A dose escalation trial of adjuvant cyclophosphamide and epirubicin in combination with 5-fluorouracil using G-CSF support for premenopausal women with breast cancer involving four or more positive nodes.

BACKGROUND: Dose-dense and dose-intensive regimens have improved the outcome of breast cancer in high-risk women with operable disease. PATIENTS AND METHODS: Sixty-three premenopausal women with Stage 2, 3 breast cancer and > or =4 positive axillary nodes were treated in three successive cohorts with 70 mg/m(2) of epirubicin, 500 mg/m(2) of 5-fluorouracil and G-CSF every 14 days for 12 cycles. Cyclophosphamide (C) was given at 700 mg/m(2), 900 mg/m(2), and 1100 mg/m(2) doses. Patients were evaluated for dose-limiting toxicities (DLTs) in the first four cycles, the primary endpoint of the trial. RESULTS: No DLTs were seen at C 700 mg/m(2); at C 900 mg/m(2) two of 16 patients experienced febrile neutropenia and poor performance status; at C 1100 mg/m(2), 1 of 31 patients experienced poor performance status. Over 6 months, febrile neutropenia, grade 4 thrombocytopenia, grade 3 anemia and severe fatigue were observed. Clinical congestive heart failure occurred in three patients over 4 years. CONCLUSION: A dose-intense and dose-dense regimen of cyclophosphamide, epirubicin and 5-fluorouracil was delivered with G-CSF without apparent increase in acute toxicity. Cyclophosphamide could be increased to more than twice the standard dose at the cost of more anemia and fatigue.

Phase I and pharmacokinetic study of BMS-184476, a taxane with greater potency and solubility than paclitaxel.

PURPOSE: To assess the feasibility, toxicity, pharmacokinetics, and preliminary activity of BMS-184476 administered as a 1-hour intravenous (IV) infusion every 3 weeks. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of BMS-184476 as a 1-hour IV infusion every 3 weeks without premedication to prevent hypersensitivity reactions (HSR). Plasma sampling and urine collections were performed to characterize the pharmacokinetics and pharmacodynamics of BMS-184474. RESULTS: Thirty-four patients were treated with 78 courses of BMS-184476 at five dose levels ranging from 20 to 80 mg/m2. Dose-limiting toxicity (DLT), consisting of severe neutropenia with fever, severe diarrhea, and/or severe mucositis, was experienced during course 1 by six of nine minimally pretreated patients treated at the 70 and 80 mg/m2 dose level. In contrast, of 15 assessable patients treated at the 60 mg/m2 dose level, which is the maximum-tolerated dose (MTD) of BMS-184476 on this administration schedule, only one heavily pretreated patient developed DLT (grade 4 neutropenia with fever and grade 3 diarrhea). One patient developed a grade 2 HSR during a second course of BMS-184476 at the 40 mg/m2 dose level. A previously untreated patient with an advanced cholangiocarcinoma experienced a partial response, and a patient with an untreated carcinoma of the gastroesophageal junction had a minor response. The pharmacokinetics of BMS-184476 seemed linear in the dose range studied. Mean +/- SD values for clearance, volume of distribution at steady-state, and terminal half-life were 220 +/- 89 mL/min/m2, 402 +/- 231 L/m2, and 40.8 +/- 21.8 hours, respectively. CONCLUSION: The MTD and recommended dose for phase II evaluations of BMS-184476 is 60 mg/m2 as a 1-hour IV infusion every 3 weeks. The results of this study suggest that BMS-184476 may have several advantages compared with paclitaxel in terms of toxicity, pharmacokinetics, pharmaceutics, and administration and warrants further clinical development.

Phase III comparative study of vinorelbine combined with doxorubicin versus doxorubicin alone in disseminated metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group Study MA8.

PURPOSE: This phase III study was performed to determine the superiority of doxorubicin (DOX) and vinorelbine (VNB) (arm 1) versus DOX alone (arm 2) in metastatic breast cancer (MBC) for overall survival (OS), time to treatment failure (TTF), toxicity, and quality of life (QOL). PATIENTS AND METHODS: Three hundred three patients were randomized to DOX 50 mg/m(2) intravenously (IV) on day 1 and VNB 25 mg/m(2) IV on days 1 and 8 (arm 1) or DOX 70 mg/m(2) IV on day 1 (arm 2). Both regimens were given every 3 weeks until a cumulative DOX dose of 450 mg/m(2). After 16 of the first 65 randomized patients experienced febrile neutropenia (FN), the doses were reduced to DOX 40 mg/m(2) on day 1 and VNB 20 mg/m(2) on days 1 and 8 versus DOX 60 mg/m(2) on day 1. Eligible patients were vinca alkaloid and anthracycline naive. Chemotherapy was first-line or second-line for MBC. RESULTS: Three patients were ineligible. Thus, 300 patients were assessable for toxicity and to determine time to disease progression (TTP), TTF, and OS. Two hundred eighty-nine patients were assessable for response, and 99 responders were assessable for response duration (RD). The response rates, QOL, and median RD, TTP, and TTF were not significantly different between the arms. Median OS was 13.8 months for arm 1 versus 14.4 months for arm 2 (P =.4). Grade 3 or 4 granulocytopenia was equivalent in both arms but more grade 3/4 neurotoxicity, mild venous toxicity, and FN were seen on arm 1. CONCLUSION: The survival with DOX and VNB is not superior to DOX alone in MBC.

Racism as a clinical syndrome.

This paper examines the clinical effects of racism on its targets and, in particular, on its agents, the individuals who, wittingly or not, partake of the culture of racial privilege. It proposes a paradigm shift in regard to the clinical study of racism, and presents a structural model of racism, analogous to addiction as a disease, which holds that racism has an etiology and a clinical taxonomy that lends itself to differential diagnosis and treatment of those who manifest symptoms.

An epidemiological review of red cell transfusions in cancer chemotherapy.

OBJECTIVE: The objective of this chart review was to determine the frequency of transfusion and prevalence of anemia (hemoglobin result < 100 g/L) in patients receiving chemotherapy. DESIGN: This study was a retrospective review of medical charts. SETTING: Patients receiving chemotherapy were included from 12 tertiary care comprehensive cancer centres across Canada. MAIN OUTCOME MEASURE: The primary study outcome measure was red blood cell transfusion rate, controlling for patient variables. RESULTS: The 616 patients included had started chemotherapy in January-June 1992. For each subject, data collection finished 4 weeks after the end of the first regimen or after a maximum follow-up period of 26 weeks. Seventy-two patients (12%; 95% confidence interval 9.5% to 14.5%) were transfused for anemia (reasons other than blood loss), and 28% (95% confidence interval 24.5% to 31.5%) of the subjects were anemic during treatment. The univariate analyses of transfusion for anemia yielded significant associations with prognostic factors. In the multivariate analyses, platinum (odds ratio [OR] = 6.69) and anthracycline (OR = 3.56) chemotherapy, baseline hemoglobin (OR = 0.96) and disease stage (OR = 1.72) were statistically significant contributors. CONCLUSION: In this patient cohort, red blood cell transfusion was infrequent (12%). However, patient groups at high risk of transfusion could be identified, with platinum-based chemotherapy being the most significant contributing factor. The information obtained from this multicentre study may prove helpful in developing supportive care guidelines for the management of chemotherapy-related anemia requiring transfusion.

Phase I-II study of 5-fluorouracil, leucovorin, doxorubicin, methotrexate, and long-term oral etoposide (FLAME) in unresectable or metastatic gastric cancer.

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/m2 intravenous bolus day 1; leucovorin 20 mg/m2 intravenous bolus days 2 through 4, starting 24 hours after the methotrexate dose; 5-fluorouracil 325 mg/m2 intravenous bolus 15 minutes after leucovorin days 2 through 4; doxorubicin 25 mg/m2 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/m2 and 5-fluorouracil was escalated to 350 mg/m2. 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.

Atherosclerosis.

Atherosclerosis presents many opportunities for the primary care provider (PCP) to positively affect the patient's outcome. The preventable nature of the disease should be a major focus of the PCP's relationship with the patient. Aggressive risk factor reduction clearly is beneficial in CAD and should be addressed at each visit with at-risk patients. Once the disease is established, the PCP's goal is prevention of complications by educating the patient about the disease and by appropriate diagnostic testing and referral when indicated.

Practical management of lipid disorders.

Hyperlipidemia is a common disease that leads to considerable morbidity and mortality. It is a major risk factor for the development of atherosclerosis. Hyperlipidemia is often undertreated by medical providers. Several large, randomized trials have established the benefit of aggressive management of hyperlipidemia. Effective treatment requires a multidisciplinary approach. There are many cholesterol-lowering medications on the market. The HMG-coA-reductase inhibitors are the most efficacious and are well tolerated.

Treatment of advanced Hodgkin's disease with chemotherapy--comparison of MOPP/ABV hybrid regimen with alternating courses of MOPP and ABVD: a report from the National Cancer Institute of Canada clinical trials group.

PURPOSE: This randomized, prospective trial compares outcomes for patients with advanced Hodgkin's disease treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, and vinblastine (ABV) hybrid regimen or alternating MOPP/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). METHODS: Three hundred one patients with advanced Hodgkin's disease were randomized to receive MOPP/ ABV hybrid regimen or alternating MOPP/ABVD after stratification for prior treatment, B symptoms, and treatment center. Eligible patients were either previously untreated and found to have stage IIIB, IVA, or IVB disease or previously treated with wide-field irradiation. Responding patients received a minimum of eight cycles of chemotherapy. Those with residual disease in a localized region received irradiation between the sixth and seventh cycle of treatment. RESULTS: Response rates to the two regimens were similar. Five-year overall survival rates were 81% and 83% for MOPP/ABV hybrid and alternating MOPP/ ABVD, respectively (P = .74; 95% confidence interval [CI] for the difference, -11% to 7%). Five-year failure-free survivals were 71% and 67% for MOPP/ABV hybrid and alternating MOPP/ABVD, respectively (P = .87; 95% CI for the difference, -9% to 17%). Significantly more episodes of febrile neutropenia and stomatitis were observed with the MOPP/ABV hybrid regimen; there was no significant difference in fatal toxicity. Patients with predefined, high-quality partial responses (PR-1s) had results similar to those with complete responses (CRs). Planned subset analysis showed no significant difference in outcome between the two arms of the trial for patients with newly diagnosed disease (5-year failure-free survival rates were 70% for MOPP/ABV hybrid and 59% for alternating MOPP/ABVD; P = .180), but superiority of alternating MOPP/ABVD for patients with prior irradiation (5-year failure-free survival 94% v 73%; P = .017). CONCLUSION: MOPP/ABV hybrid and alternating MOPP/ABVD regimens are equally effective for patients with advanced Hodgkin's disease.

5-FU or UFT combined with leucovorin for previously untreated metastatic colorectal Ca.

This phase III study compares leucovorin plus fluorouracil (5-FU) 425 mg/m2, days 1 through 5, 28-day cycle, with oral leucovorin plus oral UFT (tegafur and uracil) 300 mg/m2, days 1 through 28, 35-day cycle, in terms of efficacy, safety, quality of life, and pharmacoeconomics. Eligible patients have not been treated previously and have measurable or evaluable metastatic colorectal cancer, an Eastern Cooperative Oncology Group performance status of 2 or less, and adequate bone marrow, liver, and renal functions. Patients are evaluated for response clinically and by computed tomography. Responses are determined by World Health Organization criteria. The study is nearing completion, with no toxicity issues requiring protocol modification. The results of this study could lead to a change to oral therapy as the standard of care for metastatic colorectal cancer, providing the efficacy and toxicity of UFT/leucovorin are at least equivalent due to the ease of administration and patient preference for oral regimens.

The effect of socioeconomic status on the long-term outcome of cancer.

This study reports the 8- to 10-year follow-up of male and female patients between the ages of 25 and 70, admitted to two Ontario Regional Cancer Centres with newly diagnosed cancers of a number of common sites. Information was gathered by interview on education, occupation, and chronic illnesses other than cancer. Stage of disease at diagnosis, exact pathologic diagnosis, date of diagnosis, treatment before and after clinic admission, and status of each patient on the last date for which information was available were obtained from clinic charts. Cox's proportional hazards model was used to examine the relationship between socioeconomic status (SES) and duration of survival, with adjustment for other significant prognostic factors. For breast and prostate, there is weak evidence that high SES is associated with improved survival; for other sites, there is no evidence that SES affected survival.

Escalated as compared with standard doses of doxorubicin in BACOP therapy for patients with non-Hodgkin's lymphoma.

BACKGROUND AND METHODS: In 1981 the Clinical Trials Group of the National Cancer Institute of Canada completed a pilot study in patients with advanced-stage non-Hodgkin's lymphoma with aggressive tumor histology. That study demonstrated the potential efficacy of escalating the dose of doxorubicin used in a regimen of bleomycin, doxorubicin, cyclophosphamide, vincristine, and prednisone (BACOP). In the present study, we compared standard BACOP (s-BACOP) with BACOP that included escalated doses of doxorubicin (esc-BACOP) in 238 patients 16 to 70 years old with previously untreated, advanced-stage intermediate- or high-grade non-Hodgkin's lymphoma. During the first 28-day cycle all patients received doxorubicin in a dose of 25 mg per square meter of body-surface area on days 1 and 8. Patients randomly assigned to receive s-BACOP subsequently received five identical cycles, whereas those assigned to receive esc-BACOP received 40 mg of doxorubicin per square meter on days 1 and 8 of five subsequent cycles if granulocytopenia (< 1000 cells per cubic millimeter) had not developed during the first cycle. RESULTS: The 119 patients assigned to the esc-BACOP regimen received doxorubicin at a significantly higher mean weekly dose intensity (13.5 vs. 10.4 mg per square meter per week, P < 0.001) and mean total dose (296 vs. 231 mg per square meter, P < 0.001). Because of granulocytopenia during the first cycle of therapy, only 56 of these patients (47 percent) received the escalated doses of doxorubicin. During a median follow-up of 65 months, there were no differences between the s-BACOP and esc-BACOP groups in response rate, overall survival, or survival without disease progression. When the patients who actually received the escalated doses of doxorubicin were compared with the patients in the s-BACOP group in whom neutropenia did not develop during the first treatment cycle, no difference between their outcomes was observed. Toxicity was greater in the esc-BACOP group. CONCLUSIONS: In patients with advanced-stage intermediate- or high-grade non-Hodgkin's lymphoma, escalating the dose of doxorubicin in the BACOP regimen increases toxicity but does not improve the rate of response or survival.

The frequency of red cell transfusion for anemia in patients receiving chemotherapy. A retrospective cohort study.

The objective of this retrospective cohort study was to determine the frequency of red cell transfusion for anemia and risk factors. It was conducted at a regional cancer center and host hospital. All patients receiving chemotherapy in 1989 were studied. Complete data were available on 381; 26 were excluded. Age, diagnosis, baseline and nadir hemoglobin, transfusion history, chemotherapy regimen, and prior treatment were abstracted from the cancer center chart and hospital medical records. Transfusion for anemia was required in 18% of all patients with solid tumors; those with lung cancer had the highest rate (34%). Patients with anemia who entered chemotherapy were more likely to be transfused. Therefore, patients with leukemia, lung cancer, and/or prior anemia have higher transfusion rates and may benefit from such therapies as recombinant human erythropoietin.

The Canadian experience with intensive fluorouracil, epirubicin and cyclophosphamide in patients with early stage breast cancer.

A multicentre dose-finding pilot study was conducted to determine an intensive regimen of fluorouracil (F), epirubicin (E) plus cyclophosphamide (C) [FEC] that was tolerable and acceptable to patients with node-positive operable (n = 266) or locally advanced (n = 22) breast cancer. Consecutive patients were treated with fluorouracil and epirubicin administered intravenously on days 1 and 8, in addition to cyclophosphamide orally for 14 days. Chemotherapy cycles were repeated at monthly intervals for 6 months, and dosages were increased according to a predetermined protocol. End-points were hospital admissions due to febrile neutropenia and changes in cardiac function as assessed by radionuclide angiography. The first 46 patients were treated with doses of F = 375 mg/m2, E = 50 mg/m2 and C = 75 mg/m2 (level 1), then 42 patients received F = 500 mg/m2, E = 50 mg/m2 and C = 75 mg/m2 (level 2), 69 patients received F = 500 mg/m2, E = 60 mg/m2 and C = 75 mg/m2 (level 3), and 42 patients received F = 500 mg/m2, E = 70 mg/m2 and C = 75 mg/m2 with concurrent antibiotics (level 4). Rates of febrile neutropenia were 8.7% (level 1), 7.1% (level 2), 18.8% (level 3), and 31% (level 4) [p = 0.002]. Accrual to level 4 was discontinued according to study protocol and a further 89 patients were recruited at level 3 dosages with antibiotic prophylaxis (level 3a), resulting in a 5.6% rate of febrile neutropenia. The difference in febrile neutropenia rates between dosage levels 3 and 3a was statistically significant (p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Modified adriamycin-vincristine-dexamethasone (m-VAD) in primary refractory and relapsed plasma cell myeloma: an NCI (Canada) pilot study. The National Cancer Institute of Canada Clinical Trials Group.

The purpose of this single arm phase II study was to test a modified version of the three drug combination vincristine, adriamycin and dexamethasone (m-VAD), in which intravenous vincristine (0.4 mg/d) and adriamycin (9 mg/m2 per day) infusions are administered for only 2 h on days 1-4 of each 28 d cycle, in patients with refractory multiple myeloma. In addition, only two 4 d courses of dexamethasone 40 mg/d was given during each cycle. The entry criteria for 44 patients included plasma cell myeloma and a measurable monoclonal peak, either refractory to initial treatment with melphalan and prednisone, or resistant to melphalan and prednisone after initially responding (resistant relapsed disease, 27 patients). Patients treated previously with chemotherapy other than melphalan and prednisone were excluded. There were no complete responses. Of the 41 evaluable patients who completed at least one course of therapy 11 had a partial response (27%, 95% C.I. 14-40%). The response rates were 19% for primary refractory disease patients, and 32% for those with resistant relapsed disease. The median duration of response was 4 months. The median survival for all 44 patients was 7.6 months (5.5 months for primary refractory patients, and 10 months for relapsed resistant disease patients). Episodes of documented bacterial infection occurred in 12 patients, and 10 patients had minor viral infection. The dexamethasone dose was reduced in 12 patients. The median neutrophil nadir was 1.2 x 10(9)/l, and median platelet nadir was 147 x 10(9)/l. Five deaths were judged as treatment related and occurred during marrow cytopenia. The results of this modified form of VAD are inferior to that reported previously for 4 d continuous infusions of vincristine and doxorubicin. This could be related to either patient selection factors, or to a reduction of the efficacy of the drug combination produced by either the shortened intravenous infusions and/or omission of one 4 d course of dexamethasone.

Jaw and other orofacial pain in patients receiving vincristine for the treatment of cancer.

This prospective cohort study investigated orofacial pain occurring as a manifestation of vincristine neurotoxicity. Forty cancer patients (28 to 63 years of age) receiving vincristine were given baseline interviews and orofacial examinations, which were repeated weekly for 7 weeks of treatment. Twenty-two patients (55%) had neurotoxicity manifesting as orofacial pain. Onset was usually 3 days after vincristine administration; mean duration was 2 days. Twenty patients (50%) were affected in the first week: nine (22%) with severe and five (12%) with moderate pain. Symptoms were mild and infrequent in subsequent weeks. Eighteen control patients receiving chemotherapy without vincristine had no comparable orofacial symptoms. Multiple sites in the distribution of the trigeminal and glossopharyngeal nerves were affected: primarily the temporomandibular joint, mandible, throat, ears, and mandibular teeth. The frequency of orofacial pain increased with younger age. Pain was significantly associated with smaller body surface area (p less than 0.05), indicating a dose-related toxicity, and with sociodemographic variables including smoking (p less than 0.05).

Orofacial complications of chemotherapy for breast cancer.

The National Institutes of Health recently recommended research initiatives to investigate oral complications of cancer chemotherapy. This prospective cohort study investigated orofacial complications of combination chemotherapy (cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone) in women with breast cancer. Thirty-four patients were given baseline interviews and examinations. Each patient was given weekly orofacial examinations and biweekly interviews for the first seven cycles of cytotoxic treatment. The orofacial complications included neurotoxicity caused by vincristine, mucositis, and candidiasis. Neurotoxicity affected 22 of 34 (65%) patients, was significantly associated with age less than 50 years (p less than 0.05), and manifested as pain in 19 of 34 (56%) patients. Mucositis affected 7 of 34 (21%) patients and was significantly associated with the occurrence of lesions of the oral mucosa at baseline examination; and smaller body surface area--indicating a dose-related toxicity (p less than 0.05). In four of the patients with mucositis (57%) granulocytopenia developed during the 7 days after the onset of mucositis. Intraoral candidiasis affected 4 of 34 (12%) patients.