Adjuvant Cyclophosphamide, Methotrexate And 5-fluorouracil Research Articles

The Prosigna 50-gene profile and responsiveness to adjuvant anthracycline-based chemotherapy in high-risk breast cancer patients

The DBCG89D trial randomized high-risk early breast cancer patients to adjuvant CMF (cyclophosphamide, methotrexate and fluorouracil) or CEF (cyclophosphamide, epirubicin and fluorouracil). Prosigna assays were performed by researchers with no access to clinical data. Time to distant recurrence (DR) was the primary endpoint, time to recurrence (TR) and overall survival (OS) secondary. Among the 980 Danish patients enrolled, Prosigna results were obtained in 686. Continuous ROR score was associated with DR for CMF (adjusted hazard ratio (HR) 1.20, 95% CI 1.09–1.33), and for CEF (HR 1.04, 95% CI 0.92–1.18), Pinteraction = 0.06. DR was significantly longer in CEF compared to CMF treated patients with Her2-enriched tumors (HR 0.58, 95% CI 0.38–0.86), but not in patients with luminal tumors. Heterogeneity of treatment effect was significant for TR and OS. In this prospective-retrospective analysis, patients with Her2-enriched breast cancer derived substantial benefit from anthracycline chemotherapy whereas anthracyclines are not an essential component of chemotherapy for patients with luminal subtypes. The benefit of CEF vs. CMF correlated with increasing ROR Score.

Association between delayed initiation of adjuvant CMF or anthracycline-based chemotherapy and survival in breast cancer: a systematic review and meta-analysis

BackgroundAdjuvant chemotherapy (AC) improves survival among patients with operable breast cancer. However, the effect of delay in AC initiation on survival is unclear. We performed a systematic review and meta-analysis to determine the relationship between time to AC and survival outcomes.MethodsPubMed, EMBASE, Cochrane Database of Systematic Reviews, and Web-of-Science databases (between January-1 1978 and January-29, 2013) were searched for eligible studies. Hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) from each study were converted to a regression coefficient (β) corresponding to a continuous representation per 4-week delay of AC. Most used regimens of chemotherapy in included studies were CMF (cyclophosphamide, methotrexate, and fluorouracil) or anthracycline-based. Individual adjusted β were combined using a fixed-effects or random-effects model depending on heterogeneity.ResultsWe included 7 eligible studies with 9 independent analytical groups involving 34,097 patients, 1 prospective observational study, 2 secondary analyses in randomized trials (4 analytical groups), and 4 hospital-/population-based retrospective study. The overall meta-analysis demonstrated that a 4-week increase in time to AC was associated with a significant decrease in both OS (HR = 1.15; 95% confidence interval [CI], 1.03-1.28; random-effects model) and DFS (HR = 1.16; 95% CI, 1.01-1.33; fixed-effects model). One study caused a significant between-study heterogeneity for OS (P < 0.001; I2 = 75.4%); after excluding that single study, there was no heterogeneity (P = 0.257; I2 = 23.6%) and the HR was more significant (HR = 1.17; 95% CI, 1.12-1.22; fixed-effects model). Each single study did not fundamentally influence the positive outcome and no evidence of publication bias was observed in OS.ConclusionsLonger time to AC is probably associated with worse survival in breast cancer patients.

Do GnRH analogs protect against ovarian toxicity of chemotherapy?

Premature ovarian failure is a well described complication of adjuvant chemotherapy for breast cancer. For a variety of reasons, including fertility and quality of life concerns, individuals being treated for breast and other cancers may wish to avoid loss of ovarian function. In this issue of breast cancer research and treatment, Sverrisdottir et al. [1] report on a substudy of ovarian function outcomes following adjuvant therapy with and without goserelin coadministration among patients enrolled in the ZIPP (Zoladex in Premenopausal Patients) trial. The precise mechanism for the high sensitivity of ovarian tissue to the effects of chemotherapy is unclear. While chemotherapy preferentially affects dividing cells, only a small fraction of ovarian follicles are developing at any time in the normal premenopausal ovary. It has been hypothesized that chemotherapy induced injury to ovarian tissue may result in a feedback loop in which additional follicles are recruited in response to the initial follicle loss, putting further germ cell tissue at risk for damage [2]. It would follow that if ovarian tissue can be made relatively quiescent during chemotherapy, the risk for permanent loss of ovarian follicles should be reduced. Case series and nonrandomized trials in women with breast cancer and hematologic malignancies have suggested a high rate of preservation of menstrual function following coadministration of GnRH agonists and chemotherapy; however, published randomized data are lacking [3]. Current American society of clinical oncology guidelines discourage this approach to fertility preservation outside of a clinical trial [4]. Sverrisdottir et al. suggest that, in the absence of tamoxifen, goserelin coadministration during adjuvant CMF (cyclophosphamide, methotrexate and 5-fluorouracil) provides a protective effect on ovarian function. About 36 month follow-up was available for 94 of 123 premenopausal CMF-treated participants randomized, in a 2 9 2 factorial design, to goserelin or no goserelin and to tamoxifen or no tamoxifen, each for 2 years. Endocrine treatment began concurrently with chemotherapy. Patients receiving endocrine therapy had been off treatment for approximately 1 year at the 36 month follow-up visit. At that time, 36% of participants who had received goserelin without tamoxifen during chemotherapy had resumed menstruation, while only 10% of the remaining three groups combined resumed menses. An important question to ask, however, is why goserelin would have a differing effect on subsequent ovarian function whether or not tamoxifen was given as well. In the absence of ovarian suppression, tamoxifen use in premenopausal women has been associated with an increase in ovarian estrogen production that appears to be secondary to a rise in FSH [5]. This is consistent with tamoxifen’s known ability to induce ovulation. Theoretically, this increase in ovarian activity with tamoxifen could increase gonadal susceptibility to chemotherapy toxicity. Patients receiving tamoxifen during chemotherapy without the GnRH analog, however, did not appear to experience a higher rate of ovarian failure than controls in the study by Sverrisdottir et al. In addition, any ability of tamoxifen to increase ovarian cycling during chemotherapy ought to be prevented through suppression of the hypothalamic-pituitary axis when the GnRH analog is added. It is, therefore, unlikely that the ability of goserelin to preserve ovarian function would be significantly influenced by whether the patient also takes tamoxifen. This is an invited commentary to article doi:10.1007/s10549-009-0313-5.

DBCG trial 89B comparing adjuvant CMF and ovarian ablation: Similar outcome for eligible but non-enrolled and randomized breast cancer patients

Introduction. A cohort of premenopausal patients with primary hormone receptor positive breast cancer was prospectively identified to be eligible for the DBCG 89B trial. We perform a long-term follow-up and evaluate the external validity of the trial. Material and methods. Following registration in a population-based registry, patients were invited to be randomized to ovarian ablation (OA) versus nine courses of three-weekly cyclophosphamide, methotrexate and 5-fluorouracil (CMF). The same procedures were used in all patients, including report forms, central review, querying, and analysis of data. Multivariate analysis was used to adjust for differences in base-line characteristics. Results. Participation in the randomization varied according to center and time period. One thousand six hundred and twenty eight eligible patients were registered and 525 randomized in the DBCG 89B trial. Median estimated follow-up was 9.5 years for disease-free survival and 12.1 years for overall survival. Non-enrolled patients had a disease-free and overall survival similar to randomized patients. Within 5 years of surgery, results were similar following OA and CMF, but disease-free survival was significant inferior with OA more than five years after surgery, adjusted hazard ratio 1.38 (95% CI 1.03 to 1.85; p=0.03). This convened ten years after surgery to an inferior survival with OA, and the adjusted hazard ratio was 2.37 (95% CI 1.43 to 3.91; p<0.01). Discussion. This prospective cohort study indicates that eligible patients not participating in the DBCG 89B trial had a similar disease-free and overall survival as participants. Survival was similar after OA and CMF in the first ten years, but became inferior in the OA group 10 or more years after surgery.

Gene expression profilers and conventional clinical markers to predict distant recurrences for premenopausal breast cancer patients after adjuvant chemotherapy

A large proportion of breast cancer patients are treated with adjuvant chemotherapy after the primary operation, but some will recur in spite of this treatment. In order to achieve an improved and more individualised therapy, our knowledge in mechanisms for drug resistance needs to be increased. We have investigated to what extent cDNA microarray measurements could distinguish the likelihood of recurrences after adjuvant CMF (cyclophosphamide, methotrexate and 5-fluorouracil) treatment of premenopausal, lymph node positive breast cancer patients, and have also compared this with the corresponding performance when using conventional clinical variables. We tried several gene selection strategies, and built classifiers using the resulting gene lists. The best performing classifier with odds ratio (OR) = 6.5 (95% confidence interval (CI) = 1.4–62) did not outperform corresponding classifiers based on clinical variables. For the clinical variables, calibrated on the samples, either using all the clinical parameters or the Nottingham Prognostic Index (NPI) parameters, the areas under the receiver operating characteristics (ROC) curve were 0.78 and 0.79, respectively. The ORs at 90% sensitivity were 15 (95% CI = 3.1–140) and 10 (95% CI = 2.1–97), respectively. Our data have provided evidence for a comparable prediction of clinical outcome in CMF-treated breast cancer patients using conventional clinical variables and gene expression based markers.

Effects of adjuvant chemotherapy on the protein C anticoagulant pathway in patients with early stage breast cancer

8563 Background: Although chemotherapy treatment is associated with an increased risk of thrombosis, the pathogenic mechanisms are poorly understood. We have previously shown that treatment of endothelial cells with adriamycin and epirubicin impairs the protein C anticoagulant pathway by downregulating EPCR (endothelial protein C receptor), an endothelial receptor required for the conversion of protein C to the anticoagulant enzyme activated protein C (APC). In this study, we examined the effects of adriamycin- and epirubicin-containing chemotherapy on the protein C anticoagulant pathway in early stage breast cancer patients. Methods: We collected blood samples from 20 patients patients with early stage breast cancer undergoing adjuvant CEF (cyclophosphamide, epirubicin and 5-fluorouracil) or CMF (cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy on days 1, 2 and 8 for the first 2 cycles of treatment. Markers of protein C generation (protein C, thrombin-antithrombin (TAT) complexes, and APC) were measured on these days. Results: Plasma protein C levels were significantly lower at cycle 2 day 8 (0.88 ± 0.14 U/ml) compared to pre-chemotherapy levels (1.07 ± 0.23 U/ml) (p=0.0036). Plasma TAT levels were significantly higher at cycle 2 day 8 (2.87 ± 0.79 μg/L) compared to pre-chemotherapy levels (2.01 ± 1.24 μg/L) (p=0.02). Based on the APC levels, the patients appear to fall into two categories in terms of their ability to generate APC. The first group (n=16) has elevated APC levels that parallel the elevated TAT levels, whereas the second group (n=4) has low APC levels despite elevated TAT levels. Conclusions: Impaired ability to generate APC in a subpopulation of patients may reflect chemotherapy-induced impairment of the protein C pathway through the downregulation of EPCR. This pilot study provides new mechanistic insights into the prothrombotic effects of chemotherapy agents. No significant financial relationships to disclose.

The relationship of positive steroid receptor (SR) status with disease outcome in patients treated with adjuvant cyclophosphamide, methotrexate, and fluorouracil (A-CMF) chemotherapy (CHT) and adjuvant endocrine therapy

The relationship of positive steroid receptor (SR) status with disease outcome in patients treated with adjuvant cyclophosphamide, methotrexate, and fluorouracil (A-CMF) chemotherapy (CHT) and adjuvant endocrine therapy

Concurrent Radiotherapy Does Not Affect Adjuvant CMF Delivery but is Associated with Increased Toxicity in Women with Early Breast Cancer

We evaluated whether concurrent radiotherapy (RT) affected delivery and toxicity of adjuvant intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) in women with operable breast cancer. The medical charts of 321 consecutive breast cancer patients who received CMF either alone for 6 cycles, or for 4 cycles following of an anthracycline (A-CMF) were reviewed. One hundred forty-four women underwent radiotherapy concurrently with CMF. Optimal CMF delivery (success as opposite to failure) was defined as the combined achievement of an average relative dose intensity (aRDI) ≥85% and an average percent of the total dose (aPTD) ≥90% for the three drugs in the CMF regimen. Multivariate logistic regression analysis showed that concurrent-RT did not affect CMF delivery (OR for success 1.391 p=0.230). The sequential A-CMF regimen (OR for success 0.208, 95% C.I. 0.120-0.360, p<0.001) and age ≥56 (OR for success 0.351, 95% C.I. 0.200- 0.161, p<0.001) were independently associated with suboptimal CMF delivery. Moreover, concurrent RT was independently associated with increased leukopenia, thrombocytopenia, upper abdominal pain, mucositis and fatigue. Our retrospective analysis suggests that concurrent-RT has no impact on optimal CMF delivery, but it increases the burden of CMF-related toxicity.

Relation between chemotherapy dose, oestrogen receptor expression, and body-mass index

Clinicians often reduce chemotherapy doses when treating obese patients because of concerns about overdosing. We assessed dose-response according to body-mass index (BMI) and oestrogen receptor (ER) expression of the primary tumour in premenopausal patients with node-positive breast cancer treated with classical CMF (cyclophosphamide, methotrexate, and 5-fluorouracil). Obese patients were significantly more likely to receive a lower chemotherapy dose (<85% of expected dose) for the first course than were those with normal or intermediate BMI (39%vs 16%, p<0.0001). For obese patients and for the total population, reducing the dose of chemotherapy was associated with a significantly worse outcome for the ER-negative cohort (total population hazards ratio 85%vs <85% 0.68 [95% CI 0.54-0.86] for disease free survival; 0.72 [0.56-0.94] for overall survival) but not for the ER-positive cohort (1.16 [0.97-1.40] for disease-free survival; 1.16 [0.94-1.44] for overall survival) [interaction p values=0.0001 for disease-free survival and 0.0019 for overall survival]. Our findings suggest that for women with ER-absent or ER-low tumours, reduction in chemotherapy dose should be avoided.

Adjuvant chemotherapy for operable breast cancer: old vs new schema

In 1975 we presented our first report on the efficacy of cyclophosphamide, methotrexate and fluorouracil (CMF) as adjuvant treatment for node-positive breast cancer. Thirty years later, the results of this study demonstrate that the significant advantage in both relapse-free (reduction in relative risk for relapse of 29%) and overall survival (reduction in relative risk for death of 21%) persists over the years and that adjuvant CMF can exert a moderate but worthwhile suppression of micrometastases, regardless of anatomical sites [1]. With the aim of further improving the prognosis of operable breast cancer patients, in the early 1980s many research groups designed and carried out new randomized trials including anthracyclines. Despite the fact that many individual trials failed to observe a true benefit for the tested anthracycline regimen, the arithmetic construction on which the international overview is based (i.e. the summing up of many individual trials to increase the statistical power) allowed it to be estimated that there was a reduction in the risk for disease relapse and death of approximately 10%, corresponding to an absolute difference of approximately 3% [2]. At the Milan Cancer Institute we designed two different studies to test the effectiveness of sequential non-cross-resistant regimens containing anthracyclines. Briefly, in patients with moderate risk for relapse the sequential delivery of CMF followed by adriamycin was compared with CMF alone, whereas in a second study conducted in high-risk patient the inverse sequence (adriamycin followed by CMF) was tested. The rationale behind these studies was that switching to another regimen early in the administration of chemotherapy could overcome drug resistance. The updated 20-year results confirmed that the relative merits of anthracycline-containing adjuvant programs can also depend on the modality of administration and must be assessed in properly designed trials in which the magnitude of the benefits can be weighted against potential risks [3]. The treatment results observed after sequential adriamycin followed by CMF in a poor risk subset could probably be explained by an increased density of the anthracycline, which was delivered at full dose within the first 9 weeks of treatment. The value of dose density was recently confirmed by the National Cancer Institute's Breast Intergroup INT C9741 trial, in which patients who received the dose-dense regimens had significantly improved early treatment outcome compared with their counterparts who did not receive these regimens. The role of sequential non-cross-resistant regimens was tested in many other trials, both in the adjuvant and neoadjuvant settings. Of note, the 3-year joint efficacy analysis of the National Epirubicin Adjuvant Trial (NEAT) and of the Scottish Cancer Trials Breast Group reported a highly significant benefit in favor of the sequential regimen, supporting the hypothesis that the sequential administration of single-agent anthracyclines given upfront before CMF can indeed improve treatment outcome. Also, the addition of taxanes after delivery of adriamycin and cyclophosphamide contributed to improving therapeutic results over the nontaxane regimen both in the adjuvant and neoadjuvant settings. By contrast, in the INT C9741 trial no difference was detected in treatment outcome between the concurrent or sequential schedules of adriamycin, cyclophosphamide and paclitaxel. Similarly, the MD Anderson randomized study failed to detect superiority of the sequential arm. Thirty years ago, treating patients who were free of identifiable metastatic disease with systemic adjuvant therapy because some of them might eventually develop distant disease was a revolutionary departure from prior treatment approaches [4]. It has been estimated that improvements since the 1970s in the way in which breast cancer is managed must have prevented about 25–30% of the breast cancer deaths in middle-aged women that would otherwise have occurred in the year 2000.

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.

Variations in Dose and Dose Intensity of Adjuvant CMF Chemotherapy for Breast Cancer Throughout the UK

Cyclophosphamide, methotrexate and 5-fluorouracil (CMF) is a commonly prescribed regimen for the adjuvant treatment of early breast cancer in the UK and in other countries with a high incidence of breast carcinoma. A number of variations in dose and scheduling of these drugs have been reported in the literature, with all of these being recognized under the generic term ‘CMF’. To investigate the extent of differences in CMF regimens used for the adjuvant treatment of early breast cancer we sent a postal questionnaire to all consultant medical and clinical oncologists in the UK seeking details of their practice. CMF drug doses were then converted into dose intensity parameters for comparison. The results showed a wide variation in the number of CMF schedules (n = 36) and CMF dose intensities (n = 33) used. The potential consequencies of such variation and the evidence for and against dose intensity as an important parameter in the adjuvant treatment of early breast cancer are discussed.

Local recurrence after mastectomy and adjuvant CMF: implications for adjuvant radiation therapy.

The purpose of the present study was to evaluate the patterns of failure in a series of patients with node-positive breast cancer that was treated by total mastectomy and adjuvant chemotherapy. A retrospective review was undertaken of 217 patients with node-positive breast cancer who were referred to the oncology departments of Westmead and Nepean Hospitals following total mastectomy between January 1980 and December 1991. The majority of patients (82%) were pre- or peri-menopausal and all underwent chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) by either an oral or intravenous regimen. No patient received adjuvant radiation therapy. After a median follow up of 8.7 years, 19% of patients had developed a loco-regional recurrence (LRR). The majority of LRR (79%) occurred within the initial 3 years after mastectomy. The risk of LRR was positively associated with the size of the tumour (11% for T1 vs 53% for T3, P < 0.001) and axillary nodal status (16% for three or fewer positive nodes vs 31% for four or more positive nodes, P = 0.017). Patients with T1 or T2 tumours and 1-3 positive nodes had the lowest rate of LRR (11%) while those with T3 tumours or 4-10 positive nodes had the highest rates, ranging from 23 to 75%. Relapse at the chest wall and supraclavicular fossa (SCF) accounted for 46 and 35%, respectively, of all LRR; relapse at the internal mammary chain and axilla was uncommon. The data suggest that patients with T3 tumours (> 5 cm) and any nodal involvement or patients with four or more involved axillary nodes, regardless of T stage, are at a high risk of LRR and will benefit from adjuvant radiation therapy to the chest wall and SCF.

Feasibility of a dose-intensive CMF regimen with granulocyte colony-stimulating factor as adjuvant therapy in premenopausal patients with node-positive breast cancer.

Our aim was to study the feasibility of an intensified intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) schedule with the aim to escalate dose intensity (DI). Twenty-three premenopausal breast cancer patients received 6 cycles of adjuvant CMF intravenously on days 1 and 8 every 3 weeks and granulocyte colony-stimulating factor days 9–18. Endpoints were DI and toxicity. Twenty-one out of 23 patients (91%) received the projected total dose and reached ≥ 85% of the projected DI. Compared to ‘classical’ CMF, all patients reached ≥ 111% DI. Nine patients received the planned schedule without delay. Thirteen patients (57%) were treated for infection and four patients (17%) were hospitalized for febrile neutropenia. Twelve patients received red blood cell transfusions (52%). Radiation therapy (n= 6) had no adverse impact on dose intensity or haematological toxicity. This dose-intensified CMF schedule was accompanied by enhanced haematological toxicity with clinical sequelae, namely fever, intravenous antibiotics and red blood cell transfusions, but allows a high dose intensity in a majority of patients. © 2000 Cancer Research Campaign

Mitoxantrone, L-leucovorin and 5-fluorouracil: an effective and well tolerated first-line treatment for advanced breast cancer.

The combination of mitoxantrone plus leucovorin/fluorouracil in heavily pretreated patients with advanced breast cancer has shown significant activity and extremely good tolerability. The aim of this study was to evaluate the activity of this combination in patients not previously submitted to chemotherapy. From May 1993 to December 1995 we treated 80 patients with advanced breast cancer with a combination of mitoxantrone, l-leucovorin and 5-fluorouracil. All patients had histologically or cytologically proven breast cancer, WHO performance status 0-3, normal hematological parameters and normal serum bilirubin. Prior chemotherapy for metastatic disease was not allowed, whereas adjuvant CMF (cyclophosphamide, methotrexate and 5-fluorouracil) or adjuvant anthracycline (doxorubicin or epirubicin) therapy was allowed; a single prior hormone treatment was permitted. Chemotherapy consisted of mitoxantrone 12 mg/m2 i.v. day 1, l-leucovorin 150 mg/m2 i.v. days 1, 2 and 3 and 5-fluorouracil 350 mg/m2 i.v. days 1, 2 and 3. The courses were repeated every 3 weeks. Objective response (CR + PR) was observed in 46/80 (57%) patients (95% CI, 46%-68%). Complete response (CR) was observed in 21/80 cases (26%). Response was observed in 14/24 (58%) patients with soft tissues as the dominant site of disease, in 22/34 (65%) patients with visceral involvement and in 10/22 (45%) of those with bone as the dominant site of disease. The median duration of response and survival was 9 months (range, 3-16) and 22 months (range, 2-48+), respectively. Toxicity was very manageable, with grade 4 leukopenia and thrombocytopenia in 6/80 (7.5%) and 1/80 (1.25%) patients, respectively, and negligible non-hematological toxicity. The combination of mitoxantrone, 5-fluorouracil and high-dose l-leucovorin is a safe and effective regimen for first-line treatment of advanced breast cancer.

Adjuvant cyclophosphamide, methotrexate and fluorouracil in node-negative and estrogen receptor-negative breast cancer: Updated results

Node-negative breast cancers are considered to comprise a subgroup which is amenable to cure with local-regional therapy alone. However, approximately 30% of affected patients present new disease manifestations within 10 years after surgery. To test the hypothesis that node-negative and estrogen receptor-negative breast cancer patients can benefit from adjuvant chemotherapy, a prospective randomized study was activated at the Istituto Nazionale Tumori of Milan in 1980. The study was conducted in 90 patients operated on for unilateral breast cancer who were then assigned to receive either 12 intravenous cycles of cyclophosphamide, methotrexate and fluorouracil (CMF) every three weeks, or no further treatment. Adjuvant chemotherapy was administered in the outpatient clinic of the Division of Medical Oncology. Patient characteristics were fairly well balanced between the two treatment groups except for primary tumor size: 58% of those with a primary tumor measuring > 2 cm in its largest diameter were randomized in the control group compared with 38% in the CMF regimen (P = 0.06). At 12 years after surgery treatment outcome was significantly superior for patients given adjuvant CMF. The relapse-free survival rate was 71% (95% confidence limits (CL): 56-86) versus 43% (95% CL: 28-58), and total survival was 80% (95% CL: 68-92) versus 50% (95% CL: 34-66), respectively. The benefit from the administration of CMF was evident in all patient subsets and was not influenced by menopausal status. The long-term results of this trial of adjuvant combination chemotherapy confirm our previous observations on the efficacy of adjuvant chemotherapy in node-negative breast cancer patients at high risk of early disease relapse.

Epirubicin chemotherapy and advanced breast cancer after adjuvant CMF chemotherapy

There have been conflicting reports on the effect of prior adjuvant chemotherapy on the response of advanced breast cancer to primary chemotherapy. We report a retrospective review of the outcome of chemotherapy with epirubicin 100 mg/m 2 for advanced breast cancer in 39 patients who had previously received adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF). The response rate (complete responses plus partial responses) was 38.5%, with a median duration of response of 33 weeks. There was no significant difference in the response rate or duration of survival when these patients were compared with matched controls who had not received adjuvant chemotherapy. However, the limitations of this study were such that an adverse effect of adjuvant CMF on the response to epirubicin cannot be excluded.

The influence of adjuvant chemotherapy on outcome after relapse for patients with breast cancer

This study examines the outcome following relapse for 176 patients who had been entered into a randomised trial comparing adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with no adjuvant therapy (controls). Relapse has occurred in 65 144 (45%) of the CMF group and 111 158 (70%) of controls ( P < 0.0001). 123 176 patients received endocrine treatment after relapse with higher response rates (38 vs. 18%, P < 0.05) and longer time to progression (23 vs. 19 weeks, P = 0.03) for controls. 94 176 received chemotherapy after relapse again with higher response rates (47 vs. 23%, P = 0.05) and longer time to progression (17 vs. 9 weeks, P = 0.03) for controls. Despite this, survival after relapse was the same for the two groups (median 16 months). However, on subgroup analysis, postmenopausal patients who had received adjuvant CMF had shorter survival ( P = 0.03). These results suggest that prior adjuvant therapy should be a stratification factor in clinical trials in advanced disease.

Salvage treatment of patients suffering relapse after adjuvant CMF chemotherapy.

The efficacy of salvage treatments in 243 patients with operable breast cancer and positive axillary nodes who failed during or after adjuvant chemotherapy with CMF (cyclophosphamide, methotrexate and fluorouracil) was analyzed. Results were compared with those achieved in 100 patients who had relapses after radical mastectomy alone (control group). Salvage treatments consisted primarily of endocrine therapy (castration in premenopausal patients and tamoxifen in postmenopausal women) and chemotherapy (CMF or Adriamycin [doxorubicin] regimens). In 20 patients, however, first salvage treatment consisted of local therapy only (i.e., radiation therapy with or without surgery). In women previously treated with adjuvant CMF, complete plus partial remissions after first salvage treatment were 37% with a median duration of 17 months. In the control group, the response rate was 43% with a median duration of 16 months. The findings also indicated that drug-induced amenorrhea did not lower the objective response to salvage castration. In patients failing with a disease-free interval in excess of 12 months from end of adjuvant CMF, retreatment with the same combination was able to induce remission in 52% of the patients. Current data, derived from prospective controlled studies, confirm that, despite relatively high remission rates, all forms of salvage treatment failed to provide, in unselected cases, long-term control of relapsed breast cancer. Most important, prior adjuvant chemotherapy with CMF did not adversely affect results compared to concomitant controls.

The effect of postoperative radiotherapy on the feasibility of optimal dose adjuvant CMF chemotherapy in stage II breast carcinoma

The impact of a number of variables upon the effectiveness of adjuvant chemotherapy given to 87 patients with Stage II breast carcinoma was retrospectively analyzed. Adjuvant chemotherapy consisted of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Drugs were given in optimal doses (85% or more of the planned dose) to 17% of the patients; in intermediate doses (66 to 84% of the planned dose) to 50% of the patients; and in low doses (65% or less of the planned dose) to 33% of the patients. Myelosuppression was the main reason for giving intermediate or low doses. At a median follow-up of three years, 84% of all patients remain alive. Radiation therapy preceding chemotherapy was given to 70 % of the patients, concomitant irradiation and chemotherapy to 15 %, and 13 patients (15%) received chemotherapy only. Of the 14 patients who received optimal doses of CMF, 12 (86%) also received radiation therapy. Disease-free survival at three years is similar for irradiated and nonirradiated patients, but the latter have a higher incidence of local recurrence (5 % vs. 15 %), although the difference is not statistically significant. Delay in the initiation of chemotherapy, mostly because of the administration of postoperative irradiation, adversely affected the probability and duration of disease-free survival, particularly in premenopausal women in whom chemotherapy was started within more than 90 days of mastectomy. The administration of optimal doses of adjuvant chemotherapy should follow the primary treatment to the breast tumor as closely as possible. If radiation therapy is indicated as well, it should be delivered concomitantly with chemotherapy, given the feasibility of administering both modalities simultaneously, as demonstrated in this study.