Cyclophosphamide, Methotrexate And 5-fluorouracil Research Articles

A phase III randomised trial comparing the tolerability of dose-dense chemotherapy in older to that in younger breast cancer patients with four or more positive lymph nodes

589 Background: Recently published data showed older patients to have similar dose-related benefits in reducing breast cancer-related relapse and mortality to those of younger women. This analysis was performed to assess the feasibility of a prospective randomised dose-dense regimen in the treatment of women over the age of 60. Methods: From June 1996 to November 2000, 211 primary breast cancer patients with four or more positive lymph nodes were prospectively randomised to either four cycles of epirubicin and paclitaxel (ET) at two-week intervals followed by three cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with G-CSF support (Group A) [age < 60 years (A1), n = 79; age ≥ 60 years (A2), n = 25] –or four cycles of epirubicin and cyclophosphamide (EC) at three-week intervals followed by three cycles of CMF (Group B) [age < 60 years (B1), n = 80; age ≥ 60 years (B2), n = 27]. Results: The median age was 52 years (range 26–59) in group A1, 64 years (range 60–71) in group A2, 48.5 years (range 32–59) in group B1 and 64 years (range 60–72) in group B2. All seven cycles were administered in 95% (A1), 100% (A2), 99% (B1) and 89% (B2) of patients. A dose reduction was made only in 1% (A1), 2% (A2), 1% (B1) and 1% (B2) of the cycles. In comparing these four groups, delays in administering cycles were more frequent in the dose-intensified group of older patients (6% in A1 vs. 17% in A2; 6% in B1 vs. 11% in B2). The hematological toxicity data are shown in Table 1. NCI-CTC grade 3–4 non-hematological toxicities were rare and revealed no differences between the groups. Conclusions: The administration of a dose-dense regimen with epirubicin and paclitaxel followed by CMF with G-CSF support is feasible in elderly patients with a tolerable safety profile. Referring to the analysed data, a decreased hematopoetic potency must be considered in older patients. No significant financial relationships to disclose.

Prevalence and course of fatigue in breast cancer patients receiving adjuvant chemotherapy

BackgroundThe purpose of this study was to determine the prevalence of fatigue and the course of fatigue as a function of chemotherapy in breast cancer patients undergoing adjuvant chemotherapy. Patients and methodsIn a prospective cohort study, a sample of 157 patients with breast cancer were interviewed, using the Rotterdam Symptom Checklist and the Multidimensional Fatigue Inventory, at the first, third and fifth cycle of adjuvant chemotherapy, as well as 4 and 12 weeks after the last cycle of adjuvant chemotherapy. Patients were treated with either a doxorubicin-containing schedule, or cyclophosphamide, methotrexate and 5-fluorouracil (CMF). ResultsThe courses of general and physical fatigue are to a large extent similar. After the last cycle of chemotherapy, the CMF group reported a significant increase in fatigue, which was followed by a significant reduction. In the doxorubicin group a significant increase in fatigue was only seen during the first cycles of chemotherapy. The fatigue experienced at the first and the last measurements do not differ significantly. ConclusionsThe prevalence of fatigue increased significantly after the start of chemotherapy. After chemotherapy treatment the prevalence rate seemed to decline. A different impact of chemotherapy on the course of fatigue was found. In the doxorubicin group a direct increase in fatigue was found. In the CMF group a moderate direct increase occurred, followed by a delayed strong increase. An increase in fatigue was associated with a decrease in daily functioning. At all measurement occasions fatigue was affected by type of operation, such that women with a mastectomy were more fatigued than women that underwent a lumpectomy. Receiving radiotherapy also led to an increase in fatigue. With this knowledge breast cancer patients can be better informed about what they can expect. Further research should include interventions addressing how to reduce or cope with fatigue during as well as after receiving adjuvant chemotherapy.

The influence of classical prognostic factors and adjuvant chemotherapy on disease outcome in early grade 3 node-negative, and 1–3 node-positive breast cancer patients treated with adjuvant cyclophosphamide, methotrexate and fluorouracil (CMF), or untreated patients

The influence of classical prognostic factors and adjuvant chemotherapy on disease outcome in early grade 3 node-negative, and 1–3 node-positive breast cancer patients treated with adjuvant cyclophosphamide, methotrexate and fluorouracil (CMF), or untreated patients

Impact of neutropenia on delivering planned adjuvant chemotherapy: UK audit of primary breast cancer patients.

The UK audit was undertaken in primary breast cancer patients receiving adjuvant chemotherapy to: (1) record the incidence of neutropenic events (hospitalisation due to febrile neutropenia, dose delay of ⩾1 week or dose reduction of ⩾15% due to neutropenia); (2) evaluate the impact of neutropenic events on overall dose intensity (DI) received and (3) review the use of granulocyte colony-stimulating factor (G-CSF) in clinical practice. Data from 422 patients with Stage I–III breast cancer were collected from 15 centres. Cyclophosphamide, methotrexate and 5-fluorouracil(CMF)- or anthracycline-based regimens were the most commonly used. Only 5.2% of patients received G-CSF. Overall, 29% of patients experienced a neutropenic event, most frequently dose delay. Neutropenic events had a significant impact on the ability to deliver planned DI. Out of 422 patients, 17% did not achieve 85% of their planned DI; due to neutropenia in 11% of patients. Of the neutropenic patients receiving CMF- or anthracycline-based regimens, around 40 and 32% of patients, respectively, did not achieve 85% of their planned DI. Patients who experienced one neutropenic event had a higher risk of a second event. During adjuvant chemotherapy of primary breast cancer, neutropenic events are common, likely to occur in subsequent chemotherapy cycles, and have a significant impact on receiving planned DI.

Moderate neutropenia with adjuvant CMF confers improved survival in early breast cancer.

Despite the extensive literature clearly demonstrating the survival benefit for adjuvant chemotherapy in women with operable breast cancer, there are few data confirming this in routine practice. Some studies have suggested that not all women gain to the same extent, with older women showing a smaller benefit and lower doses achieving poorer outcomes. We therefore reviewed the case notes of 750 women treated over a 15-year period at The Edinburgh Cancer Centre with the same intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) regimen, to identify patient- and treatment-related factors influencing outcome in routine practice.The actuarial 10-year survival for these women was 59.3%, with the anticipated poorer outcome for those with more involved ipsilateral axillary nodes, higher grade and ER-negative tumours. There was no evidence that a lower delivered dose intensity or older age at presentation resulted in a poorer survival. Of particular interest was the observation that 45% of patients who had grade 2/3 neutropenia had a 10% absolute survival advantage over those with no neutropenia (P<0.001). This strongly suggests that some degree of neutropenia has more influence on outcome than age or delivered dose intensity.

Bone mineral density in premenopausal women treated for node-positive early breast cancer with 2 years of goserelin or 6 months of cyclophosphamide, methotrexate and 5-fluorouracil (CMF).

The purpose of this study was to compare changes in bone mineral density (BMD) in premenopausal patients with node-positive early breast cancer treated with goserelin (Zoladex) or cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Patients ( n=1640) were randomized to goserelin (3.6 mg every 28 days for 2 years) or CMF (sixx28-day cycles) treatment. In a protocoled sub-study involving 96 patients from eight centers (goserelin: n=53; CMF: n=43), lumbar spine (L2-L4) and femoral neck BMD were assessed by dual X-ray absorptiometry at baseline and then annually for 3 years. At the end of the 2-year goserelin-treatment period, mean BMD losses for goserelin-treated and CMF-treated patients were -10.5% and -6.5% ( P=0.0005) for lumbar spine and -6.4% and -4.5% ( P=0.04) for femoral neck, respectively. At 3 years, partial recovery of BMD was observed in goserelin recipients. In contrast, mean BMD losses for the CMF group indicated persistent BMD loss. No significant differences in BMD were observed between groups at the 3-year assessment of the spine or femoral neck. In the CMF group, based on amenorrhea status at 48 weeks, BMD losses at the lumbar spine were greater for amenorrheic than non-amenorrheic patients. Ovarian suppression resulting in amenorrhea was closely related to BMD loss in both treatment groups. Overall, patients who received CMF did not show recovery of BMD throughout follow-up, whereas partial recovery was observed 1 year after cessation of goserelin therapy, associated with the return of ovarian function in the majority of patients.

The best use of adjuvant endocrine treatments

Endocrine therapy remains important in the adjuvant treatment of pre- and postmenopausal women. Adjuvant ovarian ablation with or without tamoxifen produces effects which are equivalent to those of CMF (cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy in premenopausal women with oestrogen receptor (ER) and/or progesterone receptor (PgR) positive breast cancer. Tamoxifen alone is also effective in these women. Concurrent use of tamoxifen and ovarian ablation may be even more effective, but more studies are needed. Tamoxifen remains a standard adjuvant therapy for postmenopausal women with ER and/or PgR positive tumours. Current information supports the use of 5 years of tamoxifen but additional studies comparing 5 years to longer duration are ongoing. The aromatase inhibitor (AI) anastrozole has now been demonstrated to be better than tamoxifen in preventing recurrence in early reports from the Arimidex vs Tamoxifen And the Combination (ATAC) Trial. Ongoing trials of this and other AIs before, after, concurrent with, or substituted for tamoxifen in the adjuvant setting may soon revolutionize our approach for postmenopausal women. Adjuvant bisphosphonates have been shown to reduce the incidence of bone metastases and improve survival in two of three published adjuvant trials and are being further studied. Her-2 neu status is being explored as a predictive factor for selection of endocrine therapy, but is not yet considered standard for this purpose.

Survival analyses from the ZEBRA study: goserelin (Zoladex™) versus CMF in premenopausal women with node-positive breast cancer

The Zoladex Early Breast Cancer Research Association (ZEBRA) trial compared the efficacy and tolerability of goserelin (Zoladex™) with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy in pre-/perimenopausal women with node-positive early breast cancer. The results of disease-free survival (DFS) analyses have already been published. Here we present an update including data on overall survival (OS) from the ZEBRA trial at a median follow-up of 7.3 years. In patients with oestrogen receptor (ER)-positive tumours, non-inferiority of goserelin versus CMF for OS was shown; goserelin was again shown to be equivalent to CMF for DFS. This updated analysis has demonstrated that the two treatments are also equivalent for distant disease-free survival (DDFS). In patients with ER-negative disease, goserelin was inferior to CMF for DFS, DDFS and OS. This follow-up analysis confirms the previously reported outcomes from the ZEBRA trial and demonstrates that goserelin offers an effective alternative to CMF chemotherapy for adjuvant therapy of premenopausal patients with ER-positive, node-positive early breast cancer.

Addition of Adjuvant Tamoxifen to Cyclophosphamide, Methotrexate and 5-Fluorouracil for Premenopausal Women with Oestrogen Receptor-Positive Breast Cancer

To study the value of adjuvant tamoxifen (TAM) in premenopausal women with oestrogen receptor (ER)-positive breast cancer who received adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) polychemotherapy. Four hundred and two premenopausal ER-positive breast cancer patients who received CMF chemotherapy between January 1990 and December 1999 were retrospectively studied. Disease-free survival (DFS) and overall survival (OS) were used to evaluate the clinical value of TAM therapy. The relationships between nodal status and TAM were also analysed. After a mean of 41 months of follow-up, 43 (13.7%) patients died of breast cancer and 68 (19.9%) patients suffered recurrence. There was a significant difference between TAM and non-TAM treatment groups for DFS (p=0.0058), but no significant difference for OS. For node-negative patients, there was no significant difference between the TAM and non-TAM treatment groups for either DFS or OS. For node-positive patients, the difference between TAM and non-TAM treatment groups was significant for both DFS and OS (p=0.0497 and p=0.0285, respectively). TAM resulted in additional benefit to premenopausal patients with node-positive ER-positive breast cancer who received the CMF polychemotherapy regimen.

Randomised Trial: One Cycle of Anthracycline-Containing Adjuvant Chemotherapy Compared with Six Cycles of CMF Treatment in Node-Positive, Hormone Receptor-Negative Breast Cancer Patients

Aim: A randomised, controlled clinical trial was initiated in 1984 to test whether 1 cycle of anthracycline-containing adjuvant chemotherapy improves the outcome of breast cancer patients presenting with stage II disease and negative oestrogen and progesterone receptors (ER, PgR), as compared with 6 cycles of dose-reduced CMF. Patients and Methods: Within 7 years 263 women with stage II breast cancer were randomised either to receive 1 cycle of doxorubicin, vinblastine, cyclophosphamide, methotrexate and 5- fluorouracil (AV-CMF) or to receive 6 cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Patients were stratified for tumour stage, nodal stage, menopausal status, type of surgery and participating centre. Results: After a median follow-up of 100 months, neither disease-free (DFS) nor overall survival (OS) differed significantly between the two groups. Conclusions: Compared to 6 cycles of a non-standard low-dose CMF regimen 1 cycle of anthracycline- containing adjuvant chemotherapy failed to improve the outcome in women with stage II receptor-negative breast cancer in terms of DFS and OS.

Concurrent sequencing of full-dose CMF chemotherapy and radiation therapy in early breast cancer has no effect on treatment delivery

With the increasing use of breast-conserving therapy plus systemic chemotherapy for the treatment of early breast cancer, the optimal sequencing of radiation therapy and chemotherapy remains controversial. Sequencing of therapy may influence not only treatment delivery, but control rates, complications and cosmesis. The aim of this study was to evaluate whether concurrent sequencing of standard doses of CMF (cyclophosphamide, methotrexate and 5-fluorouracil) and adjuvant radiation therapy for early breast cancer impacted on optimum treatment delivery. As both an intravenous (i.v.) 3-week regimen and classic (standard) CMF were utilised in this study, both types of CMF were compared. The effect of sequencing on complications and treatment delays were also assessed. 116 patients treated with CMF chemotherapy and adjuvant tangent breast radiation were studied. 73 patients were treated prospectively with concurrent therapy and were retrospectively compared with a matched group of 40 patients treated with sequential or sandwich therapy. All patients had stage 1 or 2 cancers. There were no planned dose reductions introduced for either treatment modality. Concurrent sequencing had no impact on the ability to deliver optimum radiation or chemotherapy doses. There was no significant difference in acute Radiation Therapy Oncology Group (RTOG) skin reactions or complications between the two groups. Although small, there was a significant delay (1.32 days (0–15 versus 0.36 (0–7)) in the concurrent group (P=0.03) in the delivery of radiation therapy. Sequencing had no significant effect on haematological parameters. ‘Standard’ CMF had a more profound effect on treatment delivery than i.v. CMF (Radiation delay 2.2 days versus 0.26, P=0.002, % chemotherapy delivered 93% versus 99% P=0.000004). At a mean follow-up of 2.6 years, there was no difference in the cosmetic scores between the two groups. Both local and distant control rates were excellent. This study has shown that standard radiation therapy can be delivered safely concurrently with CMF chemotherapy. Whether this approach may lead to better control rates in the future needs further study.

Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer.

Capecitabine is an orally administered prodrug of fluorouracil which is indicated in the US and Europe, in combination with docetaxel, for the treatment of patients with metastatic breast cancer failing anthracycline therapy, and as monotherapy for metastatic breast cancer resistant to paclitaxel and anthracycline therapy (US) or failing intensive chemotherapy (Europe). Capecitabine is also approved for use in metastatic colorectal cancer. Capecitabine is metabolically activated preferentially at the tumour site, and shows antineoplastic activity and synergy with other cytotoxic agents including cyclophosphamide or docetaxel in animal models. Bioavailability after oral administration is close to 100%. In patients with pretreated advanced breast cancer, capecitabine is effective as monotherapy and also in combination with other agents. Combination therapy with capecitabine 1,250 mg/m(2) twice daily for 2 weeks of every 3-week cycle plus intravenous docetaxel 75 mg/m(2) on day one of each cycle was superior to intravenous monotherapy with docetaxel 100 mg/m(2) on day one of each cycle. Capecitabine plus docetaxel significantly reduced the risks of disease progression and death by 35% (p = 0.0001) and 23% (p < 0.05), respectively, and significantly increased median survival (p < 0.05) and objective response rates (p < 0.01). Efficacy has also been demonstrated with capecitabine monotherapy and combination therapy in previously untreated patients in preliminary trials. The most common adverse effects occurring in patients receiving capecitabine monotherapy include lymphopenia, anaemia, diarrhoea, hand-and-foot syndrome, nausea, fatigue, hyperbilirubinaemia, dermatitis and vomiting (all >25% incidence). While gastrointestinal events and hand-and-foot syndrome occurred more often with capecitabine than with paclitaxel or a regimen of cyclophosphamide, methotrexate and fluorouracil (CMF), neutropenic fever, arthralgia, pyrexia and myalgia were more common with paclitaxel, and nausea, stomatitis, alopecia and asthenia were more common with CMF. The incidence of adverse effects and hospitalisation was similar in patients receiving capecitabine plus docetaxel and those receiving docetaxel monotherapy. In conclusion, capecitabine, an oral prodrug of fluorouracil which is activated preferentially at the tumour site, is an effective and convenient addition to the intravenous polychemotherapeutic treatment of advanced breast cancer in pretreated patients, and also has potential as a component of first-line combination regimens. Combined capecitabine plus docetaxel therapy resulted in similar rates of treatment-related adverse effects and hospitalisation to those seen with docetaxel monotherapy. Capecitabine is also effective as monotherapy in pretreated patients and phase II data for capecitabine as first-line monotherapy are also promising. While gastrointestinal effects and hand-and-foot syndrome occur often with capecitabine, the tolerability profile was comparatively favourable for other adverse effects (notably, neutropenia and alopecia).

Pulsed electrostatic fields (ETG) to reduce hair loss in women undergoing chemotherapy for breast carcinoma: a pilot study.

To determine whether specific pulsed electrostatic fields, or electrotrichogenesis (ETG), could potentially prevent or reduce hair loss in patients undergoing adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy for breast cancer. Thirteen women were followed during their adjuvant ETG and chemotherapy treatment to determine the efficacy of ETG. All patients were treated for 12 min, twice weekly with a pulsed electrostatic field. Quantitative hair loss was measured by photographic assessment, and manual hair count. Quality of life assessment was conducted at the end of the study. Twelve out of 13 participants had good hair retention throughout the chemotherapy period and afterwards. There were no reported side effects attributable to ETG. This study shows encouraging results in an area where no other appropriate treatment is available Reducing alopecia, secondary to chemotherapy has the potential to increase CMF treatment compliance, enhance patient self-esteem, and improve overall quality of life during this stressful period.

The expanding role of epirubicin in the treatment of breast cancer.

Adjuvant treatment of early breast cancer has experienced major changes in the last 25 years. Since the mid 1970s, when cyclophosphamide, methotrexate and fluorouracil (CMF) resulted in statistically significant and clinically meaningful improvements in disease-free and overall survival, the use of adjuvant chemotherapy has become common practice worldwide. Anthracyclines are considered to be among the most active available agents to treat breast cancer and have become core components of adjuvant regimens. Anthracycline-containing polychemotherapy regimens provide a significant benefit over CMF. Regimens containing epirubicin are generally associated with prolongation in relapse-free and overall survival rates compared with standard therapies including CMF. Epirubicin-taxane combinations are active in treating metastatic breast cancer and do not appear to be associated with any pharmacokinetic interactions. Ongoing research is focusing on combining anthracyclines with taxanes in an effort to continue to improve outcomes following adjuvant therapy.

Chemotherapy of Breast Cancer

Standard adjuvant polychemotherapy for patients with breast cancer significantly improves their survival and is used for this patient group worldwide. In the beginning of this era, mainly CMF (cyclophosphamide, methotrexate and fluorouracil) was used but CMF is nowadays often replaced by anthracycline containing regimens after results favoring anthracyclines were published. The role of taxanes in the adjuvant setting is not yet fully understood; however, this should become clearer following the results from several ongoing randomized studies. In addition to the question of which drugs to use, dosage recommendations are a more complex issue. Low dosage regimens have been associated with inferior survival results compared with standard dosages in the adjuvant setting. High dosage regimens of anthracyclines have not been associated with better survival in some studies, although some investigators have shown the opposite. The use of very high doses requiring autologous bone marrow support have not resulted in survival gains in randomized studies.

Chemotherapy versus hormonal adjuvant treatment in premenopausal patients with breast cancer

Comparisons between the effects exerted by adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF)-based polychemotherapy and endocrine treatment in premenopausal breast cancer patients are validly drawn in the presence of steroid hormone receptor responsiveness. First, ovarian ablation still remains to show activity compared with chemotherapy in large patient groups. Second, tamoxifen is at least as active in this cohort and, by comparison, produces a significant effect in mortality reduction. Third, induction of reversible amenorrhoea by LHRH analogue administration has shown comparable effects in terms of recurrence-free survival. Finally, recent European investigations have indicated significant recurrence reductions with LHRH analogue-tamoxifen combination strategies. In conclusion, various endocrine treatment modalities have been substantiated as equiefficient to polychemotherapy. Tamoxifen added to a LHRH analogue further diminishes the recurrence rates and now appears to be a valid treatment alternative. We argue that selection of adjuvant systemic therapy for premenopausal breast cancer patients be increasingly guided by knowledge of the steroid hormone receptor levels.

Modeling Multi-drug Chemotherapy: Tailoring Treatment to Individuals

Background: Predicting and tailoring optimal cancer treatments presents a major challenge.Methods: A computational model (kinetically tailored treatment, or KITT model) is developed to predict drug combinations, doses, and schedules likely to be effective in reducing tumor size and prolonging patient life. Treatment strategies may be tailored to individuals based on tumor cell kinetics. The model incorporates intra-tumor heterogeneity and evolution of drug resistance, apoptotic rates, and cell division rates. Tumor growth may follow an exponential or a Gompertzian trajectory. Drug pharmacodynamic and pharmacokinetic models are used. Toxicity is modeled in several ways.Results: A key prediction of KITT is that including cytostatic drugs like tamoxifen and herceptin during treatment with cytotoxic drugs substantially increases the probability of cure and prolongs patient life. Results also suggest that altering drug scheduling may be more effective but not more toxic than dose escalation. CAF chemotherapy (cyclophosphamide, adriamycin, and 5-fluorouracil) is predicted to be more effective than CMF (cyclophosphamide, methotrexate, and 5-fluorouracil). KITT also suggests that tumors with a high proliferative index (PI) may respond better to drug combinations incorporating two cell-cycle phase-specific drugs than do tumors with a low PI. Tumors with a low PI, in contrast, are predicted to respond better to regimens involving two cell-cycle phase-non-specific drugs than do tumors with a high PI. These predictions are borne out by clinical trial results published in the literature, which are discussed.Simulated predictions of the model match well with results from a clinical trial by Silvestrini et al. (2000. Int. J. Cancer87, 405). The results of simulating the growth of 26896 tumors are used to construct a decision tree for prognosis to identify the key tumor and treatment variables.Conclusion: Additional tests of the model are needed in which physicians collect information on apoptotic and proliferative indices, cell-cycle times, and drug resistance from biopsies of each individual's tumor. Computational models may become important tools to help optimize and tailor cancer treatments.

Multi-agent chemotherapy for early breast cancer.

There have been many randomised trials of adjuvant prolonged polychemotherapy among women with early breast cancer, and an updated overview of their results is presented. In this report, the Early Breast Cancer Trialists' Collaborative Group present their updated systematic overview (meta-analysis) of treatment with polychemotherapy. Trial identification procedures for the EBCTCG overviews have been described elsewhere. See under "EBCTCG" in the Breast Cancer Collaborative Review Group module. All randomised trials that began before 1990 and involved treatment groups that differed only with respect to the chemotherapy regimens that were being compared. In 1995, information was sought on each woman in any randomised trial that began before 1990 and involved treatment groups that differed only with respect to the chemotherapy regimens that were being compared. Analyses involved about 18,000 women in 47 trials of prolonged polychemotherapy versus no chemotherapy, about 6000 in 11 trials of longer versus shorter polychemotherapy, and about 6000 in 11 trials of anthracycline-containing regimens versus CMF (cyclophosphamide, methotrexate, and fluorouracil). For recurrence, polychemotherapy produced substantial and highly significant proportional reductions both among women aged under 50 at randomisation (35% [SD 4] reduction; 2p <0.00001) and among those aged 50-69 (20% [SD 3] reduction; 2p <0.00001); few women aged 70 or over had been studied. For mortality, the reductions were also significant both among women aged under 50 (27% [SD 5] reduction; 2p <0.00001) and among those aged 50-69 (11% [SD 3] reduction; 2p=0.0001). The recurrence reductions emerged chiefly during the first 5 years of follow-up, whereas the difference in survival grew throughout the first 10 years. After standardisation for age and time since randomisation, the proportional reductions in risk were similar for women with node-negative and node-positive disease. Applying the proportional mortality reduction observed in all women aged under 50 at randomisation would typically change a 10-year survival of 71% for those with node-negative disease to 78% (an absolute benefit of 7%), and of 42% for those with node-positive disease to 53% (an absolute benefit of 11%). The smaller proportional mortality reduction observed in all women aged 50-69 at randomisation would translate into smaller absolute benefits, changing a 10-year survival of 67% for those with node-negative disease to 69% (an absolute gain of 2%) and of 46% for those with node-positive disease to 49% (an absolute gain of 3%). The age-specific benefits of polychemotherapy appeared to be largely irrespective of menopausal status at presentation, oestrogen receptor status of the primary tumour, and of whether adjuvant tamoxifen had been given. In terms of other outcomes, there was a reduction of about one-fifth (2p=0.05) in contralateral breast cancer, which has already been included in the analyses of recurrence, and no apparent adverse effect on deaths from causes other than breast cancer (death rate ratio 0.89 [SD 0.09]). The directly randomised comparisons of longer versus shorter durations of polychemotherapy did not indicate any survival advantage with the use of more than about 3-6 months of polychemotherapy. By contrast, directly randomised comparisons did suggest that, compared with CMF alone, the anthracycline-containing regimens studied produced somewhat greater effects on recurrence (2p=0.006) and mortality (69% vs 72% 5-year survival; log-rank 2p=0.02). But this comparison is one of many that could have been selected for emphasis, the 99% CI reaches zero, and the results of several of the relevant trials are not yet available. Some months of adjuvant polychemotherapy (eg, with CMF or an anthracycline-containing regimen) typically produces an absolute improvement of about 7-11% in 10-year survival for women aged under 50 at presentation with early breast cancer, and of about 2-3% for those aged 50-69 (unless their prognosis is likely to be extremely good even without such treatment). Treatment decisions involve consideration not only of improvements in cancer recurrence and survival but also of adverse side-effects of treatment, and this report makes no recommendations as to who should or should not be treated.

HER-2/neu overexpression and in vitro chemosensitivity to CMF and FEC in primary breast cancer.

Available clinical and experimental data on the effect of HER-2/neu overexpression on chemosensitivity are controversial. It was the purpose of this in vitro study to define the association between HER-2/neu overexpression and the sensitivity to the chemotherapeutic drug combinations of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) and 5-fluorouracil, epirubicin and cyclophosphamide (FEC) of breast cancer cells derived from 140 chemotherapy-naïve patients at the time of primary surgery. Both drug combinations were tested at six different concentrations ranging from 6.25-200% peak plasma concentration (PPC). Immunohistochemical detection of HER-2/neu overexpression was performed with the HER-2/neu antibodies, CB11, TAB250 and AO485, in the same tumor specimens. Immunoreactions were determined as negative (0/1+), weakly positive (2+) and strongly positive (3+). However, the antibodies varied in their degrees of sensitivity. Breast cancer samples with strong (3+) HER-2/neu overexpression demonstrated 90% growth inhibition (IC90) at significantly lower PPC values, using the CB11 (p = 0.048), TAB250 (p = 0.007) and AO485 (p < or =0.01) antibodies, and showed 50% growth inhibition (IC50) at significantly lower PPC values, using the CB11 antibody (p = 0.01) compared to their counterparts with lower levels of HER-2/neu expression. When analyzing the group of patients with intermediate and strong HER-2/neu overexpression (2+ and 3+), an association between HER-2/neu overexpression and increased chemosensitivity was seen with the TAB250 (p = 0.044) and AO485 (p = 0.032) antibodies, but not with the CB11 antibody (p =0.8) at the IC90 level. Differences in chemosensitivity between samples with strong HER-2/neu overexpression and those with lower levels were then analyzed separately for CMF and FEC. Both regimens achieved 90% tumor growth inhibition at lower PPC values in samples with strong HER-2/neu overexpression (3+) compared to their counterparts with lower expression levels (AO485 p = 0.011 for CMF, and p = 0.09 for FEC). Cumulative concentration-response plots of tumors responding in vitro with 90% tumor cell inhibition showed a stronger dose dependence for both CMF and FEC among tumor samples with strong HER-2/neu overexpression compared to those with lower levels of expression. In conclusion, the data show that HER-2/neu overexpression was not associated with in vitro drug resistance to CMF or FEC. In contrast, tumors with strong HER-2/neu overexpression demonstrated increased dose-dependent in vitro sensitivity to both the FEC and CMF regimens.

Randomized, open-label, phase II trial of oral capecitabine (Xeloda®) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer

Oral capecitabine was evaluated in terms of overall response rate, safety, and tolerability as first-line therapy in women aged > or = 55 years with advanced/metastatic breast cancer. Ninety-five patients were randomized (2:1) to either intermittent oral capecitabine 1,255 mg/m2 twice daily (two weeks' treatment followed by a one-week rest period) or intravenous CMF (cyclophosphamide. methotrexate, 5-fluorouracil [5-FU]) administered every three weeks. The overall response rate in the capecitabine group was 30% (95% confidence interval (95% CI): 19%-43%), including three complete responses (5%). The response rate observed in the CMF group was 16% (95% CI: 5%-33%), with no complete responses. Median time to disease progression was 4.1 months with capecitabine and 3.0 months with CME. Survival was similar in the two treatment groups (median 19.6 months with capecitabine. 17.2 months with CMF). The safety profiles were different for capecitabine and CMF. However, both regimens were generally well tolerated and treatment interruption and/or dose modification was effective in managing toxicities associated with capecitabine. Alopecia and myelosuppression were rare in patients receiving capecitabine while diarrhea and hand-foot syndrome were more common. Treatment interruption and/or individual dose adjustment of capecitabine was required in 34% of patients and was generally effective in managing adverse events. Treatment was stopped owing to toxicity in 16% of patients in the capecitabine arm. The incidence of deaths during or within 28 days of stopping study treatment was 8% and 6% in the capecitabine and CMF arms, respectively. An oral, twice-daily regimen of capecitabine is effective and well tolerated when used as first-line chemotherapy in older patients (> or = 55 years) with advanced/metastatic breast cancer, and is suitable for outpatient therapy.