Cyclophosphamide, Methotrexate And 5-fluorouracil Chemotherapy Research Articles

Shilajit potentiates the effect of chemotherapeutic drugs and mitigates metastasis induced liver and kidney damages in osteosarcoma rats

Osteosarcoma is a primary malignant cancer of the bone identified by the direct formation of osteoid tissue or immature bone by cancer cells. The liver and kidneys represent two major secondary organs to which osteosarcoma metastasizes. In this study, we assessed Shilajit, a phytomineral diffusion traditionally used in Ayurvedic medicine, for its possible protective effects against metastasis induced liver and kidney damages in an osteosarcoma rat model. Osteosarcoma rats displayed typical dysregulation of serum levels of hepatic and renal functional markers (p < 0.05) including aspartate aminotransferase (AST)* and alanine aminotransferase (ALT), alkaline phosphatase (ALP), total proteins, albumin, bilirubin, creatinine, urea, and uric acid. Changes in functional markers were also positively correlated with marked histopathological alterations in liver and kidney tissues. Whereas Shilajit's treatment of osteosarcoma rates in combination with CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) chemotherapy drug cocktail significantly (p < 0.05) reversed the studied functional markers to their near-normal levels. Co-treatment of shilajit and drug cocktails also markedly alleviated histopathological changes in liver and kidney tissues. Correlation co-efficient analysis of hepatic and renal functional markers revealed a significant inter-association among these markers. Collectively, present data indicate that shilajit may potentiate the effects of chemotherapy drugs and mitigate the metastasis-induced liver and kidney damage in osteosarcoma. Thus, the findings of this study substantiate the beneficial health effects of shilajit and promote its regular consumption.

Impact of Sequencing Radiation Therapy and Chemotherapy on Long-Term Local Toxicity for Early Breast Cancer: Results of a Randomized Study at 15-Year Follow-Up

To compare long-term late local toxicity after either concomitant or sequential chemoradiation therapy after breast-conserving surgery. From 1997 to 2002, women aged 18 to 75years who underwent breast-conserving surgery and axillary dissection for early breast cancer and in whom CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) chemotherapy was planned were randomized between concomitant and sequential radiation therapy.Radiation therapy was delivered to the whole breast through tangential fields to 50Gy in 20 fractions over a period of 4weeks, followed by an electron boost.Surviving patients were tentatively contacted and examined between March and September 2014. Patients in whom progressive disease had developed or who had undergone further breast surgery were excluded. Local toxicity (fibrosis, telangiectasia, and breast atrophy or retraction) was scored blindly to the treatment received. A logistic regression was run to investigate the effect of treatment sequence after correction for several patient-, treatment-, and tumor-related covariates on selected endpoints. The median time to cross-sectional analysis was 15.7years (range, 12.0-17.8years). Of 206 patients randomized, 154 (74.8%) were potentially eligible. Of these, 43 (27.9%) refused participation and 4 (2.6%) had been lost to follow-up, and for 5 (3.2%), we could not restore planning data; thus, the final number of analyzed patients was 102. No grade 4 toxicity had been observed, whereas the number of grade 3 toxicity events was low (<8%) for each item, allowing pooling of grade 2 and 3 events for further analysis. Treatment sequence (concomitant vs sequential) was an independent predictor of grade 2 or 3 fibrosis according to both the National Cancer Institute Common Terminology Criteria for Adverse Events (odds ratio [OR], 4.05; 95% confidence interval [CI], 1.34-12.2; P=.013) and the SOMA (Subjective, Objective, Management and Analytic) scale (OR, 3.75; 95% CI, 1.19-11.79; P=.018), as well as grade 2 or 3 breast atrophy or retraction (OR, 3.87; 95% CI, 1.42-10.56; P=.008).No effect on telangiectasia was detected. At long-term follow-up, concomitant chemoradiation therapy has a detrimental effect on both fibrosis and retraction with an approximately 4-fold increase in the odds of grade 2 or 3 toxicity.

Economic evaluation of a standard dosage system for an outpatient breast cancer chemotherapy regimen

Abstract Objective To develop and validate a standard dosage system for use with the cyclophosphamide, methotrexate and 5-fluorouracil (CMF) breast cancer chemotherapy regimen, and to conduct a pharmacoeconomic evaluation of the standard dosage system in the outpatient clinic. Method The standard dosage system was developed using data collected retrospectively from patients treated with the CMF chemotherapy regimen. The objective was to establish a standard dosage system that did not vary from individually calculated doses by more than 5 per cent, which was considered clinically to be of no significant consequence. The pharmacoeconomic evaluation involved a control and study period. Outcome measures were time taken for patients to progress through the clinic, time taken to dispense a prescription, and number of pharmacy staff involved in the process. Setting Two outpatient clinics in the chemotherapy unit at a large district general hospital in the West Midlands region of England. Key findings It is possible to develop a clinically acceptable standard dosage system for use with the CMF chemotherapy regimen. Doses of chemotherapy were pre-prepared and there was a significant reduction in the time that a prescription spent within pharmacy and the time taken to dispense the prescription. The overall time that a patient spent at the clinic was reduced significantly. As a result of implementing this system, it was possible to use pre-filled syringes in the pharmacy cytotoxic reconstitution unit, producing a drug cost saving of £20.13 per cycle for a typical CMF patient, with a projected annual saving to the Trust of almost £10,000. Furthermore, the system resulted in more efficient utilisation of staff time in the pharmacy, allowing 55.7 per cent more CMF chemotherapy cycles to be produced without additional investment. Conclusion This project has illustrated that a clinically acceptable standard dosage system can be developed for a chemotherapy regimen. This resulted in savings in drug costs, better utilisation of staff time in the pharmacy department, and a reduction in the overall time that a patient spends at an outpatient clinic.

Tissue inhibitor metalloproteinase type-1 (TIMP-1), a novel cancer biomarker predicting response of adjuvant anthracycline-based chemotherapy in patients afflicted with primary breast cancer

A central question relating to adjuvant systemic treatment of early breast cancer patients has been whether anthracyclines should be part of chemotherapy or whether it is appropriate to recommend the cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen instead.1 CMF chemotherapy was considered the standard adjuvant therapy for a long time but in a series of meta-analyses the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) has established the importance of anthracyclines in the adjuvant setting.

Thirty-year follow-up of chemo/hormonal therapy in node-positive breast cancer

Results of a thirty-year follow-up of a clinical trial of chemo-hormonal therapy are reported. Eligible patients had recently diagnosed operable breast cancer, positive lymph nodes, no previous history of cancer, age less than 76 years, and no evidence of metastatic disease. A total of 311 patients were stratified by estrogen receptor (ER) status and number of axillary nodes involved with tumor. After stratification, patients were randomly assigned to one of three treatment regimens: cyclophosphamide, methotrexate and 5-fluorouracil (CMF) for 1 year; CMF chemotherapy combined with anti-estrogen therapy (tamoxifen) for 1 year; or CMF plus tamoxifen with BCG during the second year. The endpoint of the trial was a first recurrence. Factors measured at diagnosis and used in the analyses were age, body mass index, ER status, menopausal status, number of positive nodes, tumor diameter, Charlson comorbidity index, socioeconomic status, and race. Causes of death and incidence of other cancer primaries were obtained from death certificates and medical records. Patients treated with tamoxifen had a marginally longer disease-free survival (hazard ratio (HR)=0.83, 95% CI identical with [0.66, 1.04]) and statistically significant longer overall survival (HR=0.77, 95% CI identical with [0.63, 0.96]) that decreased with time. Incidence of other primary cancers and causes of death were similar for the two treatment groups. The addition of 1 year of tamoxifen to CMF therapy provides an early disease-free and overall survival advantage; however long-term effects are negligible. Similarly, the survival advantage of patients diagnosed with ER+ tumors persists for the first two decades after diagnosis.

Effects of adjuvant chemotherapy on the protein C anticoagulant pathway in patients with early stage breast cancer

8563 Background: Although chemotherapy treatment is associated with an increased risk of thrombosis, the pathogenic mechanisms are poorly understood. We have previously shown that treatment of endothelial cells with adriamycin and epirubicin impairs the protein C anticoagulant pathway by downregulating EPCR (endothelial protein C receptor), an endothelial receptor required for the conversion of protein C to the anticoagulant enzyme activated protein C (APC). In this study, we examined the effects of adriamycin- and epirubicin-containing chemotherapy on the protein C anticoagulant pathway in early stage breast cancer patients. Methods: We collected blood samples from 20 patients patients with early stage breast cancer undergoing adjuvant CEF (cyclophosphamide, epirubicin and 5-fluorouracil) or CMF (cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy on days 1, 2 and 8 for the first 2 cycles of treatment. Markers of protein C generation (protein C, thrombin-antithrombin (TAT) complexes, and APC) were measured on these days. Results: Plasma protein C levels were significantly lower at cycle 2 day 8 (0.88 ± 0.14 U/ml) compared to pre-chemotherapy levels (1.07 ± 0.23 U/ml) (p=0.0036). Plasma TAT levels were significantly higher at cycle 2 day 8 (2.87 ± 0.79 μg/L) compared to pre-chemotherapy levels (2.01 ± 1.24 μg/L) (p=0.02). Based on the APC levels, the patients appear to fall into two categories in terms of their ability to generate APC. The first group (n=16) has elevated APC levels that parallel the elevated TAT levels, whereas the second group (n=4) has low APC levels despite elevated TAT levels. Conclusions: Impaired ability to generate APC in a subpopulation of patients may reflect chemotherapy-induced impairment of the protein C pathway through the downregulation of EPCR. This pilot study provides new mechanistic insights into the prothrombotic effects of chemotherapy agents. No significant financial relationships to disclose.

The best use of adjuvant endocrine treatments

Endocrine therapy remains important in the adjuvant treatment of pre- and postmenopausal women. Adjuvant ovarian ablation with or without tamoxifen produces effects which are equivalent to those of CMF (cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy in premenopausal women with oestrogen receptor (ER) and/or progesterone receptor (PgR) positive breast cancer. Tamoxifen alone is also effective in these women. Concurrent use of tamoxifen and ovarian ablation may be even more effective, but more studies are needed. Tamoxifen remains a standard adjuvant therapy for postmenopausal women with ER and/or PgR positive tumours. Current information supports the use of 5 years of tamoxifen but additional studies comparing 5 years to longer duration are ongoing. The aromatase inhibitor (AI) anastrozole has now been demonstrated to be better than tamoxifen in preventing recurrence in early reports from the Arimidex vs Tamoxifen And the Combination (ATAC) Trial. Ongoing trials of this and other AIs before, after, concurrent with, or substituted for tamoxifen in the adjuvant setting may soon revolutionize our approach for postmenopausal women. Adjuvant bisphosphonates have been shown to reduce the incidence of bone metastases and improve survival in two of three published adjuvant trials and are being further studied. Her-2 neu status is being explored as a predictive factor for selection of endocrine therapy, but is not yet considered standard for this purpose.

Addition of Adjuvant Tamoxifen to Cyclophosphamide, Methotrexate and 5-Fluorouracil for Premenopausal Women with Oestrogen Receptor-Positive Breast Cancer

To study the value of adjuvant tamoxifen (TAM) in premenopausal women with oestrogen receptor (ER)-positive breast cancer who received adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) polychemotherapy. Four hundred and two premenopausal ER-positive breast cancer patients who received CMF chemotherapy between January 1990 and December 1999 were retrospectively studied. Disease-free survival (DFS) and overall survival (OS) were used to evaluate the clinical value of TAM therapy. The relationships between nodal status and TAM were also analysed. After a mean of 41 months of follow-up, 43 (13.7%) patients died of breast cancer and 68 (19.9%) patients suffered recurrence. There was a significant difference between TAM and non-TAM treatment groups for DFS (p=0.0058), but no significant difference for OS. For node-negative patients, there was no significant difference between the TAM and non-TAM treatment groups for either DFS or OS. For node-positive patients, the difference between TAM and non-TAM treatment groups was significant for both DFS and OS (p=0.0497 and p=0.0285, respectively). TAM resulted in additional benefit to premenopausal patients with node-positive ER-positive breast cancer who received the CMF polychemotherapy regimen.

Survival analyses from the ZEBRA study: goserelin (Zoladex™) versus CMF in premenopausal women with node-positive breast cancer

The Zoladex Early Breast Cancer Research Association (ZEBRA) trial compared the efficacy and tolerability of goserelin (Zoladex™) with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy in pre-/perimenopausal women with node-positive early breast cancer. The results of disease-free survival (DFS) analyses have already been published. Here we present an update including data on overall survival (OS) from the ZEBRA trial at a median follow-up of 7.3 years. In patients with oestrogen receptor (ER)-positive tumours, non-inferiority of goserelin versus CMF for OS was shown; goserelin was again shown to be equivalent to CMF for DFS. This updated analysis has demonstrated that the two treatments are also equivalent for distant disease-free survival (DDFS). In patients with ER-negative disease, goserelin was inferior to CMF for DFS, DDFS and OS. This follow-up analysis confirms the previously reported outcomes from the ZEBRA trial and demonstrates that goserelin offers an effective alternative to CMF chemotherapy for adjuvant therapy of premenopausal patients with ER-positive, node-positive early breast cancer.

Concurrent sequencing of full-dose CMF chemotherapy and radiation therapy in early breast cancer has no effect on treatment delivery

With the increasing use of breast-conserving therapy plus systemic chemotherapy for the treatment of early breast cancer, the optimal sequencing of radiation therapy and chemotherapy remains controversial. Sequencing of therapy may influence not only treatment delivery, but control rates, complications and cosmesis. The aim of this study was to evaluate whether concurrent sequencing of standard doses of CMF (cyclophosphamide, methotrexate and 5-fluorouracil) and adjuvant radiation therapy for early breast cancer impacted on optimum treatment delivery. As both an intravenous (i.v.) 3-week regimen and classic (standard) CMF were utilised in this study, both types of CMF were compared. The effect of sequencing on complications and treatment delays were also assessed. 116 patients treated with CMF chemotherapy and adjuvant tangent breast radiation were studied. 73 patients were treated prospectively with concurrent therapy and were retrospectively compared with a matched group of 40 patients treated with sequential or sandwich therapy. All patients had stage 1 or 2 cancers. There were no planned dose reductions introduced for either treatment modality. Concurrent sequencing had no impact on the ability to deliver optimum radiation or chemotherapy doses. There was no significant difference in acute Radiation Therapy Oncology Group (RTOG) skin reactions or complications between the two groups. Although small, there was a significant delay (1.32 days (0–15 versus 0.36 (0–7)) in the concurrent group (P=0.03) in the delivery of radiation therapy. Sequencing had no significant effect on haematological parameters. ‘Standard’ CMF had a more profound effect on treatment delivery than i.v. CMF (Radiation delay 2.2 days versus 0.26, P=0.002, % chemotherapy delivered 93% versus 99% P=0.000004). At a mean follow-up of 2.6 years, there was no difference in the cosmetic scores between the two groups. Both local and distant control rates were excellent. This study has shown that standard radiation therapy can be delivered safely concurrently with CMF chemotherapy. Whether this approach may lead to better control rates in the future needs further study.

Variations in Dose and Dose Intensity of Adjuvant CMF Chemotherapy for Breast Cancer Throughout the UK

Cyclophosphamide, methotrexate and 5-fluorouracil (CMF) is a commonly prescribed regimen for the adjuvant treatment of early breast cancer in the UK and in other countries with a high incidence of breast carcinoma. A number of variations in dose and scheduling of these drugs have been reported in the literature, with all of these being recognized under the generic term ‘CMF’. To investigate the extent of differences in CMF regimens used for the adjuvant treatment of early breast cancer we sent a postal questionnaire to all consultant medical and clinical oncologists in the UK seeking details of their practice. CMF drug doses were then converted into dose intensity parameters for comparison. The results showed a wide variation in the number of CMF schedules (n = 36) and CMF dose intensities (n = 33) used. The potential consequencies of such variation and the evidence for and against dose intensity as an important parameter in the adjuvant treatment of early breast cancer are discussed.

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

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

The place of chemotherapy in the treatment of early breast cancer.

The choice of systemic treatment for breast cancer depends on the tumour characteristics and stage of disease, and the patient's age, general state of health, menopausal status and oestrogen receptor (ER) status. Traditionally, endocrine therapy has been reserved for post-menopausal women, combination chemotherapy being more commonly used in premenopausal women. Chemotherapy remains the only option for patients with ER-negative breast cancer. The 1992 EBCTCG overview showed that, overall, polychemotherapy as adjuvant treatment for early breast cancer produced significant reductions in annual odds of recurrence and mortality, with a statistically significant trend towards greater benefits in patients aged under 50 years. Several trials have shown combination chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) to be more effective than single-agent chemotherapy in premenopausal women with node-positive tumours. However, although CMF chemotherapy seems to be effective irrespective of menopausal status, this benefit appears greatest in premenopausal women. The addition of anthracyclines to combination chemotherapy regimens has extended disease-free and overall survival rates in both premenopausal and post-menopausal women, including those with ER-positive tumours. The use of high-dose chemotherapy with stem cell support in early breast cancer is unjustified outside the clinical trial setting--current data indicate that such treatment may result in increased morbidity without a reduction in disease recurrence. Tamoxifen is effective in ER-positive disease; however, as yet few large comparative trials have compared endocrine treatment with chemotherapy in early breast cancer. Combination chemoendocrine therapy may provide a greater benefit than tamoxifen alone in early breast cancer, but this requires further study.

Epirubicin chemotherapy and advanced breast cancer after adjuvant CMF chemotherapy

There have been conflicting reports on the effect of prior adjuvant chemotherapy on the response of advanced breast cancer to primary chemotherapy. We report a retrospective review of the outcome of chemotherapy with epirubicin 100 mg/m 2 for advanced breast cancer in 39 patients who had previously received adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF). The response rate (complete responses plus partial responses) was 38.5%, with a median duration of response of 33 weeks. There was no significant difference in the response rate or duration of survival when these patients were compared with matched controls who had not received adjuvant chemotherapy. However, the limitations of this study were such that an adverse effect of adjuvant CMF on the response to epirubicin cannot be excluded.

Impaired primary, but not secondary, immune response in breast cancer patients under adjuvant chemotherapy.

The antibody response after vaccination against tick-borne encephalitis (TBE) was studied in patients with breast cancer. Although sex- and age-matched control persons produced high titers of anti-TBE antibodies 2 to 4 weeks after the second of two consecutive vaccinations, patients with breast cancer who were first vaccinated after the start of adjuvant chemotherapy consisting of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) failed to do so. The lack of anti-TBE antibody production was found not only in patients under CMF chemotherapy, but also in those primarily vaccinated 6 to 12 months after the termination of CMF treatment. Patients with breast cancer who had been vaccinated either before or after the onset of disease, but before the initiation of chemotherapy, were shown to have developed significant anti-TBE antibody titers which persisted throughout the course of adjuvant treatment and could be boostered by revaccination during the course of CMF administration. The authors conclude that patients with breast cancer undergoing adjuvant chemotherapy experience a serious and prolonged defect in primary antibody production, whereas secondary immune responses remain unimpaired.

High-dose metoclopramide and dexamethasone as an antiemetic in chemotherapy of breast cancer.

Twenty-six patients with breast carcinoma who experienced severe emesis due to chemotherapy were evaluated for the antiemetic efficacy of high-dose metoclopramide (HD-MCP) and dexamethasone (DXM). Most of the patients received the CMF (cyclophosphamide, methotrexate and 5-fluorouracil) combination chemotherapy. The MCP and DXM dosage were: 2 X 2 mg/kg and 2 X 0.2 mg/kg, respectively. In 41% of eighty evaluable courses, nausea and vomiting were eliminated altogether. The common side effects were: drowsiness, restlessness and diarrhea. HD-MCP and DXM are recommended in modified dose for preventing CMF chemotherapy induced emesis.

The effect of postoperative radiotherapy on the feasibility of optimal dose adjuvant CMF chemotherapy in stage II breast carcinoma

The impact of a number of variables upon the effectiveness of adjuvant chemotherapy given to 87 patients with Stage II breast carcinoma was retrospectively analyzed. Adjuvant chemotherapy consisted of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Drugs were given in optimal doses (85% or more of the planned dose) to 17% of the patients; in intermediate doses (66 to 84% of the planned dose) to 50% of the patients; and in low doses (65% or less of the planned dose) to 33% of the patients. Myelosuppression was the main reason for giving intermediate or low doses. At a median follow-up of three years, 84% of all patients remain alive. Radiation therapy preceding chemotherapy was given to 70 % of the patients, concomitant irradiation and chemotherapy to 15 %, and 13 patients (15%) received chemotherapy only. Of the 14 patients who received optimal doses of CMF, 12 (86%) also received radiation therapy. Disease-free survival at three years is similar for irradiated and nonirradiated patients, but the latter have a higher incidence of local recurrence (5 % vs. 15 %), although the difference is not statistically significant. Delay in the initiation of chemotherapy, mostly because of the administration of postoperative irradiation, adversely affected the probability and duration of disease-free survival, particularly in premenopausal women in whom chemotherapy was started within more than 90 days of mastectomy. The administration of optimal doses of adjuvant chemotherapy should follow the primary treatment to the breast tumor as closely as possible. If radiation therapy is indicated as well, it should be delivered concomitantly with chemotherapy, given the feasibility of administering both modalities simultaneously, as demonstrated in this study.