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A prospective randomized trial of adjuvant chemotherapy with bolus versus continuous infusion of doxorubicin in patients with high-grade extremity soft tissue sarcoma and an analysis of prognostic factors.

A prospective randomized trial was conducted to compare the cardiotoxic and therapeutic effects of doxorubicin (60 mg/m2 every 3 to 4 weeks) administered by bolus or 72-hour continuous infusion as adjuvant chemotherapy in 82 eligible patients after resection of high-grade soft tissue sarcoma of the extremity or superficial trunk. Cardiac toxicity, defined as a 10% or greater decrease in left ventricular ejection fraction as assessed by radionuclide cineangiography, was evaluated in 69 patients. Cardiotoxicity was seen in 61% of patients in the bolus treatment arm with the median doxorubicin dose of 420 mg/m2. Among patients who received continuous infusion, 42% had cardiotoxicity with a median dose of 540 mg/m2. The rate of cardiotoxicity as a function of the cumulative dose of doxorubicin was significantly higher in the bolus treatment arm (P = 0.0017). Two patients in each group had clinical congestive heart failure, with one cardiac death occurring in each. There was a trend toward a lower rate of metastasis (P = 0.19) and a significantly lower rate of death of disease (P = 0.036) for patients treated with the bolus dose. Cox model analysis identified three unfavorable characteristics for the rate of developing a distant metastasis: blood transfusion within 24 hours of operation (P less than 0.00001), tumor deep to the fascia and 5 cm or more in size (P = 0.0043), and a histologic subtype other than liposarcoma (P = 0.0002). The unfavorable effect of continuous infusion was not selected in the model (P = 0.16). Adjuvant chemotherapy for patients with soft tissue sarcoma is investigational. Furthermore, the impact of perioperative blood transfusion merits further study.

Adult↗

Phytoestrogens may improve the pregnancy rate in in vitro fertilization-embryo transfer cycles: a prospective, controlled, randomized trial.

OBJECTIVE: To compare the effectiveness of i.m. P and i.m. P plus oral phytoestrogens for luteal phase support in patients undergoing IVF-ET cycles. DESIGN: Prospective, controlled, randomized trial. SETTING: University Hospital, Perugia, Italy. PATIENT(S): Two hundred thirteen infertile patients undergoing IVF-ET were included in the study. The inclusion criteria were use of a GnRH agonist for pituitary down-regulation and age <40 years. The total number of cycles performed was 274. INTERVENTION(S): Patients were assigned to receive either i.m. P (50 mg daily) plus placebo or P (50 mg daily) plus phytoestrogen supplementation (1,500 mg daily) for luteal phase support starting from the evening of oocyte retrieval until either a serum pregnancy test result was negative or embryonic heartbeat was sonographically confirmed. MAIN OUTCOME MEASURE(S): The outcomes of IVF-ET were evaluated in both study groups in terms of implantation rate, biochemical pregnancy rate (PR), clinical PR, spontaneous abortion rate, and ongoing pregnancy/delivered rate. RESULT(S): Statistically significant higher values for implantation rate, clinical PR, and ongoing pregnancy/delivered rate were recorded in the patients who received P plus phytoestrogens for luteal phase support in comparison with patients receiving P and placebo. CONCLUSION(S): Although the results of this study encourage the use of phytoestrogens for luteal phase support in patients undergoing IVF-ET program, more studies are necessary to support the hypothesis that phytoestrogens have a beneficial effect in IVF cycles.

Adult↗

Randomized trial of leaving messages on telephone answering machines for control recruitment in an epidemiologic study.

To determine whether leaving messages on answering machines would aid control recruitment via random-digit telephone dialing, a randomized trial was conducted during 1992-1994 involving 1,323 western Washington households with answering machines. For the experimental group, a message was left informing them about the study and promising a call-back; for the control group, no message was left. Leaving a message increased the response rate by about 20 percentage points (p = 0.002). More households were successfully screened for eligible controls, and individuals found eligible were more likely to participate. Leaving a message can help to improve response rates in telephone surveys.

Adult↗

A randomized trial comparing safety and efficacy of OKT3 and a monoclonal anti-interleukin-2 receptor antibody (BT563) in the prevention of acute rejection after heart transplantation.

In a prospective randomized trial, BT563, a murine IgG, anti-interleukin-2 receptor antibody, was compared with OKT3 for use as an early rejection prophylaxis after heart transplantation. Patients received either BT563 (n=31) or OKT3 (n=29) during the first 7 days after transplantation; cyclosporine was started on day 3. Median follow-up was 34 months. A cytokine release syndrome occurred in the majority of patients of the OKT3-treated group but in none of the BT563 recipients. The mean duration of electrical stimulation of the heart in the BT563 group was longer than in the OKT3 group (5.1 vs. 2.1 days). In both groups, one patient required insertion of a permanent pacemaker. Freedom from acute rejection at 3 months was not significantly different between the two groups (BT563: 5/29, 17%; OKT3: 6/29, 21%). In the BT563 group, however, rejection tended to occur earlier after transplantation. There was no difference in the overall incidence of rejection. The incidence of infectious complications was evenly distributed in both groups. Malignancies occurred in two patients, both in the OKT3 group. In conclusion, the use of this anti-interleukin-2 receptor monoclonal antibody in heart transplant recipients is safe and devoid of the side effects that accompany the use of OKT3. OKT3 and BT563 result in a similar freedom from rejection at 3 and 12 months after heart transplantation.

Adolescent↗

Prevention of postoperative venous thrombosis: a randomized trial comparing unfractionated heparin with low molecular weight heparin in patients undergoing total hip replacement.

A double blind randomized trial comparing subcutaneous enoxaparin (40 mg once daily) with standard unfractionated calcium heparin administered at a dose of 5,000 units every 8 hours in patients undergoing elective hip replacement has been performed. Treatment regimens began 12 hours preoperatively with enoxaparin, 2 hours preoperatively with standard unfractionated calcium heparin, and were continued for 15 days or until discharge. Venography was performed in all patients. Two hundred thirty-seven patients were included in the study: 113 received unfractionated heparin and 124 received enoxaparin. The incidence of proximal deep vein thrombosis was reduced from 18.5% in the unfractionated heparin group to 7.5% in the enoxaparin group (p = 0.014), and the incidence of total deep vein thrombosis was similarly reduced from 25% to 12.5% (p = 0.03). There were two major bleeding episodes and one minor bleed in the enoxaparin group compared to two minor bleeds in the unfractionated heparin group. Patients who received enoxaparin required fewer red blood cell transfusions and had a significantly higher hemoglobin on postoperative days 3 and 4. Thus prophylaxis with enoxaparin, 40 mg once daily, is simple, safe and more effective than standard low dose unfractionated heparin in preventing deep vein thrombosis in patients undergoing elective hip replacement.

Aged↗

Randomized trial of high-dose chemotherapy with autologous bone marrow support as adjuvant therapy for high-risk, multi-node-positive malignant melanoma.

BACKGROUND: Chemotherapy adjuvant to surgery in metastatic melanoma has been evaluated in only a few prospective randomized trials. In the treatment of metastatic melanoma, dacarbazine has response rates of 15%-25% and in several studies, when combined with other alkylating agents, has yielded even higher response rates. Among the highest response rates are those achieved by using high-dose chemotherapy regimens combined with autologous bone marrow support (transplantation). PURPOSE: We conducted a prospective randomized clinical trial to test the efficacy of high-dose alkylating agents in combination with autologous bone marrow support given as adjuvant therapy for high-risk stage II (World Health Organization) melanoma. METHODS: Thirty-nine patients with metastases involving five or more lymph nodes were randomly assigned to one of two treatment arms within 8 weeks of lymphadenectomy: immediate treatment or observation only. The immediate-treatment arm consisted of 19 patients who, immediately after random assignment, received high-dose chemotherapy with alkylating agents, followed 3 days later by reinfusion of autologous bone marrow. The observation arm consisted of 20 patients who were observed until relapse (confirmed by biopsy) and were then treated with the identical high-dose alkylating agent chemotherapy followed by reinfusion of autologous bone marrow. Bone marrow was harvested from the patients under general anesthesia 1-2 weeks prior to chemotherapy and was cryopreserved. Chemotherapy consisted of intravenous administration of cyclophosphamide (1875 mg/m2 as a 1-hour infusion daily for 3 days), cisplatin (55 mg/m2 per day by continuous infusion over the same 72-hour period), and carmustine (BCNU) (600 mg/m2) given immediately after cisplatin on the 4th day as a 2-hour infusion. The total doses of the three drugs were 5625, 165, and 600 mg/m2, respectively. All patients received medical evaluations every 6-12 weeks over the study period. Kaplan-Meier estimates were used to determine the time to disease progression on the basis of intent to treat. RESULTS: There was no statistically significant difference in overall survival or in time to disease progression between the two treatment arms. However, the median time to progression was 16 weeks in the observation arm and 35 weeks in the immediate-treatment arm. CONCLUSIONS: Immediate adjuvant high-dose chemotherapy with alkylating agents followed by autologous bone marrow support more than doubled the time to disease progression compared with observation alone, though the difference was not statistically significant. No differences in overall survival were noted.

Adult↗

[French randomized trials in general and digestive surgery in the last decade].

STUDY AIM: To study the characteristics of randomized trials published by general and digestive French surgeons over the last decade. MATERIAL AND METHODS: An extensive electronic and manual literature search was performed. Trials published as original articles compared two surgical techniques or a surgical procedure with a nonsurgical treatment. The characteristics of the trials and their methodology were assessed. At the same time, a survey was conducted among authors to assess the impact of application of the Huriet-Sérusclat law (ethics related to the protection of individuals subjected to bioclinical research) on the conduct of the trial. RESULTS: Forty trials (including 22 multicentre trials) were found. Twelve trials (30%) addressed a key-question and twenty (50%) addressed a particular step of the procedure (anastomosis, drainage, etc). Most trials (83%) were published in English language journals. The 18 trials with a good methodological quality mainly had a multicentre design (n = 16). The survey showed that 10 trials were conducted prior to the publication of Huriet-Sérusclat law and that 14 trials were conducted in compliance with this law. CONCLUSION: This study revealed the large number of well designed multicentre trials in France. But most trials assessed technical steps of the surgical procedures. Application (without prerequisite) of the Huriet-Sérusclat law could probably explain the rarity and the difficulties of conducting trials comparing two different procedures or a surgical with a medical treatment.

France↗

A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis.

BACKGROUND: Cerebral metastasis is a common oncologic problem that occurs in 15-30% of cancer patients; approximately half such metastases are single. Previous retrospective studies and two randomized trials reported that the addition of surgical extirpation prior to radiation therapy increased survival, neurologic function, and quality of life compared with radiation alone in patients with a single brain metastasis. METHODS: A randomized controlled trial was conducted in which patients with a single brain metastasis were allocated to undergo radiation alone or surgery plus radiation. Radiation consisted of 3000 centigray to the whole brain in 10 fractions. RESULTS: Forty-three patients received radiation alone and 41 patients surgery plus radiation. All but two of the study patients died. No difference in survival was detected between the groups; the median survival for the radiation group was 6.3 months (95% confidence interval, 3-11.4) compared with 5.6 months for the surgery plus radiation group (95% confidence interval, 3.9-7.2) (P = 0.24). Most patients died within the first year (69.8% in the radiation arm vs. 87.8% in the surgery plus radiation arm). There were no significant differences in the 30-day mortality, morbidity, or causes of death. Extracranial metastases was an important predictor of mortality (relative risk, 2.3). The mean proportion of days that the Karnofsky performance status was > or = 70% did not differ between the 2 groups. CONCLUSIONS: This trial failed to demonstrate that the addition of surgery to radiation therapy improved outcome of patients with a single brain metastasis. Thus, the efficacy of surgery plus radiation compared with radiation alone needs to be addressed by further clinical trials and/or a meta-analysis.

Brain Neoplasms↗

A randomized trial on the impact of starting day on ovarian follicular activity in very low dose oral contraceptive pills users.

In a randomized trial, the impact of starting day (the first and the seventh day of the period) on ovarian follicular activity was assessed during administration of a very low dose of oral contraceptive pills (20 microgram (mcg) ethinyl estradiol (EE) and 75 mcg gestodene (GS) [Meliane, Schering, Germany]). One hundred and sixty healthy women aged: 23-44 years, who had a regular cycle, and who were not using any type of oral contraceptive (OCs) steroid were studied at the Family Planning Clinic of King Chulalongkorn Memorial Hospital, Bangkok, Thailand. In the trial, each subject received a package of Meliane. They were blockwise randomized, 1:1 ratio; in the first group, subjects began their pills on the first day of their period (n = 80) and the other group, the seventh day of their period (n = 80). During the treatment cycle, ovarian activity was evaluated by transvaginal sonography (TVS) to determine the follicular-like structure (FLS). Ovulation was defined as the dominant FLS detected by TVS and followed-up every other day until its collapse. It occurred in 0 of 77 cases who started on the first day of their period and occurred in 8 of 78 cases of the group which started on the seventh day of their period. The difference was of statistical significance (p = 0.006). The result of this clinical trial is beneficial information for users of OCs containing 20 mcg EE who delay start of the OCs package.

Adult↗

Prevention of first bleeding in cirrhosis. A meta-analysis of randomized trials of nonsurgical treatment.

OBJECTIVE: To assess the effectiveness of beta-blockers and endoscopic sclerotherapy in the prevention of first bleeding and reduction of mortality in patients with cirrhosis and esophagogastric varices. DATA SOURCES: Pertinent studies were selected using MEDLINE (1980 to 1990), reference lists from published articles or reviews, and congress abstract lists. STUDY SELECTION: Randomized trials comparing beta-blockers or sclerotherapy with a nonactive treatment. Nine randomized clinical trials of beta-blockers and 19 trials of sclerotherapy were reviewed. Seven trials of beta-blockers and 15 of sclerotherapy were published as full papers. DATA EXTRACTION: Crude rates of bleeding and death in treated and control groups were extracted from each trial by three independent observers according to the intention-to-treat principle. The quality of published papers was systematically assessed and scored. DATA SYNTHESIS: The Mantel-Haenszel-Peto method was used for statistical evaluation of heterogeneity and for pooling of the results. No substantial heterogeneity was found, and the incidence of bleeding in trials of beta-blockers was significantly reduced (pooled odds ratio, 0.54; 95% CI, 0.39 to 0.74), particularly in patients with large or medium-sized varices or in those with varices and a hepatic vein pressure gradient above 12 mm Hg; however, only a trend toward reduced mortality was obtained. Sclerotherapy trials were highly heterogeneous in the direction of the treatment effects on both bleeding (pooled odds ratio, 0.6; CI, 0.49 to 0.74) and mortality (pooled odds ratio, 0.76; CI, 0.61 to 0.94). The quality of the trials and the rate of bleeding in the untreated groups were the major sources of heterogeneity. The favorable results of sclerotherapy were obtained in trials with high bleeding rates among controls; several of these trials had a low quality score. CONCLUSIONS: Beta-blockers may be recommended for prevention of first bleeding in cirrhotic patients with varices who have a high risk for bleeding. The effectiveness of sclerotherapy remains undetermined. Further trials in high-risk patients may prove useful if improved criteria to predict bleeding risk become available.

Adrenergic beta-Antagonists↗

Highly selective vagotomy with excision of the ulcer compared with gastrectomy for gastric ulcer in a randomized trial.

Fifty-six patients with benign gastric ulcer of the body of the stomach have been entered into a randomized trial of highly selective vagotomy with excision of the ulcer (HSVE) (26 cases) against standard Billroth I partial gastrectomy (BI) (30 cases). The operations were carried out by all grades of surgical staff. No patient died within 1 month of operation. Postoperative morbidity was greater after gastrectomy than after HSVE. At an average follow-up of about 4 years, functional results according to a modified Visick classification were similar in both groups, with about 75 per cent good results. Two recurrent ulcers occurred after gastrectomy (7 per cent) and 4 after HSVE (15 per cent). Neither operation has a distinct advantage at this stage.

Clinical Trials as Topic↗

A randomized trial of antihuman thymocyte globulin versus murine monoclonal antihuman T-cell antibodies as immunosuppressive therapy for aplastic anemia.

A prospective randomized trial was undertaken to compare the efficacy and toxicity of murine antihunman T-cell monoclonal antibody (mcAb) therapy to that of horse antihuman thymocyte globulin (ATG) in the treatment of severe aplastic anemia (AA). Patients were randomized into one of the two treatment groups as well as to receive or not receive androgens. Median duration of aplasia prior to treatment was 1.5 and 2.2 months for the mcAb and ATG groups, respectively. One of 12 patients who received mcAb therapy had a partial response, whereas four of 13 patients receiving ATG had a complete or partial response. Of the 11 patients who failed mcAb treatment, six were subsequently treated with ATG and two improved. Ten of 13 patients who received ATG are surviving compared with seven of 12 patients who received mcAb. Toxicity of mcAb therapy was less than that of ATG. Future studies are needed to determine whether mcAbs known to be immunosuppressive are of benefit as therapy for patients with AA.

Adolescent↗

Postmastectomy radiotherapy: randomized trials.

Postmastectomy radiotherapy decreases threefold the risk of locoregional recurrences according to the results of many randomized trials and overviews. This risk is mainly related to the number of involved axillary nodes (ie, about 25%, 35%, and 55% at 10 years when 1 to 3, 4 to 9, and 10 or more nodes are involved). In contrast, at 10 years, fewer than 15% of patients with negative axillary nodes relapse locally. The effect of postmastectomy radiotherapy on distant metastases and overall survival is a controversial issue. On the one hand, results are compatible with the existence of a mechanism of secondary dissemination generated from locoregional tumor nests. The beneficial effect of radiotherapy may be observed in the absence or presence of adjuvant systemic treatment. On the other hand, a deleterious late toxic, mainly cardiac, effect of radiation has also been shown. This point emphasizes the importance of radiation technique and quality to obtain a positive balance in terms of overall survival.

Breast Neoplasms↗

Ethanolamine oleate is superior to polidocanol (aethoxysklerol) for endoscopic injection sclerotherapy of esophageal varices: a prospective randomized trial.

Thirty-four consecutive patients with liver cirrhosis and esophageal varices were included in a prospective randomized trial done to investigate the efficacy and safety of two sclerosants 5% ethanolamine oleate (EO) and polidocanol (1% Aethoxysklerol [AS]) for use in endoscopic injection sclerotherapy (EIS). Eighteen patients were randomly allocated to the group given EO and 16 to the AS group. These two groups were comparable with regard to age, sex, etiology and severity of the liver disease. The bleeding rate from esophageal ulcers which developed during the course of repeated EIS was significantly (P less than 0.05) higher in the AS group (31.3%, 5/16) than in the EO group (0%, 0/18). In 4 occasions bleeding from the esophageal ulcer could not be controlled with AS. In 3 of these 4 bleeding episodes, EO successfully halted bleeding from esophageal ulcer. In the other patient, a Sengstaken-Blakemore tube was inserted to stop the hemorrhage. The period and number of sessions of EIS for eradication of esophageal varices were significantly (P less than 0.05) shorter in the EO group than the AS group (EO: 4.0 +/- 0.8 [means +/- SD] sessions during 4.7 +/- 1.5 weeks versus AS: 4.8 +/- 1.2 sessions during 5.4 +/- 1.6 weeks). The rate of early mortality did not differ between the two groups. We conclude that 5% ethanolamine oleate seems to be superior to 1% Aethoxysklerol when used for sclerosing esophageal varices.

Clinical Trials as Topic↗

Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases.

PURPOSE: This phase III randomized trial evaluated survival as well as neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd). PATIENTS AND METHODS: Patients were randomly assigned to 30 Gy of WBRT +/- 5 mg/kg/d MGd. Survival and time to neurologic progression determined by a blinded events review committee (ERC) were coprimary end points. Standardized investigator neurologic assessment and neurocognitive testing were evaluated. RESULTS: Four hundred one (251 non-small-cell lung cancer) patients were enrolled. There was no significant difference by treatment arm in survival (median, 5.2 months for MGd v 4.9 months for WBRT; P =.48) or time to neurologic progression (median, 9.5 months for MGd v 8.3 months for WBRT; P =.95). Treatment with MGd improved time to neurologic progression in patients with lung cancer (median, not reached for MGd v 7.4 months for WBRT; P =.048, unadjusted). By investigator, MGd improved time to neurologic progression in all patients (median, 4.3 months for MGd v 3.8 months for WBRT; P =.018) and in lung cancer patients (median, 5.5 months for MGd v 3.7 months for WBRT; P =.025). MGd improved neurocognitive function in lung cancer patients. CONCLUSION: The overall results did not demonstrate significant differences by treatment arm for survival and ERC time to neurologic progression. Investigator neurologic assessments demonstrated an MGd treatment benefit in all patients. In lung cancer patients, ERC- and investigator-determined time to neurologic progression demonstrated an MGd treatment benefit. MGd may improve time to neurologic and neurocognitive progression in lung cancer.

Aged↗

Appendicectomy: assessment of stump invagination versus simple ligation: a prospective, randomized trial.

The appendix stump was ligated and doubly invaginated in 374 patients and was simply ligated in 361 in a prospective, randomized trial of 735 consecutive appendicectomies. The two groups were similar with respect to sex, age, degree of appendiceal inflammation and antibiotic treatment. The incidence of wound infection and postoperative pyrexia and the postoperative hospital stay showed no significant intergroup difference. The median operating time was slightly shorter in the group without invagination. Simple ligation facilitates and shortens appendicectomy. It produces no deformation of the caecal wall that subsequently may be mistaken for a caecal neoplasm. Simple ligation is therefore recommended as standard procedure in appendicectomy.

Appendectomy↗

Effect of a transportation incentive on compliance with the first prenatal appointment: a randomized trial.

OBJECTIVE: To evaluate the effectiveness of incentives for improving compliance with the first prenatal appointment. METHODS: One hundred four low-income women, intending to enroll for prenatal care in a system of Northern California family planning clinics, were recruited for a randomized trial. Study subjects were assigned randomly to one of three groups, receiving a taxicab voucher or a baby-blanket coupon or an appointment slip (controls). Intention-to-treat analysis was used to compare compliance with the first prenatal appointment between the three groups. RESULTS: Subjects receiving the taxi voucher had a compliance rate of 82% for the first prenatal appointment, 22% higher than mean appointment compliance in the other groups. The odds ratio for missing the first appointment was 0.32 (95% confidence interval 0.12, 0.88) in the taxi voucher group. This was not affected by controlling for possible confounders. Despite better appointment compliance, only one of 34 taxi vouchers distributed was actually used. CONCLUSION: A taxi voucher incentive was effective in improving compliance with the first prenatal appointment, despite the fact that only one subject actually used the voucher.

Adult↗

Percutaneous coronary intervention versus coronary artery bypass graft surgery for patients with medically refractory myocardial ischemia and risk factors for adverse outcomes with bypass: a multicenter, randomized trial. Investigators of the Department of Veterans Affairs Cooperative Study #385, the Angina With Extremely Serious Operative Mortality Evaluation (AWESOME).

BACKGROUND: Percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG) are being applied to high-risk populations, but previous randomized trials comparing revascularization methods have excluded a number of important high-risk groups. OBJECTIVES: This five-year, multicenter, randomized clinical trial was designed to compare long-term survival among patients with medically refractory myocardial ischemia and a high risk of adverse outcomes assigned to either a CABG or a PCI strategy, which could include stents. METHODS: Patients from 16 Veterans Affairs Medical Centers were screened to identify myocardial ischemia refractory to medical management and the presence of one or more risk factors for adverse outcome with CABG, including prior open-heart surgery, age >70 years, left ventricular ejection fraction <0.35, myocardial infarction within seven days or intraaortic balloon pump required. Clinically eligible patients (n = 2,431) underwent coronary angiography; 781 were angiographically acceptable; 454 (58% of eligible) patients consented to random assignment between CABG and PCI. RESULTS: A total of 232 patients was randomized to CABG and 222 to PCI. The 30-day survivals for CABG and PCI were 95% and 97%, respectively. Survival rates for CABG and PCI were 90% versus 94% at six months and 79% versus 80% at 36 months (log-rank test, p = 0.46). CONCLUSIONS: Percutaneous coronary intervention is an alternative to CABG for patients with medically refractory myocardial ischemia and a high risk of adverse outcomes with CABG.

Aged↗