Cyclophosphamide, Methotrexate, 5-fluorouracil Research Articles

Prospective meta-analysis of randomised trials of cyclophosphamide, methotrexate & fluorouracil (CMF) vs fluorouracil, epirubicin & cyclophosphamide (FEC) chemotherapy in early breast cancer

592 Background: Our previous study of node positive (N+) patients (Coombes: JCO 1996 14:35–45) compared FEC1/2 vs. CMF1/2 (see table below). At 4.5 years there was no difference in disease free survival (DFS), p=0.61; or overall survival (OS), p=0.31. However, subset analysis suggested that FEC2 was better than CMF2 (DFS:p=0.03;OS:p=0.02). Concurrently a study in node negative (N-) patients was conducted comparing FEC2 with CMF2. This paper updates the previous N+ study, reports N- study outcome, and a combined meta analysis (MA). Methods: Prospective MA of two international randomised trials of CMF vs. FEC chemotherapy in early breast cancer: 1) N+ premenopausal trial, 2 regime options (CMF1/FEC1, CMF2/FEC2). and 2) N- trial (CMF2/FEC2). Main endpoints are OS and DFS. Sample sizes are small by today's standards, hence the prospective MA. Results: N+ recruited 759 (180 CMF1, 180 FEC1, 199 CMF2, 200 FEC2) patients between 1984–1992, median follow-up 100 months. N- recruited 950 (477 CMF2, 473 FEC2) patients between 1990–2000, median follow-up 70 months. Median age was 44 (N+) and 48 (N-) years. Grade 3/4 toxicity (sore mouth, vomiting/nausea, diarrhoea, anorexia, alopecia) occurred twice as often with FEC (54%) than CMF (24%), p<0.001. Grade 3/4 toxicity in N+ (56%) was twice that of N- (25%) patients, p<0.001. MA hazard ratios showed that for OS, CMF was better 1.08 (95% CI 0.87 –1.35, p=0.49) but for DFS, FEC was better 0.97 (95% CI 0.82–1.16, p=0.76). Tests showed OS trial results were heterogeneous (p=0.04) with FEC1 better than CMF1 (p=0.04), and CMF2 better than FEC2 (p=0.06) for N+ but no difference for N- (p=0.87). Conclusions: MA showed no difference between the treatments in terms of OS or DFS. Individual trial results for OS were not homogeneous. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis; Eli Lilly

Neoadjuvant Chemotherapy of Breast Cancer

The use of neoadjuvant chemotherapy in the treatment of breast cancer has been evolving during the past two decades. Fisher's group accomplished the scientific rationale in mouse models in the 1970s. The Milan group was the first to use neoadjuvant therapy in locally advanced breast cancer and also determined that adjuvant sequential doxorubicin with cyclophosphamide/methotrexate/fluorouracil (CMF) offered improved survival when compared to alternating CMF with doxorubicin. Other groups (M. D. Anderson and NSABP) have evaluated similar doxorubicin-based neoadjuvant therapies in locally advanced breast cancer (LABC) and in early disease. These studies have shown an increase in breast-conserving therapy (BCT) and an increase in pathologic complete response (pCR) when neoadjuvant therapy was used. Due to anthracycline resistance, taxanes were added to the doxorubicin-based neoadjuvant chemotherapy regimen with an increase in BCT and pCR than when an anthracycline regimen was used alone. Overall survival has yet to be determined when comparing an anthracycline-based regimen to the same regimen with the addition of a sequential taxane. Therefore, a combined treatment of an anthracycline/cyclophosphamide/taxane regimen is the recommended neoadjuvant chemotherapy for patients with breast cancer.

Population-based sentinel lymph node biopsy (SLNB) in early invasive breast cancer (EIBC)

125 stage III breast cancer patients, including 51 cases of inflammatory carcinoma, were treated with the following combined modality approach: three courses of primary 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) chemotherapy followed by locoregional treatment and subsequent adjuvant chemotherapy consisting of three courses of FAC alternating with three courses of cyclophosphamide, methotrexate, 5-fluorouracil (CMF). Clinical response to primary FAC was 65% (complete 10%). Residual tumour mass in the mastectomy specimen was > 1 and ≤ 1 cm in 82 and 18% of cases, respectively. Complete pathological response following primary chemotherapy was achieved in only 3.5% of cases. After primary FAC and local treatment, 97% of patients were disease-free. Overall survival (S) and progression-free survival (PFS) at 5 years were 56 and 34%, respectively. Univariate analysis showed that age, receptor status and clinical and pathological response to primary chemotherapy did not appear to influence treatment outcome significantly, whereas stage, presence of inflammatory disease and number of involved nodes had a significant impact on both S and PFS.

Goserelin (‘Zoladex’)—offering patients more choice in early breast cancer

The luteinising hormone-releasing hormone analogue goserelin ('Zoladex') suppresses ovarian oestrogen production in pre- and perimenopausal women. Goserelin is a biodegradable, sustained-release 3.6 mg depot that is administered by subcutaneous injection every 28 days. Clinical trials in premenopausal women with hormone-sensitive early breast cancer have demonstrated that goserelin alone, or in combination with tamoxifen, is at least as effective as cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy. Goserelin plus tamoxifen after cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) chemotherapy resulted in improved disease-free survival compared with CAF alone. These trials have also shown that goserelin is well tolerated and is associated with less acute toxicity than cytotoxic chemotherapy. Early improvements in quality of life over the first 3-6 months of goserelin treatment support the use of this agent as an alternative to chemotherapy in this patient population. Patients should be provided with information on the benefits and risks associated with available treatment options so that they can be involved in the decision-making process.

Antiemetic prescription in Italian breast cancer patients submitted to adjuvant chemotherapy

The aim of this study was to investigate if the Multinational Association of Supportive Care in Cancer (MASCC) antiemetic guidelines for the prevention of both acute and delayed emesis induced by highly-moderately emetogenic chemotherapy were transferred in daily clinical practice in Italy 2 years after their publication. From 16 to 23 March 2000, all consecutive breast cancer patients referred to 87 Italian oncological centers to receive any cycle of adjuvant chemotherapy were monitored. Of 715 evaluable patients submitted to chemotherapy, 533 received cyclophosphamide, methotrexate, 5-fluorouracil (CMF) and 151 anthracyclines. Patients receiving taxanes or other experimental therapies (31) were not considered. The MASCC-recommended antiemetic prophylaxis against acute/delayed emesis was prescribed in 56.3/45.9% patients. Antiemetic prophylaxis against delayed emesis was not prescribed to 30.6% of patients. The MASCC-recommended prescription against acute emesis was more frequently followed in research centers, in Northern Italy, and in centers with experience on antiemetic research. Two years after the publication of the MASCC antiemetic guidelines, strong discrepancies between these and antiemetic prescriptions in daily clinical practice in Italy were observed. The similarity of these results with those obtained in our previous drug utilization study on antiemetics, carried out before the publication of the MASCC guidelines, leads us to conclude that the transferability of antiemetic guidelines to daily clinical practice in Italy has been modest. A great effort should be made in Italy by the National Health Service to accelerate the process of implementation of antiemetic guidelines.

The use of gonadotrophin-releasing hormone (GnRH) agonists in early and advanced breast cancer in pre- and perimenopausal women

Gonadotrophin-releasing hormone (GnRH) agonists, in particular goserelin (‘Zoladex’), are increasingly being used for the treatment of breast cancer in women with functioning ovaries. They act by downregulating pituitary GnRH receptors, thereby suppressing the release of luteinising hormone (LH) and follicle stimulating hormone (FSH), which, in turn, reduce the main source of oestradiol production in the ovaries. GnRH agonists have been shown to be as effective therapeutically as surgical ovarian ablation in pre- and perimenopausal women with advanced breast cancer. The combination of a GnRH agonist such as goserelin with the peripheral oestrogen antagonist, tamoxifen, may be used to produce ‘combined oestrogen blockade’. In advanced breast cancer, this regimen prolongs progression-free survival and increases both the response rate and duration relative to the use of a GnRH agonist alone. In patients with early breast cancer, the addition of goserelin to ‘standard treatment’ (i.e. surgery±tamoxifen, chemotherapy or radiotherapy) results in a significant benefit in recurrence-free survival and overall survival. This benefit was most apparent in patients with oestrogen receptor (ER) +ve tumours. Goserelin, when used either alone or in combination with tamoxifen as an adjuvant systemic therapy in women with ER +ve tumours, has been shown in clinical trials to produce recurrence-free survival rates equivalent to cytotoxic chemotherapy such as cyclophosphamide, methotrexate, 5-fluorouracil (CMF). Evidence suggests that at least part of the effect of adjuvant cytotoxic chemotherapy in premenopausal women is produced by ovarian ablation. Endocrine therapy with goserelin or goserelin plus tamoxifen should now be considered a treatment option in the management of premenopausal women with ER +ve early breast cancer.

Continuing chemotherapy or not after the induction treatment in advanced breast cancer patients: clinical outcomes and oncologists’ preferences

The optimal duration of cytostatic treatment for metastatic breast cancer is still a matter of debate. Possible gain in the duration of remission has to be weighed against the side-effects of treatment. Our aim was to define the optimal duration of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) treatment by studying the time to treatment failure, overall survival and using a Q-TWiST analysis. The treating physician's opinion was asked. The European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Group conducted a randomised trial in 204 non-progressing metastatic breast cancer patients after induction chemotherapy (CMF) to stop or continue treatment. Progression-free (PFS) and overall survival (OS) were studied. To gain more insight into the burden of treatment-related side-effects, Q-TWiST was analysed. In addition, we asked for oncologists’ preferences as patients are likely to be influenced by their physicians’ opinion. Continuation of CMF had a significantly longer time to treatment failure (TTF) 5.2 versus 3.5 months (P=0.011). There was no overall survival (OS) difference 14.0 versus 14.4 months (P=0.77). Mean quality-adjusted survival time was equal to 8.4 months for no further treatment and decreased to 7.9 months for continuation of CMF (95% Confidence Interval (CI) of difference equals 0.5±2.5 months). Almost half of the oncologists said they would favour continuous treatment for a 3-month gain in time to progression—a difference which was not found in this study. Based on these data, an interruption of chemotherapy (CMF), if this is the wish of the patient, is justified.

Accelerated versus standard cyclophosphamide, epirubicin and5-fluorouracil or cyclophosphamide, methotrexate and5-fluorouracil: a randomized phase III trial in locally advanced breast cancer

The purpose of this study was to evaluate the impact of a dose-dense primary chemotherapy on pathological response rate (pCR) in patients with locally advanced breast cancer (LABC) treated with combined modality therapy. Stage IIIA/IIIB patients received three courses of induction chemotherapy (ICT) with cyclophosphamide, epirubicin and 5-fluorouracil (CEF) followed by local therapy (total mastectomy or segmental mastectomy with axillary nodes dissection) and adjuvant chemotherapy (ACT) with three courses of CEF alternated with three courses of cyclophosphamide, methotrexate, 5-fluorouracil (CMF). Patients were randomized to receive ICT and ACT every 3 weeks (arm A, 'standard treatment') or every 2 weeks with granulocyte-macrophage colony-stimulating factor (GM-CSF) support (arm B, 'dose-dense treatment'). In both arms radiotherapy was administered after the end of chemotherapy (in selected cases) and patients with hormonal receptor-positive tumors received tamoxifen for 5 years. A total of 150 patients were randomized (77 arm A and 73 arm B) and demographics were well balanced between the two arms. Compliance to treatment was excellent: 95% and 93% of patients in arms A and B, respectively, completed the treatment program with no modification or delay. Median duration of treatment (ICT+local+ACT) was 183 days (range 0-265) in arm A and 139 days (0-226) in arm B. The average relative dose intensity (ARDI) of chemotherapy was 1.3 with a 30% increase in the dose intensity in arm B in comparison with arm A. No difference in clinical [62%; 95% confidence interval (CI) 49% to 73.2%] and pathological response rates to ICT was observed between the two arms. Median follow-up was 5 years (range 1-96 months); median disease-free survivals were 4.8 years in arm A and 4.5 years in arm B. Median overall survival was 7.8 years in standard therapy: this figure has not yet been reached in the dose-dense treatment. In LABC a dose-dense regimen, while allowing a 30% increase in the dose intensity of chemotherapy, did not provide significant improvement in pathological response rates. However, accelerated chemotherapy reduced the duration of the combined-modality program (6.1 versus 4.6 months) with no additional toxicities.

Goserelin (Zoladex™) – its role in early breast cancer in pre- and perimenopausal women

British Journal of Cancer (2002) 87, 1480–1480. doi:10.1038/sj.bjc.6600652 www.bjcancer.com© 2002 Cancer Research UKCorrection to: British Journal of Cancer 2001; 85 (Suppl 2): 1–5. doi:10.1054/bjoc.2001.1981

Epirubicin versus CMF as adjuvant therapy for stage I and II breast cancer: a prospective randomised study

We compared a relatively short regimen of monochemotherapy with epirubicin versus polychemotherapy with CMF (cyclophosphamide, methotrexate, 5-fluorouracil) as adjuvant treatment for stage I and II breast cancer patients. 348 patients with oestrogen receptor negative (ER−) node negative and ER− or ER+ node-positive with <10 nodes were accrued. CMF was given intravenously (i.v.) on days 1 and 8, every 4 weeks, for six courses; epirubicin was given weekly for 4 months. Postmenopausal patients received tamoxifen for 3 years. The primary endpoints were overall survival (OS), relapse-free survival (RFS) and event-free survival (EFS). Outcome evaluation was performed both in eligible patients and in all randomised patients according to the intention-to-treat principle. 8 randomised patients were considered ineligible. At a median follow-up of 8 years, there was no difference in OS (Hazard Ratio (HR)=1.11, 95% Confidence Interval (CI): 0.77–1.61, P=0.58), EFS (HR=1.14, 95% CI: 0.78–1.64, P=0.48), and RFS (HR=1.14, 95% CI: 0.8–1.64, P=0.48) between the two arms for all of the patients. At 8 years, the RFS percentages (±Standard Error (S.E.)) were 65.4% (±4%) in the CMF arm and 62.7% (±4%) in the epirubicin arm; for EFS these were 64.2% (±4%) for CMF and 60.8% (±4%) for epirubicin, respectively. A significant difference in RFS (P=0.015) was observed in patients with 4–9 positive nodes in favour of the CMF arm. Toxicity in the two arms was superimposable except for more frequent grade 3 alopecia in the epirubicin-treated patients (P=0.001). Overall, at a median follow-up of 8 years, there were no differences between the two arms in terms of OS, EFS and RFS.

Overview of luteinizing hormone-releasing hormone agonists in early breast cancer-benefits of reversible ovarian ablation.

Goserelin ('Zoladex'), a luteinizing hormone-releasing hormone (LHRH) agonist induces reversible ovarian ablation in premenopausal women. It is the most extensively studied LHRH agonist for the treatment of breast cancer and data from a large clinical trial program show that, alone or in combination with tamoxifen, goserelin is at least as effective as cyclophosphamide-methotrexate-5-fluorouracil (CMF) chemotherapy in patients with hormone-sensitive, early disease. Furthermore, goserelin has been shown to add benefit when used in addition to standard adjuvant therapy (surgery +/- radiotherapy +/- chemotherapy +/- tamoxifen) and may be beneficial when used after chemotherapy. In patients with hormone-sensitive, early breast cancer, treatment-induced amenorrhea has been associated with an improved prognosis and goserelin provides a highly effective and reliable method of achieving amenorrhea. The reversibility of amenorrhea upon cessation of goserelin treatment may confer long-term advantages compared with permanent methods of ovarian ablation. Ultimately, patients should be provided with sufficient information on the risks and benefits of the treatment options available to them so that they can be involved in treatment decisions.

Anemia in oncology practice: relation to diseases and their therapies.

Anemia is common in patients with cancer and is a frequent complication of myelosuppressive chemotherapy. In this study, we investigated the incidence and severity of chemotherapy-induced anemia caused by the most common chemotherapy regimens, including the new generation of chemotherapeutic agents, used in the treatment of the major nonmyeloid malignancies in adults. Five hundred fifty-two patients with histologically proven carcinoma originating from breast (n = 165), lung (n = 128), colon (n = 75), ovary (n = 84), and malignant lymphoma (n = 100) were included in this study. Hemoglobin levels for each patient were measured with an automatic counter during both pretreatment and before each chemotherapy cycle during therapy. To document the incidence of anemia, the National Cancer Institute grading system was used. Before chemotherapy, 44% of patients with breast carcinoma had anemia. There was a 16% increase in the incidence of anemia after chemotherapy. Severe anemia was observed in less than 1% of patients. No difference was found in the incidence of anemia between the fluorouracil, doxorubicin, cyclophosphamide (FAC) and cyclophosphamide, methotrexate, fluorouracil (CMF) regimens used in the adjuvant setting. However, single-agent chemotherapy with newer generation caused more anemia when compared with the FAC regimen (p < 0.005). Chemotherapy resulted in a significant decrease in hemoglobin levels when compared with pretreatment values in patients with lung cancer (p < 0.001). During treatment, the increase in the incidence of grade II anemia was associated with a parallel decrease in the incidence of grade I anemia. The incidence of severe anemia did not exceed 15%. The incidence of anemia was equivalent in both patients with small-cell lung cancer and those with non-small-cell lung cancer treated with the etoposide and cisplatin (EP) combination. Seventy-one percent of patients with colon cancer had anemia before initiation of chemotherapy. No difference was observed in posttreatment hemoglobin values compared with pretreatment values. Patients treated with irinotecan and fluorouracil and leucovorin (FUFA) combination showed similar rates of anemia. Incidence of anemia in patients with ovarian cancer at admission was 68%. Chemotherapy resulted in a prominent increase in incidence of anemia, which increased to 91.5%. There was an increase in grade II anemia, which corresponded to the decrease in grade I anemia. Less than 10% of patients developed severe anemia. No difference in the incidence of anemia was observed in patients with ovarian cancer treated with either cisplatin and cyclophosphamide or cisplatin combination. Showing a high incidence of anemia (82%) at presentation, hemoglobin levels in patients with malignant lymphoma were unaltered with chemotherapy. Severe anemia occurred in less than 3% of patients. There was a higher incidence of anemia in patients with non-Hodgkin's lymphoma receiving the cyclophosphamide, epirubicin, vincristine, prednisone (CEOP) regimen in contrast to patients with Hodgkin's lymphoma treated with the doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) combination. There was a prominent decline in the hemoglobin levels with cisplatin-based combinations in contrast to combinations including noncisplatin agents (p < 0.001). In this study, we have observed equivalent rates of treatment-related anemia when compared with previous data in patients with specific tumor types. The incidence of pretreatment anemia was high in various malignancies. The mechanisms underlying the propensity for a higher risk of pretreatment anemia in patients with malignant disorders and its influence on the outcome has to be elucidated by further population-based and molecular studies.

Indications and complications of latissimus dorsi myocutaneous flaps in oncologic breast surgery.

The use of the latissimus dorsi myocutaneous flap (LDMF) in reconstructive breast surgery is well documented. Few reports exist of its use in oncologic breast surgery. This series describes indications and complications of the LDMF in locally advanced cancer. The records of 83 patients were analysed for age and sex, menstrual status, stage, indication, margins of resection, chemotherapy, radiotherapy, complications, and survival. The indication was to cover defects caused by resection of locally advanced breast cancer (67 cases), recurrent breast cancer (13 cases), radiation damage (2 cases), and surgical complications (1 case). The mean age of the patients was 50.2 years; 52% were postmenopausal. The flaps had mean diameters of 32 by 14 cm. The donor site was skin grafted. Clear margins were achieved in 83%. At the LDMF insertion site, wound infection required drainage in 1 case; flap necrosis required reintervention in 7 cases. In 2 cases a second skin graft was done for the LDMF donor site. The proportions of wound infections and incomplete skin graft take were significantly greater in patients receiving preoperative cyclophosphamide/methotrexate/5-fluorouracil (CMF) versus cyclophosphamide/doxorubicin/5-fluorouracil (CAF) chemotherapy (p < 0.001 and p < 0.05, respectively). The late complication rate was 7.2%. The mean follow-up is 40.0 months. The complication rates for CMF versus CAF chemotherapy suggest an adverse effect of methotrexate, which warrants further investigation. The use of the LDMF made wide resection of locally advanced lesions and radionecrosis possible; major complications were rare. LDMF has its place in the armamentarium of the surgeon who regularly sees locally advanced breast cancer.

Update on pharmacogenetics in cancer chemotherapy

This review describes how genetic differences among patients may change the therapeutic outcome in cancer chemotherapy. Severe toxicity in genetically predisposed patients is predominantly associated with mutations in drug metabolism enzyme genes, and an update on genetic intolerance to 6-mercaptopurine, 5-fluorouracil, and irinotecan is provided. Moreover, recent findings pointed out that the methylenetetrahydrofolate reductase (MTHFR) C677T mutation might change patient susceptibility to the toxic effects of the cyclophosphamide, methotrexate, 5-fluorouracil (CMF) regimen and raltitrexed. Finally, it is emerging that not only toxicity, but also response to chemotherapy could be influenced by pharmacogenetic determinants, and the clinical relevance of polymorphisms in thymidylate synthase (TS) and glutathione-S-transferase (GST) genes is discussed.

Effect of CMF-chemotherapy on blood coagulation in patients with breast cancer

BACKGROUND: Influences of CMF (cyclophosphamide, methotrexate,5-fluorouracil) chemotherapy on blood coagulation were investigated in 30 patients receiving adjuvant chemotherapy and in 30 patients receiving chemotherapy for metastatic breast cancer. METHODS: In plasma samples of 60 patients (median age 49.5), we evaluated the following parameters 1)Markers of in vivo clotting activation thrombin-antithrombin complex (ELISA) and D-dimer (ELISA), 2) Natural anticoagulants (protein C [PC] and antithrombin III [AT III] by chromogenic methods). The coagulation studies were performed at the beginning and at the end of the first cycle of CMF protocol. RESULTS: Before CMF therapy, significant difference was observed between patients with early stage and patients with metastatic breast cancer in the PC (p&lt;0.01), AT III (p&lt;0.01) and TAT (p&lt;0.01) levels. After CMF therapy, patients with stage II (adjuvant) disease manifested a significant decrease in the level of PC and AT III activity (p&lt;0.01) and an increase in TAT level (p&lt;0.01). In patients with disseminated breast cancer CMF therapy provoked an increased level of TAT and D-dimer with a decreased activity of protein C and antithrombin III. There was significant difference in value of TAT, D- dimer, protein C and antithrombin III between the patients with adjuvant and metastatic breast cancer patients after CMF chemotherapy CONCLUSION: Our results suggest that the application of cytotoxic therapy provokes hypercoagulable condition in breast cancer patients. This effect should be considered when chemotherapy is employed in advanced cancer patients at high risk for thrombosis, or in patients with other risk factors.

Future treatment options with capecitabine in solid tumours

The oral fluoropyrimidine, capecitabine is attracting great interest in the context of tumour-selective therapy and rationally designed combination regimens. Agents such as taxanes upregulate thymidine phosphorylase (TP), and there is therefore a clear rationale for their combination with capecitabine. Preclinical studies of capecitabine/taxane combination therapy demonstrated synergistic antitumour activity and phase I studies showed encouraging efficacy. Therefore, a randomised, phase III trial (docetaxel versus docetaxel/capecitabine) has been initiated in anthracycline-refractory metastatic breast cancer patients. Recruitment is complete. In colorectal cancer, capecitabine/oxaliplatin combination therapy is promising and a phase I, dose-finding trial has been conducted in patients with refractory metastatic solid tumours. A similar trial has evaluated capecitabine/irinotecan combination treatment. Capecitabine is also being investigated as adjuvant therapy for colorectal and breast cancers. The primary objective of the ongoing X-ACT trial in almost 2000 Dukes' C colon cancer patients is to demonstrate at least equivalent disease-free survival between capecitabine and the Mayo Clinic regimen. In addition, the CALGB is planning a randomised, phase III trial of capecitabine versus doxorubicin/cyclophosphamide or cyclophosphamide/methotrexate/5-fluorouracil (CMF) as adjuvant treatment in high-risk, node-negative breast cancer patients aged >65 years.

Taxanes in the adjuvant treatment of breast cancer: why not yet?

The taxanes paclitaxel and docetaxel represent the most active chemotherapeutic agents developed for the treatment of advanced breast cancer in the last decade, and they are now being incorporated into adjuvant chemotherapy trials for lymph node-positive breast cancer with the hope of improving on the results achieved with CMF (cyclophosphamide, methotrexate, 5-fluorouracil) or anthracycline-based regimens. So far, three randomized paclitaxel-based adjuvant clinical trials enrolling 3170 women (Cancer and Leukemia Group B [CALGB] 9344), 3060 women (National Surgical Adjuvant Project for Breast and Bowel Cancers [NSABP]-B28), and 524 women (M. D. Anderson), respectively, have been reported with respective median follow-up times of 52, 34, and 43 months. This article critically reviews these three studies and gives an overview of the many other randomized clinical trials, due to accrue more than 17 000 women, which are investigating the potential of taxanes in adjuvant breast cancer therapy. Given that the early promise of taxanes suggested by CALGB 9344 is not yet confirmed by the two other trials, only level 2 evidence has been reached to date in regard to a positive contribution of these agents to breast cancer outcome in the adjuvant setting. It is argued that level 1 evidence is highly desirable before adopting taxane-based regimens in standard practice. It is anticipated that a meta-analysis will be needed to comprehensively define the value of taxanes in early breast cancer, and a new model of international collaboration is proposed to find a balance between the need to offer new, more effective therapies to patients as soon as possible and the danger of drawing wrong, premature conclusions regarding the magnitude of benefit of a new regimen.

Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD) in premenopausal breast cancer patients. The effect of adjuvant clodronate treatment

We present the 5-year results of the effect of adjuvant chemotherapy on bone mineral density (BMD) and the efficacy of clodronate in the prevention of bone loss in 73 premenopausal women with primary breast cancer. All patients were treated with cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy. The patients were randomised to oral clodronate 1600 mg daily for 3 years or to a control group. At 5 years, patients were divided into those with preserved menstruation and those with amenorrhoea. Changes in BMD correlated significantly with the menstrual function after chemotherapy. The change in the lumbar spine BMD at 3 and 5 years were +0.6 and −1.3% in the menstruating group and −7.5 and −10.4% in the amenorrhoeic group ( P=0.0001 and 0.0001, respectively), and in femoral neck +1.7 and −0.3%, and −3.5 and −5.8% ( P=0.002 and P=0.001, respectively). Three-year clodronate treatment significantly reduced the bone loss in the lumbar spine −3.0% compared with controls −7.4% at three years ( P=0.003), but no significant difference was found in the femoral neck: −1.7% versus −2.8%, respectively ( P=0.86). These differences between the study groups were still seen at 5 years: in the lumbar spine −5.8% versus −9.7% ( P=0.008) and femoral neck −3.5% versus −5.1% ( P=0.91). In conclusion, chemotherapy-induced ovarian failure in premenopausal women caused a temporary accelerated bone loss of the lumbar spine. Adjuvant clodronate treatment significantly reduced this bone loss. Two years after the termination of treatment, the bone loss was still significantly less in the clodronate group compared with the control group.

Meta-Analysis of Adjuvant Cyclophosphamide/Methotrexate/5-Fluorouracil Chemotherapy in Postmenopausal Women with Estrogen Receptor–Positive, Node-Positive Breast Cancer

Conflicting results have been published regarding the efficacy of adjuvant cyclophosphamide/methotrexate/5- fluorouracil (CMF)-type chemotherapy in postmenopausal, estrogen receptor (ER)-positive women. The Oxford overview suggests real but limited benefit of any chemotherapy in this group of patients but avoids analyzing smaller subsets. We wished to better quantitate the benefit of adding CMF to tamoxifen in postmenopausal ER-positive women with tumor involvement of axillary lymph nodes. Six randomized studies comparing CMF plus tamoxifen to tamoxifen alone in postmenopausal, ER-positive, node-positive women have been published since 1992. They include 2368 patients. We performed a meta-analysis of 6 endpoints: survival, disease-free survival, locoregional recurrence, distant recurrence, contralateral breast recurrence, and thromboembolic complications. There was a statistically significant increase in disease-free survival from the addition of CMF-type chemotherapy to tamoxifen in this population; the absolute risk of relapse was reduced by 5.5% at 5 years. Effects of locoregional recurrence were greater than those on overall recurrence. No significant survival benefit was observed.

Dual role of vitamin C on lipid profile and combined application of cyclophosphamide, methotrexate and 5-fluorouracil treatment in fibrosarcoma-bearing rats

Combined application of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) has been followed in the treatment of breast cancer. The combined effect of CMF and vitamin C on plasma lipid and lipoprotein is important, since vitamin C encumbers the lipid abnormalities instigated by CMF. Hence, the study was launched to appraise the salubrious role of vitamin C in CMF administered fibrosarcoma-bearing rats. Fibrosarcoma cell line-induced rats were treated with CMF (cyclophosphamide 10 mg/kg b.w., methotrexate 1 mg/kg b.w., 5-fluorouracil 10 mg/kg b.w. and vitamin C 200 mg/kg b.w.) individually and in combination for 120 days. The concentration of plasma lipids and lipoprotein was determined in control and experimental rats. The untreated as well as CMF administered fibrosarcoma-bearing rats divulged significantly in increased levels of plasma total cholesterol, triglycerides, phospholipids, very low density lipoprotein (VLDL) and low density lipoprotein (LDL) cholesterol, as compared with their respective control animals. Whereas ester and high density lipoprotein (HDL) cholesterol levels exhibited a marked decrease in these animals. However, these lipid abnormalities were found to be moderated by co-administration of vitamin C. These results suggested that some clinical entanglement of CMF was refrained by co-administration of vitamin C in tumor stress condition.