Positron emission tomography for the evaluation of metastases in patients with carcinoma of the cervix: a retrospective review.

OBJECTIVES: The aim of this study was to assess the usefulness of 18-fluorodeoxyglucose positron emission tomography (PET) scanning for the evaluation of metastases (nodal and distant) in patients with carcinoma of the cervix. METHODS: A retrospective review was performed of 13 patients with carcinoma of the cervix who had a 18-fluorodeoxyglucose PET scan as part of their workup (10 during initial workup, 3 at time of relapse). Ten patients also underwent a fine needle aspiration (FNA) under imaging guidance for verification. RESULTS: All 10 patients with positive sites identified by PET scan who underwent an FNA were positive for cancer. In 3 situations PET identified sites where other imaging studies were negative. CONCLUSIONS: PET scanning is a useful imaging tool in the evaluation of patients with carcinoma of the cervix. This review supports other limited published data in this regard and suggests that further prospective studies are needed.

Influence of British national curriculum physical education on teachers' behaviours associated with pupils' psychosocial development: a case study in one English town.

The purpose of this study was to assess the influence of British National Curriculum Physical Education on the quality of physical education instruction in the five state secondary schools in one southwestern English town in terms of teachers' use of behaviours related with pupils' psychosocial development during the 1994 summer term. Subjects were the 20 physical education teachers employed at the five schools. Two lessons of each teacher's choice in which they taught any activity to pupils in Years 7, 8, and 9 were videotaped. Lessons were coded with the Coaching Behavior Assessment System, an observational instrument designed to record the rate at which teachers use behaviours positively and negatively related with pupils' psychosocial development. Data generated by this system were entered into an SPSS programme to produce descriptive statistics. Regardless of the activity being taught, teachers used behaviours related to pupils' positive psychosocial development much more frequently than they used behaviours linked with pupils' negative psychosocial development. A comparison of the data collected at these five schools during the present study with those collected in the summer term of 1992 indicated that the introduction of the National Curriculum Physical Education did not affect teachers' use of behaviours associated with pupils' psychosocial development when teaching summer activities.

Clinical trials to study pain in patients with advanced cancer: practical difficulties.

Cancer is a common cause of death in our society and associated pain is prevalent in cancer patients. Despite this, pain is often not treated optimally. Although education (patient and caregiver) might improve the situation, many difficulties remain in carrying out clinical trials of new drugs or therapies in this particular group of patients. Appropriate controlled clinical trials need to be designed to maximise validity (randomised, blinding, quality of collected data, enough evaluable patients, statistical analyses) and effectiveness. Patient numbers are often small, the diseases and mechanisms of pain non-homogenous, and assessment techniques and analgesic requirements (and tolerance) may be variable. Furthermore, pain may be unstable, polypharmacy is often involved, behavioral and other cognitive factors may change, patient compliance may be suspect, and side effect profiles may be difficult to interpret (disease, patient status, polypharmacy). Strategies that may increase validity constrain the feasibility of the study and the generalisability of the study results obtained.

Phase I pharmacokinetic study of cyclosporin A combined with doxorubicin.

We performed a phase I trial of cyclosporin A (CsA) in combination with doxorubicin (dox) to determine the maximally tolerated dose (MTD) of the combination in man, to define the quantitative and qualitative toxicities of the combination, and to determine the pharmacokinetics of the two drugs when used together. CsA was administered as a continuous infusion for 6 days, and dox was administered as a single 10-min infusion 24 h after the initiation of CsA. The starting CsA infusion rate was 5 micrograms/kg/min, and the dox starting dose was 30 mg/m2. Courses were administered every 4 weeks with first CsA and then dox being escalated in consecutive cohorts of patients until the MTD was determined. Twenty-three patients and 40 courses were evaluable for toxicity. Pharmacokinetic analysis was performed in 23 patients on the first course for whole blood CsA and plasma dox and doxorubicinol. The MTD of CsA was 6 micrograms/kg/min, and for dox it was 45 mg/m2. Dose-limiting toxicity was neutropenia. Serum creatinine and creatinine clearance did not change over the infusion period. Bilirubin increased from a median of 10 mumol/liter at the initiation of the infusion to a median of 40.4 mumol/liter at the end of the infusion but returned to normal before the next cycle of therapy. Nausea and vomiting were common and marked, whereas thrombocytopenia was mild. Two patients, one with small cell lung cancer and one with breast cancer, had stable disease while receiving treatment for 5 and 6 months, respectively. Mean whole blood steady state concentrations of CsA were 2210 ng/ml during the infusion with total body clearance of 0.177 liter/h/kg. The area under the concentration x time curve (AUC) increased linearly with dose of dox, and total body clearance was independent of dose. The mean total body clearance was 2.46 liters/h/m2, and terminal half-life was 49.6 h. The AUC for dox was greater and clearance was less than has been previously reported at the doses administered in this study. The ratio of AUC for doxorubicinol to AUC for dox was less than expected, suggesting that the metabolism and/or excretion of dox was decreased when administered with CsA. We conclude that dox can be combined with infusioned CsA but at a lower dose than when given alone. This may be due to altered metabolism and/or excretion of dox or increased bone marrow stem cell sensitivity to dox.

Phase I study of 5-fluorouracil and leucovorin by a 14-day circadian infusion in metastatic adenocarcinoma patients.

Initial experimental and clinical studies have indicated that 5-fluorouracil (5-FU) toxicity can be reduced by delivering 5-FU at around 4 a.m. More recent data have suggested that the toxicity might be reduced even more with delivery at around 9-10 p.m. The current study determined the maximum tolerated dose (MTD) for 5-FU and leucovorin (LV) delivered as a continuous circadian infusion over 14 days every 28 days, with the peak of the infusion occurring at around 3-4 a.m. The peak drug delivery was shifted to 9-10 p.m. in all patients developing toxicity of > or = grade II (Eastern Cooperative Oncology Group) to determine if this timing further reduced toxicity and enabled increased dose intensity. A total of 14 patients with metastatic adenocarcinoma received an admixture of 5-FU and LV via a programmable portable infusion pump, with 62.5% of the 24-h dose being given over 7 h around the infusion peak. The starting dose level of 5-FU (200 mg/m2 daily) and LV (5 mg/m2 daily) was that established as the highest tolerable dose rate in a previously reported phase I study using a 14-day flat infusion of 5-FU and LV. The LV dose was first escalated to 20 mg/m2 daily, followed by escalations of the 5-FU dose. A total of 51 courses were evaluable for toxicity. The dose-limiting toxicity was oral mucositis and hand-foot syndrome. More dose intensity could be delivered using a circadian infusion peaking at around 3-4 a.m. than was possible with a flat infusion of these drugs. Toxicity was reduced even further with peak drug delivery at around 9-10 p.m. The recommended dose for phase II studies using this schedule is 250 mg/m2 5-FU daily and 20 mg/m2 LV daily with the peak of the infusion occurring at 9-10 p.m. This is a 300% and 25% higher dose for LV and 5-FU, respectively, than was found to be safe for a flat infusion.

Phase I pharmacokinetic and pharmacodynamic study of a new anthrapyrazole, CI-937 (DUP937).

We performed a phase I trial of CI-937 (DUP937), an anthrapyrazole, with the following objectives: (a) to determine the maximally tolerated dose in humans; (b) to define the toxicity spectrum of this agent; (c) to describe the pharmacokinetics of the drug; (d) to test a pharmacokinetics based hypothesis of dose escalation; and (e) to relate drug pharmacokinetics to pharmacodynamics. CI-937 was administered as a single bolus injection every 3-4 weeks at doses ranging from 3.6 to 25.2 mg/m2. Thirty-two patients and 57 courses were evaluable for toxicity. Pharmacokinetic analysis was performed in 30 patients on the first course using a sensitive and selective radioimmunoassay. The maximally tolerated dose in patients with no prior therapy was 25.2 mg/m2 and dose-limiting toxicity was neutropenia. Thrombocytopenia, nausea, vomiting, stomatitis, and alopecia were mild. A partial response was recorded in a patient with mesothelioma. The area under the curve increased linearly with dose, and total body clearance of CI-937 was independent of dose. The mean total body clearance was 107 +/- 55.8 ml/min/m2, mean steady state volume of distribution was 492 +/- 469 liters/m2, and terminal half-life was 3.78 +/- 2.86 days. The extended factors of 2 methods of pharmacologically guided dose escalation were intended for use but ultimately were equivalent to that of the modified Fibonacci dose escalation method. Dose and the area under the curve were significant predictors of a percentage change in WBC and neutrophil count in a univariate analysis. Only dose and baseline neutrophil count predicted a percentage change in WBCs in a multifactor analysis. Dose and prior chemotherapy predicted percentage change in neutrophil count in a multifactor analysis. We conclude that the dose-limiting toxicity of CI-937 is neutropenia and that the recommended phase II starting dose is 22 mg/m2.

Transdermal scopolamine use in the control of narcotic-induced nausea.

Nausea affects from 40% to 70% of cancer patients who received narcotics to manage their pain. This occurs more frequently when they are ambulatory than when they are recumbent and may be the result of narcotic-enhanced labyrinthine sensitivity to motion. Scopolamine has previously been found to be an effective antiemetic for motion sickness. In a prospective pilot study, 9 (69%) of 13 cancer patients experienced rapid relief of their narcotic-induced nausea when they used Scopolamine Transderm-V patches alone. Only two patients experienced side effects with the scopolamine, and in one patient, the side effects may have been dose related. Although tolerance to the increased vestibular sensitivity may occur, this was not universal. Further prospective trials are necessary to establish whether transdermal scopolamine is useful in controlling the narcotic-induced nausea experienced by cancer patients.

A cost-minimization study of cancer patients requiring a narcotic infusion in hospital and at home.

We conducted a retrospective, non-randomized, cost-minimization study, from the perspective of the Ministry of Health, to compare the cost of managing cancer patients who required narcotic infusions, in hospital and at home. Our medical costs averaged $369.72 per inpatient day and $150.24 per outpatient day (saving $219.48 per diem, 1988 Canadian dollars), while narcotic costs were the same for any given patient in both settings. Sensitivity analysis showed that no reasonable changes in the quantity and cost of services reduced our savings by more than 50%. During incremental analysis, savings increased as more outpatient days were managed by our centre, from $0.00 for 318 days, to more than $500,000 for over 2000 days per annum. As this program has been extremely cost effective and preferred by our patients, other hospitals and central funding agencies might consider establishing a regional outpatient narcotic infusion program to reduce their costs.

Phase II study of trimetrexate in recurrent anaplastic glioma. National Cancer Institute of Canada Clinical Trials Group Study.

The National Cancer Institute of Canada Clinical Trials Group conducted a phase II trial of trimetrexate given in a daily x 5 intravenous bolus schedule every 3 weeks in patients with measurable recurrent anaplastic glioma and limited prior treatment. There were no responses in 14 evaluable patients. We conclude that trimetrexate, given as described, is not an active agent in this disease.

Inpatient narcotic infusions for patients with cancer pain.

Morphine and hydromorphone infusions of 6 or more (average 25.75) days in duration were used with increasing frequency (up to 7%) by our oncology inpatients. Eighty-six percent of the 135 inpatients we reviewed realized good pain control with dose rates up to 700 morphine-equivalent (ME) mg/h. Local toxicity occurred on only 10 occasions. Systemic side effects secondary to the infusion were reported 75 times and were generally readily reversed. Myoclonus was seen in 11% of our patients at dose rates as low as 60-90 ME mg/h. Adjuvant therapies were not used as frequently as might be warranted. We believe that narcotic infusions, particularly subcutaneous ones, are safe and effective. Further prospective trials are needed to clarify how they should be combined with other therapies to control cancer pain that is poorly responsive to narcotics, and to better understand the etiology and management of serious side effects.

Continuous narcotic infusion with patient-controlled analgesia for chronic cancer pain in outpatients.

STUDY OBJECTIVE: To determine the feasibility and safety of outpatient continuous narcotic infusions with additional bolus capabilities (patient-controlled analgesia) in patients with cancer pain. DESIGN: A single arm (non-randomized) series. SETTING: Outpatient with contact by telephone and through outpatient clinic. PATIENTS: Consecutive series of 18 patients with poorly controlled cancer pain or significant side effects from regular administration of various narcotics. INTERVENTIONS: Patients taught and supervised to use portable pump capable of delivering a continuous narcotic infusion with bolus capabilities. MEASUREMENTS AND MAIN RESULTS: All patients had improvement in pain control as judged by the use of a linear analogue scale. Side effects and safety profile were highly acceptable. Narcotics used and maximum doses were meperidine, 50 mg/h; morphine, 80 mg/hr; and hydromorphone, 60 mg/hr. Infusion duration ranged from 7 to 225 days (mean, 54 days). CONCLUSIONS: Continuous narcotic infusions using a programmable portable pump with bolus capabilities is a safe and reliable method of delivering narcotics to outpatients.

Re-evaluating the cost of outpatient cancer chemotherapy.

Chemotherapy for common malignant tumours has historically been considered relatively expensive. An examination of costs at the Toronto-Bayview Regional Cancer Centre and Sunnybrook Medical Centre, Toronto, suggests that this perception is not accurate. The cost of chemotherapeutic agents administered on an outpatient basis over 4 to 6 months in established drug protocols ranged from $260 to $5374 (mean $2224). The total cost of outpatient administration was estimated to be $152.53 per dose, compared with $185.39 for inpatient administration of the same protocol, a difference of 22%. The difference was predominantly due to a higher allocated per-diem charge at the medical centre. The results indicate that outpatient administration reduces the overall cost of chemotherapy.

Drug extravasation along the route of a peritoneal catheter during intraperitoneal chemotherapy.

A patient receiving intraperitoneal chemotherapy with cisplatin and cytosine arabinoside developed an abdominal skin rash similar in appearance to Cullen's sign. She subsequently received intraperitoneal mitoxantrone, which became visible in the skin close to the peritoneal catheter tract in the region of the skin rash within 24 hours of drug administration. There was no evidence for drug extravasation from the entry portal of the peritoneal catheter or visible fluid leakage. Although the clinical picture was dramatic there was no significant clinical sequela to the extravasation of these drugs. The potential significance of this event is discussed.

Phase I and pharmacokinetic study of high volume intraperitoneal aclacinomycin-A (Aclarubicin).

Aclacinomycin-A (Aclarubicin) is a relatively new anthracycline antibiotic with potential activity against ovarian cancer. Eight patients with various malignancies (4 ovary, 1 breast and ovary, 1 breast, 1 colon, 1 leiomyosarcoma) and intraperitoneal disease were treated in a Phase I trial with escalating doses of intraperitoneal Aclacinomycin. Drug treatments were administered through a peritoneal catheter in a 2 liter fluid volume (1.5% Dianeal). Seventeen cycles were administered with doses ranging from 25 to 75 mg of Aclacinomycin. Pharmacokinetic studies were carried out in 7 patients. Although high concentrations of Aclacinomycin could be obtained in the peritoneal cavity no drug was detected in the plasma. The major dose-limiting toxicity was chemical peritonitis. Two patients had reduction in the amount of ascites. The recommended dose for Phase II trials is Aclacinomycin 50 mg in 2 liters given every 2 weeks.

Phase I and pharmacokinetic study of tiazofurin (TCAR, NSC 286193) administered by continuous infusion.

Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, TCAR) is a synthetic C-nucleoside that demonstrated significant in vivo activity against a variety of animal tumors as well as in vitro activity against human tumor-derived cell lines. Thirteen patients were treated with TCAR administered as a 5-day continuous infusion in this Phase I trial. Seventeen complete cycles were administered in three dose levels ranging from 550 to 1450 mg/M2. Dose-limiting toxicities were myelosuppression and neurotoxicity including severe lethargy. Other toxicities including superficial skin peeling, myalgias, and tearing were seen at all doses. One patient had chest pain on day 4 resulting in stopping the drug, however, there was no evidence of cardiac or pericardial disease. Uric acid levels rose within one day in the absence of allopurinol treatment. There were no treatment related deaths. HPLC measurement of drug levels demonstrated steady-state plasma levels during the infusion, and a half-life following the infusion of 7.7 +/- 0.6 hours. Minor abnormalities in renal function were associated with dramatic changes in pharmacokinetics and toxicity. No clinical responses were observed in this trial.