Fax technology for collecting outcomes data in a computer database.

In this era of cost containment, outcomes research is becoming more prevalent. Therefore, various technologies allowing for flexibility in study design and the capture of specific clinical information need to be examined and used. These technologies include fax data systems, pocket scanners, automated telephone equipment, and hand-held computer devices. Fax data systems convert a fax machine into an automated data-entry system. Data-filled forms are faxed to a computer, the fax is converted, and the data are entered into preset fields in a database. Applications for fax systems include acute care-based and ambulatory care-based drug-use evaluations, drug recall systems, and patient-completed surveys of health status. Pocket scanners are hand-held instruments for rapid data entry and transport. Applications for pocket scanning include patient interview responses, procedure and disease analysis, and procedure coding. Options for automated telephone equipment include surveys with interactive voice-mail responses or keypad data entry, pharmacist-monitored drug information and survey services, fax-back and mail-out services, and patient-generated disease intervention programs. Hand-held computer technology is a source of information on multiple protocols and care pathways. All these technologies improve data collection with respect to accuracy and speed, facilitate data analysis, and promote cost-efficient information sharing. The purpose of this study was to evaluate the use of fax technology in data collection for a prospective, multicenter study of the outcomes and cost-effectiveness of two drugs used in the treatment of cancer. Details for the pharmacoeconomic study can be found elsewhere. Fax technology was selected because of the ease with which those responsible for managing the data collection could be trained to use it, the affordability and efficiency of the technology, the ease with which data could be analyzed, and the accuracy of data collection.

Economic analysis of carboplatin versus cisplatin in lung and ovarian cancer.

OBJECTIVE: To conduct an economic analysis on the use of carboplatin versus cisplatin over multiple courses in patients with lung [nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC)] or ovarian cancer. DESIGN: This 1-year study was a prospective, multicentre, cost-minimisation evaluation. Direct medical resource utilisation and costs associated with carboplatin and cisplatin administration over 3 to 6 courses of treatment were measured and compared. The perspective of this evaluation was that of the payer. SETTING: A convenience sample of 16 sites representing a mix of cancer centres, outpatient clinics, medical centres and managed-care sites in a general practice oncology setting participated. PATIENTS AND INTERVENTIONS: Patients were included in this study if they were newly diagnosed with NSCLC, SCLC or ovarian cancer, had not received prior chemotherapy, received either carboplatin or cisplatin as their treatment (additional chemotherapy agents were allowed), and received at least 3 courses of carboplatin or cisplatin therapy up to a maximum of 6 courses. Patients receiving more than 6 courses of therapy were included in this study, but data collection on those patients stopped after the sixth course. Individuals involved with data collection at all sites were trained via on-site and/or teleconference training. Site visits were made to assure reliability of at least 0.80. Data were collected and compiled via a fax transmission process that scans directly through optical mark and character recognition into a computer database. Outcome measures included costs of: medications, emergency room visits, physician/clinic/laboratory visits, home healthcare visits, transfusions, special procedures, consultations, hospitalisations and other/miscellaneous costs. MAIN OUTCOME MEASURES AND RESULTS: Of 220 patients, 164 met the study criteria (response rate = 74.2%) with 95 patients in the carboplatin group (NSCLC = 45, SCLC = 18, ovarian = 32) and 69 in the cisplatin group (NSCLC = 36, SCLC = 21, ovarian = 12). The average number of courses were: NSCLC = 4.3 and 4.2, SCLC = 4.3 and 4.8, and ovarian = 4.7 and 5.1, respectively, for carboplatin and cisplatin. The total costs (treatment and toxicity) associated with the use of carboplatin were higher in NSCLC, similar in SCLC but lower in ovarian cancer. CONCLUSIONS: These results indicate that overall treatment costs may vary depending on cancer type, even when the same drugs are used. The total costs (treatment plus toxicity costs) associated with the use of carboplatin were higher than those of cisplatin in patients with NSCLC, similar in SCLC, but lower in ovarian cancer.

Procedure costs and outcomes associated with pharmacologic management of peripheral arterial disease in the Department of Defense.

This study was undertaken to determine if differences existed between pharmacologic treatments of peripheral arterial disease (PAD) with respect to PAD-related costs and health care outcomes in the United States Department of Defense health care system. We performed a retrospective review of hospital and prescription data to explore the effects of at least 90 days of aspirin, pentoxifylline, papaverine, or dipyridamole on 4 PAD-related outcomes: number of PAD-related invasive procedures (INV), number of PAD-related examination procedures (EXM), number of PAD-related hospitalization days (HDAYS), and cost of PAD-related procedures (COST) during 5 years. A covariate representing the number of PAD-related hospitalizations before the study period was used to attempt to control for severity of disease state. General linear models were used in the analyses. A statistically significant difference was seen between treatment groups for a linear combination of INV, EXM, HDAYS, and COST when controlling for past PAD-related hospitalizations (P < 0.014). A statistically significant relationship existed between treatment groups and INV (P < 0.041). The pentoxifylline treatment group had a statistically significant higher covariate-adjusted mean INV compared with the aspirin treatment group (P < 0.043). Also, PAD-related past hospitalizations were significantly related to EXM (P < 0.006). Our results appear to support the use of aspirin as a preventive treatment in PAD compared with pentoxifylline or dipyridamole.

Clinical guidelines for the treatment of cancer-related anemia.

Defining clinical guidelines for the treatment of cancer-related anemia requires investigation into causes and characteristics of this malady, uses, benefits, and adverse effects of current treatments; and recognition of currently accepted guidelines set forth by the American College of Physicians and the American Association of Blood Banks. Anemia, the most common hematologic abnormality in patients with cancer, originates from a variety of causes, including occult blood loss, hypoproliferation, and hemolysis, and often involves more than one mechanism. Clinical manifestations include fatigue, dyspnea, tachycardia, dizziness, anorexia, and hypersensitivity to cold. Although the majority of cancer-related anemias are hypoproliferative, establishing their pathophysiology in individual patients is critical to effective treatment. Anemia usually, but not always, resolves with successful treatment of underlying disease. Symptomatic relief can be managed in accordance with established treatment guidelines.

Deoxyspergualin: phase I clinical, immunologic and pharmacokinetic study.

Deoxyspergualin (DSG) is an analog of the polyamine spergualin with preclinical evidence of activity in murine and human tumor models. This phase I study examined a 120 h continuous infusion schedule in 56 patients with refractory solid tumors at doses ranging from 80 to 2792 mg/m2/day. Dose-limiting toxicity was reversible hypotension and appeared to be associated with plasma levels of DSG > 4 micrograms/ml. Other dose-dependent effects noted were pruritus and circumoral paresthesias. Myelosuppression and gastrointestinal toxicities were mild and sporadic. Two patients with refractory head and neck cancer had minor responses. The recommended phase II dose on this schedule is 1800 mg/m2. Additional monitoring to identify immunologic properties included immunophenotyping of peripheral lymphocytes and cytotoxic activity by means of standard 51Cr-release assays. These studies revealed a non-dose-dependent increase in the number of cells expressing T cell antigens predominantly the T suppressor (CD8) phenotype posttreatment. In three patients, a mild increase in LAK activity was noted post-treatment without a consistent relationship to dose or change in cell surface antigens. Pharmacokinetic studies were completed on 26 patients ranging from doses of 80 to 2792 mg/m2. The average plasma concentration ranged from 0.07 to 7 micrograms/ml. DSG was rapidly cleared from the plasma with a mean terminal half-life of 1.9 h. Mean total body clearance was 25.24 l/h/m2. Further in vivo immunologic studies should be pursued while the agent is studied in fixed dosage phase II clinical trials.

Recombinant interleukin-2.

Recombinant interleukin (IL)-2 is a newly approved immunoregulatory protein produced by lymphocytes that exhibits a wide range of immunologic effects. It is a true biologic response modifier in that is has no known direct antitumor activity, but mediates its cytotoxicity through activation of effector cells including T cells, natural killer cells, and lymphokine-activated killer cells. Recombinant IL-2 has demonstrated activity in patients with renal cell carcinoma and melanoma, with objective response rates of approximately 15-20%. The median duration of response in renal cell carcinoma is 23 months. Toxicity experienced with high-dose IL-2 can be significant. The most common dose-limiting toxicities are hypertension, weight gain, oliguria, respiratory insufficiency, and neurotoxicity. These effects are generally manageable and reversible on discontinuation of therapy. Administration of low-dose IL-2 has emerged as a means of substantially reducing toxicity. At least in renal cell carcinoma, it appears that the response rate to low-dose IL-2 is comparable to that with higher dosages.

Nutritional parameters observed during 28-day infusion of recombinant human tumor necrosis factor-alpha.

In conjunction with a Phase I investigation of the antineoplastic activity of recombinant human tumor necrosis factor-alpha (TNF-alpha), administered as a 28-day continuous infusion, selected nutritional parameters were evaluated to identify any effect that might be attributed to the TNF infusion. Seven clinically stable men with a variety of tumor types were studied. None had clinical or laboratory evidence of significant malnutrition before entry into the study. Five patients received 10 micrograms of recombinant human TNF-alpha per square meter per day and two patients received 25 micrograms/m2 per day. Indirect calorimetry assessment of resting energy expenditure, body weight, serum TNF concentration, and laboratory analysis of common nutritional markers (albumin, prealbumin, and triglycerides) were performed at baseline, day 14, day 28, and 2 weeks (day 42) after completion of the infusion. There were no statistically significant differences by analysis of variance observed in any parameter during the study period compared with baseline values and values on day 42. Also, there were no differences between any parameters when stratified by dose administered, although the number of patients studied was small. Measured serum TNF concentrations ranged from 0.02 to 1.56 ng/mL and did not correlate with study day or dose of TNF infused. No correlation was observed between serum TNF concentrations and resting energy expenditure. Although others have reported significant metabolic changes associated with acute administration of TNF in humans and animals, our experience does not support a hypermetabolic state in patients receiving low daily dose, long-term (28-day) continuous infusion of recombinant human TNF-alpha, a state that may be consistent with many neoplastic conditions.

A phase I clinical and pharmacokinetic trial of hepsulfam.

Hepsulfam (1,7-heptanediol-bis-sulfamate) is one of a series of bis-sulfamate acid esters that was synthesized in an attempt to improve the antitumor efficacy of busulfan. Hepsulfam has shown broad antineoplastic activity in preclinical studies. This Phase I trial evaluated hepsulfam given as a single i.v. dose every 21-35 days. Twenty-nine patients with refractory solid tumors participated in this study. Twenty-six of these patients had had either prior chemotherapy or radiation therapy. Fifty-two courses of treatment were given at doses ranging from 30 to 360 mg/m2/day. The dose limiting toxicity was prolonged thrombocytopenia and granulocytopenia. This toxicity was cumulative with Grade 3 or 4 thrombocytopenia occurring in 3 of 15, 4 of 9, and 2 of 2 patients in the first, second, and third courses of greater than or equal to 210 mg/m2, respectively. This toxicity was noted in patients with less than or equal to 1 prior chemotherapeutic regimen, as well as in patients with greater than 1 prior chemotherapeutic regimens. Nonhematological toxicities included Grade 1 or 2 nausea and vomiting and fatigue. There was no evidence of pulmonary toxicity. Plasma levels of hepsulfam were quantified by gas chromatography in 12 patients. The plasma and blood half-lives were 15.9 +/- 4.6 and 90 +/- 13 h, respectively. No objective tumor responses were seen. We conclude that the maximally tolerated dose when hepsulfam is given as a single dose every 35 days is 210 mg/m2, but that there is significant risk of cumulative hematological toxicity at this level.

Intrapleural therapy for malignant pleural effusions. A randomized comparison of bleomycin and tetracycline.

Between December 1985 and August 1988, there were 115 patients at 13 centers who were entered on a randomized comparison of tetracycline and bleomycin for treatment of malignant pleural effusions. Fifteen patients were not treated, primarily due to rapid progression of systemic cancer. Fifteen patients entered on a high-dose regimen of bleomycin (120 units) were excluded from this analysis (following early closure of that arm), leaving 85 patients randomized to low-dose bleomycin (60 units; 44 patients) or tetracycline (1 g; 41 patients). Patients were required to have a cytologically positive pleural effusion, good performance status (0, 1, or 2), lung reexpansion following tube thoracostomy with drainage rates of 100 ml/24 or less, no prior intrapleural therapy, no prior systemic bleomycin therapy, no chest irradiation, and no recent (four weeks) change in systemic therapy. A total of 11 patients (five with bleomycin and six with tetracycline) were not evaluable due to technical problems with tube drainage (one), loss to follow-up (two), sudden death due to pulmonary embolus (one), and rapid progression of systemic disease (seven). There were no clinically significant differences in demographic factors, primary site, performance status, or presence of metastases other than pleural effusion. Overall survival did not differ between the two groups. Median time to recurrence or progression of the effusion was 32 days for tetracycline-treated patients and at least 46 days for bleomycin-treated patients (p = 0.037). The recurrence rate within 30 days of instillation was 36 percent (10/28) with bleomycin and 67 percent (18/27) with tetracycline (p = 0.023) (not all patients were restudied in the first 30 days). By 90 days the corresponding recurrence rates were 30 percent (11/37) for bleomycin and 53 percent (19/36) for tetracycline (p = 0.047). Toxicity was similar between groups.

Phase I evaluation of 773U82.HCl, a member of a new class of DNA intercalators.

The arylmethylaminopropanediols (AMAPs) are a new class of DNA intercalators. 773U82.HCl is the second of these compounds to enter clinical trial. Significant antitumor activity for 773U82.HCl was documented in a variety of murine and human tumor models. This phase I study examined a 1-, 2- and 6-hour infusion given every 28 days. Thirty-six patients received 58 courses of drug at doses ranging from 15 mg/m2 to 980 mg/m2. The dose-limiting toxicity of 773U82.HCl was hemolysis noted at 980 mg/m2. Change in color of the plasma and decreases in haptoglobin were correlated with drug concentrations of the infusate greater than or equal to 3 mg/ml. Clinically significant changes in hemoglobin levels requiring blood transfusions did not occur. Neurologic toxicity occurred at 720 mg/m2 with the most severe neurologic toxicity occurring in a patient with the highest peak plasma concentration (4.1 micrograms/ml). With an increase in duration of the infusion and amount of fluid administered, the neurologic toxicity resolved. Other toxicities included mild nausea and vomiting and a dose-related phlebitis. Pharmacokinetic studies were completed in 22 patients. The mean terminal t1/2 beta was 4.4 h with a mean apparent volume of distribution at steady state (Vdss) of 314 l/m2. The mean total body clearance was 72 l/h/m2. Peak plasma levels ranged from 0.04 to 4.14 micrograms/ml. Further studies with 773U82.HCl on this schedule at the doses studied are not recommended. Hematologic monitoring for evidence of intravascular hemolysis should be included in future studies with 773U82.HCl.

A phase I trial of taxol given by a 6-hour intravenous infusion.

Taxol is a unique mitotic inhibitor that has entered phase II investigation. Phase I studies demonstrated hypersensitivity reactions that were related to the cremophor vehicle and to the rate of drug infusion. As a result, the time span of intravenous (IV) infusion of taxol was routinely prolonged to 6 hours or beyond, and premedication with diphenhydramine, dexamethasone, and cimetidine was initiated. Early studies showed antitumor activity, especially against malignant melanoma and ovarian carcinoma. This phase I trial was performed giving taxol, as a 6-hour IV infusion every 21 days, without premedication. The purpose was to study the necessity of premedication and its impact on toxicity and pharmacokinetics. Thirty-one patients received 64 assessable courses of taxol. One patient had a hypersensitivity reaction, which was easily controlled using routine measures. Myelosuppression was dose-limiting, but sporadic, with two fatalities due to sepsis. Nonhematologic toxicity was of grade 1 and 2 except for one patient with grade 3 mucositis and two patients with grade 3 neuropathy. The neuropathy consisted of reversible painful paresthesias, requiring discontinuation of drug in two patients. Four partial responses were seen (three in patients with non-small-cell lung cancer, one in a patient with adenocarcinoma of unknown primary). Pharmacokinetic values were consistent with those previously reported. The occurrence of myelosuppression or neurotoxicity appeared to be associated with the area under the concentration x time curve (AUC) of taxol. The recommended phase II starting dose on this schedule is 225 mg/m2. Taxol merits broad investigation at the phase II level.

Idarubicin: a second-generation anthracycline.

Because of its in vitro activity in leukemic cell lines and Phase I studies of acute leukemia, Phase II and III clinical trials with idarubicin hydrochloride were conducted in patients with acute lymphocytic leukemia or acute nonlymphocytic leukemia. In the Phase III comparative trials between the combinations of idarubicin and cytarabine and daunorubicin hydrochloride and cytarabine, the idarubicin/cytarabine combination resulted in significantly greater complete remission rates and longer overall survival in two of three studies conducted in the US. As a result, the Food and Drug Administration approved intravenous idarubicin with a Class 1A rating in September 1990 for use in combination with other antileukemic drugs (e.g., cytarabine) for the treatment of acute myelogenous leukemia in adults. The recommended dose of idarubicin is 12 mg/m2 daily for three days by slow intravenous injection in combination with cytarabine. Although idarubicin causes myelosuppression similar to that described with daunorubicin, the incidence of cardiotoxicity in animal models is lower. Idarubicin also has the advantage of oral administration, but the oral formulation of the drug remains investigational. The use of idarubicin in pediatric patients also remains to be established.

Phase I clinical and pharmacokinetic trial of flavone acetic acid.

Flavone acetic acid is a synthetic benzopyrone derivative with an unknown mechanism of action. Thirty-eight patients (30 men and 8 women) were treated once a week for 4 weeks every 5 weeks with doses of flavone acetic acid ranging from 0.33 to 12.5 g/m2. At doses less than or equal to 3.9 g/m2, the drug was administered intravenously over 1 hour; at doses greater than or equal to 5.28 g/m2, the infusion period was lengthened to 6 hours. Treatment of all patients included hydration before and after treatment and alkalization to maintain urine pH at greater than or equal to 6.5. A dose-limiting toxic effect was hypotension at 10 g/m2. Pharmacokinetic studies revealed linear behavior in the eight patients studied, beginning at 3.9 g/m2. Peak plasma levels ranged from 125 to 630 micrograms/mL, with a mean terminal half-life of 22.4 hours. Immunologic monitoring was performed in three patients at 10 g/m2. A transient increase in CD16- and/or Leu-19-positive cells was noted in all three patients. In one patient, this increase correlated with a 10-fold increase in K562 cell killing. There were no objective tumor responses seen in this trial. The recommended phase II dose on this schedule is 8 g/m2. Further studies to elucidate the drug's mechanism of action and to define its immunologic properties are recommended.

Phase I evaluation of crisnatol (BWA770U mesylate) on a monthly extended infusion schedule.

Crisnatol is an arylmethylaminopropanediol derivative that has shown promise as an antitumor agent in preclinical testing. In a phase I trial using a monthly six-hour infusion schedule the recommended dose for future phase II trials was found to be 388 mg/m2. Neurologic toxicity was dose-limiting in that trial and correlated with the attainment of a threshold plasma concentration of greater than 4.5 micrograms/ml. In this study we treated 15 patients with escalating doses of crisnatol from 450 mg/m2 to 900 mg/m2 administered at a rate of 50 mg/m2/hr over 9, 12, 15, and 18 hours. Toxicity was mild to moderate at all dose levels. However, serious central nervous system effects were noted in one patient at 900 mg/m2 over 18 hours whose plasma level was 6.5 micrograms/ml. This study has demonstrated higher total doses of crisnatol can be given if the drug is administered as a prolonged infusion in an attempt to avoid high plasma levels of the agent.

Rational use of antibiotics in the critically ill patient.

Despite the advent of newer broad-spectrum antibiotics, infection in critically ill patients still is associated with significant morbidity and mortality. For these patients, who frequently receive inappropriate and excessive empiric antibiotic therapy, it is important to develop rational drug usage criteria. Current economic forces, including personnel shortages and the effects of diagnosis-related groups, are also a critical factor in this patient population. Criteria for rational antibiotic selection are based on patterns of infection and knowledge of the pharmacokinetic and pharmacodynamic properties of individual antibiotics. The development and use of treatment protocols, or algorithms, will provide quality patient care for the lowest overall cost.

Understanding cancer pain.

The pathogenesis of cancer pain, the incidence of pain associated with specific types of malignant tumors, and the nature of acute and chronic pain are discussed, and alternative delivery systems for pain management are described. More than 80% of cancer patients with advanced metastatic disease suffer moderate to severe pain. Most cancer pain is caused by direct tumor infiltration; approximately 20% of cancer pain may be attributed to the effects of surgery, radio-therapy, or chemotherapy. The incidence of cancer pain is related to tumor type; 70% or more of patients with tumors of the bone, cervix, and ovaries suffer cancer-related pain, while only 5% of patients with leukemia have pain. Pain is defined by the organs involved. Somatic pain is usually dull and well localized; visceral pain is generalized and difficult to describe. Other types of pain, including deafferentation pain and referred pain, are particularly difficult to manage. Cancer pain may be acute or chronic. The latter may cause psychological reactions that make effective treatment more challenging. Opiate analgesic agents, administered by the epidural or intrathecal routes, block pain more selectively and produce fewer adverse reactions than systemic analgesic agents. The duration and onset of analgesia depend on the lipophilicity of the agent used. Because pain is the most common complaint of the patient with cancer, clinicians should be aware of the range of pharmacologic and nonpharmacologic analgesic modalities available to them. Familiarity with newer modalities and delivery routes, such as spinal administration of opiate analgesics, is recommended.

Head and neck cancer: detection and therapeutics.

The stage of disease remains the major prognostic indicator for head and neck cancer. Five-year survival declines as the disease stage progresses. Currently, only stage I and stage II head and neck cancers are curable; thus, early detection is imperative. Treatment for stage III and stage IV disease is only palliative. Pharmacists can promote early detection by educating high-risk populations (patients who drink and smoke) and monitoring their use of nonprescription medications for palliation of symptoms. Patients with risk factors and symptomatology of head and neck cancer should be referred for proper medical evaluation. Thus, through education and communication, pharmacists can play an important role in the early detection and treatment of head and neck cancers.