The International (Ludwig) Breast Cancer Study Group Trials I-IV: 15 years follow-up

BACKGROUND: Adjuvant systemic therapy prolongs disease-free and overallsurvival in both pre- and postmenopausal patients. Availabledata shown benefit from multi-agent chemotherapy, prolongedtamoxifen treatment, and ovarian ablation, and that the combinationof chemo- and endocrine therapy might be advantageous. In 1978the International (Ludwig) Breast Cancer Study Group (IBCSG)initiated four complementary randomized controlled clinicaltrials to evaluate the roles of chemo-endocrine combinationsor endocrine therapy alone in specific populations defined byrisk (for pre- and perimenopausal patients) or by age (for postmenopausalpatients). The results at 10 and 13 years' median follow-upfor these trials are summarized in this report and are comparedto those of the Overview meta-anal-ysis with regard to chemo-endocrineor endocrine therapy combinations. Furthermore, types of firstrelapses by sites and second malignant diseases are reported. PATIENTS AND METHODS: 1601 evaluable patients with node positive disease were includedinto the studies I–IV. In Trial I (491 premenopausal patientswith 1–3 positive axillary nodes) we studied the additionof low-dose continuous prednisone (p) to a cyclophosphamide-methotrexate-fluorouracil(CMF) combination. In Trial n 327 premenopausal patients withfour or more positive axillary nodes were randomized to oneyear CMFp or to a surgical oophorectomy followed by CMFp. InTrial III (463 postmenopausal patients 65 years old or younger),combined chemoendocrine therapy (one year of CMFp plus tamoxifen(T)) was compared to endocrine therapy (1 year of p + T) orto surgery alone. In Trial IV 320 postmenopausal patients 66to 80 years old were treated either by surgery alone or by surgeryfollowed by 1 year prednisone and tamoxifen. RESULTS: In Trial I the addition of prednisone allowed a higher doseof cytotoxics to be administered compared with CMF alone. Despitethis increased dose intensity, 13-year disease-free survival(DFS) and overall survival (OS) were similar for the two treatmentgroups (49% vs. 52% DFS, 59% vs. 65% OS for CMFp vs. CMF). InTrial II the addition of surgical oophorectomy to CMFp yieldedan improved outcome which approached statistical significancefor the subset of 107 patients known to have estrogen receptor-positivetumors (DFS, 23% vs. 15%, p     

Adjuvant treatment for early breast cancer: the Ludwig breast cancer studies

The Ludwig Breast Cancer Study Group conducted four concomitant trials involving adjuvant chemotherapy and endocrine therapy. In Ludwig I, adjuvant combination chemotherapy was used with or without prednisone to treat premenopausal and perimenopausal women with metastases in 1-3 axillary lymph nodes. The impact of adding low-dose, continuous prednisone (7.5 mg/day) to an adjuvant, chemotherapy regimen of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) was investigated in a randomized trial of 491 premenopausal and perimenopausal patients with operable breast cancer and metastases in 1-3 axillary lymph nodes. As a consequence of lower hematologic toxicity, a significantly higher dose of CMF could be administered with added prednisone (P less than 0.0001). However, at the 4-year median follow-up, no significant improvement was observed in disease-free survival (DFS) (73% vs. 77%; P = 0.35) or overall survival (OS) (both 86%; P = 0.73). Induced amenorrhea was associated with a longer DFS for younger patients, those who received lower CMF doses, and those with tumors that were estrogen receptor (ER) positive. In Ludwig III, adjuvant therapy was administered to younger postmenopausal women in a study of chemotherapy plus endocrine therapy versus endocrine therapy alone versus mastectomy alone. In this randomized trial of 463 postmenopausal women 65 years of age or younger with axillary node metastases, treatment with the combination of CMF plus low-dose prednisone and tamoxifen (CMFp + T), was compared to endocrine therapy alone (p + T) or to no further treatment after total mastectomy and axillary clearance. At a median follow-up of 4 years, the DFS was 61% for the CMFp + T group, compared with 48% for the p + T group (P = 0.01) and 31% for the observation group (P less than 0.0001). The 4-year OS rates were not statistically different (76%, 67%, and 68%, respectively; P = 0.30). Treatment with CMFp + T reduced local, regional, and distant metastases and was equally effective in improving DFS in patients with ER-positive or ER-negative tumors. In Ludwig II, chemotherapy was given with or without oophorectomy in premenopausal and perimenopausal patients with metastases in 4 or more axillary nodes.(ABSTRACT TRUNCATED AT 400 WORDS)     

Retreating recurrent breast cancer with the same CMF-containing regimen used as adjuvant therapy

Breast cancer metastases appearing soon after adjuvant chemotherapy (within 12 months of its completion) are usually resistant to retreatment with the same cytotoxic agents, while relapses occurring later (beyond 12 months) regress when rechallenged with the same agents, showing similar response rates observed in non-pretreated patients with advanced disease. The International Breast Cancer Study Group (IBCSG) prospectively explored the efficacy of retreatment for patients upon relapse using the same therapy administered during the adjuvant programme. 87 patients previously treated with an adjuvant CMF (cyclophosphamide, methotrexate, 5-fluorouracil) combination chemotherapy (with or without the addition of low-dose prednisone and tamoxifen), who had measurable first breast cancer relapse, usually after at least 6 months of completion of the adjuvant treatment, were treated with CMF. Pretreatment consisted of 1–3 CMF courses in 27 patients and 4 or more courses in 60 patients. 17 patients were retreated with additional tamoxifen or had tamoxifen stopped at relapse. The data of these patients are shown separately. 47 of the 86 fully evaluable patients (55%) had an objective response, which was complete in 25 (29%). The dominant metastatic type and the number of involved sites were the most important factors influencing response to retreatment. Patients with soft tissue metastases had a high response rate (36/52, 69%) compared with those who had visceral involvement (9/24, 38%) or those with bony disease (2/10, 20%) (P = 0.002). In conclusion, response rates to retreatment with CMF were similar to those expected in a non-pretreated population. The patterns of relapse and the number of metastatic sites were the most important factors predicting response to retreatment, while treatment-free interval (usually longer than 6 months due to the study design) did not influence response rates. This study supports the hypothetic effectiveness of late reintroduction of adjuvant cytotoxic therapy (prior to evidence of systemic relapse), upon which several current trials are based.     

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

BACKGROUND:: Node-negative breast cancers are considered to comprise a subgroupwhich is amenable to cure with localregional therapy alone.However, approximately 30% of affected patients present newdisease manifestations within 10 years after surgery. To testthe hypothesis that node-negative and estrogen receptor-negativebreast cancer patients can benefit from adjuvant chemotherapy,a prospective randomized study was activated at the IstitutoNazionale Turnori of Milan in 1980. PATIENTS AND METHODS:: The study was conducted in 90 patients operated on for unilateralbreast cancer who were then assigned to receive either 12 intravenouscycles of cyclophosphamide, methotrexate and fluorouracil (CMF)every three weeks, or no further treatment. Adjuvant chemotherapywas administered in the outpatient clinic of the Division ofMedical Oncology. Patient characteristics were fairly well balancedbetween the two treatment groups except for primary tumor size:58% of those with a primary tumor measuring>2 cm in its largestdiameter were randomized in the control group compared with38% in the CMF regimen (P=0.06). RESULTS:: At 12 years after surgery treatment outcome was significantlysuperior for patients given adjuvant CMF. The relapse-free survivalrate was 71% (95% confidence limits (CL): 56–86) versus43% (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 allpatient subsets and was not influenced by menopausal status. CONCLUSIONS:: The long-term results of this trial of adjuvant combinationchemotherapy confirm our previous observations on the efficacyof adjuvant chemotherapy in node-negative breast cancer patientsat high risk of early disease relapse. adjuvant treatment, node-negative breast cancer     

Adjuvant chemohormonal therapy with cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen compared with CMF for premenopausal breast cancer patients. An Eastern Cooperative Oncology Group trial

The current trial was designed to assess whether the addition of prednisone or prednisone + tamoxifen would enhance the therapeutic effectiveness of 1 year of adjuvant CMF therapy. Premenopausal women with ipsilateral axillary node-positive breast carcinoma and known estrogen receptor (ER) status were randomized to receive 1 year of postoperative treatment with 12 28-day cycles of cyclophosphamide, methotrexate, 5-fluorouracil (CMF), CMF plus prednisone (CMFP), or CMFP plus tamoxifen (CMFPT). There were 553 analyzed cases with 188 receiving CMF, 183 CMFP, and 182 CMFPT. The overall time to relapse (TTR) and survival comparisons between the regimens are not statistically different at a median follow-up time of 7.7 years. The major subgroups currently with a suggestive TTR difference are greater than 3N+ (CMFPT greater than CMF, P = 0.07) and estrogen receptor-negative (ER-) greater than 3N+ (CMFPT greater than CMF, P = 0.03). Patients receiving CMFPT appeared to have a superior survival to CMF in the ER- greater than 3N+ cohort (P = 0.02). The following patient characteristics were associated with a significantly longer TTR: decreasing nodal involvement or tumor size, positive ER status, age greater than or equal to 40 years, and decreasing obesity. The favorable effects of decreasing nodal involvement, positive ER status, age 40 years or greater, and decreasing obesity carried over to survival. Development of amenorrhea was also significantly associated with improved survival (P = 0.001). Toxicity was increased by the addition of prednisone to CMF and by the addition of tamoxifen to CMFP. Overall relapse patterns were similar among the three regimens. The results of the current trial do not currently suggest an overall therapeutic benefit for adding prednisone or only 1 year of tamoxifen to CMF adjuvant treatment.     

Relapse of breast cancer after adjuvant treatment in premenopausal and perimenopausal women: patterns and prognoses

Eight hundred eighteen premenopausal or perimenopausal breast cancer patients with axillary node metastases were treated with adjuvant chemotherapy (CMF) with or without endocrine treatment (prednisone, oophorectomy) in two concurrent prospective trials. Three hundred fifty-two (43%) had recurrent disease at a median follow-up time of 6 years. The 2-year survival percentages from time of first relapse were 16% for patients with initial metastases in visceral or multiple sites (including bone and soft tissue), 41% for those with regional metastases or skeletal relapse alone and 70% for patients with isolated local recurrence or contralateral breast cancer. The features that most influenced prognosis within the categories defined by site of first relapse were disease-free interval (less than 24 months v greater than or equal to 24 months), and estrogen receptor content in the primary tumor. These features had clinical importance (identifying patients with at least a 50% 2-year survival percentage) only in those patients with local, contralateral breast, regional, or bony disease alone. The treatment of individual patients after relapse must be directed toward optimized palliation. The results of this study are important for defining groups of patients who relapse after CMF for whom the subsequent therapeutic approach might be differentiated (eg, experimental treatments for dire prognosis, accent on minimal side effect treatment for intermediate prognosis, and investigation of adjuvant systemic therapy for isolated local recurrence).     

Activity of first-line epirubicin and paclitaxel in metastatic breast cancer is independent of type of adjuvant therapy

To evaluate the impact of prior adjuvant chemotherapy on response rate (RR), progression-free (PFS) and overall survival (OS) of metastatic breast cancer patients treated with epirubicin/paclitaxel (ET) regimens. In all, 291 patients enrolled in five studies in metastatic breast cancer were analysed: 101 (35%) were chemonaive, 109 (37%) had received adjuvant CMF and 81 (28%) adjuvant anthracyclines. Response rate to ET was 66%. Response rate was 63% for cyclophosphamide plus methotrexate plus 5-fluorouracil (CMF), 67% for prior anthracyclines and 68% in chemonaive patients (P=0.5). By multivariate analysis, adjusted odds ratio for response was 0.81 (95% CI: 0.37-1.79) for CMF and 0.92 (95% CI 0.43-2.01) for anthracyclines (P=0.86). The CR rates were 14% for both CMF and anthracyclines and 22% for chemonaive patients (P=0.2). By multivariate analysis, the relative odds of CR for CMF or anthracyclines were 0.40 and 0.39 as compared to chemonaive patients (P=0.036). The median PFS was 11.0 months for prior CMF, 10.2 months for anthracyclines and 12.5 months in chemonaive patients (P=0.33). In multivariate Cox's model, a nonsignificant increase in the risk of progression was seen in patients treated with adjuvant CMF or anthracyclines. The median OS was 23.8 months for CMF, 20.2 months for anthracyclines and 27.5 months in chemonaive patients (P=0.61). The same, nonsignificant, association was seen in multivariate analysis. The ET regimens provide satisfactory results in metastatic breast cancer, regardless of previous adjuvant chemotherapy.     

Risk of new primaries after chemotherapy and/or tamoxifen treatment for early breast cancer

BACKGROUND:: Both chemotherapy and tamoxifen are widely used either aloneor in combination as adjuvant treatment following mastectomy.Despite the fact that both of them exhibit carcinogenic propertiesin experimental models, detailed reports on the incidence ofnew primaries following chemotherapy and/or tamoxifen in patientswith early breast cancer are limited. PURPOSE:: To investigate the incidence of new primaries (including oppositebreast tumors and skin cancers) in untreated patients and inpatients treated with either tamoxifen or chemotherapy or withboth modalities. PATIENTS AND METHODS:: A total of 1696 patients with early breast cancer, 1286 of whomwere treated with either CMF-based adjuvant chemotherapy (n= 410), tamoxifen (n = 656) or with a combination of the two(n = 220) were considered for the present analysis. Patientswere operated on between November 1983 and December 1991 andwere followed up to June 1994. Detailed information about secondmalignancies were available for all patients. RESULTS:: Overall, 53 new primaries, 19 of them opposite breast tumors,occurred in 53 patients. The actuarial cumulative incidencerates at 5 years were: 3.1% (95% CI: 1.4%– 4.8%) in untreatedpatients; 1.7% (95% CI: 0.0%–3.5%) in tamoxifen-treatedpatients; 4.2% (95% CI: 1.3%–7.1%) in chemotherapy-treatedpatients and 2.6% (95% CI: 0.0%%5.2%) in the chemo-tamoxifengroup (all groups: P = n.s.; chemotherapy-treated versus tamoxifen-treated:P = 0.01). The corresponding figures, after exclusion of thepatients with opposite-breast and skin tumors, were: untreatedpatients: 2% (95% CI: 0.6%–3.4%); tamoxifen-treated patients0.95% (95% CI: 0.0%–2.4%); chemotherapy-treated patients:2.6% (95% CI: 0.4%–4.8%); chemotherapy plus tamoxifen:1.65% (95% CI: 0.4%–3.8%); (all groups: P = n.s.; CT versusTAM P = 0.05). Chemotherapy-treated patients showed a risk thatwas about two-fold that of the one to be expected in the generalpopulation. By contrast, a decrease in the total risk was observedin patients treated with tamoxifen. Patients who received chemotherapyand tamoxifen as well as those in the no-treatment group showeda risk which was comparable to that of the general population. CONCLUSIONS:: Adjuvant chemotherapy appears to increase the risk of secondmalignancies. By contrast, tamoxifen seems to exert an overallprotective effect in this regard, and it also appears to counteract,at least partially, the carcinogenic effect of chemotherapy. IMPLICATIONS:: While there is plenty of evidence that the benefit achievedby adjuvant chemotherapy considerably exceeds the risk of secondmalignancies, the indiscriminate use of chemotherapy shouldbe avoided, particularly in patients with a low risk of relapse.Moreover, it seems reasonable to prefer tamoxifen over chemotherapyfor patients likely to obtain comparable therapeutic benefitfrom antiestrogenic treatment. adjuvant chemotherapy, adjuvant tamoxifen, adjuvant chemo-tamoxifen therapy, early breast cancer, second malignancies     

Natural history of more than 20 years of node-positive primary breast carcinoma treated with cyclophosphamide, methotrexate, and fluorouracil-based adjuvant chemotherapy: a study by the Cancer and Leukemia Group B.

PURPOSE: Breast cancer heterogeneity dictates lengthy follow-up to assess outcomes. Efficacy differences for three regimens that are based on adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) are presented in this article, but cancer recurrence sites, time of relapse, subsequent primary cancers, and causes of death in the natural history of node-positive breast cancer are emphasized. PATIENTS AND METHODS: Beginning in 1975, 905 patients with node-positive cancer were randomly assigned to receive CMF or two regimens of CMF plus other agents. Median follow-up is 22.6 years. The natural-history analysis was performed on a subset of 814 patients. RESULTS: Eighty percent of the 599 women known to have died, died of metastatic breast cancer. Only 8.5% of the deceased women died of a cause other than breast cancer, a second or third cancer, or adjuvant chemotherapy toxicity. One hundred five women (12.8%) developed other primary cancers, with 49 (46.6%) occurring in the contralateral breast. Therapeutic efficacy differences of the CMF regimens reported earlier have been maintained more than 20 years later. For certain subsets, the five-drug regimen had advantages over CMF. Bone was the most common recurrence site. The longest interval to relapse has been 23.5 years, and 18% of those who relapsed did so more than 10 years later. CONCLUSION: Despite adjuvant chemotherapy, a large majority (80%) of women with node-positive breast cancer die of the disease, and many recurrences develop more than 10 years later. CMF plus vincristine and prednisone provides a benefit compared with CMF, but the magnitude varies with the number of involved nodes. Outcome trends in earlier analyses of this study were maintained even years later.     

Adjuvant CMF effect on site of first recurrence,and appropriate follow-up intervals,in operable breast cancer with positive axillary nodes

Summary From June 1973 to May 1978 a total of 845 patients with operable breast cancer were entered into different adjuvant programs. The medical records of the 278 patients showing relapse were carefully re-evaluated to assess the pattern(s) of first recurrence and the consistency of follow-up modulation. Ninety-one of 179 patients treated with surgery alone, 130 of 414 given 12 cycles of adjuvant CMF and 57 of 252 treated with 6 cycles of CMF showed treatment failure within 5 years from radical mastectomy. Thefrequency of new disease manifestations was significantly affected by primary treatment, since patients given adjuvant CMF showed a lower tendency to recur in local-regional area(s) and in bone(s). However, in relapsed patients,patterns of new lesions were not substantially altered by type of primary treatment. The most frequently involved sites were soft tissues (37.8%) and bones (37%) followed by viscera (34.2%). Retrospective evaluation of X-rays revealed that in 26.2% of osseous metastases, diagnosis could have been assessed earlier, with a median delay of 4 months (range 1–8). Present analysis also revealed that short-term repeated X-ray examinations yielded findings more controversial than reliable for assessing the exact time of relapse, thus preventing firm conclusions in the presence of suspicious recurrence. A new follow-up schedule after completion of adjuvant chemotherapy is proposed, since on the basis of our experience, in asymptomatic patients frequently repeated examinations are not necessary and some can safely be omitted. Address for reprints: Gianni Bonadonna, M.D., Instituto Nazionale Tumori, Via Venezian 1, 20133 Milano, Italy.     

Cardiac safety,efficacy, and correlation of serial serum HER2-extracellular domain shed antigen measurement with the outcome of the combined trastuzumab plus CMF in women with HER2-positive metastatic breast cancer: results from the EORTC 10995 phase II study

Purpose

Cardiotoxicity is a side effect of trastuzumab. We assessed efficacy and cardiac safety of CMF with trastuzumab (CMF+T) in HER2-positive metastatic breast cancer patients (MBC).

Methods

In this phase II study, centrally confirmed, previously treated HER2-positive MBC patients with measurable disease (per RECIST v 1.0) were enrolled. Initially, patients were randomized between 8 CMF cycles alone or combined with trastuzumab during chemotherapy, followed by 3-weekly trastuzumab maintenance till progression. A protocol amendment dropped the CMF arm and thereafter all patients received CMF+T. Translational research for prediction of treatment benefit was performed through serial serum HER2-shed antigen assessments.

Results

Ninety patients (CMF: 19; CMF+T: 71) were enrolled between 2002 and 2006. Median age was 54 years. 42 patients had prior chemotherapy (33 with anthracyclines) and 41/71 patients who received CMF+T continued trastuzumab monotherapy for a median duration of 40 weeks. Overall response rate was 50% for CMF+T (35/70) and 32% for CMF (6/19). Median duration of response was 10.3 months and 5.4 months, respectively. Median progression-free survival was 9.4 months (95% CI 8.1–11.6) and 4.8 months (95% CI 2.8–7.9), respectively. In the CMF+T arm, 13(18%) patients had an absolute LVEF decline, including 3 patients developing any grade of New York Heart Association cardiac dysfunction. Patients with an increase of 30% over baseline shed antigen had a higher progression risk (95% CI 7.6, 3.9–14.8).

Conclusions

CMF+T is effective, with an acceptable cardiotoxicity profile. LVEF declines were mostly asymptomatic and occurred irrespective of previous anthracycline exposure. CMF+T can be considered for these patients, if other cytotoxics are contraindicated.

     

The utility of mitotic index, oestrogen receptor and Ki-67 measurements in the creation of novel prognostic indices for node-negative breast cancer.

INTRODUCTION: Prognostic factors can be useful to identify node-negative patients at increased risk of relapse who should receive adjuvant treatment. In the past, oestrogen receptor status and mitotic index have been shown to be significant predictors of prognosis. Different techniques for the measurement of these prognostic factors are available. METHODS: Paraffin-embedded tumour specimens from 441 pre-menopausal patients with node-negative breast cancer who were previously randomized onto a trial comparing peri-operative chemotherapy with no further therapy were studied. Oestrogen receptor status was determined by the classical biochemical assay and by immunohistochemistry (ER-IA). Mitotic index was assessed by counting the number of mitoses and by calculating the percentage of tumour cells positively staining for the antibody Ki-67. RESULTS: There was a good correlation between ER-IA and the biochemical ER-assay (P<0.01), and the percentage of Ki-67 positive tumour cells and mitotic counts (P<0.01) respectively. However, ER-IA significantly predicted disease-free survival (RR=2.67, 95% CI: 1.60-4.44, P<0.01) whereas the biochemical assay was only borderline significant (RR=1.54, 95% CI: 1.00-2.36, P=0.05). Similarly, Ki-67 was a stronger indicator of prognosis (RR=2.84, 95% CI: 1.80-4.48, P<0.01) than mitotic counts (RR=1.56, 95% CI: 1.22-2. 00, P<0.01). CONCLUSIONS: We conclude that ER-IA performs better in predicting prognosis than the classical biochemical oestrogen receptor assay. Ki-67 is a more accurate marker for tumour cell proliferation and predicts prognosis of patients with breast cancer better than do mitotic counts.     

Quality of adjuvant chemotherapy in primary breast cancer in a non-trial setting. A comprehensive cancer centre study

The quality of adjuvant chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) and the compliance with guidelines for this treatment were studied in 323 premenopausal patients with node positive breast cancer, who were treated in the Comprehensive Cancer Centre East of The Netherlands (IKO) from 1988 to 1992, outside the setting of a clinical trial. The interval surgery–chemotherapy, the duration of chemotherapy, dose intensity (DI) and relative dose intensity (RDI) of CMF chemotherapy and validations of dose modifications were evaluated. 295 of 323 patients (91%) received adjuvant chemotherapy. CMF chemotherapy was used in 230 patients (78% of the chemotherapy receiving patients). The median time to the start of chemotherapy was 62 (range-35–139) days after surgery. Forty-two per cent of the patients finished their CMF chemotherapy within 168 days. Two per cent of the patients did not finish the six courses of CMF chemotherapy. The mean DI and RDI of the eligible patients in all CMF using hospitals were 80.4±28.8% and 78.2±28.4%, respectively. Aberrations of recommended guideline procedures resulted more often in suboptimal treatment than haematological toxicity. Adherence to the guidelines was variable and resulted in suboptimal adjuvant chemotherapy. The median follow-up of the patients treated in hospitals that agreed to the use of CMF was 5 years. The mean RDI of CMF in the eligible patients who relapsed was 72.2±32.7%, compared with 81.4±25.2% for the patients who did not relapse (P 0.01), suggesting a possible influence of the RDI on disease free survival. However, when the patients who did not receive chemotherapy were excluded, the mean RDI of the patients who relapsed was 85.0±12.6% and of the patients who did not relapse 87.4±12.6%, which was not significantly different (P=0.20).     

Classical CMF regimen as adjuvant chemotherapy for triple-negative breast cancer may be more effective compared with anthracycline or taxane-based regimens

Patients suffering from triple-negative breast cancer (TNBC) have poor prognosis mainly because no standard treatment is currently available. Our objectives were to explore the prognostic factors for first relapse of patients with TNBC. A cohort of 687 patients with TNBC, diagnosed and treated between January 1995 and December 2008 at Sun Yat-sen University Cancer Center, were retrospectively analyzed. Cox proportional hazards models were fitted to explore factors that predict relapse development. Survival rate was computed using the Kaplan?CMeier product limit method. The median age of the 687 patients was 46 (range 16?C76?years), and 64.8% of the patients were pre-menopausal. The median follow-up time was 56?months (range 14?C156?months), in which 194 patients had recurrence, and 115 died. The median recurrence-free time was 25?months (range 4?C143?months), with 118 (60.8%) of the cases first relapsing at a single site. The three- and five-year disease-free survival rates were 79.7 and 72.6%, respectively. Primary tumor size at diagnosis, lymph node status, and type of regimen used in the (neo)adjuvant chemotherapy were considered independent predictors of first relapse. CMF-containing adjuvant chemotherapy significantly decreased recurrence compared with the anthracycline- or taxane-based regimens (RR?=?0.66, 95%; CI 0.45?C0.96; P?=?0.030). The median time from first relapse to death was 26?months (range 2?C121?months). The two- and five-year survival rates were 60.6 and 36.6%, respectively. Liver metastasis at first recurrence and progression-free survival over 12?months after first-line therapy were two important factors that affected survival rate after recurrence. The median relapse time of TNBC was about 2?years after diagnosis. CMF regimens for TNBC patients may be more effective than anthracycline- or taxane-based regimens. Liver metastasis at first recurrence signifies unfavorable prognosis.     

Leucocyte nadir as a marker for chemotherapy efficacy in node-positive breast cancer treated with adjuvant CMF.

The purpose of this study was to examine the association between the leucocyte nadir and prognosis in breast cancer patients receiving adjuvant chemotherapy consisting of cyclophosphamide, methotrexate and fluorouracil (CMF). Three hundred and sixty-eight patients with node-positive breast cancer without distant metastases were treated with six cycles of adjuvant CMF. Some patients (n = 60) also received tamoxifen. All patients underwent surgery and received radiotherapy to the axillary and supraclavicular lymph nodes and the chest wall. The effect of leucopenia caused by CMF on distant disease-free survival (DDFS) and overall survival (OS) was assessed. A low leucocyte nadir during the chemotherapy was associated with a long DDFS in univariate analysis when tested as a continuous variable (the relative risk (RR) 1.3, 95% confidence interval (CI) 1.04-1.06, P = 0.02). Similarly, when the leucocyte nadir count was divided into tertiles, the patients who had the highest nadir values during the six-cycle treatment had worst outcome (RR 1.6, 95% CI 1.07-2.5, P = 0.02). However, in a multivariate analysis only the number of affected lymph nodes, tumour size, progesterone receptor status, surgical procedure, age and adjuvant tamoxifen therapy retained prognostic significance, whereas the leucocyte nadir count did not. A low leucocyte nadir during the adjuvant CMF chemotherapy is associated with favourable DDFS and it may be a useful biological marker for chemotherapy efficacy.     

Clinical relevance of different sequencing of doxorubicin and cyclophosphamide, methotrexate, and Fluorouracil in operable breast cancer.

PURPOSE: To assess the clinical relevance of different sequences of doxorubicin (DOX) and cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with operable breast cancer at risk of disease relapse. PATIENTS AND METHODS: Two randomized trials were activated in the early 1980s. The first study, in patients with one to three involved nodes, was intended to assess the effectiveness of intravenous (i.v.) CMF given every 3 weeks for 12 courses versus eight courses of the same CMF regimen followed by four courses of full-dose DOX (CMF-->DOX). The second study, in patients with more than three involved nodes, compared four courses of full-dose DOX sequentially followed by eight courses of i.v. CMF (DOX-->CMF) versus alternating two courses of the same CMF regimen with one course of DOX (CMF/DOX) for a total of 12 courses. RESULTS: After a median observation of 210 months, no statistically significant difference was documented in the first study (relapse-free survival hazard rate [HR], 1.06; total survival HR, 1.03). In contrast, the delivery of DOX first, followed by CMF significantly reduced the risk of disease relapse (HR, 0.68; 95% CI, 0.54 to 0.87; P =.0017) and death (HR, 0.74; 95% CI, 0.57 to 0.95; P =.018) compared with the alternating regimen. CONCLUSION: Anthracycline-containing regimens can further reduce the odds of relapse and death compared with CMF. However, the findings observed in our trials emphasize that the relative merits of anthracycline adjuvant programs also can depend on the modality of administration and must be assessed in properly designed trials in which the magnitude of the benefits can be weighed against potential risks.     

Timing of CMF chemotherapy in combination with tamoxifen in postmenopausal women with breast cancer: role of endocrine responsiveness of the tumor.

BACKGROUND: Controversy persists about whether chemotherapy benefits all breast cancer patients. PATIENTS AND METHODS: In the International Breast Cancer Study Group (IBCSG) trial VII, 1212 postmenopausal patients with node-positive disease were randomized to receive tamoxifen for 5 years or tamoxifen plus three concurrent courses of cyclophosphamide, methotrexate and 5-fluorouracil ('classical' CMF) chemotherapy, either early, delayed or both. In IBCSG trial IX, 1669 postmenopausal patients with node-negative disease were randomized to receive either tamoxifen alone or three courses of adjuvant classical CMF prior to tamoxifen. Results were assessed according to estrogen receptor (ER) content of the primary tumor. RESULTS: For patients with node-positive, ER-positive disease, adding CMF either early, delayed or both reduced the risk of relapse by 21% (P=0.06), 26% (P=0.02) and 25% (P=0.02), respectively, compared with tamoxifen alone. There was no difference in disease-free survival when CMF was given prior to tamoxifen in patients with node-negative, ER-positive tumors. CONCLUSIONS: CMF given concurrently (early, delayed or both) with tamoxifen was more effective than tamoxifen alone for patients with node-positive, endocrine-responsive breast cancer, supporting late administration of chemotherapy even after commencement of tamoxifen. In contrast, sequential CMF and tamoxifen for patients with node-negative, endocrine-responsive disease was ineffective.     

Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab

BackgroundCentral nervous system (CNS) disease as the site of first relapse after exposure to adjuvant trastuzumab has been reported. We carried out comprehensive meta-analysis to determine the risk of CNS metastases as the first site of recurrence in patients with HER2-positive breast cancer who received adjuvant trastuzumab.MethodsEligible studies include randomized trials of adjuvant trastuzumab administered for 1 year to patients with HER2-positive breast cancer who reported CNS metastases as first site of disease recurrence. Statistical analyses were conducted to calculate the incidence, relative risk (RR), and 95% confidence intervals (CIs) using fixed-effects inverse variance and random-effects models.ResultsA total of 9020 patients were included. The incidence of CNS metastases as first site of disease recurrence in HER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) compared with 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvant trastuzumab. The RR of the CNS as first site of relapse in trastuzumab-treated patients was 1.35 (95% CI 1.02–1.78, P = 0.038) compared with control arms without trastuzumab therapy. The ratio of CNS metastases to total number of recurrence events was 16.94% (95% CI 10.85% to 24.07%) and 8.33% (95% CI 6.49% to 10.86%) for the trastuzumab-treated and control groups, respectively. No statistically significant differences were found based on trastuzumab schedule or median follow-up time. No evidence of publication bias was observed.ConclusionsAdjuvant trastuzumab is associated with a significant increased risk of CNS metastases as the site of first recurrence in HER2-positive breast cancer patients.     

Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study.

PURPOSE: Current adjuvant therapies have improved survival for premenopausal patients with breast cancer but may have short-term toxic effects and long-term effects associated with premature menopause. PATIENTS AND METHODS: The Zoladex Early Breast Cancer Research Association study assessed the efficacy and tolerability of goserelin (3.6 mg every 28 days for 2 years; n = 817) versus cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy (six 28-day cycles; n = 823) for adjuvant treatment in premenopausal patients with node-positive breast cancer. RESULTS: Analysis was performed when 684 events had been achieved, and the median follow-up was 6 years. A significant interaction between treatment and estrogen receptor (ER) status was found (P =.0016). In ER-positive patients (approximately 74%), goserelin was equivalent to CMF for disease-free survival (DFS) (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.84 to 1.20). In ER-negative patients, goserelin was inferior to CMF for DFS (HR, 1.76; 95% CI, 1.27 to 2.44). Amenorrhea occurred in more than 95% of goserelin patients by 6 months versus 58.6% of CMF patients. Menses returned in most goserelin patients after therapy stopped, whereas amenorrhea was generally permanent in CMF patients (22.6% v 76.9% amenorrheic at 3 years). Chemotherapy-related side effects such as nausea/vomiting, alopecia, and infection were higher with CMF than with goserelin during CMF treatment. Side effects related to estrogen suppression were initially higher with goserelin, but when goserelin treatment stopped, reduced to a level below that observed in the CMF group. CONCLUSION: Goserelin offers an effective, well-tolerated alternative to CMF in premenopausal patients with ER-positive and node-positive early breast cancer.     

Phase III randomized multicenter study on the effects of adjuvant CMF in patients with node-negative, rapidly proliferating breast cancer: twelve-year results and retrospective subgroup analysis

The randomized multicenter study on rapidly proliferating breast cancer, assessed according to thymidine labelling index (TLI), was activated at the end of the 1980s. The present work investigated whether and to what degree the short-term advantages observed from adjuvant CMF (cyclophosphamide, methotrexate, 5-fluorouracil) were maintained at a longer follow-up. Two hundred and eighty-one patients with node-negative and high TLI tumors were randomized to receive six cycles of CMF or no further treatment. At a median follow-up of 12 years, CMF produced a 25% and 20% relative reduction in relapse and death cumulative incidence, respectively. A breakdown analysis identified a subgroup of patients with intermediate proliferating tumors for whom a 70% and 73% reduction in relapse and death was observed in the intention-to-treat population. An even higher reduction of 80% and 84% in relapse and death was seen for the patients who had received the full CMF dose. We identified a subgroup of patients with intermediate proliferating tumors in whom the high benefit obtained from adjuvant CMF was maintained at a long-term follow up.