Adjuvant Chemotherapy with a Combination of Mitoxantrone,Methotrexate, 5-Fluorouracil for Node-Positive Breast Cancer: Phase II Pilot Study

Abstract

A phase II pilot study was carried out on 30 patients to ascertain the toxicity and efficacy of combination chemotherapy with mitoxantrone, methotrexate, 5-fluorouracil (NMF) in the adjuvant setting for axillary lymph node-positive breast cancer. The NMF regimen was mitoxantrone 10 mg/m², methotrexate 40 mg/m², and 5-fluorouracil 600 mg/m² administered i.v. on day 1, repeated every 3-4 weeks for 6 cycles. The median nadir WBC count was 2,000/ml; grade 4 leukocytopenia occurred only in 1 patient. Nausea and vomiting appeared as grade 0 and 1 severity in 26/30 patients. Alopecia was extremely mild, appeared as grade 0 and 1 in 29/30 patients. The overall and relapsefree survival rates were 67.8% and 68.4% at the 82-month follow-up, respectively. The overall survival rate in premenopausal patients was significantly better than that in postmenopausal patients (P<0.05). NMF is a well-tolerated combination regimen, suitable as adjuvant chemotherapy for node-positive breast cancer.     

Doxorubicin and Cyclophosphamide versus Cyclophosphamide,Methotrexate, and 5-Fluorouracil as Adjuvant Chemotherapy in Breast Cancer

Abstract

This study evaluated whether doxorubicin and cyclophosphamide are superior to cyclophosphamide, methotrexate and 5-fluorouracil as adjuvant chemotherapy in breast cancer patients. Between July 1976 and December 2004, 1045 breast cancer patients received adjuvant chemotherapy at the Radiotherapy Unit of the University of florence. 927 were administered i.v. CMF (cyclophosphamide 600 mg/m², methotrexate 40mg/m² and 5-fluorouracil 600 mg/m² on days 1 and 8, repeated every 28 days for a total of six cycles) and 118 i.v. DC (doxorubicin 60 mg/m2and cyclophosphamide 600 mg/m² on day 1 repeated every 21 days for a total of four cycles). All patients under-went adjuvant radiotherapy as well. The survival analysis, stratified according to treatment, did not show any significant difference in metastasis occurrence between the two groups (log rank test p=0.42). According to multivariate analysis four parameter semerged as independent prognostic factors for distant metastases in patients treated with the CMF regimen: pT (p=0.0005), number of positive axillary lymph nodes(p=<0.0001), tamoxifen use (p=0.0109) and local relapses (p=<0.0001). Only number of positive axillary lymph nodes and local relapses were significant predictors of metastases occurrence according to multivariate analysis in the DC group, 17 and p=0.028, respectively. No significant difference between the two regimens was ob-served with regards to number of involved nodes. DC and CMF produced similar out-come in breast cancer patients.     

Neoadjuvant chemotherapy in locally advanced breast cancer

Thirty-eight patients with locally advanced breast cancer (Stage III) were treated over a 3-year period. All patients initially received two cycles of CMF (cyclophosphamide, 100 mg/m² p.o. d1–14; methotrexate 40mg/m² intravenously (iv), d1 and d8., 5 Fluorouracil 500 mg/m² iv d1 and d8). They were then subjected to surgery and external beam irradiation to the chest field and drainage areas. Four more cycles of chemotherapy completed the treatment protocol. A response to initial chemotherapy was seen in 75.7% patients, with two patients achieving a complete response. No patient had disease progression while on chemotherapy. Tumor reduction of a degree to allow breast conservation procedures was seen in eight patients. The chemotherapy was well tolerated. Twelve patients failed to complete the treatment protocol. Follow-up for the remaining 26 ranges from 9–40 months (mean 18 months). Ten patients developed a recurrence. Of those, only one had isolated local recurrence, two had local and systemic recurrence, and seven had systemic disease alone. Patients with recurrence were salvaged with further chemotherapy (Adriamycin and cyclophosphamide). © 1996 Wiley-Liss, Inc.     

Randomized trial of high-dose adjuvant chemotherapy with autologous hematopoietic stem-cell support versus standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: overall survival after 6 years of follow-up

Investigation of high-dose chemotherapy (HD-CT) compared with standard-dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and ≥10 axillary lymph nodes. From November 1993 to September 2000, 307 patients were randomized to receive after four cycles of epirubicin (90 mg/m²), cyclophosphamide (600 mg/m²) i.v. (every 21 days) and either HD-CT of cyclophosphamide (1500 mg/m²), thiotepa (150 mg/m²) and mitoxantrone (10 mg/m²) i.v. for four consecutive days followed by stem cell transplantation or a SD-CT of three cycles CMF (cyclophosphamide 500 mg/m², methotrexate 40 mg/m², 5-fluorouracil 600 mg/m², i.v. on day 1 and 8, respectively, every 28 days). After a median follow-up of 6.1 years, 166 events with respect to event-free survival (EFS) (SD-CT: 91, HD-CT: 75) have been observed. The hazard ratio of HD-CT versus SD-CT is estimated as 0.80 [95% confidence interval (0.59, 1.08)], P = 0.15. The trend to a superiority of HD-CT as compared with SD-CT with respect to EFS seems to be more pronounced in premenopausal patients as compared with postmenopausal patients and in patients with tumor grade 3 as compared with patients with tumor grade 1/2. With a follow-up of 6 years, there was a trend in favor of HD-CT with respect to EFS not being significant. A proper meta-analysis needs to be undertaken for an evaluation of subgroups of patients who might benefit from HD-CT.     

Intensified chemotherapy supported by DMSO-free peripheral blood progenitor cells in breast cancer patients

Background:The majority of high-dose chemotherapy (HDC)-related complications results from bone marrow aplasia, but the graft infusion per se may cause adverse reactions due to the injection of both dimethyl sulfoxide (DMSO) and cell lysis products. We evaluated the feasibility of a two-step chemotherapy regimen with peripheral blood progenitor cell (PBPC) support in association with a novel procedure to remove DMSO and products of cell lysis from the cryopreserved cells. Patients and methods:Stage III and IV breast cancer patients received induction chemotherapy with three cycles of CEF (cyclophosphamide 600 mg/m², epirubicin 100 mg/m², 5-fluorouracil 600 mg/m²) followed by three cycles of HDC consisting of escalating doses of cyclophosphamide (dose range 1200–3000 mg/m²) and carboplatin (dose range 600–1000 mg/m²), supported by DMSO-free PBPC reinfusion. DMSO was removed by a washing/enzymatic digestion procedure. Results:Twenty patients received induction chemotherapy and eighteen completed the entire chemotherapy program; a total of fifty-four cycles of HDC were administered. Dose limiting toxicity of HDC was long-lasting grade 4 neutropenia associated with documented infection. The maximum tolerated dose (MTD) was cyclophosphamide 3000 mg/ m² and carboplatin 600 mg/m². No side effects related to PBPC reinfusion were observed. Conclusions:The proposed two-step chemotherapy regimen, associated with a novel washing/enzymatic digestion procedure, is feasible in advanced breast cancer patients in the absence of complications related to the specific toxicity of PBPC reinfusion.     

The potential risk of neoadjuvant chemotherapy in breast cancer patients—results from a prospective randomized trial of the Austrian Breast and Colorectal Cancer Study Group (ABCSG-07)

Purpose To evaluate the impact that pre- and postoperatively administered chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF) and postoperative chemotherapy vs. postoperative chemotherapy alone have on long-term prognosis. Patients and Methods The ABCSG conducted a nationwide randomized phase III trial in high-risk endocrine non-responsive breast cancer patients comparing pre- and postoperative chemotherapy containing CMF as preoperative treatment vs. postoperative chemotherapy alone between 1991 and 1999. From 1996 the ABCSG-07 protocol was amended to also allow randomization of high-risk endocrine-responsive patients. Of 423 eligible patients with high-risk primary breast cancer, 203 patients were randomly assigned to preoperatively receive three cycles of CMF (cyclophosphamide, methotrexate, fluorouracil; 600/40/600 mg/m²) intravenously on day 1 and 8, while 195 patients received postoperative chemotherapy alone. In both groups, three cycles of CMF were given initially, and another three cycles of CMF were administered in node-negative patients, whereas node-positive patients received three cycles of EC (epirubicin, cyclophosphamide; 70/600 mg/m²). Results Overall response rate to preoperative chemotherapy with three cycles of CMF was 56.2%; complete pathological response was achieved in 12 patients (5.9%). Recurrence-free survival was significantly better in patients receiving chemotherapy postoperatively (HR 0.7, 0.515–0.955; P = 0.024). No survival difference was observed between the two therapy groups (HR 0.800, 0.563–1.136; P = 0.213). Discussion Preoperative chemotherapy with CMF has to be considered as insufficient in high-risk breast cancer patients. Delayed surgery and anthracycline-based chemotherapy result in shorter recurrence-free survival but not overall survival.     

High dose chemotherapy as adjuvant treatment in operable Breast Cancer with 10 or more involved axillary lymph nodes

BACKGROUND: it is well known that breast cancer patients with more than 10 axillary lymph nodes involved have poor prognosis even with extensive adjuvant chemotherapy. To improve this poor outcome, high-dose adjuvant chemotherapy has been applied to the these patients. This study was intended to clarify the efficacy and usefulness of high dose adjuvant chemotherapy (HDC) for high-risk breast cancer patients and its efficacy was compared with conventional adjuvant chemotherapy (non-HDC group). PATIENTS AND METHODS: Twelve patients with breast cancer involving more than 10 axillary nodes received high-dose chemotherapy with peripheral progenitor-stem cell transplantation (PBSCT). This regimen consists of BCNU (carmustine) 130 mg/m(2) x 3, CBDCA (carboplantin) 500 mg/m(2) x 3 and CPA (chyclophosphamide) 50 mg/kgx 2 after induction chemotherapy with 3 cycles of CE (chyclophosphamide 600 mg/m(2), epirubicin 60 mg/m(2)). RESULTS: Twelve patients completed the high-dose chemotherapy regimen as planned, no patient died of chemotherapy related toxicity. After a median follow-up period of 44 months, disease-free and overall survival at 48 months after the operation for 12 patients determined by Kaplan-Meier methods was 63 % and 83 %, respectively. Disease-free survival was superior in the high-dose chemotherapy group compared with the control group but a statistical difference was not observed. CONCLUSION: High-dose chemotherapy seems to be an effective and feasible treatment for high-risk breast cancer patients. However, the usefulness of high-dose adjuvant chemotherapy for high-risk breast cancer patients should be confirmed by a large-scale randomized trial.     

A phase III randomized trial of cyclophosphamide,mitoxantrone, and 5-fluorouracil (CNF) versus cyclophosphamide,adriamycin, and 5-fluorouracil (CAF) in patients with metastatic breast cancer

Summary One hundred patients with metastatic breast cancer were randomly selected to receive combined chemotherapy treatment with adriamycin (50 mg/m²) or mitoxantrone (12 mg/m²) associated with 5-fluorouracil (600 mg/m²) and cyclophosphamide (600 mg/m²) administered intravenously every 21 days with a maximum of ten cycles. All patients included in this study were under 75 years of age and had ECOG performance status of less than 4. They had not been treated previously with chemotherapy for metastatic disease. Patients treated with adjuvant chemotherapy, which could not have included anthracyclines, had to have relapsed at least 12 months after the completion of therapy. There were no statistically significant differences in pretreatment characteristics or metastatic disease location between the two groups. Ninety-four patients were assessable for response. No differences were observed in response rate or in survival between the groups. The response rate (complete response (CR) and partial response (PR)) was 68% (13% CR and 55% PR for CAF; 0% CR and 68% PR for CNF). Median survival for all patients was 19 months (18 months with CAF and 19 months with CNF). All patients were assessable for toxicity. There were no differences in gastrointestinal and cardiac toxicity. More grade I-II hematologic toxicity episodes (p < 0.001) and treatment delays (p = 0.05) due to leucopenia were observed with the CNF group, and more grade III alopecia (p < 0.001) was observed with the CAF group. Patients received further therapeutic manoeuvres after finishing the study with a sequential treatment consisting of hormonal therapy and chemotherapy with mitomycin (M) -vinblastine (Vbl) (M 10 mg/m² day 1, Vbl 5 mg/m² days 1, 15 and 29; maximum 5 cycles). This chemotherapy treatment was received by 32 patients, with a response rate of 34% and grade III-IV hematologic toxicity of 37%. Treatment with CNF can be considered a good alternative to CAF for first-line treatment of metastatic breast cancer. M-Vbl treatment is useful as second-line treatment in patients with prior adriamycin exposure.     

Oral ftorafur plus intramuscular thiotepa as adjuvant chemotherapy in patients with breast cancer

In this study, we evaluated the safety and efficacy of a combination of oral ftorafur administered together with intramuscular thiotepa as adjuvant chemotherapy for “early” breast cancer patients. A total of 30 patients with operated breast cancer were treated with 500 mg/m² oral ftorafur for 10 consecutive days plus 20 mg/m² intramuscular (im) administered thiotepa on d 1 and 8 every 28 d adjuvant chemotherapy. Eleven patients were premenopausal and 19 were postmenopausal, with a median age of 53 yr. The total number of cycles delivered was 259 (median: 10 cycles per patient). Toxicity was low and usually consisted of leukopenia WHO grade I–II (14%) and neutropenia grade I–II (6%). Gastrointestinal toxicity was minimal. The 5-yr disease-free survival and overall survival were 55% and 84%, respectively. Relapse occurred as bone metastases (50%), local recurrence (25%), and liver (17%) and brain (8%) metastases. Our preliminary data showed that oral ftorafur and im thiotepa is a well-tolerated regimen and could be a useful alternative to the intravenous parenteral route as adjuvant treatment for early breast cancer. Randomized trials are needed to assess the possible advantage of this regimen over intravenous schedules.     

Double-Blind Randomized Trial of Lorazepam versus Placebo with Methylprednisolone for Control of Emesis Due to Non-Cisplatin Containing Chemotherapy

Summary

Fifty-three breast cancer patients receiving adjuvant chemotherapy entered a double-blind randomized trial of lorazepam 2.5 mg orally prior to chemotherapy and repeated after 12 hours (Arm A) versus placebo (Arm B) with methylprednisolone (MPN) 375 mg in 3 equal doses: 125 mg i.v. prior to chemotherapy and repeated i.m. 6 and 12 hours later. Adjuvant therapy with 5-fluorouracil 600 mg/m², 4’-epi-doxorubicin 60 mg/m², cyclophosphamide 600 mg/m² (FEC) day 1 was alternated every 21 days with cyclophosphamide 600 mg/m², methotrexate 40 mg/m², 5-fluorouracil 600 mg/m² (CMF) day 1 for a total of 12 courses. The majority of patients experienced ≥ 5 emetic episodes with FEC therapy (Arm A = 52%; Arm B = 55%). Mild and moderate nausea were reported by 60% and 68% of patients in Arms A and B, respectively. With CMF therapy complete control of emesis was observed in 33% (Arm A) and 35% (Arm B) of patients. The addition of lorazepam did not improve results either with FEC or CMF. Sedation was experienced by 86 to 92% of patients treated with lorazepam and amnesia was observed in 48–50% of cases. FEC therapy must be considered a highly emetic regimen and antiemetic therapy planned accordingly.     

Biweekly docetaxel and gemcitabine as neoadjuvant chemotherapy followed by adjuvant doxorubicin and cyclophosphamide therapy in stage II and III breast cancer patients: results of a phase II study

Introduction The purpose of this phase II study was to evaluate the efficacy and safety of neoadjuvant docetaxel/gemcitabine treatment in a biweekly regimen. Materials and methods Patients with stage II/III breast cancer were treated with docetaxel (65 mg/m²) followed by gemcitabine (2500 mg/m²) every 2 weeks for 6 cycles. Patients with a clinical response or stable disease underwent mastectomy or breast-conserving surgery plus axillary dissection. After surgery, patients received 4 cycles of standard doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 21 days. Results Thirty-five patients were included in the trial. The overall response rate was 71.4% (95% CI: 53.7–85.4), with 8 complete and 17 partial responses. Breast conservation was possible in 59% of the patients. Toxicity was manageable. Conclusions We consider biweekly docetaxel and gemcitabine could be an active and tolerable regimen option in the neoadjuvant setting sequentially with standard adjuvant doxorubicin-cyclophosphamide in patients with stage II or III breast cancer.     

Health‐related quality of life in long‐term breast cancer survivors

BACKGROUND:

The Survivor's Health and Reaction (SHARE) study examined health‐related quality of life (HRQL) in breast cancer patients who had participated in Cancer and Leukemia Group B Trial 8541 from 1985 to 1991.

METHODS:

In total, 245 survivors (78% of eligible patients) who were 9.4 to 16.5 years postdiagnosis (mean, 12.5 years postdiagnosis) completed HRQL surveys relating to 5 domains. Analyses examined HRQL domains according to 3 different chemotherapy dose levels that were administered in the original treatment trial: low‐dose cyclophosphamide, doxorubicin, and fluorouracil (CAF) at 300 mg/m², 30 mg/m², and 300×2 mg/m², respectively, over 4 cycles; standard‐dose CAF at 400 mg/m², 40 mg/m², and 400×2 mg/m², respectively, over 6 cycles; and high‐dose CAF at 600 mg/m², 60 mg/m² and 600×2 mg/m², respectively, over 4 cycles.

RESULTS:

In univariate analyses, a statistically significant difference was observed on the Medical Outcomes Study 36‐item short form Physical Role Functioning subscale by treatment group, with lower mean scores in the standard treatment arm (mean, 65.05) compared with mean scores in the low‐dose arm (mean, 74.66) and the high‐dose arm (mean, 84.94; P.0001). However, multivariate analysis revealed that treatment arm no longer was statistically significant, whereas the following factors were associated with decreased physical role functioning: age ≥60 years (odds ratio [OR], 3.55; P = .006), increased comorbidity interference total score (OR, 1.64; P = .005), lower vitality (OR, 1.05; P = .0002), and increased menopausal symptoms (OR, 1.04 P = .02).

CONCLUSIONS:

At 9.4‐16.5 years after their original diagnosis, differences in physical role functioning among breast cancer survivors who had received 3 different dose levels of chemotherapy were explained by clinical and demographic variables, such as age, fatigue, menopausal symptoms, and comorbidities. Prospective studies are needed to further assess the role of these factors in explaining HRQL and physical role functioning among long‐term survivors. Cancer 2009. © 2009 American Cancer Society.     

A multicenter phase III prospective randomized trial of high-dose epirubicin in combination with cyclophosphamide (EC) versus docetaxel followed by EC in node-positive breast cancer. GOIM (Gruppo Oncologico Italia Meridionale) 9902 study

BackgroundThe Gruppo Oncologico Italia Meridionale 9902 trial compared four cycles of high-dose epirubicin plus cyclophosphamide (EC) with four cycles of docetaxel (Taxotere, D) followed by four cycles of EC as adjuvant treatment of node-positive breast cancer.Patients and methodsPatients were randomly assigned to EC (E 120 mg/m², C 600 mg/m², arm A) for four cycles or four cycles of D (100 mg/m²) followed by four cycles of EC (arm B), both regimens every 21 days. Hormone receptor-positive patients were given hormonal therapy for 5 years. Primary end point was 5-year disease-free survival (DFS). Secondary objectives were overall survival (OS) and safety.ResultsThere were 750 patients enrolled. With a median follow-up of 64 months, 5-year DFS was 73.4% in both arms, and 5-year OS was 89.5% versus 90.7% in arm A and B [hazard ratio was 0.99 (95% confidence interval for DFS 0.75–1.31; P = 0.95)], respectively. Grade 3–4 toxicity was more common in arm B.ConclusionsThis study did not show advantages from the addition of docetaxel to high-dose EC as adjuvant chemotherapy in node-positive breast cancer. The small sample size and low number of DFS events may have limited the ability to observe statistically significant difference between the two arms.     

Four-step high-dose sequential chemotherapy with hematopoietic progenitor-cell support as induction treatment for patients with solid tumors

Background: Despite recent progress in modern chemotherapy, metastatic solid tumors still have a poor outcome. The delivery of increased dose intensities of cytotoxic agents could improve response rates. We assessed the feasibility and safety of a high-dose sequential chemotherapy program in chemotherapy-naive patients with solid tumors.Patients and methods: Thirty patients (14 with carcinoma of unknown primary site, seven with metastatic breast cancer, six with small-cell lung cancer, and three with other diseases) were treated by an induction therapy regimen consisting of four cycles of high-dose chemotherapy with hematopoietic progenitor cell and growth factor support. Peripheral blood progenitor cells were collected by apheresis as the leukocyte counts recovered from the nadir induced by the first cycle of chemotherapy (doxorubicin 75 mg/m², cyclophosphamide 6000 mg/m²). Patients then received two cycles of etoposide (800 mg/m²) and carboplatin (900 mg/m²) separated by one cycle of doxorubicin (75 mg/m²) and cyclophosphamide (3000 mg/m²). G-CSF (5 µg/kg/d) was given until engraftment. Cycles were scheduled to be delivered every three weeks.Results: A total of 108 cycles of chemotherapy were administered. Six patients went off study before the end of the program (three because of progressive disease, three because of toxicity). After the first cycle, a median number of 10 × 10⁶/kg CD34+ cells (range 8–30) were collected. The median number of apheresis procedures was 1 (range 1–3). From cycle 2 to cycle 4, the median number of days when there was an absolute neutrophil count of less than 500/µl increased from three to five, and the median number of days when the platelet count was less than 25,000/µl increased from three to six. Episodes of febrile neutropenia occurred in 36%, 50% and 46% of cycles during cycles 2, 3 and 4, respectively. The median numbers of days between cycle 1 and cycle 2, cycle 2 and cycle 3, cycle 3 and cycle 4 were 24 (range 20–30), 22 (range 20–36) and 22 (range 18–35), respectively. There were no treatment-related deaths. Non-hematologic toxicity included severe (WHO grades 3 or 4) nausea/vomiting in 19 (18%) cycles, mucositis in 8 (7%) cycles and diarrhea in 7 (6%) cycles.Conclusion: Support with hematopoietic progenitor cells and growth factors allows the timely administration of repetitive cycles of high-dose chemotherapy in chemotherapy-naive patients, resulting in a significant increase in dose intensity. Toxicity is noteworthy but manageable and does not compromise further therapy.     

The cost-utility of adjuvant chemotherapy using docetaxel and cyclophosphamide compared with doxorubicin and cyclophosphamide in breast cancer

Purpose

The adoption of a chemotherapeutic regimen in oncologic practice is a function of both its clinical and its economic impacts on cancer management. For breast cancer, U.S. Oncology trial 9735 reported significant improvements in disease-free and overall survival favoring adjuvant tc (docetaxel 75 mg/m² and cyclophosphamide 600 mg/m² every 3 weeks for 4 cycles) compared with ac (doxorubicin 60 mg/ m² and cyclophosphamide 600 mg/m² every 3 weeks for 4 cycles). We carried out an economic evaluation to examine the cost–utility of adjuvant tc relative to ac, in terms of cost per quality-adjusted life year (qaly) gained, given the improved breast cancer outcomes and higher costs associated with the tc regimen.

Methods

A Markov model was developed to calculate the cumulative costs and qalys gained over a 10-year horizon for hypothetical cohorts of women with breast cancer treated with ac or with tc. Event rates, costs, and utilities were derived from the literature and local resources. Efficacy and adverse events were based on results reported from U.S. Oncology trial 9735. The model takes a third-party direct payer perspective and reports its results in 2008 Canadian dollars. Costs and benefits were both discounted at 3%.

Results

At a 10-year horizon, tc was associated with $3,960 incremental costs and a 0.24 qaly gain compared with ac, for a favorable cost–utility of $16,753 per qaly gained. Results were robust to model assumptions and input parameters.

Conclusions

Relative to ac, tc is a cost-effective adjuvant chemotherapy regimen, with a cost-effectiveness ratio well below commonly applied thresholds.     

Long-term follow-up of a phase II trial studying a weekly doxorubicin-based multiple drug adjuvant therapy for stage II node-positive carcinoma of the breast

Background. Combination chemotherapy improves outcomes in women with breast cancer (BC) that involves axillary nodes. This single-arm study aimed to evaluate the effectiveness of an intensive doxorubicin-based multi-drug regimen as adjuvant therapy in women with stage II, node positive breast cancer. Patients and methods. Between 7/80 and 8/85, 654 women, aged 25–73, who had a mastectomy for stage IIB BC were accrued. Patients with prior RT, chemotherapy, or surgical or radiation castration within 1 year of diagnosis were excluded. Treatment consisted of: 6 weekly courses of IV cyclophosphamide (C) 400 mg/m², doxorubicin (A) 10 mg/m², vincristine (V) 1 mg/m², fluorouracil (F) 400 mg/m², and a tapering course of prednisone followed by 12 courses of C 400 mg/m², A 20 mg/m², V 1 mg/m², F 400 mg/m² given every 2 weeks. Patients with estrogen receptor positive tumors received Tamoxifen 10 mg bid between weeks 8 and 30. Treatment did not exceed 8 months. Median follow-up is 13.1 years. Results. Six hundred thirty six patients are eligible. Fewer positive (+) nodes, premenopausal status, and positive progesterone receptor status are significantly (p < 0.05) associated with longer survival. At 10 years, 61% were relapse-free in the 1–3 +node group compared to 37 and 21% in the 4–9 and ≥10 +node groups, respectively (p = 0.0001). Relapse-free survival at 10 years is 50% for premenopausal and 45% for postmenopausal patients. Severe or life-threatening hematological toxicity was seen in 6/630 (<1%) patients. Four patients had severe (grade 3) neurotoxicity which resolved. No cardiac toxicity was observed. Conclusion. This adjuvant regimen compares favorably to other published adjuvant treatments with similar length of follow-up.     

Clinical and pathological predictors of the response to neoadjuvant anthracycline chemotherapy in locally advanced breast cancer

Purpose The aim of this study is to determine clinical and histopathological characteristics correlated to responsiveness to anthracycline-based neoadjuvant chemotherapy in breast cancer. Patients and methods We studied primary tumor specimens with local advanced breast cancer from 40 patients. Patients received anthracycline-based chemotherapy. Neoadjuvant regimen consisted in 600 mg/m² 5-fluorouracil, 60 mg/m² doxorubicin, and 600 mg/m² cyclophosphamide (FAC). The World Health Organization criteria were used to classify the tumors. We performed immunohistochemical staining for ER, PgR, HER-2, PCNA (proliferation cell nuclear antigen), Ki-67, p53, and Bcl-2. Clinical and histopathological characteristics were associated with clinical response and histopathological changes induced by chemotherapy. Results The mean age was 47±14 yr. Twenty-three percent of patients were in stage IIB and 77% were in stages IIIA and IIIB. Seven percent of patients had progression of the disease. Stable disease was observed in 42% of patients and 45% had partial response. Only 7% of patients had a complete response. Factors associated with a better and major percentage of clinical response were the administration of doxorubicin-based chemotherapy, administration of more than three cycles, clinical N1, atypia, more than 10 mitosis per high-power field, moderate to severe SBR grade, and a major index of cellular proliferation. Conclusion We found that tumors with large volumes, N2 node status, low cellular proliferation rate, positive immunoreactivity to p53, and low differentiation grade have a lower response to neoadjuvant chemotherapy with anthracycline. These patients could benefit from a different chemotherapy scheme to obtain a better control and resection.     

Concurrent bevacizumab with a sequential regimen of doxorubicin and cyclophosphamide followed by docetaxel and capecitabine as neoadjuvant therapy for HER2- locally advanced breast cancer: a phase II trial of the NSABP Foundation Research Group

Background

Bevacizumab with chemotherapy improves outcomes in patients with metastatic breast cancer (MBC). The purpose of this trial was to determine the activity and safety profile of neoadjuvant bevacizumab with chemotherapy in women with locally advanced breast cancer (LABC).

Methods

Between November 2006 and August 2007, 45 women with HER2^– LABC began preoperative standard AC (doxorubicin [Adriamycin], cyclophosphamide) × 4 cycles followed by docetaxel 75 mg/m² intravenously (I.V.) on day 1 and capecitabine 825 mg/m² twice daily on days 1-14 (TX, docetaxel [Taxotere] and capecitabine [Xeloda]) every 21 days for 4 cycles. Bevacizumab 15 mg/kg I.V. was given concurrently with chemotherapy every 21 days for a total of 6 preoperative doses. Postoperatively bevacizumab was resumed for a total of 10 doses. The primary endpoint was pathologic complete response (pCR) in the breast.

Results

Thirty patients (66.7%) had stage IIIA disease, 12 (26.7%) patients had stage IIIB, and 3 patients (6.7%) had stage IIIC. Of these, 10 (22%) had inflammatory breast cancer (IBC), and 27 (60%) had estrogen receptor (ER)⁺ disease. A pCR in the breast with negative axillary nodes was documented in 4 (9%) of 45 patients. Toxicities that were seen with AC and bevacizumab included fatigue (grade 2/3; 31% and 9%, respectively), mucositis (grade 2/3; 29% and 2%, respectively), and headache (grade 2/3; 16% and 7%, respectively). Toxicities seen with TX and bevacizumab included mucositis (grade 2/3; 48% and 25%, respectively), fatigue (grade 2/3; 43% and 18%, respectively), and hand-foot syndrome (grade 2/3; 34% and 23%, respectively).

Conclusions

This regimen demonstrated only modest activity with substantial toxicity and does not appear to warrant further evaluation.     

Adjuvant six cycles of high-dose adriamycin,cyclophosphamide, methotrexate, 5-fluorouracil (ACMF) vs. 12 cycles of low-dose acmf with tamoxifen for premenopausal,node-positive breast cancer patients: Results of a prospective randomized study

A prospective randomized study was conducted to compare the adjuvant efficacy of six cycles of high-dose ACMF (Adriamycin, ADM; cyclophosphamide, CPA; methotrexate, MTX; 5-fluorouracil, 5-FU) with that of 12 cycles of low-dose ACMF in premenopausal, node-positive breast cancer patients. The six-cycle ACMF group (93 patients) received, intravenously (iv), 130 mg/m² CPA, 26 mg/m² MTX, and 600 mg/m² 5-FU on days 1 and 8, and 26 mg/m² ADM on day 1 of each cycle. The 12-cycle ACMF group (97 patients) received, iv, 65 mg/m² CPA, 13 mg/m² MTX, and 300 mg/m² 5-FU on days 1 and 8, and 13 mg/m² ADM on day 1 of each cycle. These treatments were repeated every 4 weeks, and all the patients took tamoxifen (30 mg/day) for 2 years. The background factors of the two groups were comparable. There were non-significant trends toward better disease-free and overall survival rates in the high-dose, six-cycle ACMF group. Both treatments were well tolerated, but more patients in the low-dose, 12-cycle group refused to continue to receive chemotherapy. These data suggest that escalating doses of ACMF over a shorter period, even with doses within the conventional range, are superior to low-dose, prolonged therapy. © 1995 Wiley-Liss, Inc.     

含脂质体阿霉素方案在乳腺癌术后辅助化疗中的安全性评价

目的 评价含脂质体阿霉素方案在乳腺癌术后辅助化疗中的安全性。方法 收集2014年9月至2016年8月接受术后辅助化疗的乳腺癌患者29例。化疗方案分别为：3周FAC方案（5-FU 500 mg／m2,脂质体阿霉素30 mg／m2,环磷酰胺500 mg／m2,每21天重复,共3个周期）14例;2周AC方案（脂质体阿霉素30 mg／m2,环磷酰胺600 mg／m2;每14天重复,共4个周期）11例;3周AC方案（脂质体阿霉素30 mg／m2,环磷酰胺600 mg／m2;每21天重复,共4个周期）4例。毒副反应按照NCI CTCAE 4.0.3版本分为1～5级。心脏毒性的评估包括定期检查心电图、心脏超声等。结果 所有患者中最显著的毒副反应为中性粒细胞减少,发生率为79.3％（23／29）;其次为手足综合征和口腔炎,发生率分别为51.7％（15／29）、27.6％（8／29）。AC方案组患者3级手足综合征的发生率为26.7％（4／15）,高于FAC方案组的0（0／14）。本组中无1例左心室射血分数降低10％以上;无1例出现充血性心力衰竭。结论 含脂质体阿霉素方案在乳腺癌术后辅助化疗中是安全的。