Organizational ethics in Catholic health care: honoring stewardship and the work environment.

Organizational ethics refers to the integration of values into decision making, policies, and behavior throughout the multi-disciplinary environment of a health care organization. Based upon Catholic social ethics, stewardship is at the heart of organizational ethics in health care in this sense: stewardship provides the hermeneutic filter that enables basic ethical principles to be realized practically, within the context of the Catholic theology of work, to concerns in health care. This general argument can shed light on the specific topic of non-executive compensation programs as an illustration of organizational ethics in health care.

Ethical perspectives on life sciences research after mapping the human genome.

The essay discusses ethical perspectives of life sciences research that can help us navigate a path across the genetic landscape that opens before us with the map of the human genome that was announced recently. We can rightly anticipate many drug discoveries and genetic therapies to cure, prevent, or alleviate devastating conditions. But we must also pause with appropriate apprehension about the possible dangers and difficulties we may encounter.

Biological study of R24 mouse monoclonal antibody in patients undergoing thoracotomy for pulmonary metastases from soft tissue sarcoma.

The disialoganglioside GD3 is expressed on the surface of soft tissue sarcoma, malignant melanoma, and other malignant cells and is, therefore, a potential target for therapeutic monoclonal antibodies. Intravenously administered R24, a murine IgG3 monoclonal antibody to GD3, induces inflammation and tumor regression at sites of metastatic malignant melanoma. R24 5 mg/m2 was given intravenously every other day for six doses to 10 patients with pulmonary metastases from a primary soft tissue sarcoma of the extremity for whom thoracotomy was planned. Resected tissue was available from 7 patients. All metastases expressed GD3; however, expression was heterogeneous within tumors, and in no tumor were more than 80% of the cells GD3 positive. A mild to moderate infiltrate consisting of mononuclear cells with T-cell markers was identified around or within pulmonary metastases in 6 patients. Tolerable acute allergic reactions occurred in all patients, but 3 patients had severe chest tightness and bronchospasm that limited the planned therapy. The setting of thoracotomy for metastatic disease provides an ideal system for studies on the pharmacology and biological effects of monoclonal antibodies that target soft tissue sarcoma antigens.

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.

A phase II trial of PALA + dipyridamole in patients with advanced soft-tissue sarcoma.

A total of 21 patients with advanced soft tissue sarcoma enrolled in a phase II trial of 3.5 g/m2 N-phosphonacetyl-L-aspartate (PALA) given intravenously every 3 weeks plus 50 mg/m2 dipyridamole (Persantine) given orally every 6 h. Dipyridamole administration was initiated 1 week before the first dose of PALA. Peak and trough plasma concentrations of dipyridamole were measured before and after the first dose of PALA in 14 patients. In all, 19 patients were evaluable for therapeutic response. One subject experienced partial regression of a pulmonary metastasis; no other major response was observed. Diarrhea was the most prominent toxicity; in one patient it was life-threatening and was associated with a severe rash. On the day preceding PALA administration, the median peak plasma concentration of dipyridamole was 2,208 ng/ml and the median trough value was 904 ng/ml. Similar values were obtained on the day of PALA administration. Although the levels achieved were similar to those required to modulate the activity of PALA in preclinical systems, the therapeutic results obtained in the present study were not superior to those reported for PALA alone in previously treated patients with soft-tissue sarcoma.

Phase-1 trial of high-dose intravenous cisplatin with simultaneous intravenous sodium thiosulfate.

Previous pharmacological and clinical data have suggested that it is possible to increase significantly the dose of "active" cisplatin delivered systemically by the simultaneous administration of intravenous sodium thiosulfate. In order to define more critically the toxicity and potential efficacy of this therapeutic approach, 36 patients with a variety of solid tumors and limited pretreatment were entered into a phase-1 trial of high-dose intravenous cisplatin plus sodium thiosulfate. The maximally tolerated dose of cisplatin was found to be 200 mg/m2, excessive renal toxicity being observed at a dose of 225 mg/m2 (6/14 courses associated with serum creatinine rise to greater than 2.0 mg-%). Following several courses of high-dose cisplatin, peripheral neuropathy becomes the limiting toxicity (9/15 patients receiving at least three courses of cisplatin at greater than or equal to 150 mg/m2 experienced at least grade-1 neuropathy). Significant ototoxicity developed after only one or two treatment courses, but with continued treatment hearing loss appeared to stabilize in the moderately severe range in most patients. Major responses (PR/CR) were observed in 7/27 evaluable patients. We conclude that cisplatin can be administered at a dose at 200 mg/m2 as a 2-h infusion (with simultaneous sodium thiosulfate) with significant but acceptable toxicities and without evidence of loss of anti-neoplastic activity (secondary to the presence of thiosulfate). However, owing to the development of neurotoxicity most patients will be unable to receive more than three courses of this high-dose treatment regimen.

Phase II trial of carboplatin and vinblastine in adenocarcinoma of the stomach.

Twenty-five previously untreated patients with advanced adenocarcinoma of the upper gastrointestinal tract were treated with a combination of carboplatin and vinblastine. Two partial responses (duration three months and six months) were seen among 22 evaluable patients. Myelosuppression was the most common toxicity and was generally mild. The 8% response rate, (95% confidence interval 2 to 24%) observed in this study indicated that carboplatin-vinblastine has only modest activity in adenocarcinoma of the upper gastrointestinal tract. Although less toxic, this regimen appears to be less effective than previously reported cisplatin-containing regimens in adenocarcinoma of the upper GI tract.

Central venous catheter complications in sarcoma patients receiving adjuvant chemotherapy.

As part of a prospective randomized study in patients with high grade soft tissue sarcoma (STS), 47 patients received post-operative adjuvant Adriamycin. The method of administration was randomized to intravenous bolus (B) or to continuous 72 hour infusion (CI) via a Silastic right atrial catheter. Both groups received 60 mg/m2 every 3 weeks. There were nine hospital admissions for treatment related complications in four of the 26 CI patients compared to none in the 21 B patients (P = 0.03). All of the admissions related to complications involving the central venous catheter (CVC). This apparent increased risk for hospital admission secondary to treatment related complications in patients treated with CI must be considered in the planning of future therapeutic trials.

Phase II study of CHIP chemotherapy in advanced adenocarcinomas of the upper gastrointestinal tract.

Iproplatin (CHIP) is a second generation cisplatin analogue which has completed its Phase I trials. We studied the efficacy and toxicity of CHIP in 36 previously untreated patients with advanced upper gastrointestinal tract adenocarcinomas (GE junction, cardia, antrum and body of the stomach). The starting dose was 275 mg/m2; course were repeated on an every four week schedule. Thirty-five patients were evaluable for response. Three partial remissions (8.5%) [95% confidence limits 2.5-15%] were seen. Toxicity was tolerable and included mild myelosuppression and mild nausea and vomiting. Although well tolerated, in patients with gastric and GE junction adenocarcinomas, CHIP chemotherapy was not more and probably slightly less, effective than the parent analogue cisplatin.

Advanced pancreatic cancer: a phase I-II trial of cisplatin, high-dose cytarabine, and caffeine.

In a phase I-II study, 28 patients with advanced pancreatic adenocarcinoma were treated with cisplatin, high-dose cytarabine (ARA-C), and caffeine. This clinical trial was based on a nude mouse-human tumor xenograft model, which demonstrated synergism of these agents by inhibiting the growth of human pancreatic tumors. Toxic effects noted in the clinical study included myelosuppression, moderate nausea and vomiting, and mild renal insufficiency. No toxic effects were directly attributable to caffeine. Eighteen of the 28 patients had measurable or assessable disease; seven (39%) had partial responses (95% confidence intervals, 18%-63%). The median response duration was 6.2 months. Median survival for responders was 9.5 months with two patients surviving for more than 18 months. Median survival for all patients was 6.1 months. The combination of cisplatin, ARA-C, and caffeine is an active and tolerable regimen in the treatment of advanced pancreatic cancer. A phase III trial in which this regimen is being compared with standard therapy is in progress.

The influence of antineoplastic chemotherapy on antipyrine metabolism in man.

When either Doxorubicin or Mitomycin-C was administered to patients, antipyrine clearance was respectively unaltered or increased. Antipyrine was administered to patients two days prior to and one day after their first course of the chemotherapeutic drug. Antipyrine clearance increased an average of 11.2% in the 5 patients that received Doxorubicin (not significant) and 15.2% in the six patients that received Mitomycin-C (P = 0.033, students t-test). The altered clearance is likely due to a rapid induction of the mixed function oxidase system by the chemotherapy as other parameters that could influence clearance were stable throughout the study (volume of distribution, weight, creatinine clearance and liver function tests). It is unlikely that the prechemotherapy antipyrine dose accounted for this change. The administration of these two antitumor antibiotics in humans may modestly increase the mixed function oxidase activity that is responsible for the metabolism of antipyrine. These findings are in direct contrast to markedly decreased mixed-function oxidase activity observed in the rodent pretreated with the same chemotherapy.