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The objective of this phase I-II study was to determine the efficacy and toxicity of combination chemotherapy with 5-fluorouracil, leucovorin, doxorubicin, methotrexate, and oral etoposide (FLAME) in patients with measurable unresectable or metastatic gastric cancer. Starting doses on the phase I study were as follows: methotrexate 50 mg/m 2 intravenous bolus day 1; leucovorin 20 mg/m 2 intravenous bolus days 2 through 4, starting 24 hours after the methotrexate dose; 5-fluorouracil 325 mg/m 2 intravenous bolus 15 minutes after leucovorin days 2 through 4; doxorubicin 25 mg/m 2 intravenous bolus day 8; and oral etoposide 50 mg/day for 14 days, starting on day 8. A new cycle started on day 28. A total of 42 patients were treated-10 patients in the phase I study and 32 patients in the phase II study. Dose-limiting toxicity was encountered in the phase I study on the second escalation step, when doxorubicin was escalated to 30 mg/m 2 and 5-fluorouracil was escalated to 350 mg/m 2 . In the phase II study 28 patients (109 courses) were evaluable for toxicity. Neutropenia grade 3 or more was dose limiting and was documented in 12 patients (43%) during 22 treatment courses (20%). Neutropenia was associated with febrile neutropenia requiring hospitalization in four patients during five courses of therapy. Grade 3 stomatitis and grade 3 diarrhea was infrequent, documented in two patients (two courses) and three patients (four courses), respectively. All other toxicity was grade 1 and grade 2. The combined objective response rate in 38 evaluable patients entered in both studies was 23.3% (six partial responses and one complete response). Stable disease was documented in 15 patients (39.5%). The median survival for the 42 patients entered in both trials was 6.9 months (95% confidence interval, 5.9-8.5 months). The objective response rate and median survival for the combined group is comparable with that reported for the etoposide, leucovorin, and 5-fluorouracil (ELF), and 5-fluorouracil and methotrexate (FMTX) regimens in a recently reported, multicenter, phase III study.

PURPOSE Taxol (paclitaxel; Bristol-Myers Squibb, Wallingford, CT) is a new anticancer agent with activity in a number of human tumors, including epithelial ovarian cancer. In nonrandomized trials, doses studied have ranged from 135 mg/m2 to 250 mg/m2 administered over 24 hours with premedication to avoid hypersensitivity reactions (HSRs). This study addressed two questions: the dose-response relationship of Taxol in relapsed ovarian cancer and the safety of a short infusion given with premedication. METHODS Women with platinum-pretreated epithelial ovarian cancer and measurable recurrent disease were randomized in a bifactorial design to receive either 175 or 135 mg/m2 of Taxol over either 24 or 3 hours. Major end points were the frequency of significant HSRs and objective response rate. Secondary end points were progression-free and overall survival. RESULTS Of 407 patients randomized, 391 were eligible and 382 assessable for response. Analysis was performed according to the bifactorial design. Severe HSRs were rare (1.5% patients) and were not affected by either dose or schedule. Response was slightly higher at the 175-mg/m2 dose (20%) than at 135 mg/m2 (15%), but this was not statistically significant (P = .2). However, progression-free survival was significantly longer in the high-dose group (19 v 14 weeks; P = .02). Significantly more neutropenia was seen when Taxol was administered as a 24-hour infusion. Response rates were similar in the 24- and 3-hour groups (19% and 16%, respectively; P = .6). No survival differences were noted. CONCLUSION The 3-hour infusion of Taxol is safe when given with premedication and is associated with less neutropenia. There is a modest dose effect with longer time to progression at 175 mg/m2. The observation that longer infusion produces more myelosuppression but does not yield higher response rates should lead to further studies to determine the optimal dose and schedule of this interesting new agent.

PURPOSE: To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic (PK) profile of paclitaxel and carboplatin when administered every 3 weeks with the oral semisynthetic cyclosporine analog valspodar (PSC 833), an inhibitor of P-glycoprotein function. PATIENTS AND METHODS: Fifty-eight patients were treated with escalating doses of paclitaxel ranging from 54 to 94.5 mg/m2 and carboplatin area under the plasma concentration versus time curve (AUC) ranging from 6 to 9 mg·min/mL, every 21 days. The dose of valspodar was fixed at 5 mg/kg every 6 hours for a total of 12 doses from day 0 to day 3. The MTD was determined for the following two groups: (1) previously treated patients, where paclitaxel and carboplatin doses were escalated; and (2) chemotherapy-naïve patients, where paclitaxel dose was escalated and carboplatin AUC was fixed at 6 mg·min/mL. PK studies of paclitaxel and carboplatin were performed on day 1 of course 1. RESULTS: Fifty-eight patients were treated with 186 courses of paclitaxel, carboplatin, and valspodar. Neutropenia, thrombocytopenia, and hepatic transaminase elevations were DLTs. In previously treated patients, no DLTs occurred at the first dose level (paclitaxel 54 mg/m2 and carboplatin AUC 6 mg·min/mL). However, one of 12, two of six, two of four, four of 11, and two of five patients experienced DLTs at doses of paclitaxel (mg/m2)/carboplatin AUC (mg·min/mL) of 67.5/6, 81/6, 94.5/6, 67.5/7.5, and 67.5/9, respectively. In chemotherapy-naïve patients, one of 17 developed DLT at paclitaxel 81 mg/m2 and carboplatin AUC 6 mg/mL·min. There was prolongation of the terminal phase of paclitaxel elimination as evidenced by an increased time that plasma paclitaxel concentration was ≥ 0.05 μmol/L, ranging from 16.6 ± 6.7 hours to 41.5 ± 9.8 hours for paclitaxel doses of 54.5 mg/m2 to 94.5 mg/m2, respectively. CONCLUSION: The recommended phase II dose in chemotherapy-naïve patients is paclitaxel 81 mg/m2, carboplatin AUC 6 mg·min/mL, and valspodar 5 mg/kg every 6 hours. In previously treated patients, the recommended phase II dose is paclitaxel 67.5 mg/m2, carboplatin AUC 6 mg·min/mL, and valspodar 5 mg/kg every 6 hours. The acceptable toxicity profile supports the rationale for performing disease-directed evaluations of paclitaxel, carboplatin and valspodar on the schedule evaluated in this study.

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.

A total of 23 women with stage II breast cancer receiving adjuvant cyclophosphamide, methotrexate and 5-fluorouracil had detailed pharmacokinetic monitoring performed on the first and third courses of therapy. The area under the concentration time curve (AUC) of each of these three drugs varied by a factor of 3–4 among patients. No systematic change in pharmacokinetics between the first and third courses was seen for cyclophosphamide, methotrexate or 5-fluorouracil, and the mean AUC for each of the three drugs did not change. However, significant intrapatient variability in drug pharmacokinetics was observed for all three drugs such that the AUC, clearance and half-life in an individual on the third course could not be reliably predicted from data generated on the first course. On the basis of these results, cyclophosphamide, methotrexate, and 5-fluorouracil pharmacokinetic data from one treatment would not be useful information from which the doses for subsequent courses could be determined.

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.

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.

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 Acla-cinomycin 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.

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.

The National Cancer Institute of Canada Clinical Trials Group conducted a phase II study of spirogermanium given daily for 5 days every 3 weeks to previously untreated patients with malignant melanoma. In 21 evaluable patients one complete response was seen (response rate 5%). Disease progression occurred in the other 20 patients. Toxicity was primarily neurologic and mild or moderate in most patients, though there was one treatment related death. In this schedule spirogermanium has extremely limited activity against malignant melanoma and will not contribute significantly to the systemic therapy of this disease.

Eighteen evaluable patients were studied to determine whether individual methotrexate (MTX) kinetics, determined by test-dose bolus injection, could be used to predict plasma drug concentrations during and after high-dose infusion. Small nontoxic doses of MTX (10 mg/m2) was given to patients who were followed for 12 to 24 hr and the kinetic data were used to predict subsequent kinetic behavior of moderate- and high-dose methotrexate infusions (150 to 1500 mg/m2 over 12 to 18 hr). After test-dose injection, MTX clearance varied from 36 to 138 ml/min/m2 and decreased with advancing age (r = -0.49, P less than 0.05). MTX clearance varied from 24 to 100 ml/min/m2 after high-doses. Although there was a trend to decreasing clearance with advancing age, this was not as clear as with the test dose (r = -0.42, P greater than 0.05). There was no correlation between MTX clearance and creatinine clearance in this group of patients in whom creatinine clearance varied from 32 to 63 ml/min/m2. When the kinetic parameters derived from the test-dose data were used, accurate predictions could be made of the infusion plateau (r = 0.89, P less than 0.001) and 24-hr (r = 0.92, P less than 0.001) MTX concentrations after high-dose infusions. Our results indicate that test-dose MTX kinetics may serve as a guide to dose modification of MTX infusions in some high-risk patients.

To determine the feasibility and safety of outpatient continuous narcotic infusions with additional bolus capabilities (patient-controlled analgesia) in patients with cancer pain.A single arm (non-randomized) series.Outpatient with contact by telephone and through outpatient clinic.Consecutive series of 18 patients with poorly controlled cancer pain or significant side effects from regular administration of various narcotics.Patients taught and supervised to use portable pump capable of delivering a continuous narcotic infusion with bolus capabilities.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).Continuous narcotic infusions using a programmable portable pump with bolus capabilities is a safe and reliable method of delivering narcotics to outpatients.

Excerpt To the editor: In their recent report, Reed and associates (1) suggest that venous access ports should only be used for short-duration drug infusions and that alternate devices (for example...