Biomedical subjects

V Bramwell

Publications and source records attributed to V Bramwell.

At least 19 recordsLinked to original sources

PubMed2006

A phase II study of perifosine (D-21226) in patients with previously untreated metastatic or locally advanced soft tissue sarcoma: A National Cancer Institute of Canada Clinical Trials Group trial.

UNLABELLED: BACKGROUND/PATIENTS AND METHODS: 16 adult patients with untreated measurable locally advanced or metastatic inoperable soft tissue sarcoma were treated with oral perifosine, a synthetic alkylphospholipid, believed to inhibit MAP kinase (MAP-K), protein kinase C (PKC), Akt and other regulatory proteins. Perifosine was administered orally in cycles for 21 days out of 28. Loading doses were given day 1 each cycle (900 mg cycle 1, 300 mg cycle 2+) and 150 mg daily was given days 2-21 of each cycle. Cycles were repeated until disease progression, unacceptable toxicity or patient refusal. RESULTS: Seventeen patients were enrolled; 16 and 15 were evaluable for toxicity and response, respectively. A total of 30 cycles of perifosine were administered. Most toxic effects were grade 1 or 2 and commonly included nausea, vomiting, diarrhea, and fatigue (> or =40%). Hematologic toxicity was generally mild. There were no significant biochemical abnormalities due to the drug reported. There were 4 serious adverse events (SAE)-none of which was related to perifosine. No objective responses were seen; 4 patients had stable disease for 1.3 to 8.2 months and the remainder of the patients had progressive disease. CONCLUSIONS: Perifosine when given according to this dosing schedule does not show evidence of activity in a mixed population of adult soft tissue sarcoma patients.

Academies and Institutes↗

PubMed1999

The treatment of distant metastases in soft tissue sarcoma.

This article reviews the current standard approaches to the treatment of metastatic soft tissue sarcoma (STS) and evaluates new chemotherapy agents and novel approaches. A computerized search strategy was used to identify articles examining the role of chemotherapy and surgery in metastatic STS, which were published between January 1992 and December 1998. This search was supplemented by key articles from our files published before 1992. In selecting articles for inclusion in this review, emphasis was placed on randomized data and novel approaches. Only three agents-doxorubicin, ifosfamide, and dacarbazine-have shown significant activity in metastatic STS. Numerous studies have examined the efficacy and toxicity of combining the known active agents in standard doses or in high doses with cytokine support. Promising results, in terms of increased response rates, often have not been reproduced in randomized trials, and there is no convincing evidence of enhanced overall survival. New regimens should be evaluated in randomized trials incorporating quality-of-life endpoints. High-dose chemotherapy with bone marrow/stem cell rescue remains an investigational procedure of uncertain efficacy. Pilot studies have established the feasibility of intraperitoneal chemotherapy, after cytoreductive surgery, in patients with peritoneal sarcomatosis. To date, the efficacy of this approach has not been validated in phase II or III trials. The role of surgery in the treatment of isolated pulmonary metastases is well established. Results of small series raise the possibility that resection of hepatic metastases is beneficial in selected patients. Current chemotherapy options for patients with STS are limited. There is reason to hope that the situation will change with the further development of new agents that have novel and specific mechanisms of action.

Antineoplastic Agents, Alkylating↗

PubMed1999

Use of dexrazoxane as a cardioprotectant in patients receiving doxorubicin or epirubicin chemotherapy for the treatment of cancer. The Provincial Systemic Treatment Disease Site Group.

GUIDELINE QUESTIONS: 1) Should dexrazoxane be used routinely in patients with advanced or metastatic cancer who are at risk of developing cardio toxicity when receiving chemotherapy containing doxorubicin or epirubicin? 2) Do the available data support the use of dexrazoxane when anthracyclines are being used in the adjuvant setting for patients at risk of developing cardiotoxicity? OBJECTIVE: To make recommendations regarding the use of dexrazoxane to prevent cardiotoxicity in patients with nonhematological malignancies who are receiving anthracycline- containing chemotherapy. OUTCOMES: Clinical and subclinical cardiotoxicity, noncardiac toxicity and impact on efficacy outcomes such as response and overall survival are considered. PERSPECTIVE (VALUES): Evidence was selected, reviewed and synthesized by 2 members of Cancer Care Ontario's Systemic Treatment Disease Site Group (STDSG), formerly the Systemic Treatment Program Committee. Drafts of this document have been circulated and reviewed by members of the STDSG. The STDSG comprises medical oncologists, pharmacists, supportive care personnel and administrators. Community representatives did not participate in the development of this guideline, but they will be included in future guidelines. QUALITY OF EVIDENCE: Seven randomized controlled trials (RCTs), 2 with placebo control, were available for analysis. BENEFITS: Data for clinical cardiotoxicity from 6 trials were pooled (n = 1070). The meta-analysis indicated that the risk of experiencing clinical cardiotoxicity was significantly reduced by dexrazoxane (risk ratio 0.24; 95% confidence interval [CI] 0.11 to 0.52; p = 0.00031). There was no significant benefit shown in individual trials for objective response or survival. HARMS: One of the RCTs revealed a significantly lower objective response rate in the dexrazoxane arm. However, a meta-analysis of objective response across 5 trials of breast cancer patients (n = 818) did not confirm this effect (odds ratio 0.85; 95% CI 0.61 to 1.18; p = 0.33). The use of dexrazoxane increased the incidence of myelosuppression and other noncardiac toxicities, but these were generally mild. PRACTICE GUIDELINE: The evidence supports the use of dexrazoxane to provide protection against the cardiotoxicity associated with conventional-dose doxorubicin in patients with advanced but anthracycline-sensitive cancer, in whom the continued use of anthracycline-containing chemotherapy is indicated in the opinion of the treating physician and who have received 300 mg/m2 or more of doxorubicin. The evidence supports the use dexrazoxane to provide protection against the cardiotoxicity associated with conventional-dose epirubicin in patients with advanced but anthracycline-sensitive cancer, in whom the continued use of anthracycline-containing chemotherapy is indicated in the opinion of the treating physicians. There are no data indicating the optimal cumulative dose of epirubicin at which dexrazoxane should be instituted. For doxorubicin, use of dexrazoxane is recommended after the cumulative dose reaches 300 mg/m2 (i.e., 55% of the recommended maximum). A similar formula could be used for epirubicin, that is, institution of dexrazoxane when the cumulative dose of epirubicin reaches 550 mg/m2, as the recommended maximum cumulative dose in Canada is 1000 mg/m2. Preclinical studies did not show any cardioprotectant effect for dexrazoxane when used with mitoxantrone, and no clinical studies have been done. Therefore, dexrazoxane is not recommended for use with mitoxantrone. There is no evidence for or against the use of dexrazoxane in the adjuvant setting for any tumour type. Because of concerns that dexrazoxane may reduce the efficacy of anthracyclines, and because data are not yet available on long-term toxicities, further studies should be performed before the drug is used in this setting.

Aged↗

PubMed1998

Use of granulocyte colony-stimulating factor (G-CSF) in patients receiving myelosuppressive chemotherapy for the treatment of cancer. Provincial Systemic Treatment Disease Site Group.

GUIDELINE QUESTIONS: 1) Does G-CSF reduce the incidence of important adverse clinical outcomes due to infections in patients with cancer treated with myelosuppressive therapy? 2) Does G-CSF allow maintenance of the chemotherapy dose with the goal of improving survival? OBJECTIVE: To evaluate the evidence for the role of G-CSF in patients receiving myelosuppressive chemotherapy for the treatment of cancer. OUTCOMES: Clinical outcomes reflecting events that may affect quality of life and/or resource utilization (e.g., rates and duration of hospitalization, antibiotic use); outcomes reflecting the effect of treatment on infection rates, tumour response and survival and those related to the biological effect of G-CSF. PERSPECTIVE (VALUES): Evidence was selected, reviewed and synthesized by members of the Provincial Systemic Treatment Disease Site Group (DSG) of the Cancer Care Ontario Practice Guidelines Initiative. Drafts of this document have been circulated and reviewed by members of the Systemic Treatment DSG. The DSG comprises medical oncologists, pharmacists, supportive care personnel and administrators. Evaluation by clinicians was considered in the final practice guideline. Community representatives did not participate in the development of this report but will in future reports. Guidelines approval does require participation by community representatives. QUALITY OF EVIDENCE: Two published guidelines and an update of one guideline were identified. Ten eligible randomized controlled trials published in English were included. BENEFITS: A meta-analysis of data from 8 trials showed that the odds of experiencing febrile neutropenia with G-CSF were significantly reduced (odds ratio 0.38; 95% confidence interval [CI] 0.27 to 0.52; p < 0.00001). G-CSF reduced the risk of febrile neutropenia by 34% (risk ratio 0.66; 95% CI 0.51 to 0.86; p = 0.0015). The use of G-CSF was associated with a significant reduction in antibiotic usage and days spent in hospital in 2 trials and had no effect in the other 4 in which it was measured. Five trials reported no difference in overall median survival, with 2 small trials detecting a significant increase related to G-CSF. However, further research is necessary to confirm these results. HARMS: The toxic effects of G-CSF are relatively mild. The most consistent clinical symptom attributed to G-CSF is bone pain, reported in incidence rates ranging from 20% to 50% in 3 trials. Except for one case, reported bone pain was mild. PRACTICE GUIDELINE: In cancer patients receiving myelosuppressive chemotherapy, granulocyte colony-stimulating factor (G-CSF) may be beneficial for some patients. If a reduction in the number of febrile neutropenic episodes, or in the duration of such episodes, is expected to improve quality of life, then G-CSF is a reasonable treatment option for selected patients. A clear justification for the use of G-CSF should be stated. If the objective of using G-CSF is to maintain dose intensity of antitumour agents, then G-CSF can be recommended where reduction in dose intensity has been shown in randomized controlled trials to reduce survival or disease-free survival. Although the evidence is weaker, the Systemic Treatment DSG would support the practice endorsed by other guidelines (American Society of Clinical Oncology, Ontario Drug Benefit Plan) and would recommend G-CSF for patients receiving potentially curative chemotherapy: i) as primary prophylaxis; that is, where dose reductions below a specified level are required because of a known high risk of febrile neutropenia, or ii) as secondary prophylaxis in patients receiving chemotherapy of established efficacy who have suffered a prior serious episode of febrile neutropenia due to the same chemotherapy regimen. The exact cut-off for dose reductions is unknown at this time and ought to be left to the judgement of the clinician. In general, the use of G-CSF for dose reductions lower than 20% is not recommended. (ABSTRACT TRUNCATED)

Adult↗

PubMed1996

Quantification of osteopontin in human plasma with an ELISA: basal levels in pre- and postmenopausal women.

OBJECTIVES: To develop an immunoassay for osteopontin (OPN), a secreted phosphoglycoprotein that is implicated in a number of human diseases, and establish basal plasma OPN levels in healthy women. DESIGN AND METHODS: An antigen-capture ELISA was developed to quantity OPN in plasma using a combination of mouse monoclonal and rabbit polyclonal antibodies. Basal OPN levels were determined in blood plasma of 21 pre- and 14 postmenopausal women obtained at 7-day intervals over a 4-week period. RESULTS: A group of 35 healthy women had a median OPN level of 31 micrograms/L (range = 14-64 micrograms/L). Comparison between pre- and postmenopausal women showed that their 4-week average OPN levels did not differ significantly (p > 0.16, Mann-Whitney test), and that levels in each premenopausal individual remained constant during the menstrual cycle, unaffected by cyclical levels of leuteinizing hormone and progesterone. CONCLUSION: Systematic quantification of plasma OPN can now be done by ELISA, which was used to establish basal plasma OPN levels in a group of healthy women. Levels in pre- and postmenopausal women appeared relatively stable over a 4-week period.

Adult↗

PubMed1996

The predictive power of semiquantitative immunohistochemical assessment of p53 and c-erb B-2 in lymph node-negative breast cancer.

A series of 107 lymph node-negative (LNN) breast cancers was stained immunohistochemically with a combination of p53 and c-erb B-2. The immunohistochemical results were semiquantitated using a previously described system by Allred et al. p53 immunopositive cases were further screened for DNA mutations by the polymerase chain reaction-single-strand conformation polymorphism method (PCR-SSCP). Three representative cases showing mobility shifts were directly sequenced. One hundred of 103 invasive carcinomas were of no special type (infiltrating ductal carcinomas not otherwise specified). The three special type carcinomas included a tubular carcinoma, a classic infiltrating lobular carcinoma, and a mucinous carcinoma. Twenty-six patients (25.2%) had grade I carcinomas, and 77 patients (75%) had grade 2 or 3 carcinomas. There were four cases composed predominantly of ductal carcinoma in situ (DCIS) with foci of microinvasion. Twenty-seven of 107 patients (25%) died of disease. All those who died had grade 2 or 3 tumors. Univariate analysis showed that p53 and c-erb B-2 positivity (score > 6) were associated with a decreased overall survival (OS) (P = .0012 and P = .010, respectively), and a decreased disease-free survival (DFS) (P = .0009 and P = .027, respectively). The multivariate model selected these two variables as the best predictors of both OS and DFS (all P = or < .01). These results suggest that semiquantitative immunohistochemical analysis of p53 and c-erb B-2 provides prognostic information in LNN disease.

Adult↗

PubMed1995

Osteosarcoma and other tumors of bone.

Although no major advances in local or systemic therapy have been reported, further progress has been made in the identification of genetic alterations and prognostic factors in primary as well as recurrent osteosarcoma. Further reports on the use of a variety of imaging techniques in the quantification of tumor response to neoadjuvant chemotherapy have also appeared. Publications describing high-dose methotrexate pharmacokinetics, the impact of this therapy on patient outcome, and a report of a pilot study evaluating the feasibility of higher dose intensity cisplatin and doxorubicin may lead to new and important randomized clinical trials in the future.

Antineoplastic Agents↗

PubMed1994

Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer.

Patients receiving chemotherapy for metastatic breast cancer are at high risk of thromboembolic disease. Long-term oral anticoagulant therapy is needed but increases the risk of haemorrhagic complications. We have assessed the safety and efficacy of warfarin in very low doses as prophylaxis. Women receiving chemotherapy for metastatic breast cancer were randomly assigned either very-low-dose warfarin (152 patients) or placebo (159). The warfarin dose was 1 mg daily for 6 weeks and was then adjusted to maintain the prothrombin time at an international normalised ratio (INR) of 1.3 to 1.9. Study treatment continued until 1 week after the end of chemotherapy. The average daily dose from initiation of titration was 2.6 (SD 1.2) mg for the warfarin group and the mean INR was 1.52. The mean time at risk of thrombosis was 199 (126) days for warfarin-treated patients and 188 (137) days for placebo recipients (p = 0.45). There were 7 thromboembolic events (6 deep-vein thrombosis, 1 pulmonary embolism) in the placebo group and 1 (pulmonary embolism) in the warfarin group, a relative risk reduction of about 85% (p = 0.031). Major bleeding occurred in 2 placebo recipients and 1 warfarin-treated patient. There was no detectable difference in survival between the treatment groups. Very-low-dose warfarin is a safe and effective method for prevention of thromboembolism in patients with metastatic breast cancer who are receiving chemotherapy.

Antineoplastic Agents↗

PubMed1994

Timing of surgery in relation to the menstrual cycle in premenopausal women with operable breast cancer.

Recent studies have suggested that the timing of surgery in relation to the menstrual cycle might influence survival of premenopausal women with operable breast cancer. The data of 96 premenopausal patients who underwent primary surgery for operable breast carcinoma between 1975 and 1988 were analysed. At 10 years, disease-free and overall survival rates of patients whose initial surgery was 1-12 days after the starting date of the last menstrual period (follicular phase) were significantly poorer compared with survival of those who underwent operation more than 12 days after the last menstruation (luteal phase) (disease-free survival rate 40 versus 72 per cent, P = 0.002; overall survival rate 40 versus 79 per cent, P = 0.001). These differences in survival remained significant in a second analysis based on the menstrual phase at the time of both initial and definitive operation. Menstrual phase had the greatest impact on the survival of patients with positive axillary nodes (P = 0.009). Prospective studies are required to elucidate the relationship between the timing of all surgical procedures during the menstrual cycle and survival.

Adult↗

PubMed1994

Timing of surgery influences survival in receptor-negative as well as receptor-positive breast cancer.

Analysis of oestrogen and progesterone receptor (ER, PR) status was interpreted in relation to menstrual phase at the time of surgery and survival in 84 women diagnosed with breast cancer between 1975 and 1988. We showed previously (Br J Surgery 1994, 81, 217-220) that long-term survival was significantly poorer when surgery was performed during the follicular phase of the menstrual cycle compared to luteal phase; we now demonstrate that this effect on survival is at least as important in receptor-negative as receptor-positive patients. At 10 years, overall survival (OS) of ER-positive patients who had their biopsy during the follicular phase was significantly poorer than for those whose biopsy was performed during the luteal phase of their menstrual cycle (52 versus 88%, P = 0.02). OS for the ER-negative follicular phase group was also significantly poorer than that for the ER-negative luteal phase group (33 versus 76%, P = 0.009). The OS difference between the PR-positive follicular phase group and PR-positive luteal phase group was of borderline significance (60 versus 87%, P = 0.06), while the difference in OS between the PR-negative follicular phase group and that of the PR-negative luteal phase group was highly significant (13 versus 76%, P = 0.001). Disease-free survival for these groups followed a similar trend. The survival differences in receptor-negative women suggest that hormonal fluctuations at the time of surgery may have complex indirect effects on tumour growth and metastasis. The mechanism, if indeed independent of the tumour steroid receptors, could also apply in other cancers.

Adult↗

PubMed1994

Phase II trial of 10-EDAM in advanced soft tissue sarcoma. A study of the Canadian Sarcoma Group and the National Cancer Institute of Canada Clinical Trials Group.

BACKGROUND: Inoperable locally recurrent soft tissue sarcomas (STS) are incurable with chemotherapy. Therefore the National Cancer Institute of Canada Clinical Trials Group are performing phase II studies in an attempt to find better drugs. PATIENTS AND METHODS: Thirty-one evaluable patients with incurable soft tissue sarcoma were treated with the antifol 10-EDAM at a dose of 80 mg per m2/week. RESULTS: Mucositis was the most common toxicity. Only 41% of patients received > or = 90% of the planned dose time because of dose modification mainly for grade 1 mucositis. Two patients died after neutropenic episodes. Toxicity otherwise was generally mild (< grade 2). One patient had a pathologically confirmed complete response but relapsed after four months. Another had a partial response lasting 16 weeks. Eleven other patients had stabilization of disease. CONCLUSIONS: In this study, 10-EDAM was not found to be an effective agent to treat advanced soft tissue sarcoma.

Adult↗

PubMed1994

Osteosarcoma and other tumors of bone.

Steady progress has been made in the identification of genetic alterations and prognostic factors in osteosarcoma. Imaging studies continue to be employed not only for preoperative staging, but to quantify factors such as tumor bulk and tumor response to neoadjuvant chemotherapy. Although there have been no major refinements of local or systemic therapy, continuing research into novel agents (eg, liposomal muramyl, tripeptide phosphatidylethanolamine, and antisense oligonucleotides to insulin-like growth factor receptors) hold promise for new therapies for this disease in the future.

Adolescent↗

PubMed1994

Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma--reduced local recurrence but no improvement in survival: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.

PURPOSE: To evaluate the benefit of adjuvant chemotherapy in adult patients with soft tissue sarcomas. The principal end points were freedom from local recurrence and/or metastases and overall survival. PATIENTS AND METHODS: Between January 1977 and June 1988, 468 patients entered this randomized study and 317 were considered eligible. Following complete surgical resection with or without radiotherapy, outcome in 145 eligible patients receiving cyclophosphamide 500 mg/m2 intravenously (IV) bolus on day 1, vincristine 1.4 mg/m2 IV bolus on day 1, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) 50 mg/m2 IV bolus on day 1, and dacarbazine (DTIC) 400 mg/m2 by 1-hour infusion on days 1 to 3 (CYVADIC) cycles repeated every 28 days for eight courses was compared with that in 172 control patients. RESULTS: With a median follow-up duration of 80 months (range, 39 to 165), actuarial percentage survival figures at 7 years were compared. Relapse-free survival rates were higher for CYVADIC, 56% versus 43% (P = .007), and local recurrence was significantly reduced in the CYVADIC arm at 17% versus 31% (P = .004). In contrast, distant metastases occurred with similar frequency in both arms, 32% for CYVADIC versus 36% for control patients (P = .42), and overall survival rates were not significantly different at 63% versus 56% (P = .64). A reduction in local recurrence was only apparent in the group of head, neck, and trunk sarcomas (P = .002), but not in limb tumors (P = .31). CONCLUSION: Adjuvant chemotherapy with CYVADIC cannot be recommended outside the context of a clinical trial. Experience from this study has been used to plan a trial of neoadjuvant chemotherapy with doxorubicin/ifosfamide, which is currently in progress.

Adolescent↗

PubMed1993

Grading of soft tissue sarcomas: experience of the EORTC Soft Tissue and Bone Sarcoma Group.

A practical grading system for soft tissue sarcomas was developed, based on 282 eligible patients entered in an EORTC adjuvant clinical trial. The primary tumours in this trial had to be adequately treated. Histopathological parameters, which appeared significant in two preceding studies, were tested. These parameters were differentiation of the tumour, presence and amount of necrosis, the presence and amount of myxoid areas and the number of mitoses. In addition, the size of the tumour was also analysed. The quantitative data (mitotic count and size of the tumour) were not a priori grouped, but were divided into categories based on the results of the statistical analysis. Based on a multivariate analysis only mitotic count, the presence or absence of necrosis and the size of the tumour were significantly correlated with the duration of survival or the time to distant metastases. Of these parameters, the mitotic count was the most important.

Adolescent↗

PubMed1993

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)

Administration, Oral↗

PubMed1993

Soft tissue sarcomas: a plea for proper management.

Although soft tissue sarcomas are relatively uncommon, they often occur in young patients and if properly treated are often curable. Unfortunately, inappropriate approaches to biopsy before adequate staging may compromise a successful outcome. The roles of diagnostic imaging (particularly magnetic resonance imaging) in adequate preoperative evaluation and staging and the fundamental principles of surgical management are discussed.

Adolescent↗

PubMed1992

A pilot study of intensive cyclophosphamide, epirubicin and fluorouracil in patients with axillary node positive or locally advanced breast cancer.

A multicentre pilot study has been conducted to determine an intensive regimen of cyclophosphamide, epirubicin, and fluorouracil which was tolerable and acceptable to patients with node positive breast cancer. Consecutive patients with operable axillary node positive breast cancer (T1-3, N1-2, M0), 266 patients, or locally advanced breast cancer (T4), 22 patients, were treated with cyclophosphamide post-operatively for 14 days and epirubicin and fluorouracil, both intravenously on days 1 and 8. Each cycle was repeated monthly for 6 months. Dosages were increased according to predetermined guidelines. Outcome measures were admission to hospital for febrile neutropenia and change in cardiac function as assessed by radionuclide angiography. The first 46 patients were treated at the doses of cyclophosphamide = 75 mg/m2, epirubicin = 50 mg/m2, fluorouracil = 375 mg/m2 (level 1), then 42 patients at cyclophosphamide = 75 mg/m2, epirubicin = 50 mg/m2 and fluorouracil = 500 mg/m2 (level 2), 69 patients at cyclophosphamide = 75 mg/m2, epirubicin = 60 mg/m2, and fluorouracil = 500 mg/m2 (level 3), and 42 patients at cyclophosphamide = 75 mg/m2, epirubicin = 70 mg/m2, and fluorouracil = 500 mg/m2 with concurrent antibiotics (level 4). The rates of febrile neutropenia were 8.7% (level 1), 7.1% (level 2), 18.8% (level 3), and 31% (level 4), respectively, P = 0.002. Accrual to level 4 was discontinued according to study guidelines 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 levels 3 and 3a was statistically significant. There were no toxic deaths and 2 cases of heart failure. In conclusion, through a careful dose-finding study in patients with operable or locally advanced breast cancer, an intensive epirubicin-containing adjuvant regimen has been established which is presently being compared with standard CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy in a randomised trial. In addition, this study suggests that antibiotic prophylaxis reduces the risk of febrile neutropenia in breast cancer patients receiving intensive chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1992

The effect of systemic adjuvant chemotherapy on local breast recurrence in node positive breast cancer patients treated by lumpectomy without radiation.

A randomised trial has previously been repeated in which 437 women with node positive breast cancer received either a 12-week chemohormonal regimen consisting of cyclophosphamide, methotrexate, fluorouracil, vincristine, prednisone, adriamycin and tamoxifen or 36 weeks of CMFVP. The present analysis concerns the local recurrence rates for the 122 lumpectomy patients who did not receive breast irradiation. The cumulative rate of local breast recurrence was greater in the 12-week than the 36-week group, P = 0.02. Similarly, in the lumpectomy patients, the cumulative rate of distant recurrence was greater in the 12-week than the 36-week group, P = 0.04. In conclusion, our results suggest that adjuvant chemotherapy impacts on local breast recurrence in a similar manner to other sites in Stage II breast cancer patients treated by lumpectomy without radiation. Despite the use of a conventional 36-week adjuvant chemotherapy regimen, the local breast recurrence rate was substantial.

Antineoplastic Combined Chemotherapy Protocols↗