Courses Of CMF Research Articles

Abstract P5-13-01: Patterns of Breast Cancer Relapse According to Breast Cancer Subtypes in Lymph Node-Negative Breast Cancer — Results from International Breast Cancer Study Group Trials VIII and IX

Abstract Background: To explore the patterns of breast cancer (BC) relapse according to BC subtypes in a lower risk (lymph node (LN)-negative) population we classified pts from two trials according to a molecular classification using IHC surrogates. IBCSG Trial VIII randomized 1109 premenopausal pts with LN-negative BC to sequential treatment with six cycles of CMF followed by 18 months of goserelin, six courses of CMF alone, or 24 months of goserelin alone. The IBCSG Trial IX randomized 1669 postmenopausal pts with LN-negative BC to sequential treatment with 3 courses of CMF followed by tamoxifen for 57 months or tamoxifen alone for 5 years. Retrospective central pathology evaluation including ER, PgR, HER2 and Ki67 was used to define a molecular classification. Patients & Methods: Of the 2778 pts enrolled in both trials the present analysis includes 2033 (824 from trial VIII and 1209 from trial IX) who also had centrally-reviewed pathology data. The BC molecular subtypes were defined as following: Luminal-A (ER and/or PR-present, HER2-negative and Ki67<14%); Luminal-B (ER and/or PR-present, HER2-negative and Ki67 ≥14%); HER2 (HER2-positive independent of ER and PgR status); basal (HER2-, ER-, and PR-negative). Time to the first recurrence in a specific site was calculated from randomization and evaluated using cumulative incidence analysis and competing-risks regression analysis. Wald tests were used to determine the interaction effect of treatment group and molecular subtypes. Results: In the population analyzed (N = 2033), 25.9% had luminal-A (LA) tumors, 40.3% had luminal B (LB) tumors, 17.7% had HER2-positive tumors, and 16.0% had basal tumors. At 12.7 years median follow-up, a total of 699 (34.4%) pts had BC recurrence or non-BC events (secondary malignancy or death): LA = 152 (28.8%), LB = 291 (35.5%), HER2- positive = 134 (37.2%), and Basal = 122 (37.4%). Among 2033 pts, no significant differences were observed among the molecular subtypes for time to local recurrence (LA 6.1%, LB 6.7%, HER2 7.8%, basal 6.7%, p = 0.98), contralateral BC (LA 3.4%, LB 4.1%, HER2 2.5%, basal 4.9%; p = 0.36), and non-BC events (LA 12%, LB 10%, HER2 8.3%, basal 7.7%; p=0.39). Patients with LB disease had more bone recurrences (LB 5.5%, LA 2.5%, HER2 3.3%, basal 1.8%; p=0.004). The patterns over time of soft tissue nodes and visceral recurrence varied according to the adjuvant treatment received (interaction tests P<0.001 and p=0.007, respectively). Among pts receiving chemotherapy (N = 1139), HER2-positive pts had more and earlier visceral recurrence (HER2 11%, Basal 8%, LB 8.5%, LA 3.1%; p=0.005). Among pts not receiving chemotherapy (N=859), basal and HER2-positive pts had more visceral recurrences than luminal pts (HER2 15.3%, Basal 15.0%, LB 4.2%, LA 4.0%; P<0.001). Conclusion: In this large retrospective analysis we observed a higher incidence of bone recurrence among all LB tumors, while among those allocated chemotherapy LB tumors had a similar incidence of visceral recurrence when compared to basal tumors. Patterns of other DFS events were similar in all subtypes. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-01.

Concurrent Cyclophosphamide, Methotrexate, and 5-Fluorouracil Chemotherapy and Radiotherapy for Early Breast Carcinoma

The optimal sequencing of adjuvant chemotherapy (CT) and radiation therapy (RT) in patients with early-stage breast cancer remains unclear. We retrospectively compared 485 patients treated with conservative breast surgery and postoperative whole-breast RT and six courses of CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and 5-fluorouracil 600 mg/m(2)) with 300 patients who received postoperative CMF only and with 509 patients treated with postoperative whole-breast RT only. The mean radiation dose delivered was 50 Gy (range, 46-52 Gy) with standard fractionation. The boost dose was 6-16 Gy according to resection margins and at the discretion of the radiation oncologist. Acute and late RT toxicity were scored using respectively the Radiation Therapy Oncology Group and the Late Effects in Normal Tissues Subjective, Objective, Management and Analytic scale. A slightly higher Grade 2 acute skin toxicity was recorded in the concurrent group (21.2% vs. 11.2% of the RT only group, p < 0.0001). RT was interrupted more frequently in the CMF/RT group respective to the RT group (8.5% vs. 4.1%; p = 0.006). There was no difference in late toxicity between the two groups. All patients in the concurrent group successfully received the planned dose of RT and CT. Local recurrence rate was 7.6% in CT/RT group and 9.8% in RT group; this difference was not statistically significant at univariate analysis (log-rank test p = 0.98). However, at multivariate analysis adjusted also for pathological tumor, pathological nodes, and age, the CT/RT group showed a statistically lower rate of local recurrence (p = 0.04). Whole-breast RT and concurrent CMF are a safe adjuvant treatment in terms of toxicity.

Updated 12-year results of a randomized clinical trial comparing standard-dose to high-dose myeloablative chemotherapy in the adjuvant treatment of breast cancer with more than three positive nodes (LN+)

549 Aims: We conducted a multicenter randomized trial comparing sequential adjuvant standard-dose with high-dose chemotherapy in breast cancer patients younger than 60 years, with 4 or more positive nodes. Patients: Following surgery, patients were stratified by number of positive nodes (4–9 or 9), and randomly assigned to either conventional Epi–CMF (3 courses of epirubicin 120 mg/m2, followed by 6 courses of CMF), or high-dose chemotherapy (HDS) with stem cells support (one course of cyclophosphamide 7 g/m2, followed by one course of methotrexate 8 g/m2 with leukovorin rescue, by two courses of epirubicin 120 mg/m2, and by one course of thiotepa 600 mg/m2 plus melphalan 160–180 mg/m2 with stem cell autografting). Tamoxifen (20 mg/d × 5 yr) was also planned regardless of menopausal and receptor status. The study was designed with a power of 80% to detect a 15% increase in progression-free survival at 5 years in the HDS arm. Results: Of the initially enrolled 398 patients, 16 were ineligible, and the remaining 382 patients (Epi–CMF: 197 patients, HDS: 185 patients) were analyzed according to intent-to- treat. One patient treated with HDS (0.5%) died of interstitial pneumonia. With a median follow-up of 136 months, the 12-year progression-free survival rates were 44% and 52% for the Epi–CMF and the HDS groups, respectively, and the overall survival rates were 51% and 60%, respectively. However, among the 68 patients younger than 36 years, and the 189 patients with 4–9 LN+, those in the HDS group showed a trend for a progression-free survival advantage (HR 0.76 and 0.74, respectively). Conclusions: In the intent-to-treat analysis the 9% overall survival advantage associated with the HDS regimen failed to reach statistical significance in a study powered to detect a 15% difference. To reliably define the role of high-dose therapy, meta-analysis of patient data from all relevant randomized trials (such as that planned by the Early Breast Cancer Trialists’ Collaborative Group) is needed. Supported in part by AIRC and Pharmacia &amp; Upjohn, Milano, Italy. No significant financial relationships to disclose.

Age of menopause among women who remain premenopausal following treatment for early breast cancer: Long-term results from International Breast Cancer Study Group Trials V and VI

Background The likelihood of premature menopause has not been thoroughly explored in women who remain premenopausal after adjuvant chemotherapy for breast cancer. Methods We used data from the International Breast Cancer Study Group (IBCSG) Trials V and VI. Trial V enrolled 1407 eligible premenopausal women randomised to no systemic therapy (No CT) or 1 cycle of perioperative CMF-based chemotherapy (PeCT) if node negative, and 6 cycles of CMF-based chemotherapy postoperatively (CMF × 6) or 1 cycle perioperative CMF-based chemotherapy plus CMF × 6 postoperatively (CMF × 7) if node positive. From Trial VI (a 2 × 2 factorial designed study of 3 versus 6 initial cycles of CMF and a reintroduction of three additional courses of CMF), we included 375 women randomised to receive only six initial cycles of CMF (CMF × 6). Findings We excluded women who reported no menses during 12–24 months after randomisation ( N = 934), hysterectomy ( N = 16) or bilateral oophorectomy ( N = 8), or missing menses data ( N = 57), creating a cohort of 767 women; 540 women had been randomised to PeCT or no CT, 227 randomised to CMF × 6 or 7. A Cox proportional hazards model revealed that CMF × 6 or 7 (HR = 2.03, p < 0.0001) and temporary amenorrhea (HR = 1.96, p < 0.0001) were associated with premature menopause. Interpretation Women who remain premenopausal after 6 or 7 cycles of CMF-based chemotherapy have a higher likelihood of going through menopause at an earlier age than women who received little or no chemotherapy. Temporary cessation of menses appears to be a marker for earlier onset of menopause. These findings may assist women and clinicians when making treatment and reproductive decisions after a diagnosis of breast cancer.

Primary chemotherapy with cyclophosphamide, methotrexate, and 5‐fluorouracil in operable breast carcinoma

Primary chemotherapy (PC) is becoming an accepted practice to treat large tumors to avoid mastectomies and as a surrogate of outcome. A series of 305 patients with tumors >3 cm with T2-3N0-1M0 classification were treated with a multimodal approach that consisted of 3 courses of primary cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) followed by appropriate local treatment and 3 more courses of CMF or 4 courses of doxorubicin. Response was assessed by mammography. The overall response rate was 48% (a 3% pathologic complete response rate). Conservative surgery was achieved in 79.64% of the patients with a low rate of local disease recurrences (5%). Toxicity was minimal. With a median follow-up of 104 months, the 8-year disease-free survival (DFS) rate was 57.63% and the 8-year overall survival (OS) was 67.65%. The DFS and OS rates for patients with a clinical response were significantly longer, i.e., 70% (P=0.0048) and 90% (P=0.0042), respectively. PC with CMF was feasible. A high rate of breast-conservative surgery was achieved. The current results stressed the value of PC to increase conservative surgery and as a predictor of outcome.

Retrospective Analysis of the Results of Adjuvant Chemotherapy in Breast Cancer Patients with 10 or More Positive Nodes: Nonrandomized Comparison of Adriamycin-Containing Regimens

To evaluate the results of adriamycin-based adjuvant chemotherapy with or without high dose chemotherapy (HDC) with stem cell transplantation (SCT) in breast cancer with 10 or more positive axillary nodes. Seventy-one breast cancer patients who had undergone surgery and had 10 or more positive axillary nodes were included in this study held between January 1997 and December 1999. The pathologic and clinical records were reviewed retrospectively. Twenty-nine patients were treated with adriamycin followed by 8 courses of CMF (group I); 22 patients received 4 courses of adriamycin and 7 patients received 3 courses of adriamycin. Twenty-six patients received median 6 courses of CAF (group II) and 16 patients underwent HDC and autologous SCT (group III). With a median follow-up of 27.1 months, relapses were observed in 24 patients (33.8%) and the 3-year disease-free survival (DFS) rate was 57.1%; group I/II 55.4%, and group III 62.7%. The three-year overall survival (OS) rate was 86.1%; group I/II 83.0%, group III 93.8%. There were no difference in the 3-year DFSs or in the OSs of group I and group II. However, patients who received only 3 courses of the sequential adriamycin in group I showed a significantly poorer 3-year OS than those that received 4 courses of adriamycin (42.9% vs. 95.5%). Our study shows that adriamycin-containing combination chemotherapy is as effective as HDC with SCT in patients with 10 or more positive axillary lymph nodes judging by 3-year DFS and OS, and shows that three courses of adriamycin seems to be inadequate.

Primary chemotherapy in locally advanced breast cancer (LABC): effects on tumour proliferative activity, bcl-2 expression and the relationship between tumour regression and biological markers

The rate of tumour cell proliferation evaluated by the [ 3H]-thymidine labelling index ([ 3H]-dT-LI) is known to be an independent prognostic factor in patients with operable breast cancer and significantly predicts the response to chemotherapy in patients with advanced disease. In locally advanced breast cancer (LABC), we examined whether chemotherapy induced modifications in [ 3H]-dt-LI, and bcl-2 expression and their relationship with tumour regression and prognosis. 70 LABC patients received three courses of primary chemotherapy (FEC: 5-fluorouracil 600 mg/m 2, epidoxorubicin 60 mg/m 2, cyclophosphamide 600 mg/m 2, followed by surgery and subsequent adjuvant chemotherapy consisting of three courses of FEC alternated with three courses of CMF (cyclophosphamide 600 mg/m 2, methotrexate 40 mg/m 2, 5-fluorouracil 600 mg/m 2). Tumour biological markers were evaluated on diagnostic biopsy, before primary chemotherapy and at surgery. Tumour cell proliferation was determined by [ 3H]-dT-LI, whilst bcl-2 expression was examined by immunohistochemical staining. The overall response rate to primary FEC was 74.3% (95% confidence interval 57.6–83.2%). The response rate correlated with high [ 3H]-dT-LI: 88% (29/33) of patients with high [ 3H]-dT-LI achieved an objective response compared with 62% (23/37) of patients with low [ 3H]-dT-LI ( P=0.014). The 3 patients achieving a pathological complete response after induction treatment had high proliferative tumours. The highest 2-year relapse free survival (66.6%) was observed in patients with low [ 3H]-dT-LI after primary chemotherapy. The median bcl-2 expression values before and after primary chemotherapy were 0% (range 0–80) and 30% (range 0–90), respectively ( P=0.03). Our data indicate that primary chemotherapy can modulate tumour cell kinetics and apoptosis-related genes. Pretreatment proliferative activity correlated with tumour response, whilst post-treatment [ 3H]-dT-LI correlated with relapse free survival.

Rationalisation of chemotherapy services in the University Hospital Birmingham National Health Science Trust

Objectives. To audit chemotherapy prescribing in out-patient clinics in order to develop a novel ap proach for the provision of chemotherapy services to peripheral clinics. Method. Two audits of CMF (cyclophospha mide, methotrexate, and 5-fluorouracil) chemother apy were performed to initially determine the feasi bility and cost effectiveness of a centralised chemotherapy service. Subsequently, an audit was performed to develop a system for the rationalisation of chemotherapy prescribing using dose-banding. Results. The results from the first audit showed that of the 97 courses of chemotherapy prescribed in the peripheral out-patient clinic, 13.5% were de ferred. All deferred chemotherapy was reissued amounting to a saving of £681.00 over the 6 months studied. The second audit compiled data from 380 courses of CMF and enabled a dose-banding system to be developed. A system was devised so that an agreed 5% variance from the dose prescribed enabled pre filled chemotherapy syringes to be supplied, with no more than two syringes being used per dose. Conclusion. In conclusion, the prefilled syringe programme has improved patient waiting times, re duced drug wastage, and has enabled rationalisation of chemotherapy services in this health district.

Effectiveness of adjuvant chemotherapy in combination with tamoxifen for node-positive postmenopausal breast cancer patients.

Adjuvant tamoxifen has been shown to reduce relapse and mortality among node-positive post-menopausal breast cancer patients. The value of adding chemotherapy to tamoxifen is controversial. Between July 1986 and April 1993, 1,266 postmenopausal breast cancer patients with node-positive disease were randomly assigned to receive one of four adjuvant therapy regimens: (A) tamoxifen alone for 5 years; (B) tamoxifen plus three courses of early cyclophosphamide, methotrexate, and fluorouracil (CMF) on months 1, 2, and 3; (C) tamoxifen plus delayed single courses of CMF on months 9, 12, and 15; (D) tamoxifen plus early and delayed CMF on months 1, 2, 3, 9, 12, and 15. The two-by-two factorial design allowed two direct comparisons: early CMF (B and D) versus no early CMF (A and C), and delayed CMF (C and D) versus no delayed CMF (A and B). Estrogen receptor (ER) status was known for all patients and was used to stratify the randomization. A total of 1, 212 patients (96%) were eligible and assessable. The median follow-up duration was 60 months. The results of the two-by-two factorial comparisons were as follows: (1) early CMF added to tamoxifen significantly improved 5-year disease-free survival (DFS; 64% v 57%; hazards ratio [HR], 0.79; 95% confidence interval [CI], 0.66 to 0.95; P = .01); and (2) delayed CMF added to tamoxifen did not improve DFS (5-year DFS, 61% v 60%; HR, 0.97; 95% CI, 0.81 to 1.17; P = .77). For patients with ER-positive tumors, the addition of CMF, either early or delayed or both, reduced the relative risk of relapse by 22% to 36%. In contrast, for patients with ER-negative tumors, tamoxifen with delayed CMF was associated with a nonsignificant increased risk of relapse (HR, 1.27; 95% CI, 0.92 to 1.76; P = .15). Postmenopausal patients with node-positive breast cancer should be offered combination chemotherapy in addition to tamoxifen. Tamoxifen should not be initiated before CMF, as this might be detrimental, especially for patients with ER-negative tumors.

Sequential or Alternating Doxorubicin and CMF Regimens in Breast Cancer With More Than Three Positive Nodes

To improve current adjuvant results in patients with resectable mammary carcinoma and more than three positive axillary lymph nodes. A prospective randomized study was carried out to compare the effectiveness of four courses of doxorubicin hydrochloride followed by eight courses of cyclophosphamide, methotrexate, and fluorouracil (CMF) (sequential regimen) vs two courses of CMF alternated with one course of doxorubicin for a total of 12 courses (alternating regimen). All drug courses were recycled every 3 weeks. The median duration of follow-up at the time of current analysis was 9 years. The study was conducted on patients operated on for primary unilateral breast cancer at the Istituto Nazionale Tumori of Milan, Italy. Adjuvant chemotherapy was delivered in the outpatient clinic of the Division of Medical Oncology. A total of 405 women were entered into the study, 403 of whom met the protocol criteria. Patient characteristics were fairly well balanced between the two treatment groups, with the exception of extent of nodal involvement: 38% with more than 10 positive nodes were randomized to the alternating regimen compared with 29% in the sequential regimen (P = .08). Relapse-free and total survival at 10 years after surgery estimated according to the Kaplan-Meier product limit method. Treatment outcome was significantly superior for patients who received the sequential regimen compared with those given the alternating chemotherapy. The relapse-free survival was 42% vs 28% (P = .002) and total survival was 58% vs 44% (P = .002), respectively. The benefit of the sequential regimen was evident in all patient subsets. Treatment was fairly well tolerated, but we documented four cases of congestive heart failure, which was fatal in two patients. Current findings indicate that in women with extensive nodal involvement, sequential chemotherapy with doxorubicin followed by CMF yields superior results compared with the alternating administration of the same regimens or with classical CMF.

Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes.

To improve current adjuvant results in high-risk breast cancer, in February 1982 we activated a prospective randomized trial using both intravenous cyclophosphamide, methotrexate, and fluorouracil (CMF) and Adriamycin (doxorubicin; Farmitalia-Carlo Erba, Milan, Italy) involving patients with resectable mammary carcinoma and more than three positive axillary lymph nodes. The objective of the study was to assess the effectiveness of four courses of Adriamycin followed by eight courses of CMF versus two courses of CMF alternated with one course of Adriamycin for a total of 12 courses. All drug courses were recycled every 3 weeks. Rather than temporarily reducing doses in the event of myelosuppression on the planned day of treatment, drug administration was delayed for 1 to 2 weeks. At a median follow-up of 59 months, treatment outcome was significantly superior for patients who received Adriamycin followed by CMF (Adriamycin----CMF) than for those given alternating regimens (CMF/Adriamycin). The 5-year relapse-free survival was superior post-Adriamycin----CMF (61%) compared with post-CMF/Adriamycin administration (38%; P = .001). The corresponding figures for the 5-year total survival were 78% and 62%, respectively (P = .005). The benefit of Adriamycin----CMF was observed in all patient subsets. Treatment was fairly well tolerated, and we documented only one case of fatal congestive heart failure in a patient who received postoperative irradiation to the left breast in addition to Adriamycin. Present findings indicate that in women with extensive nodal involvement, Adriamycin----CMF yielded superior results compared with CMF/Adriamycin.

Cyclophosphamide, methotrexate, and 5-fluorouracil in a three-drug admixture. Phase I trial of 14-day continuous ambulatory infusion.

The compatibility and stability at room temperature for up to 7 days of a three-drug admixture of cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF) was established permitting the practical delivery of the combination as an infusion in an ambulatory setting. Fourteen patients received 20 courses of CMF administered on a continuous infusion schedule for 14 days of a 28-day cycle. The dose rates were fixed for 5-FU (300 mg/M2/day) and methotrexate (0.75 mg/M2/day). The cyclophosphamide dose was escalated from 25 to 50, 75, and 100 mg/M2/d. Leukopenia and thrombocytopenia were observed in two of five patients receiving the maximal dose of cyclophosphamide. No other toxicities were observed including alopecia, stomatitis or liver function abnormalities. This Phase I trial suggests that the cumulative doses of cyclophosphamide, methotrexate, and 5-FU are comparable to the maximum doses delivered as single agent infusions. Furthermore, when the infusion CMF is compared to the "standard" bolus schedule for CMF, the infusion schedule delivers 116%, 8%, and 350% of the respective three component drugs (cyclophosphamide, methotrexate, and 5-FU).