant interferon alfa-2b for patients with lymphoma and Hodgkin's disease.

PURPOSE: To evaluate the safety and toxicity of interferon alfa-2b (IFN) following an intensive preparative transplantation regimen in patients with relapsed Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Thirty-two patients with NHL or HD underwent autologous transplantation following cyclophosphamide 7,200 mg/m2, carboplatin 1,600 mg/m2, and etoposide 1,600 mg/m2 (CCV). Fourteen patients received an escalating dose of IFN. IFN was started at 1 x 10(6) U/m2 subcutaneously (SC) three times per week with a monthly dose escalation to a maximum of 3 x 10(6) U/m2 SC three times per week. IFN was continued for a total of 6 months. RESULTS: The preparative regiment was well tolerated. Renal dysfunction was noted more frequently in patients with a history of pretransplant cisplatin treatment, and cardiac dysfunction was responsible for the single transplant-related death (3%). IFN was well tolerated with no serious complications. Transient neutropenia and thrombocytopenia were noted in several patients. The mean maximal-dose IFN achieved was 2 x 10(6) IU/m2. The median duration of treatment with IFN was 5.2 months. The overall probability of survival (OS) and event-free survival (EFS) at 36 months, with a median follow-up duration of 18 months, was 42% OS and 14% EFS in HD and 70% OS and 56% EFS in NHL. The EFS at 36 months was 73% for all NHL patients who received IFN and 50% for patients who refused IFN treatment (P = .12), with OS estimates of 100% in the IFN group and 35% in the untreated group (P = .0002). CONCLUSION: CCV is a safe, effective conditioning regimen in patients with NHL or HD. Posttransplant IFN can be safely administered at 2.0 x 10(6) U/m2 three times per week for 6 months and may have a meaningful antitumor effect.

A phase II study of docetaxel in patients with paclitaxel-resistant metastatic breast cancer.

PURPOSE: To evaluate the efficacy and safety of docetaxel in patients with paclitaxel-resistant metastatic breast cancer (MBC). PATIENTS AND METHODS: Docetaxel (100 mg/m2) was administered every 3 weeks to 46 patients registered at four centers. Patients had previously received < or = two chemotherapy regimens for MBC. All patients had progressive disease while receiving paclitaxel therapy. Treatment was repeated until there was evidence of disease progression or for a maximum of three cycles after best response. RESULTS: Objective responses were seen in eight of 44 assessable patients (18.1%; 95% confidence interval [CI], 6.7% to 29.5%). Seven patients had partial responses and one patient responded completely. Response rates were not significantly different by previously received paclitaxel dose or resistance. No responses were seen in 12 patients who had previously received paclitaxel by 24-hour infusion, but the response rate in 32 patients who had received paclitaxel by 1- to 3-hour infusion was 25%. The median response duration was 29 weeks and the median time to disease progression was 10 weeks. Median survival was 10.5 months. Clinically significant (severe) adverse events included neutropenic fever (24% of patients), asthenia (22%), infection (13%), stomatitis (9%), neurosensory changes (7%), myalgia (7%), and diarrhea (7%). CONCLUSION: Docetaxel is active in patients with paclitaxel-resistant breast cancer, particularly in those who failed to respond to brief infusions of paclitaxel. Response rates were comparable to or better than those seen with other therapies for patients with paclitaxel-resistant MBC. This confirms preclinical studies, which indicated only partial cross-resistance between paclitaxel and docetaxel.

Decreased thyroid function and high plasma prolactin levels in rats of the Buffalo strain.

Rats of the inbred Buffalo strain have previously been reported to be susceptible to thyroiditis, as defined by histology. We have studied the endocrinology of the pituitary-thyroid axis of this strain by making direct measurements of the plasma concentrations of TSH and T4 in untreated, adult Buffalo rats of both sexes. Plasma PRL levels were also measured. All hormone determinations were by RIA. In addition, relative thyroid weights were noted and, in many cases, preliminary assessment of thyroid histology was made. Our principle findings were as follows. 1) Decreased thyroid function, in addition to the previously reported histological abnormalities, was found to occur spontaneously among the rats studied. Indications of decreased function included elevations of plasma TSH and thyroid weight and depressions of plasma T4. We estimated the incidence of unequivocal thyroid disease as approximately 3% in each sex. 2) Basal plasma PRL concentrations of Buffalo rats averaged three to four times higher than those of outbred CD rats. Our findings strongly suggest that rats of the Buffalo strain will provide a good model for the study of thyroid failure of varying degrees and concomitant changes in the circulating levels of pituitary hormones.

Factors determining outcome for breast-conserving irradiation with margin-directed dose escalation to the tumor bed.

PURPOSE: A prospectively applied treatment policy for breast-conserving therapy used margin assessment as the exclusive guide to the intensity of therapy directed at the tumor-bearing quadrant. METHODS AND MATERIALS: From 1982-1994, there were 509 treated Stage I and II breast carcinomas with a median follow-up of 72 months. For operational purposes, tumor excision margins were prospectively defined as: > 5 mm, 2.1-5 mm, > 0 < or = 2 mm, and positive. If a margin was assessed as < or = 2 mm or indeterminate, and it was deemed cosmetically feasible, a reexcision of the tumor bed would be performed. All patients received whole breast irradiation to 50-50.4 Gy. The following scheme for tumor bed boost irradiation as a function of final margin status (FMS) was observed: (a) Minimal risk = no tumor found on reexcision, no boost performed; (b) low risk = FMS > 5 mm, boost of 10 Gy; intermediate risk = FMS 2.1-5 mm, boost to 14 Gy; high risk = FMS < or = 2 mm or positive, boost to 20 Gy. Cases were analyzed for local failure (LF) with respect to histology (invasive ductal (IDC), IDC with associated DCIS (IDC/DCIS), invasive lobular (ILC)), age, tumor size, total excision volume, reexcision, total dose, tamoxifen therapy, and chemotherapy. RESULTS: There were 19 breast recurrences for a Kaplan-Meier local failure rate for all cases at 5 and 10 years of 2.7% and 7.1%, respectively. Local failure in the first 4 years of follow-up was rare, with a mean annual incidence rate of 0.25% that rose to a mean of 1.1% in subsequent years. Univariate results of Cox proportional hazards regression survival models found positive FMS (p = 0.02), IDC/DCIS (p = 0.04) and age (0.0006) as significantly associated with local failure. In a multivariable model of FMS and IDC/DCIS, FMS retained significance (p = 0.01) but IDC/DCIS was borderline (p = 0.06). When FMS and age were included in a multivariable model, there was a significant interaction (p = 0.01) between the two variables. There was a significant increase in the relative risk of LF for age < or = 45 years (range 11.1-17.4), irrespective of FMS category. Although excellent overall control rates were achieved for patients > 45 years, for younger patients LF rates appeared to remain proportional to the relative closeness of the FMS, despite rigorous dose escalation. CONCLUSIONS: Graded tumor-bed dose escalation in response to FMS results in an exceptionally low risk of "early" local recurrence within the first 5 years of follow-up. However, this strategy is unable to completely overcome the longer term adverse influence of young age and positive FMS.

The importance of local-regional radiotherapy with conventional or high-dose chemotherapy in the management of breast cancer patients with > or = 10 positive axillary nodes.

PURPOSE: To assess the effect of local-regional radiotherapy (RT) on the outcome of breast cancer patients with > or = 10 positive axillary lymph nodes who have received modern conventional or high-dose systemic therapy. METHODS AND MATERIALS: A total of 55 women with local-regionally confined breast cancer involving 10 or more axillary nodes were treated between October 1983 and January 1996. Local-regional therapy consisted of modified radical mastectomy in 39 and breast-conserving surgery in 16. Postoperative radiotherapy was given to 44 of the 55 patients. Radiotherapy consisted of tangential fields to the chest wall or intact breast to a median dose of 50.40 Gy. A total of 86% (38 of 44) received regional nodal irradiation as follows: 35 patients received RT to the supraclavicular (SC) region and axillary midplane to a median dose of 50.40 Gy and 46.20 Gy, respectively; 3 patients received RT to the SC region without inclusion of the axilla to a median dose of 50. 40 Gy. All patients received adjuvant standard-dose systemic chemotherapy, 9 of whom received additional intensification chemotherapy followed by autologous bone-marrow transplant (ABMT) or peripheral blood stem-cell transplant (PBSC). Twenty-five patients received adjuvant tamoxifen. RESULTS: With a median follow-up of 30 months, the crude overall survival (OS) and disease-free survival (DFS) for the entire group were 67% and 53%, respectively. On univariate analysis of various clinical, pathological, and therapy-related features, radiotherapy emerged as the most important factor influencing the relapse rate. The addition of RT was significantly associated with an improved DFS (p = 0.003), specifically by prolonging the time to disease progression. The median time to failure was 61 months and 12.5 months with and without RT, respectively. Patients receiving RT also appeared to survive longer; however, the groups were not statistically different (p = 0.10). Analysis of the patterns of failure showed local-regional recurrence (LRR) as the first site of failure in 12 (22%) of 55 and distant failure in 20 (36%) of 55. Univariate results revealed both radiotherapy and tamoxifen to be significantly associated with decreased LRR rates (p = 0.0001 and p = 0.03, respectively); only RT remained independently significant on multivariate analysis. CONCLUSION: Local-regional radiotherapy is an essential component of the management of breast cancer patients with extensive nodal involvement, despite the use of contemporary adjuvant chemotherapy including high-dose regimens with autologous rescue. In addition to the expected improvement in LRR, radiotherapy is also associated with significantly prolonged DFS and a trend for improvement in OS.

Megestrol and tamoxifen in patients with advanced endometrial cancer: an Eastern Cooperative Oncology Group Study (E4882).

To investigate the effect of adding tamoxifen to megestrol in the hormonal therapy for advanced endometrial cancer, 66 patients were entered in this study. Initially, 41 patients were randomized to either the standard progestin therapy of megestrol or to the combination of megestrol and tamoxifen between October 1982 and October 1984. The megestrol arm was terminated because of poor accrual and 25 patients were directly assigned to the combination arm. Among the 20 eligible cases on the megestrol arm, the response rate of 20% consisted of I complete response and 3 partial responses. The response rate on the megestrol plus tamoxifen arm was 19% with 1 (2%) complete response and 7 (17%) partial responses among 42 eligible cases. The median survival times were 12.0 months and 8.6 months, respectively. Only mild and moderate toxicities were observed on megestrol compared with more toxic complications observed on the combination of megestrol and tamoxifen, including a life-threatening case of pulmonary embolism. Although we could not carry out a comparative evaluation as intended, we conclude that the combination of megestrol and tamoxifen offers no clinical advantage over megestrol alone in the treatment of advanced endometrial carcinoma.

Hepatic perfusion changes in patients with cirrhosis indices of hepatic arterial blood flow.

PURPOSE: This study used radionuclide angiography to evaluate semiquantitatively the hepatic arterial blood flow changes associated with cirrhosis. METHODS: The parameters of net arterial hepatic perfusion were estimated by analysis of first-pass flow studies in 11 control participants and in 15 patients with cirrhosis (Child-Pugh classification B-C). Hepatic, renal, and splenic time-activity curves were generated, normalized per pixel, and corrected for background. The rate of hepatic arterial blood flow was compared with the reference kidney and spleen perfusion using the hepatorenal and hepatolienal perfusion indices, respectively. These indices were defined as: PI = area under hepatic curve limited by time of the renal (splenic) curve peak/area under renal (splenic) curve to its peak RESULTS: The values of both these perfusion indices are significantly greater in the patients with cirrhosis than in controls (hepatorenal perfusion index, P < 0.01; hepatolienal perfusion index, P < 0.05). The values of the hepatic perfusion index (the ratio of the arterial to the total liver blood flow), which were also calculated, were elevated in the patients with cirrhosis (P < 0.01). CONCLUSIONS: The results confirm that the net hepatic arterial blood flow is increased in patients with cirrhosis. Radionuclide angiography accompanied by calculation of arterial perfusion indices may provide semiquantitative parameters of net hepatic arterial blood flow.

[5-year experience with the Heimox system in the treatment of patients with chronic respiratory insufficiency]. / Petileté zkusenosti se systémem Heimox v lécbe nemocných s chronickou respiracní insuficiencí.

BACKGROUND: Long-term oxygen therapy using oxygen concentrators has been introduced in the Czech Republic as a standard method since October 1992. Since August 1996 there has been a possibility of treating patients with chronic respiratory insufficiency with devices exploiting liquid oxygen. In our study we analyzed a group of patients treated with Heimox system during the period August 1996 to December 2000. METHODS AND RESULTS: Heimox system has been indicated in 85 patients (49 males, 31 females and five children). Mean survival time was 10 months, no patient survived three years. Two-year survival was 8.2% (7 patients) and one-year survival 17.6% (15 patients). Compared to our results in 1296 patients treated with oxygen concentrators in 1996 (mean survival time 17.3 months, four-year survival 3%, three-year survival 14.4%, two-year survival 21.1%, one-year survival 26.0%) patients treated with Heimox system had shorter survival time. CONCLUSIONS: Indication criteria for Heimox system approve using this system for patients with terminal stage of pulmonary illness and therefore the survival time is very short.

[The occurrence of circadian rhythm in respiration in healthy persons and in patients with bronchial asthma]. / Výskyt cirkadiánních rytmu ventilace zdravých a nemocných s bronchiálním astmatem.

The authors examined in 69 healthy young men at times 0, 3, 6, 9, 12, 15, 18 and 21 hours values of FVC, FEV1, FEF50 a PEF. In 149 patients with bronchial asthma after the same time intervals FEV1 was assessed, whereby the interval at 3 a.m. was used as the mean of values at times 0 and 6 a.m. By analysis of variance the minima of the majority of investigated indicators were assessed in healthy subjects at 3 a.m. and 9 a.m. By cosinor analysis a statistically insignificant circadian rhythm for values FEC and FEV1 was proved in the entire group of healthy subjects and in subgroups of smokers and non-smokers. No rhythm was found in values of FEF50 and PEF. Rhythms in the ventilation values were detected in 40-60% of the subjects, in the remainder no rhythms were detected. In patients with bronchial asthma a significant circadian rhythm of FEV1 changes was found in groups with a morning or variable type of respiration. In groups with a stabilized ventilation a rhythm was detected but was not significant. In the group with an apparently irreversible obstruction no circadian rhythm was found.

[3 years of long-term home oxygen therapy in the Czech Republic]. / Tri roky dlouhodobé domácí oxygenoterapie v Ceské republice.

BACKGROUND: Long-term domiciliary oxygen therapy was introduced in the Czech Republic as a standard therapeutic method in patients with chronic respiratory failure in October 1992. As a source of oxygen almost exclusively oxygen concentrators are used which are allocated to the patients according to criteria elaborated by the European Respiratory Society. METHODS AND RESULTS: From October 1, 1992 to October 1, 1995 the mean number of installed concentrators is 10,24/100000 population. From a total of 1064 patients by October 1, 1995 3.8% were treated for three years, 20.7% for two years and 34.4% for more than one year. In the course of three years a total of 490 patients died. The mean survival period of patients treated for prolonged periods by domiciliary oxygen therapy was 8.88 months. The high mortality rate is due to the fact that patients in a very serious state are treated. On account of chronic pulmonary disease oxygen therapy was indicated in 93.4%, on account of interstitial pulmonary processes (KFA and other fibroses) in 3.9, on account of kyphoscoliosis in 2.4% and on account of cystic fibrosis in 0.3% of the group. The mean costs of treatment were 114.40 Ke/day which is a third of the costs when the patient is hospitalized. CONCLUSIONS: Domiciliary oxygen therapy proved effective and economical in patients with chronic respiratory failure.

[Possibilities in the use of ambulatory oxygen therapy in practice]. / Moznosti uplatnení ambulantní oxygenoterapie v praxi.

Of 524 patients suffering from chronic obstructive bronchopulmonary disease and cryptogenic fibrotizing alveolitis according to accepted criteria 49 patients were selected fro long-term domestic oxygen treatment. In the course of 3-4 weeks comprehensive treatment of the basic disease 10 patients improved to such an extent that ambulatory oxygen therapy was no longer indicated. One patient was eliminated from treatment because he was a heavy cigarette smoker. In eight patients ambulatory oxygen therapy was started. The remaining 30 patients, i.e. 61%, fully indicated for oxygen treatment did not have ambulatory treatment because oxygen concentrators are not available. This shortage must be rapidly resolved.

[Bronchogenic carcinoma in women]. / Bronchogenní karcinom u zen.

A total of 440 women with morphologically tested primary bronchogenic carcinoma were hospitalized in 1961-1987. The patients' average age was 57 years, 22% persons were under 50 years. In 32% women carcinoma was found accidentally in the asymptomatic stage of the illness, 4% women had subjective complaints which they considered insignificant, however, subjective complaints in 64% patients helped to diagnose it. The most frequent complaints were temperature, breathlessness, chest pain and loss of weight. In 2% women, the first sign was hemoptysis found most frequently as an isolated symptom. The history of 9.5% patients showed pulmonary TB, in 27% women bronchogenic carcinoma was first regarded as pulmonary TB and treated with anti-tuberculotics. The family history of 32% patients showed malignant diseases, most frequently gastric carcinoma, while bronchogenic carcinoma was found in 5.7%, of family members. The group consisted of 46% smokers and 54% non-smokers. The women smokers had smoked for 29 years on average, had smoked 205 thousand cigarettes on average, the average daily amount was 20 cigarettes. Regardless of their smoking habits, the most frequent histological type was found to be adenocarcinoma in 47% cases, with the squamous-cell type prevailing in the smokers (37%), and adenocarcinoma in non-smokers (59%). 36% of the patients underwent surgery, the most frequent contraindication for surgery were generalization of the process and lymph node metastases. Lobectomy was the most common operation performed (62%). 5 patients died within the first post-operative month.

A proposal for integrated efficacy-to-effectiveness (E2E) clinical trials.

We propose an "efficacy-to-effectiveness" (E2E) clinical trial design, in which an effectiveness trial would commence seamlessly upon completion of the efficacy trial. Efficacy trials use inclusion/exclusion criteria to produce relatively homogeneous samples of participants with the target condition, conducted in settings that foster adherence to rigorous clinical protocols. Effectiveness trials use inclusion/exclusion criteria that generate heterogeneous samples that are more similar to the general patient spectrum, conducted in more varied settings, with protocols that approximate typical clinical care. In E2E trials, results from the efficacy trial component would be used to design the effectiveness trial component, to confirm and/or discern associations between clinical characteristics and treatment effects in typical care, and potentially to test new hypotheses. An E2E approach may improve the evidentiary basis for selecting treatments, expand understanding of the effectiveness of treatments in subgroups with particular clinical features, and foster incorporation of effectiveness information into regulatory processes.