Concurrent cyclophosphamide,methotrexate, and 5-fluorouracil chemotherapy and radiotherapy for breast carcinoma: a well tolerated adjuvant regimen

BACKGROUND: The current study was conducted to assess the toxicity of concurrent adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy and radiotherapy (RT) for early breast carcinoma. METHODS: In the current study, the authors reviewed the records of 680 consecutive breast carcinoma patients who received adjuvant CMF at the Princess Margaret Hospital between 1980-1990. Surgery was comprised of mastectomy in 64% of patients, breast conservation in 35% of patients, and was unknown in 1% of patients. Two hundred two patients received concurrent CMF/RT that was defined as an overlap in CMF and RT administration of at least 21 days. Forty-seven patients received sequential CMF/RT (defined as no overlap or an overlap of < 7 days in CMF and RT administration). Other patients received CMF alone. Adverse effects of RT were graded retrospectively using the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) system. Reasons for interruption or failure to complete RT were recorded. The magnitude of chemotherapy dose reductions and delays also were noted. RESULTS: The median age of the patients was 44 years (range, 26-68 years) and 88% of the patients had lymph node-positive disease. RT was interrupted or discontinued due to side effects in 4% of patients (95% confidence interval [95% CI], 1.7-7.7%) and 0% (95% CI, 0-7.6%), respectively, of the concurrent and sequential groups (P = 0.36). The incidence of Grade 3 or Grade 4 RT toxicity was 1.5% (95% CI, 0.3-4.3%) and 2.1% (95% CI, 0.1-11.3%), respectively, for the concurrent and sequential groups (P = 0.57). The median relative dose intensity of chemotherapy for patients receiving concurrent CMF/RT, sequential CMF/RT, and CMF alone was 0.87, 0.84, and 0.85, respectively (P = 0.22). CONCLUSIONS: The results of the current study demonstrate that the concurrent administration of CMF and RT is associated with a low risk of serious toxicity and is an acceptable adjuvant regimen for patients with breast carcinoma.     

Clinical role of multidrug resistance protein 1 expression in chemotherapy resistance in early-stage breast cancer: the Austrian Breast and Colorectal Cancer Study Group.

PURPOSE: The multidrug resistance protein 1 (MRP1) is expressed in human breast cancer cells and may contribute to the clinical drug resistance of breast cancer patients. Therefore, we determined the impact of MRP1 expression on the clinical outcome of adjuvant therapy in patients with early-stage breast cancer. PATIENTS AND METHODS: Immunostaining for MRP1 was performed on tissue sections from 516 premenopausal, hormone receptor-positive breast cancer patients with stage I and II disease. Statistical analyses were performed to assess the effect of MRP1 expression on survival and to test for interaction between MRP1 expression and treatment. RESULTS: MRP1 expression independently predicted shorter relapse-free survival (RFS) and overall survival (OS) in patients treated with cyclophosphamide, methotrexate, and fluorouracil (CMF; RFS: hazard ratio [HR] = 1.48; 95% CI, 1.16 to 1.88; P = .002; OS: HR = 1.82; 95% CI, 1.10 to 3.01; P = .02), but it did not predict shorter RFS and OS in patients who received tamoxifen plus goserelin (RFS: HR = 0.99; 95% CI, 0.74 to 1.31; P = .9; OS: HR = 0.68; 95% CI, 0.40 to 1.15; P = .1). Tests for interaction between MRP1 expression and treatment were statistically significant for both RFS (P = .04) and OS (P = .006). CONCLUSION: Our data suggest that MRP1 expression plays an important role in the clinical resistance to adjuvant CMF chemotherapy but does not seem to affect response to adjuvant endocrine treatment with tamoxifen plus goserelin. Thus, MRP1 may be a useful marker for the selection of patients with early-stage breast cancer for the appropriate adjuvant therapy after prospective confirmatory evaluation.     

Positive surgical margins and ipsilateral breast tumor recurrence predict disease-specific survival after breast-conserving therapy

BACKGROUND: The current study identified determinants of systemic recurrence and disease-specific survival (DSS) in patients with early-stage breast carcinoma treated with breast-conserving surgery and radiation therapy (breast-conserving therapy, or BCT). METHODS: The study population consisted of 1,043 consecutive women with Stages I or II breast carcinoma who underwent BCT between 1970 and 1994. Clinical and pathologic characteristics evaluated included age, tumor size, tumor grade, estrogen and progesterone receptor status, surgical margins, axillary lymph node involvement, and use of adjuvant therapy. RESULTS: At a median follow-up time of 8.4 years, 127 patients (12%) had developed an ipsilateral breast tumor recurrence (IBTR), and 184 patients (18%) had developed a systemic recurrence. On multivariate logistic regression analysis, tumor size greater than 2 cm, positive lymph nodes, lack of adjuvant tamoxifen therapy, and positive margins (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.1-12.3; P = 0.034) were predictors of systemic recurrence. When IBTR was added into the model, adjuvant therapy and surgical margins were not independent predictors; however, IBTR was an independent predictor of systemic recurrence (IBTR vs. no IBTR; OR, 6.2; 95% CI, 3.1-12.3; P < 0.001). The 10 year DSS rate after BCT was 87%. On multivariate Cox proportional hazards model analysis, the following factors were independent predictors of poor DSS: tumor size greater than 2 cm (vs. < or = 2 cm; relative risk [RR], 2.3; 95% CI, 1.2-4.3; P = 0.010), negative progesterone receptor status (vs. positive; RR, 2.7; 95% CI, 1.4-5.1; P = 0.003), positive margins (vs. negative; RR, 3.9; 95% CI, 1.4-11.5; P = 0.011), and IBTR (vs. no IBTR; RR, 5.5; 95% CI, 2.8-11.0; P < 0.001). CONCLUSIONS: Positive surgical margins and IBTR are predictors of systemic recurrence and disease-specific survival after BCT. Aggressive local therapy is necessary to ensure adequate surgical margins and to minimize IBTR.     

Prognostic role of adjuvant radiotherapy in triple‐negative breast cancer: A historical cohort study

The value of adjuvant radiotherapy in triple‐negative breast cancer (TNBC) is currently debated. We assessed the association between adjuvant radiotherapy and survival in a large cohort of Asian women with TNBC. Women diagnosed with TNBC from 2006 to 2011 in five Asian centers (N = 1,138) were included. Survival between patients receiving mastectomy only, breast‐conserving therapy (BCT, lumpectomy and adjuvant radiotherapy) and mastectomy with radiotherapy were compared, and adjusted for demography, tumor characteristics and chemotherapy types. Median age at diagnosis was 53 years (range: 23–96 years). Median tumor size at diagnosis was 2.5 cm and most patients had lymph node‐negative disease. The majority of patients received adjuvant chemotherapy (n = 861, 76%) comprising predominantly anthracycline‐based regimes. In 775 women with T1‐2, N0‐1, M0 TNBCs, 5‐year relative survival ratio (RSR) was highest in patients undergoing mastectomy only (94.7%, 95% CI: 88.8–98.8%), followed by BCT (90.8%, 95% CI: 85.0–94.7%), and mastectomy with radiotherapy (82.3%, 95% CI: 73.4–88.1%). The adjusted risks of mortality between the three groups were not significantly different. In 363 patients with T3‐4, N2‐3, M0 TNBCs, BCT was associated with highest 5‐year RSR (94.1%, 95% CI: 81.3–99.4%), followed by mastectomy with radiotherapy (62.7%, 95% CI: 54.3–70.1%), and mastectomy only (58.6%, 95% CI: 43.5–71.6%). Following multivariable adjustment, BCT and mastectomy with radiotherapy remained significantly associated with lower mortality risk compared to mastectomy only. Overall, adjuvant radiotherapy was associated with higher survival in women aged <40 years, but not in older women. Adjuvant radiotherapy appears to be independently associated with a survival gain in locally advanced as well as in very young TNBC.     

Sequencing of tamoxifen and radiotherapy after breast-conserving surgery in early-stage breast cancer.

PURPOSE: Tamoxifen (TAM) is thought to exert a cytostatic effect on hormone-sensitive breast cancer cells. Some preclinical studies show reduced radiosensitivity in irradiated malignant mammary epithelial cells when pretreated with TAM; other studies refute these results. Recent randomized clinical trials suggest an antagonistic effect of TAM on cytotoxic therapy, with improved disease-free survival (DFS) with sequential versus concurrent TAM. An exploratory analysis was undertaken to evaluate the optimal sequencing of TAM and radiotherapy (RT) after breast-conserving surgery. PATIENTS AND METHODS: Southwest Oncology Group trial 8897 (Intergroup 0102) randomly assigned node-negative women with T1-3 breast cancers to cyclophosphamide, doxorubicin, fluorouracil (CAF); CAF --> TAM; cyclophosphamide, methotrexate, fluorouracil (CMF); and CMF --> TAM. For this analysis, data are reported only in the TAM groups. RT was allowed either before adjuvant therapy (sequential [SEQ] RT; 107 patients) or after chemotherapy but concurrent with TAM (concurrent [CONC] RT; 202 patients). Survival data were adjusted for receptor status, age, and tumor size. RESULTS: With a median follow-up of 10.3 years, 10-year DFS values were 83% and 83% for CONC versus SEQ RT groups (log-rank P = .73; P = .76 adjusted for patient characteristics), and 10-year overall survivals were 88% and 90%, respectively (log-rank P = .59; adjusted P = .65). Patterns of failure showed no increase in in-breast recurrence rates between CONC RT and SEQ RT groups, with 10-year local recurrence rates of 7% for CONC RT and 5% for SEQ RT (hazard ratio, 0.73; 95% CI, 0.26 to 2.04; P = .54). CONCLUSION: The current analysis does not suggest an adverse effect on local or systemic control with CONC versus SEQ TAM and RT in node-negative breast cancer. A randomized trial is encouraged to validate these results.     

Timing of adjuvant chemotherapy and tamoxifen in women with breast cancer: findings from two consecutive trials of Gruppo Oncologico Nord-Ovest-Mammella Intergruppo (GONO-MIG) Group.

BACKGROUND: The timing of adjuvant chemotherapy and tamoxifen (TAM) has been investigated only in postmenopausal women with breast cancer. We analyzed the outcome of both pre- and postmenopausal women who entered two randomized trials (Gruppo Oncologico Nord-Ovest-Mammella Intergruppo studies) on adjuvant chemotherapy and received either concomitant or sequential TAM. PATIENTS AND METHODS: Patients who received anthracycline-based regimens and either concomitant or sequential TAM were eligible. The primary end point was overall survival (OS). Hazard ratios (HRs) of death or recurrence for treatment comparisons were estimated by Cox proportional hazards regression models. RESULTS: Among the 1096 eligible patients, 507 (46.3%) and 589 (53.7%) received concomitant and sequential TAM, respectively. The median follow-up time was 6.6 years. Ten-year OS was 83% [95% confidence interval (CI) 78-88%] and 80% (95% CI 74-86%) in the concomitant and sequential groups, respectively. Multivariate analyses confirmed no significant difference in the hazard of death (HR = 1.13; 95% CI 0.78-1.64; P = 0.534) and recurrence (HR = 1.03; 95% CI 0.80-1.33; P = 0.88) between the two groups. A decreasing trend (P = 0.015) in HR of death with increasing age was observed indicating, that concomitant therapy might be more effective than sequential therapy in young patients. CONCLUSIONS: We observed no outcome difference between sequential and concomitant chemo-endocrine therapy. The potential advantage of concomitant TAM in young patients needs to be further addressed in prospective trials.     

Sequence of radiotherapy with tamoxifen in conservatively managed breast cancer does not affect local relapse rates.

PURPOSE: To evaluate whether the sequencing of tamoxifen (TAM) relative to radiation (RT) affects outcome in breast cancer patients treated with conservative surgery (CS) plus RT (lumpectomy with RT). METHODS: Between 1976 and 1999, 1,649 patients with stage I or II breast cancer were treated with CS plus RT at Yale-New Haven Hospital (New Haven, CT). TAM was administered to 500 patients. The timing of TAM relative to RT was documented for each patient. Of the 500 patients, the timing of TAM was unclear in five patients, was administered concurrently with RT in 254 patients (CON-TAM), and was administered sequentially after completion of RT in 241 patients (SEQ-TAM). RESULTS: There were no differences between the CON-TAM and SEQ-TAM group in T stage, estrogen and progesterone status, nodal status, histology, or margin status. The CON-TAM group was slightly older than the SEQ-TAM group (62 v 58 years) and received chemotherapy in addition to TAM less frequently (14% v 38%). As of September 2002, with a median follow-up of 10.0 years, there were no significant differences between the CON-TAM and SEQ-TAM groups in overall survival (84% v 82%; hazard ratio [HR], 1.234; 95% CI, 0.42 to 2.05; P = .45), distant-metastasis-free rate (82% v 78%; HR, 1.55; 95% CI, 0.89 to 2.68; P = .12), ipsilateral breast-relapse-free rate (90% v 86%; HR, 0.932; 95% CI, 0.42 to 2.05; P = .86), or contralateral breast-relapse-free rate (95% v 93%; HR, 0.892; 95% CI, 0.53 to 1.48; P = .66). CONCLUSION: Although the concurrent use of TAM with RT may theoretically render cancer cells less responsive to RT, this retrospective study suggests that in practical application, concurrent administration of TAM with RT does not compromise local control.     

Randomized trial of adjuvant tamoxifen combined with postoperative radiation therapy or adjuvant chemotherapy in postmenopausal breast cancer

From 1976 to 1984, 427 postmenopausal women with high-risk breast cancer (pN + or pT greater than 30 mm) were randomized between postoperative radiation therapy (RT), radiation therapy plus tamoxifen (RT-TAM), adjuvant chemotherapy (CT), or chemotherapy plus tamoxifen (CT-TAM). Surgery was a modified radical mastectomy in all cases. The radiation therapy was given with high-voltage techniques and included the chest wall and regional nodes. The dose was 4600 cGy/4 1/2 weeks. Tamoxifen was given at a dose of 40 mg daily for 2 years. The adjuvant chemotherapy consisted of 12 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (or chlorambucil, methotrexate, and 5-fluorouracil [LMF] for patients entered before 1978). At a median follow-up time of 6 1/2 years the recurrence-free survival was significantly better for patients allocated to radiation therapy compared to chemotherapy and for patients allocated to tamoxifen compared to no adjuvant endocrine treatment (P less than 0.01). At 10 years the recurrence-free survival for patients in the RT-TAM, RT, CT-TAM, and CT groups was 63%, 57%, 47%, and 31%, respectively. A significant reduction of treatment failures with tamoxifen was only observed among patients with estrogen receptor-positive tumors. The overall survival difference in favor of patients allocated to radiation therapy or tamoxifen was not significant: the respective survival percentage at 10 years in the RT-TAM, RT, CT-TAM, and CT group was 65%, 62%, 52%, and 50%. The results indicate that postoperative radiation therapy continues to play an important role in the primary management of postmenopausal women with high-risk breast cancer and that the addition of tamoxifen may further improve the results among ER-positive patients.     

Predictors of long-term outcome following high-dose chemotherapy in high-risk primary breast cancer

We report on a predictive model of long-term outcome in 114 high-risk breast cancer patients treated with high-dose chemotherapy between 1989 and 1994. Paraffin-blocks from 90 of the 114 primaries were assessed for the presence of five risk factors: grade, mitotic index, protein expression of p53, HER2/neu, and oestrogen/progesterone receptor status; we could analyse the effect of risk factors in 84 of these 90 tumours. Seven-year relapse-free and overall survival was 58% (95% confidence interval 44-74%) and 82% (95% confidence interval 71-94%) vs 33% (95% confidence interval 21-52%) and 41% (95% confidence interval 28-60%) for patients whose primary tumours displayed > or =3 risk factors vs patients with < or =2 risk factors. For the entire group of 168 high-risk breast cancer patients, inflammatory stage IIIB disease and involved post-mastectomy margins were associated with decreased relapse-free survival and overall survival; patients treated with non-doxorubicin containing standard adjuvant therapy experienced worse overall survival (RR, 2.08; 95% confidence interval 1.04 to 4.16; P=0.04), while adjuvant tamoxifen improved overall survival (RR, 0.65; 95% confidence interval 0.41-1.01; P=0.054). Future trial designs and patient selection for studies specific for high-risk breast cancer patients should include appropriate prognostic models. Validation of such models could come from recently completed randomised, prospective trials.     

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     

Cyclin D1 expression in breast cancer patients receiving adjuvant tamoxifen-based therapy.

PURPOSE: The objective of our study was to determine the clinical relevance of cyclin D1 expression in hormone receptor-positive breast cancer patients who were treated with tamoxifen-based therapy. EXPERIMENTAL DESIGN: We assessed expression of cyclin D1 in surgical specimens of breast carcinoma by means of immunohistochemistry. Patients had been enrolled in either Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 05 or ABCSG Trial 06 and received tamoxifen as part of their adjuvant treatment. Overall survival and relapse-free survival were analyzed with Cox models adjusted for clinical and pathologic factors. RESULTS: Cyclin D1 was expressed in 140 of 253 (55%) tumors of ABCSG Trial 05 and in 569 of 948 (60%) tumors of ABCSG Trial 06. Expression of cyclin D1 was associated with poor outcome in both cohorts. Overall survival was significantly shorter in patients with cyclin D1-positive tumors compared with patients with cyclin D1-negative tumors [adjusted hazard ratio (HR) for death (ABCSG Trial 05), 2.47; 95% confidence interval (95% CI), 1.08-5.63; P = 0.03; adjusted HR for death (ABCSG Trial 06), 1.78; 95% CI, 1.36-2.34; P < 0.0001]. Relapse-free survival was also shorter in patients with cyclin D1-positive tumors than in patients with cyclin D1-negative tumors [adjusted HR for relapse (ABCSG Trial 05), 2.73; 95% CI, 1.50-4.96; P = 0.001; adjusted HR for relapse (ABCSG Trial 06), 1.52; 95% CI, 1.14-2.04; P = 0.005]. CONCLUSION: Cyclin D1 expression is an independent poor prognostic factor in women with early-stage, hormone receptor-positive breast cancer who received adjuvant tamoxifen-based therapy.     

Overexpression of p53 is correlated with poor outcome in premenopausal women with breast cancer treated with tamoxifen after chemotherapy

The aim of this study was to evaluate the difference in outcomes based on p53 overexpression of patients with breast cancer who received adjuvant therapy following local treatment for invasive ductal carcinoma, not otherwise specified. We analyzed data from 4,683 patients with cancer enrolled in two institutions between 1997 and 2006. We analyzed the correlation between p53 overexpression and relapse, response to adjuvant therapy, breast cancer-specific survival (BCSS), and relapse-free survival (RFS) in patients with primary breast cancer. Overexpression of p53 was noted in 1,091 patients (23.3%). A significant correlation existed between p53 overexpression and poor prognostic factors, an increased frequency of regional recurrence, visceral metastasis, and worse BCSS and RFS. Based upon subgroup analyses, combined age (<35, 35–50, and >50 years) and adjuvant therapy (hormone therapy only, chemotherapy only, and hormone therapy following chemotherapy), the greatest reduction of survival based on p53 overexpression was noted in patients 35–50 years of age who received hormone therapy following chemotherapy (P < 0.05). Multivariate analysis showed that p53 overexpression is an independent prognostic factor in patients treated with hormone therapy and chemotherapy (relative risk for BCSS, 2.003; 95% CI, 1.105–3.631; P = 0.022). The p53-overexpressing patients with breast cancer between 35 and 50 years of age who received tamoxifen following chemotherapy had the greatest adverse effect on outcome. Overexpression of p53 is significantly associated with tamoxifen resistance in premenopausal women with breast cancer.     

Early switch with aromatase inhibitors as adjuvant hormonal therapy for postmenopausal breast cancer: pooled-analysis of 8794 patients

BACKGROUND: The magnitude of the survival benefit of aromatase inhibitors (AIs) after 2-3 years of tamoxifen as adjuvant hormonal therapy for early breast cancer is still unclear. We performed a literature-based meta-analysis, to look how much advantages adjuvant the "early switch" strategy add over standard tamoxifen for 5 years. METHODS: A pooled analysis of all phase-III trials was accomplished, and event-based relative risk ratios (RR) with 95% confidence interval (CI) were derived. Significant differences in primary outcome (EFS and RFS, event- and relapse-free survival), and secondary outcomes (OS, overall survival, deaths without progression, other cancers and toxicities), were explored. Magnitude outcome measures were absolute benefits and number of patients needed to treat. Heterogeneity test was applied as well. RESULTS: Five trials (8794 patients) were gathered. The risk of any event is reduced with AIs of 23%, with an absolute benefit of 3.8% (RR 0.67, 95% CI 0.59, 0.76). Again, RFS (RR 0.68, 95% CI 0.59, 0.79) or both LRFS and DFRS, were significantly improved with AIs. OS was significantly prolonged with AIs, with an absolute benefit of 1.2% (RR 0.76, 95% CI 0.62, 0.93), without significant heterogeneity. Bone fractures were significantly higher in patients receiving AIs (RR 1.50, 95% CI 1.12, 2.02), and endometrial cancer in patients who continued to receive tamoxifen (RR 0.32, 95% CI 0.13, 0.77), without significant heterogeneity. CONCLUSIONS: The early switch strategy improves survival over standard tamoxifen for 5 years, with a different toxicity profile. The lack of significant heterogeneity in the analysis underscores the homogenous effect across all trials.     

Locoregional failure of postmastectomy patients with 1-3 positive axillary lymph nodes without adjuvant radiotherapy

PURPOSE: To analyze the incidence and risk factors for locoregional recurrence (LRR) in patients with breast cancer who had T1 or T2 primary tumor and 1-3 histologically involved axillary lymph nodes treated with modified radical mastectomy without adjuvant radiotherapy (RT). MATERIALS AND METHODS: Between April 1991 and December 1998, 125 patients with invasive breast cancer were treated with modified radical mastectomy and were found to have 1-3 positive axillary nodes. The median number of nodes examined was 17 (range 7-33). Of the 125 patients, 110, who had no adjuvant RT and had a minimum follow-up of 25 months, were included in this study. Sixty-nine patients received adjuvant chemotherapy and 84 received adjuvant hormonal therapy with tamoxifen. Patient-related characteristics (age, menopausal status, medial/lateral quadrant of tumor location, T stage, tumor size, estrogen/progesterone receptor protein status, nuclear grade, extracapsular extension, lymphovascular invasion, and number of involved axillary nodes) and treatment-related factors (chemotherapy and hormonal therapy) were analyzed for their impact on LRR. The median follow-up was 54 months. RESULTS: Of 110 patients without RT, 17 had LRR during follow-up. The 4-year LRR rate was 16.1% (95% confidence interval [CI] 9.1-23.1%). All but one LRR were isolated LRR without preceding or simultaneous distant metastasis. According to univariate analysis, age <40 years (p = 0.006), T2 classification (p = 0.04), tumor size >==3 cm (p = 0.002), negative estrogen receptor protein status (p = 0.02), presence of lymphovascular invasion (p = 0.02), and no tamoxifen therapy (p = 0.0006) were associated with a significantly higher rate of LRR. Tumor size (p = 0.006) was the only risk factor for LRR with statistical significance in the multivariate analysis. On the basis of the 4 patient-related factors (age <40 years, tumor >==3 cm, negative estrogen receptor protein, and lymphovascular invasion), the high-risk group (with 3 or 4 factors) had a 4-year LRR rate of 66.7% (95% CI 42.8-90.5%) compared with 7.8% (95% CI 2.2-13.3%) for the low-risk group (with 0-2 factors; p = 0.0001). For the 110 patients who received no adjuvant RT, LRR was associated with a 4-year distant metastasis rate of 49.0% (9 of 17, 95% CI 24.6-73.4%). For patients without LRR, it was 13.3% (15 of 93, 95% CI 6.3-20.3%; p = 0.0001). The 4-year survival rate for patients with and without LRR was 75.1% (95% CI 53.8-96.4%) and 88.7% (95% CI 82.1-95.4%; p = 0.049), respectively. LRR was independently associated with a higher risk of distant metastasis and worse survival in multivariate analysis. CONCLUSION: LRR after mastectomy is not only a substantial clinical problem, but has a significant impact on the outcome of patients with T1 or T2 primary tumor and 1-3 positive axillary nodes. Patients with risk factors for LRR may need adjuvant RT. Randomized trials are warranted to determine the potential benefit of postmastectomy RT on the survival of patients with a T1 or T2 primary tumor and 1-3 positive nodes.     

The combination of radiotherapy, adjuvant chemotherapy (cyclophosphamide-doxorubicin-ftorafur) and tamoxifen in stage II breast cancer. Long-term follow-up results of a randomised trial.

Two hundred patients with node positive stage II breast cancer were randomised to four groups after radical mastectomy and axillary evacuation: (1) Postoperative radiotherapy, (2) Adjuvant chemotherapy with eight courses of CAFt (cyclophosphamide 500 mg m-2 + doxorubicin 40 mg/m-2 + ftorafur 20 mg kg-1 orally day 1-14) every fourth week, (3) Postoperative radiotherapy and adjuvant chemotherapy and (4) postoperative radiation, adjuvant chemotherapy and tamoxifen 40 mg daily for 2 years. Thirty-two per cent of the patients discontinued treatment due to GI-toxicity, while 26% required dose reductions due to leukopenia. Radiation pneumonitis was more frequent after the combination of postoperative radiotherapy with chemotherapy. There was a better relapse-free survival in the groups receiving chemotherapy compared to radiotherapy alone (P = 0.05), which was highly significant in a multivariate Cox analysis (P = 0.004). No significant survival differences were seen. Tamoxifen had no clear overall effect but there were better relapse-free (P = 0.04) and overall (P = 0.004) survival with tamoxifen in estrogen receptor positive patients, while estrogen receptor negative patients had a somewhat poorer survival (P = 0.07) after tamoxifen. Local control was better (NS) after the combination (93%) radiotherapy and chemotherapy compared to either treatment alone (76% with radiotherapy and 74% with chemotherapy at 5 years).     

Randomized trial to evaluate the addition of tamoxifen to cyclophosphamide, 5-fluorouracil, prednisone adjuvant therapy in premenopausal women with node-positive breast cancer

A randomized clinical trial was performed to determine if the addition of hormonal therapy with tamoxifen to a combination chemotherapy regimen was superior to the chemotherapy alone for adjuvant treatment of premenopausal women after mastectomy for node-positive breast cancer. The chemotherapy regimen utilized consisted of cyclophosphamide (C), 5-fluorouracil (F), and prednisone (P), and the doses employed were: C, 150 mg/m2 IV days 1 to 5; F, 300 mg/m2 IV days 1 to 5; and P, 10 mg orally three times daily on days 1 to 7. A total of ten courses of therapy, given every 6 weeks, was planned. Tamoxifen (T) was given at a dose of 10 mg twice daily and was stopped 6 weeks after the last course of CFP. Four hundred patients are fully eligible and evaluable. With a median observation time of 5.3 years, the proportion of recurrences on each arm were: CFP, 95 of 202 (47%); CFPT, 77 of 198 (39%). The relapse-free survival distribution for CFPT was superior to that for CFP, at a borderline level of significance (two-sided P = 0.06). When significant prognostic factors were considered in covariate analysis, CFPT was not significantly better than CFP (P = 0.43). This marked change in level was due to imbalance in several factors not considered in stratification. Currently, 31% of CFP and 25% of CFPT patients have died, and although there is a slight separation of the survival curves in favor of CFPT, the difference is not significant (P = 0.21). Analysis within receptor subsets also showed no significant advantage for the addition of tamoxifen. This study does not establish a significant advantage for the concurrent administration of tamoxifen with the CFP regimen. It does, however, clearly demonstrate the importance of examination of clinically important prognostic factors, even those not utilized in stratification, and consideration of these factors in covariate analysis if imbalances are present.     

Adjuvant!? Online estimation of chemotherapy effectiveness when added to ovarian function suppression plus tamoxifen for premenopausal women with estrogen-receptor-positive breast cancer

Adjuvant!^? Online (Adjuvant!) is a user-friendly, web-based tool that provides estimates of adjuvant therapy outcomes for individual patients. While reliable evidence underpins estimates for most patient cohorts, there is a paucity of data on the effect of adding chemotherapy to complete estrogen blockade for premenopausal women with estrogen-receptor positive breast cancer. International Breast Cancer Study Group (IBCSG) Trial 11-93 enrolled 174 premenopausal women with estrogen-receptor positive, node-positive breast cancer. Among these patients, 55% had one positive axillary lymph node and 97% had three or fewer positive nodes. Patients were randomized to receive ovarian function suppression plus 5 years of tamoxifen with or without anthracycline-based chemotherapy. Estimated hazard rates and corresponding 10-year relapse-free survival percentages obtained from Trial 11-93 data were compared with those predicted using Adjuvant!. The 10-year relapse-free survival percentages predicted from Adjuvant! were 64.4% (95% CI, 61.9–67.2%) for endocrine therapy alone and 74.9% (95% CI, 73.1–76.8%) for chemoendocrine therapy. By contrast, these estimates in Trial 11-93 were 76.4% (95% CI, 65.8–84.0%) for endocrine therapy alone and 74.9% (95% CI, 64.5–82.7%) for chemoendocrine therapy. The Adjuvant! estimate for the endocrine-alone control group is lower than that observed in Trial 11-93 (P = 0.03), while the estimates for the two chemoendocrine therapy groups are similar. Adjuvant! appears to underestimate the effectiveness of adjuvant endocrine therapy alone for premenopausal women with endocrine responsive breast cancer, thus overestimating the added benefit, if any, from chemotherapy for this patient population.     

Patterns of care and survival for patients with glioblastoma multiforme diagnosed during 2006

Standard treatment for glioblastoma multiforme (GBM) changed in 2005 when addition of temozolomide (TMZ) to maximal surgical resection followed by radiation therapy (RT) was shown to prolong survival in a clinical trial. In this study, we assessed treatment patterns and survival of patients with GBM in community settings in the United States. Patients with newly diagnosed GBM who were aged ≥20 years in 2006 (n = 1202) were identified as part of the National Cancer Institute 's Patterns of Care Studies. We assessed treatment patterns, and in the subset of patients who received total or partial surgical resection, we used multivariable regression analysis to assess patient, clinical, and health system factors associated with receipt of adjuvant chemotherapy and RT and survival through 2008. Approximately 65% of patients with GBM received total or partial surgical resection, and approximately 70% of these patients received adjuvant TMZ and RT. Receipt of adjuvant therapy was associated with patient age, marital status, health insurance, and tumor location. Median survival in all patients was 10 months (95% confidence interval [CI], 9-11 months). Receipt of adjuvant therapy following resection was associated with a lower risk of dying in adjusted analyses for patients who received TMZ and RT (hazard ratio [HR], 0.25; 95% CI, 0.18-0.35) and other adjuvant therapies (HR, 0.55; 95% CI, 0.37-0.81), compared with no adjuvant therapy. We observed rapid diffusion of a new standard of treatment, adjuvant and concurrent TMZ with RT, among adult patients with newly diagnosed GBM in the community setting following publication of a pivotal clinical trial.     

Carbonic anhydrase-9 expression levels and prognosis in human breast cancer: association with treatment outcome

Here, we set out to assess CA9 expression levels by real-time quantitative RT-PCR in breast cancer tissue samples obtained from 253 patients, and correlated those with relapse-free (RFS) survival. The median follow-up time was 75 months (range 2-168 months). CA9 expression was mainly found in high-grade, steroid receptor negative cancer tissues. CA9 levels were not significantly associated with RFS (P=0.926, hazard ratio (HR)=0.99, 95% CI=0.80-1.22) in the total cohort of 253 patients. In multivariate analysis with other clinicopathological factors, CA9 (P=0.018, HR=0.77, 95% CI=0.62-0.96), the interaction of adjuvant chemotherapy with CA9 (P=0.009, HR=1.31, 95% CI=1.07-1.61) and the interaction of adjuvant endocrine therapy with CA9 (P<0.001, HR=1.41, 95% CI=1.20-1.66) all contributed significantly to the final model. These results indicate that patients with low CA9 levels benefit more from adjuvant treatment than do patients with high levels. Thus, the determination of CA9 levels could aid in the selection of patients who will not benefit from adjuvant therapy, and whose prognosis will more likely improve with other treatment modalities.     

Breast-conserving therapy and modified radical mastectomy for primary breast carcinoma: a matched comparative study

Background

To compare two types of therapy for primary breast carcinoma, breast-conserving therapy (BCT) and modified radical mastectomy (MRM), in a matched cohort study.

Methods

A series of 1,746 patients with primary breast cancer treated with BCT or MRM in a single Chinese institute between January 2000 and February 2009 were analyzed retrospectively to compare their outcomes with respect to the incidence of local recurrence (LR), distant metastasis, and survival. The patients were matched with regard to age at diagnosis, spreading to axillary lymph nodes, hormone receptor status, the use of neoadjuvant chemotherapy and maximal tumor diameter. The match ratio was 1:1, and each arm included 873 patients.

Results

The median follow-up period was 71 months. The 6-year disease-free survival (DFS) and 6-year distant disease-free survival (DDFS) rates differed significantly between two groups. The 6-year local recurrence-free survival (LRFS) rates were 98.2% [95% confidence interval (CI): 0.973-0.989] in the BCT group and 98.7% (95% CI: 0.980-0.994) in the MRM group (P=0.182), respectively. DFS rates in BCT and MRM groups were 91.3% (95% CI: 0.894-0.932) and 86.3% (95% CI: 0.840-0.886) (P<0.001), respectively, whereas the DDFS rates in BCT and MRM groups were 93.6% (95% CI: 0.922-0.950) and 87.7% (95% CI: 0.854-0.900) (P<0.001), respectively.

Conclusions

BCT in eligible patients is as effective as MRM with respect to local tumor control, DFS and DDFS, and may result in a better outcome than MRM in Chinese primary breast cancer patients.