Cyclophosphamide, Methotrexate, 5-fluorouracil Chemotherapy Research Articles

Response of a chemo-resistant triple-negative breast cancer patient to a combination of p62-encoding plasmid, Elenagen, and CMF chemotherapy.

Triple-negative breast cancers are often characterized by aggressive behavior and short clinical course once they become chemotherapy-resistant. We describe below a patient who has shown a response to combination of chemotherapy with Elenagen, a plasmid encoding p62. Elenagen was tested in a previous phase I/II study in patients with refractory solid tumors and shown to be safe. Also, plasmid ability to halt tumor progression and restore sensitivity to chemotherapy was found. Preclinical data supports effects on tumor grade and change the tumor’s microenvironment in spontaneous canine breast cancers. We describe here a 48-year old female with triple-negative and BRCA1/2-negative breast cancer who had a primary resistance to chemotherapy and negative dynamics despite the use of multiple lines of treatments. Elenagen was applied intramuscularly at a dose of 1 mg weekly in combination with standard chemotherapy scheme CMF (cyclophosphamide, methotrexate, fluorouracil). In this patient we observed partial tumor regression (by 33%) and 19 weeks of progression-free survival. This first observed objective response to a combination of Elenagen with chemotherapy demonstrates that even in heavily pretreated chemo-resistant triple-negative tumor, the addition of Elenagen to a chemotherapy regimen can cause an objective response and increase in progression-free survival. Such a regimen is worthy of further study in a larger number of patients.

Postmastectomy Radiation Therapy

Postmastectomy Radiation Therapy

The RAD51 135G>C polymorphism is related to the effect of adjuvant therapy in early breast cancer.

RAD51, a central player in the response to DNA damage, has been suspected to contribute to tumour resistance to therapy. A single-nucleotide polymorphism, RAD51 135G>C, in the untranslated region of the RAD51 gene elevates breast cancer risk among BRCA2 carriers. In this study, it was investigated whether this polymorphism is related to prognosis of breast cancer and RAD51 protein expression and whether it is indicative of resistance to radiotherapy or cyclophosphamide/methotrexate/5-fluorouracil (CMF) chemotherapy. We genotyped 306 patients with early breast cancer, who were randomised to receive post-operative radiotherapy or CMF chemotherapy, for the RAD51 135G>C polymorphism. RAD51 protein expression was evaluated with immunohistochemistry. 15.4 % of the patients had at least one C-allele (three were C homozygotes). There was no correlation between genotype and protein expression. Patients who were G homozygotes benefitted from radiotherapy with decreased risk of local recurrences (RR = 0.32, 95 % C.I. 0.16-0.64, p = 0.001). CMF chemotherapy reduced the risk of distant recurrence for patients carrying at least one C-allele (RR = 0.29, 95 % C.I. 0.10-0.88, p = 0.03), whereas G homozygotes had no benefit from chemotherapy. There was a significant interaction between chemotherapy and genotype (p = 0.02). The results suggest that the RAD51 135G>C polymorphism predicts CMF chemotherapy effect in early breast cancer.

Conservative Surgery Plus Axillary Radiotherapy vs. Modified Radical Mastectomy in Patients With Stage I Breast Cancer

BackgroundThe objective of this study was to explore the effect of conservative surgery plus postoperative axillary radiotherapy without axillary lymph node dissection vs. modified radical mastectomy in patients with stage I breast cancer. Patients and MethodsIn this study, 186 patients with stage I breast cancer were enrolled. Among them, 98 patients underwent breast-conserving surgery without axillary node dissection. From the first day after surgery, each of them received 6 cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy, and thereafter radical radiotherapy for 5 to 6 weeks. Eighty-eight patients received modified radical mastectomy with postoperative chemotherapy and radiotherapy. The clinical data of these 186 patients were analyzed. ResultsThere was no significant difference (P > .05) in local recurrence and survival rates between the conservative plus axillary radiotherapy group and the modified radical mastectomy group, although a significantly greater incidence of upper limb dysfunction and edema were observed in the modified mastectomy group (P < .05). ConclusionThe efficacy of conservative surgery plus axillary radiotherapy alone is superior to that of axillary node dissection for stage I breast cancer patients.

Ten-year analysis of the prospective multicentre Chemo-N0 trial validates American Society of Clinical Oncology (ASCO)-recommended biomarkers uPA and PAI-1 for therapy decision making in node-negative breast cancer patients

AimFinal 10-year analysis of the prospective randomised Chemo-N0 trial is presented. Based on the Chemo-N0 interim results and an European Organisation for Research and Treatment of Cancer (EORTC) pooled analysis (n=8377), American Society of Clinical Oncology (ASCO) and Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) guidelines recommend invasion and metastasis markers urokinase-type plasminogen activator (uPA)/plasminogen activator inhibitor-1 (PAI-1) for risk assessment and treatment decision in node-negative (N0) breast cancer (BC). MethodsThe final Chemo-N0 trial analysis (recruitment 1993–1998; n=647; 12 centres) comprises 113 (5-167) months of median follow-up. Patients with low-uPA and PAI-1 tumour tissue levels (n=283) were observed. External quality assurance guaranteed uPA/PAI-1 enzyme-linked immunosorbent assay (ELISA) standardisation. Of 364 high uPA and/or PAI-1 patients, 242 agreed to randomisation for CMF chemotherapy (n=117) versus observation (n=125). ResultsActuarial 10-year recurrence rate (without any adjuvant systemic therapy) for high-uPA/PAI-1 observation group patients (randomised and non-randomised) was 23.0%, in contrast to only 12.9% for low-uPA/PAI-1 patients (plog-rank=0.011). High-risk patients randomised to cyclophosphamide-methotrexate-5-fluorouracil (CMF) therapy had a 26.0% lower estimated probability of disease recurrence than those randomised for observation (intention-to-treat (ITT)-analysis: hazard ratio (HR) 0.74 (0.44–1.27); plog-rank=0.28). Per-protocol analysis demonstrated significant treatment benefit: HR 0.48 (0.26–0.88), p=0.019, disease-free survival (DFS) Cox regression, adjusted for tumour stage and grade. ConclusionsChemo-N0 is the first prospective biomarker-based therapy trial in early BC defining patients reaching good long-term DFS without adjuvant systemic therapy. Using a standardised uPA/PAI-1 ELISA, almost half of N0-patients could be spared chemotherapy, while high-risk patients benefit from adjuvant chemotherapy. These 10-year results validate the long-term prognostic impact of uPA/PAI-1 and the benefit from adjuvant chemotherapy in the high-uPA/PAI-1 group at highest level of evidence. They thus support the guideline-based routine use of uPA/PAI-1 for risk-adapted individualised therapy decisions in N0 breast cancer.

Responsiveness of Intrinsic Subtypes to Adjuvant Anthracycline Substitution in the NCIC.CTG MA.5 Randomized Trial

Recent studies suggest that intrinsic breast cancer subtypes may differ in their responsiveness to specific chemotherapy regimens. We examined this hypothesis on NCIC.CTG MA.5, a clinical trial randomizing premenopausal women with node-positive breast cancer to adjuvant CMF (cyclophosphamide-methotrexate-fluorouracil) versus CEF (cyclophosphamide-epirubicin-fluorouracil) chemotherapy. Intrinsic subtype was determined for 476 tumors using the quantitative reverse transcriptase PCR PAM50 gene expression test. Luminal A, luminal B, HER2-enriched (HER2-E), and basal-like subtypes were correlated with relapse-free survival (RFS) and overall survival (OS), estimated using Kaplan-Meier plots and log-rank testing. Multivariable Cox regression analyses determined significance of interaction between treatment and intrinsic subtypes. Intrinsic subtypes were associated with RFS (P = 0.0005) and OS (P < 0.0001) on the combined cohort. The HER2-E showed the greatest benefit from CEF versus CMF, with absolute 5-year RFS and OS differences exceeding 20%, whereas there was a less than 2% difference for non-HER2-E tumors (interaction test P = 0.03 for RFS and 0.03 for OS). Within clinically defined Her2(+) tumors, 79% (72 of 91) were classified as the HER2-E subtype by gene expression and this subset was strongly associated with better response to CEF versus CMF (62% vs. 22%, P = 0.0006). There was no significant difference in benefit between CEF and CMF in basal-like tumors [n = 94; HR, 1.1; 95% confidence interval (CI), 0.6-2.1 for RFS and HR, 1.3; 95% CI, 0.7-2.5 for OS]. HER2-E strongly predicted anthracycline sensitivity. The chemotherapy-sensitive basal-like tumors showed no added benefit for CEF over CMF, suggesting that nonanthracycline regimens may be adequate in this subtype although further investigation is required.

Differential efficacy of three cycles of CMF followed by tamoxifen in patients with ER-positive and ER-negative tumors: Long-term follow up on IBCSG Trial IX

BackgroundThe benefit of adjuvant chemotherapy in postmenopausal patients with estrogen receptor (ER)-positive lymph node-negative breast cancer is being reassessed. Patients and methodsAfter stratification by ER status, 1669 postmenopausal patients with operable lymph node-negative breast cancer were randomly assigned to three 28-day courses of ‘classical’ CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy followed by tamoxifen for 57 months (CMF→tamoxifen) or to tamoxifen alone for 5 years. ResultsERs were positive in 81% of tumors. At a median follow-up of 13.1 years, patients with ER-positive breast cancers did not benefit from CMF [13-year disease-free survival (DFS) 64% CMF→tamoxifen, 66% tamoxifen; P = 0.99], whereas CMF substantially improved the prognosis of patients with ER-negative breast cancer (13-year DFS 73% versus 57%, P = 0.001). Similarly, breast cancer-free interval (BCFI) was identical in the ER-positive cohort but significantly improved by chemotherapy in the ER-negative cohort (13-year BCFI 80% versus 63%, P = 0.001). CMF had no influence on second nonbreast malignancies or deaths from other causes. ConclusionCMF is not beneficial in postmenopausal patients with node-negative ER-positive breast cancer but is highly effective within the ER-negative cohort. In the future, other markers of chemotherapy response may define a subset of patients with ER-positive tumors who may benefit from adjuvant chemotherapy.

Comparison of CVF (Cyclophosphamide+Vinorelbine+5-Fluorouracil) and CMF (Cyclophosphamide+Methotrexate+5-Fluorouracil) Adjuvant Chemotherapy in Early Breast Cancer.

PurposeOur study aimed to evaluate the feasibility of adjuvant cyclophosphamide/vinorelbine/5-fluorourail (CVF) chemotherapy as an alternative to cyclophosphamide/methotrexate/5-fluorouracil (CMF) chemotherapy for treating early breast cancer.MethodsOne hundred and forty-nine patients were randomly assigned to CMF or CVF adjuvant chemotherapy for treating their early stage breast cancer between September 2000 and December 2007. The disease-free survival (DFS), the overall survival (OS), and the toxicity profiles of both groups were compared.ResultsSixty-seven patients underwent CMF chemotherapy whereas 82 patients underwent CVF chemotherapy. The DFS and OS were 88 months (95% confidence interval [CI], 76-101 months) and 94 months (95% CI, 83-104 months), respectively for the CMF group, and 97 months (95% CI, 93-101 months), and 101 months (95% CI, 98-104 months), respectively for the CVF group. However, those survival gains of the CVF group were not statistically significant (p-value=0.069 for the DFS and 0.99 for the OS). The CVF group showed a favorable toxicity profile in terms of the grade 3/4 hematologic toxicities as compared to that of the CMF group.ConclusionClinical outcome of CVF chemotherapy was comparable to CMF with a favorable toxicity profiles. However, it is difficult to conclude the feasibility of CVF regimen because of small number of studied patients.

Abstract P5-10-12: Adherence, Persistence and Toxicity with Oral CMF in Older Women with Early Stage Breast Cancer in CALGB 49907 (Adherence Companion Study 60104)

Abstract Background: Cyclophosphamide-methotrexate-fluorouracil (CMF) is often selected as adjuvant chemotherapy for older patients with early stage breast cancer due to perceived better tolerability compared to other standard regimens such as doxorubicin-cyclophosphamide (AC). We sought to measure adherence and persistence with oral cyclophosphamide and the relationship with toxicity among women who were prescribed CMF in CALGB49907. Patients and Methods: CALGB49907 (NEJM 2009) was a randomized trial that compared standard chemotherapy (CMF or AC) versus capecitabine in patients age ≥65 with stage 1-3 breast cancer. Those randomized to standard chemotherapy were treated with either AC or CMF. For those given CMF, cyclophosphamide was prescribed at 100 mg/m2 daily for 14 consecutive days of each of six 28 day cycles. Persistence was defined as completing all six cycles. Adherence was measured using patient self-report medication calendars, and was calculated as the number of doses that women reported they had taken divided by the doses they were prescribed, taking into account toxicity-related dosing changes. Results: Of the 317 patients randomized to standard chemotherapy, 133 elected to receive CMF. CMF patients were older (p=0.009) and less likely to be Hispanic (P&amp;lt;0.001) than patients who received AC. Median age of CMF patients was 73 (range 65 to 88); only 86 patients (65%) persisted with CMF to completion of planned protocol therapy. In a multivariable logistic regression model, non-persistence was associated with the report of a non-hematologic adverse event (p &amp;lt;0.001), but not with a hematologic adverse event (p = 0.578). Febrile neutropenia occurred in 21% of the non-persistent patients, but only in 1 % of the persistent patients (P&amp;lt;0.001). Fatigue also occurred in 21% of the non-persistent patients, but only in 6% of the persistent patients (p=0.009). Other non-significant covariates included age, race, performance status at enrollment, type of surgery, nodal status, ER status, and PgR status. Ninety-four of 133 (71%) CMF-treated patients submitted medication calendars documenting their use of cyclophosphamide. The only characteristic that was found to differ between women who submitted medication calendars and those who did not was that the former were less likely to be ER-positive (p=0.010). Average adherence across all cycles with available data was 97%, and adherence did not vary by cycle (p=0.46). Five percent of participants reported taking fewer than 80% of expected doses and were deemed non-adherent. In a logistic regression model, there were no significant variables predicting non-adherence. Conclusions: In this substudy of a large clinical trial of older women with early stage breast cancer, self-reported adherence to oral cyclophosphamide as part of standard CMF chemotherapy was high. However, only 65% of older women were persistent with CMF, lower than the 92% observed among patients who elected to receive AC in the trial. Further research is needed to study how non-persistence impacts outcomes in this population and whether persistence can be increased by improving management of toxicities in older women. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-12.

Therapy-related acute lymphoblastic leukemia with t(9;22)(q34;q11.2):a case study and review of the literature

Therapy-related acute lymphoblastic leukemia (t-ALL) with t(9;22)(q34;q11.2) is rarely reported as a secondary malignant neoplasm. To our knowledge, only 10 Ph+ t-ALL cases have been reported in the literature. However, 8/10 cases were not reported individually but constituted parts of larger studies reporting cytogenetic abnormalities in secondary leukemia. Snyder et al. first reported Ph+ t-ALL in two patients who had been treated successfully for Ewing sarcoma. We present a novel case of t-ALL with t(9;22) in a patient with primary breast cancer. The interval between diagnosis of breast cancer and the appearance of ALL was 4 years. The patient was treated with partial mastectomy and axillary lymph node dissection followed by six cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy and radiation therapy. Bone metastases were found 3 years after surgery, and she was treated with epirubicin and paclitaxel. This case has the following unique features: BCR/ABL gene rearrangement in t-ALL, and two types of malignant cells (leukemic lymphoblasts and metastatic breast cancer cells) coexisted in the bone marrow.

Anemia Is a Significant Prognostic Factor in Local Relapse-Free Survival of Premenopausal Primary Breast Cancer Patients Receiving Adjuvant Cyclophosphamide/Methotrexate/5-Fluorouracil Chemotherapy

To determine the effects of anemia on local relapse-free, relapse-free, and overall survival (LRFS, RFS, and OS, respectively) in premenopausal, primary breast cancer patients receiving adjuvant polychemotherapy, and to determine which conventional prognostic factors affected these outcomes. Four hundred twenty-four premenopausal patients with early-stage primary breast cancer and hormone receptor-expressing tumors were treated with i.v. cyclophosphamide/methotrexate/5-fluorouracil (CMF) polychemotherapy as part of an adjuvant phase III trial (Austrian Breast and Colorectal Cancer Study Group Trial 5). The influence of anemia (hemoglobin <12 g/dL) on LRFS, RFS, and OS was evaluated in a retrospective analysis. Of 424 patients, 77 (18.2%) developed anemia on CMF chemotherapy. After a median follow-up time of 5 years, 8.9% of nonanemic patients had local relapse compared with 19.6% of anemic patients (P=0.0006). Although mastectomy was associated with anemia (26% versus 13.7% in breast conserving surgery; P=0.002), multivariate analysis did not show mastectomy per se to be a significant risk factor for LRFS. Age, lymph node status, and hemoglobin had an independent significant influence on LRFS (P<0.005). Anemic patients had a relative risk of 2.96 (95% confidence interval, 1.41-6.23) for developing local relapse in comparison with nonanemic patients. Premenopausal breast cancer patients who developed anemia during the CMF regimen had significantly worse LRFS. In Austrian Breast and Colorectal Cancer Study Group Trial 5, anemia may have contributed to an almost doubled incidence of local recurrence in the chemotherapy arm. Molecular targets associated with tumor hypoxia and distinct from erythropoiesis should receive further attention in experimental and clinical settings.

Persistent Neurocognitive Problems After Adjuvant Chemotherapy for Breast Cancer

Background Neurocognitive problems have been observed in a number of women previously treated with adjuvant chemotherapy for breast cancer. The present study aims to combine the results of neuropsychological and electrophysiological techniques collected in patients with breast cancer treated with cyclophosphamide/methotrexate/5-fluorouracil (CMF) at different time points. Patients and Methods Patients with breast cancer treated with adjuvant CMF chemotherapy (n = 63) were examined with neuropsychological tests 1 year after treatment and compared with healthy women (n = 60; T1 portion of the study). Based on neuropsychological test performance, patients were classified as cognitively impaired or unimpaired. Four years later, behavioral and neurophysiological measures (T2 portion of the study) were collected during an information-processing task in a subgroup of patients (n = 26). At T2, we compared the results of cognitively impaired patients (n = 8) with those of patients classified as cognitively unimpaired at T1 (n = 18). Results In the initial neuropsychological assessment, 33.3% of the patients were classified as cognitively impaired, compared with 10% of healthy women. At T2, impaired patients who received CMF showed longer P3 latencies, lower P3 amplitudes, longer reaction times, and made more errors in an informationprocessing task compared with unimpaired patients who received CMF. Conclusion The results indicate the persistence of neurocognitive problems ≤ 5 years after completion of chemotherapy and consistency across different assessment techniques.

Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials

Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5 year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxorubicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modern aromatase inhibitors. Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0.0001 for recurrence, 2p<0.00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, > or =70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0.00001 for recurrence, 2p=0.01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14,000); anthracycline-based versus CMF-based chemotherapy (14,000); about 5 years of tamoxifen versus none (15,000); about 1-2 years of tamoxifen versus none (33,000); and about 5 years versus 1-2 years of tamoxifen (18,000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.

Prospective meta-analysis of randomised trials of cyclophosphamide, methotrexate &amp; fluorouracil (CMF) vs fluorouracil, epirubicin &amp; cyclophosphamide (FEC) chemotherapy in early breast cancer

592 Background: Our previous study of node positive (N+) patients (Coombes: JCO 1996 14:35–45) compared FEC1/2 vs. CMF1/2 (see table below). At 4.5 years there was no difference in disease free survival (DFS), p=0.61; or overall survival (OS), p=0.31. However, subset analysis suggested that FEC2 was better than CMF2 (DFS:p=0.03;OS:p=0.02). Concurrently a study in node negative (N-) patients was conducted comparing FEC2 with CMF2. This paper updates the previous N+ study, reports N- study outcome, and a combined meta analysis (MA). Methods: Prospective MA of two international randomised trials of CMF vs. FEC chemotherapy in early breast cancer: 1) N+ premenopausal trial, 2 regime options (CMF1/FEC1, CMF2/FEC2). and 2) N- trial (CMF2/FEC2). Main endpoints are OS and DFS. Sample sizes are small by today's standards, hence the prospective MA. Results: N+ recruited 759 (180 CMF1, 180 FEC1, 199 CMF2, 200 FEC2) patients between 1984–1992, median follow-up 100 months. N- recruited 950 (477 CMF2, 473 FEC2) patients between 1990–2000, median follow-up 70 months. Median age was 44 (N+) and 48 (N-) years. Grade 3/4 toxicity (sore mouth, vomiting/nausea, diarrhoea, anorexia, alopecia) occurred twice as often with FEC (54%) than CMF (24%), p<0.001. Grade 3/4 toxicity in N+ (56%) was twice that of N- (25%) patients, p<0.001. MA hazard ratios showed that for OS, CMF was better 1.08 (95% CI 0.87 –1.35, p=0.49) but for DFS, FEC was better 0.97 (95% CI 0.82–1.16, p=0.76). Tests showed OS trial results were heterogeneous (p=0.04) with FEC1 better than CMF1 (p=0.04), and CMF2 better than FEC2 (p=0.06) for N+ but no difference for N- (p=0.87). Conclusions: MA showed no difference between the treatments in terms of OS or DFS. Individual trial results for OS were not homogeneous. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis; Eli Lilly

Indications and complications of latissimus dorsi myocutaneous flaps in oncologic breast surgery.

The use of the latissimus dorsi myocutaneous flap (LDMF) in reconstructive breast surgery is well documented. Few reports exist of its use in oncologic breast surgery. This series describes indications and complications of the LDMF in locally advanced cancer. The records of 83 patients were analysed for age and sex, menstrual status, stage, indication, margins of resection, chemotherapy, radiotherapy, complications, and survival. The indication was to cover defects caused by resection of locally advanced breast cancer (67 cases), recurrent breast cancer (13 cases), radiation damage (2 cases), and surgical complications (1 case). The mean age of the patients was 50.2 years; 52% were postmenopausal. The flaps had mean diameters of 32 by 14 cm. The donor site was skin grafted. Clear margins were achieved in 83%. At the LDMF insertion site, wound infection required drainage in 1 case; flap necrosis required reintervention in 7 cases. In 2 cases a second skin graft was done for the LDMF donor site. The proportions of wound infections and incomplete skin graft take were significantly greater in patients receiving preoperative cyclophosphamide/methotrexate/5-fluorouracil (CMF) versus cyclophosphamide/doxorubicin/5-fluorouracil (CAF) chemotherapy (p < 0.001 and p < 0.05, respectively). The late complication rate was 7.2%. The mean follow-up is 40.0 months. The complication rates for CMF versus CAF chemotherapy suggest an adverse effect of methotrexate, which warrants further investigation. The use of the LDMF made wide resection of locally advanced lesions and radionecrosis possible; major complications were rare. LDMF has its place in the armamentarium of the surgeon who regularly sees locally advanced breast cancer.

Effect of CMF-chemotherapy on blood coagulation in patients with breast cancer

BACKGROUND: Influences of CMF (cyclophosphamide, methotrexate,5-fluorouracil) chemotherapy on blood coagulation were investigated in 30 patients receiving adjuvant chemotherapy and in 30 patients receiving chemotherapy for metastatic breast cancer. METHODS: In plasma samples of 60 patients (median age 49.5), we evaluated the following parameters 1)Markers of in vivo clotting activation thrombin-antithrombin complex (ELISA) and D-dimer (ELISA), 2) Natural anticoagulants (protein C [PC] and antithrombin III [AT III] by chromogenic methods). The coagulation studies were performed at the beginning and at the end of the first cycle of CMF protocol. RESULTS: Before CMF therapy, significant difference was observed between patients with early stage and patients with metastatic breast cancer in the PC (p&lt;0.01), AT III (p&lt;0.01) and TAT (p&lt;0.01) levels. After CMF therapy, patients with stage II (adjuvant) disease manifested a significant decrease in the level of PC and AT III activity (p&lt;0.01) and an increase in TAT level (p&lt;0.01). In patients with disseminated breast cancer CMF therapy provoked an increased level of TAT and D-dimer with a decreased activity of protein C and antithrombin III. There was significant difference in value of TAT, D- dimer, protein C and antithrombin III between the patients with adjuvant and metastatic breast cancer patients after CMF chemotherapy CONCLUSION: Our results suggest that the application of cytotoxic therapy provokes hypercoagulable condition in breast cancer patients. This effect should be considered when chemotherapy is employed in advanced cancer patients at high risk for thrombosis, or in patients with other risk factors.

Sequential Adjuvant CMF Chemotherapy Followed by Radiotherapy in the Treatment of Early-Stage Breast Cancer: The Lankenau Hospital Experience

: The optimal timing of systemic cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy and local radiation in adjuvant breast cancer has been a debatable subject. To evaluate the Lankenau Hospital experience with sequential CMF chemotherapy followed by radiation in the adjuvant therapy of stage I and stage II breast cancer we reviewed the records of patients at our center. This group of 34 patients was treated in a homogenous manner, all receiving standard CMF for six cycles followed by radiotherapy after lumpectomy with axillary lymph node dissection. The radiation course was 5040cGy to the entire breast (28 fractions in 45 elapsed days) followed by a boost to the tumor site of 1800cGy in 10 fractions. Thirty-four patients were identified and followed for an average of 5 years (range 1.5–11.5 years). One patient had local recurrence and with subsequent treatment is disease-free at 5 years postrecurrence (8 years from initial diagnosis). Two deaths were not breast-cancer related (1 myocardial infarction at year 3, 1 melanoma at year 7.5). The estimated probability of no relapse at 5 years and 8 years by Kaplan-Meier analysis is 79% and 60% respectively. Overall and disease-free survival in this group of patients treated with breast-conserving surgery and CMF chemotherapy followed by radiation is excellent. There appears to be no detriment to delaying radiotherapy until full doses of systemic treatment are given as local recurrence was rare (6%) and was amenable to further treatment.

The effect of adjuvant prednisone combined with CMF on patterns of relapse and occurrence of second malignancies in patients with breast cancer

The addition of low-dose prednisone (p) to the adjuvant regimen of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) allowed patients to receive a larger dose of cytotoxics when compared with those on CMF alone. However, disease-free survival and overall survival were similar for the two groups. To test the hypothesis that low-dose prednisone might influence the efficacy of the cytotoxic regimen used, the toxicity profiles of the two treatment regimens and the patterns of treatment failure (relapse, second malignancy, or death) were examined. 491 premenopausal and perimenopausal patients with one to three positive axillary lymph nodes included in International (Ludwig) Breast Cancer Study Group (IBCSG) trial I from 1978 to 1981 and randomized to receive CMF or CMFp were analyzed for differences in long-term outcome and toxic events. The 250 patients assigned to CMF and prednisone received on the average 12% more cytotoxic drugs than those who received CMF alone. The 13-year DFS for the CMFp group was 49% as compared to 52% for CMF alone, and the respective OS percents were 59% and 65%. Several toxic effects such as leukopenia, alopecia, mucositis and induced amenorrhea were reported at a similar incidence in the two treatment groups. Using cumulative incidence methodology for competing risks, we detected a statistically significant increase in first relapse in the skeleton for the CMFp group at 13 years follow-up with a relative risk (RR) of 2.06 [95% confidence interval (CI), 1.23 to 3.46; P = 0.004]. Patients with larger tumors in the CMFp regimen were especially subject to this increase with a RR for failure in the skeleton of 3.32 (95% CI, 1.57 to 7.02; P = 0.0005). CMFp-treated patients also had a larger proportion of second malignancies (not breast cancer), with RR of 3.34 (95% CI, 0.91 to 12.31; P = 0.09). Low-dose continuous prednisone added to adjuvant CMF chemotherapy enabled the use of higher doses of cytotoxics. This increased dose had no beneficial effect on treatment outcome, but was associated with an increased risk for bone relapses and a small, not statistically significant increased incidence of second malignancies. The effects of steroids, which are widely used as antiemetics (oral or pulse injection) together with cytotoxics, should be investigated to identify their influence upon treatment outcome.

Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast carcinoma: the Scottish trial

There are no previous reports of trials that have directly compared the effects of adjuvant chemotherapy with oophorectomy in premenopausal women with node-positive breast cancer. During 10 years we recruited 332 such women who were randomised, after mastectomy or conservation therapy, to receive either ovarian ablation or cyclophosphamide/methotrexate/ 5-fluorouracil (CMF) chemotherapy, each with or without prednisolone 7·5 mg daily for 5 years. After a maximum follow-up of 12 years, we detected no significant overall differences in relapse rates, or in event-free or total survival for ovarian ablation compared with chemotherapy or for prednisolone versus no prednisolone, nor any suggestion of an interaction between these factors. Actuarial total survival at 8 years was 60% overall, irrespective of treatment, with a hazard ratio and 95% Cl of 1·12 (0·76-1 ·63) for the comparison of CMF with ovarian ablation and 1·26 (0·86-1·84) for prednisolone versus no prednisolone. Oestrogen receptor (ER) assays were done in 270 (81%) primary tumours but these results played no part in the randomisation procedure. When patient outcome was analysed in relation to the concentration of ER in the tumour, there was a statistically significant interaction between ER content and treatment, such that ovarian ablation was associated with improved survival in patients with ER concentrations 20 fmols/mg protein or more and CMF was more beneficial for patients with values less than 20 fmols/mg protein. No such interaction was seen for prednisolone therapy. Oestrogen receptor content has a role in decisions about treatment for primary breast cancer.

A pilot study of intensive cyclophosphamide, epirubicin and fluorouracil in patients with axillary node positive or locally advanced breast cancer

A multicentre pilot study has been conducted to determine an intensive regimen of cyclophosphamide, epirubicin, and fluorouracil which was tolerable and acceptable to patients with node positive breast cancer. Consecutive patients with operable axillary node positive breast cancer (T1–3, N1–2, M0), 266 patients, or locally advanced breast cancer (T4), 22 patients, were treated with cyclophosphamide post-operatively for 14 days and epirubicin and flourouracil, both intravenously on days 1 and 8. Each cycle was repeated monthly for 6 months. Dosages were increased accoring to predetermined guidelines. Outcome measures were admission to hospital for febrile neutropenia and change in cardiac function as assessed by radionucleide angiography. The first 46 patients were treated at the doses of cyclophosphamide = 75 mg/m 2, epirubicin = 50 mg/m 2, fluorouracil = 375 mg/m 2 (level 1), then 42 patients at cyclophosphamide = 75 mg/m 2, epirubicin = 50 mg/m 2 and fluorouracil = 500 mg/m 2 (level 2), 69 patients at cyclophosphamide = 75 mg/m 2, epirubicin = 60 mg/m 2, and fluorouracil = 500 mg/m 2 (level 3), and 42 patients at cyclophosphamide = 75 mg/m 2, epirubicin = 70 mg/m 2, and fluorouracil = 500 mg/m 2 with concurrent antibiotics (level 4). The rates of febrile neutropenia were 8.7% (level 1), 7.1% (level 2), 18.8% (level 3), and 31% (level 4), respectively, P = 0.002. Accrual to level 4 was discontinued according to study guidelines and a further 89 patients were recruited at level 3 dosages with antibiotic prophylaxis (level 3a), resulting in a 5.6% rate of febrile neutropenia. The difference in febrile neutropenia rates between levels 3 and 3a was statistically significant. There were no toxic deaths and 2 cases of heart failure. In conclusion, through a careful dose-finding study in patients with operable or locally advanced breast cancer, an intensive epirubicin-containing adjuvant regimen has been established which is presently being compared with standard CMF (cyclophosphamide,methotrexate, 5-fluorouracil) chemotherapy in a randomised trial. In addition, this study suggests that antibiotic prophylaxis reduces the risk of febrile neutropenia in breast cancer patients receiving intensive chemotherapy.