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1.  Quality of Life and Neutropenia in Patients with Early Stage Breast Cancer: A Randomized Pilot Study Comparing Additional Treatment with Mistletoe Extract to Chemotherapy Alone 
Background:
Chemotherapy for breast cancer often deteriorates quality of life, augments fatigue, and induces neutropenia. Mistletoe preparations are frequently used by cancer patients in Central Europe. Physicians have reported better quality of life in breast cancer patients additionally treated with mistletoe preparations during chemotherapy. Mistletoe preparations also have immunostimulant properties and might therefore have protective effects against chemotherapy-induced neutropenia.
Patients and Methods:
We conducted a prospective randomized open label pilot study with 95 patients randomized into three groups. Two groups received Iscador® M special (IMS) or a different mistletoe preparation, respectively, additionally to chemotherapy with six cycles of cyclophosphamide, adriamycin, and 5-fluoro-uracil (CAF). A control group received CAF with no additional therapy. Here we report the comparison IMS (n = 30) vs. control (n = 31). Quality of life including fatigue was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30). Neutropenia was defined as neutrophil counts <1,000/μl and assessed at baseline and one day before each CAF cycle.
Results:
In the descriptive analysis all 15 scores of the EORTC-QLQ-C30 showed better quality of life in the IMS group compared to the control group. In 12 scores the differences were significant (p < 0.02) and nine scores showed a clinically relevant and significant difference of at least 5 points. Neutropenia occurred in 3/30 IMS patients and in 8/31 control patients (p = 0.182).
Conclusions:
This pilot study showed an improvement of quality of life by treating breast cancer patients with IMS additionally to CAF. CAF-induced neutropenia showed a trend to lower frequency in the IMS group.
PMCID: PMC3086310  PMID: 21556248
mistletoe thereapy; breast cancer; randomized clinical trial; quality of life; neutropenia
2.  Quality of life, immunomodulation and safety of adjuvant mistletoe treatment in patients with gastric carcinoma – a randomized, controlled pilot study 
Background
Mistletoe (Viscum album L.) extracts are widely used in complementary cancer therapy. Aim of this study was to evaluate safety and efficacy of a standardized mistletoe extract (abnobaVISCUM® Quercus, aVQ) in patients with gastric cancer.
Patients and Methods
32 operated gastric cancer patients (stage Ib or II) who were waiting for oral chemotherapy with the 5-FU prodrug doxifluridine were randomized 1:1 to receive additional therapy with aVQ or no additional therapy. aVQ was injected subcutaneously three times per week from postoperative day 7 to week 24 in increasing doses. EORTC QLQ-C30 and -STO22 Quality of Life questionnaire, differential blood count, liver function tests, various cytokine levels (tumor necrosis factor (TNF)-alpha, interleukin (IL)-2), CD 16+/CD56+ and CD 19+ lymphocytes were analyzed at baseline and 8, 16 and 24 weeks later.
Results
Global health status (p <0.01), leukocyte- and eosinophil counts (p ≤0.01) increased significantly in the treatment group compared to the control group. Diarrhea was less frequently reported (7% vs. 50%, p=0.014) in the intervention group. There was no significant treatment effect on levels of TNF-alpha, IL-2, CD16+/CD56+ and CD 19+ lymphocytes and liver function tests measured by ANOVA.
Conclusion
Additional treatment with aVQ is safe and was associated with improved QoL of gastric cancer patients. ClinicalTrials.Gov Registration number NCT01401075.
doi:10.1186/1472-6882-12-172
PMCID: PMC3488325  PMID: 23033982
Qol; EORTC QLQ-C30; QLQ-STO22; 5-FU; Viscum album
3.  Clinical practice guidelines for the care and treatment of breast cancer: 15. Treatment for women with stage III or locally advanced breast cancer 
Objective
To define the optimal treatment for women with stage III or locally advanced breast cancer (LABC).
Evidence
Systematic review of English-language literature retrieved from MEDLINE (1984 to June 2002) and CANCERLIT (1983 to June 2002). A nonsystematic review of the literature was continued through December 2003.
Recommendations
· The management of LABC requires a combined modality treatment approach involving surgery, radiotherapy and systemic therapy.
Systemic therapy: chemotherapy
Operable tumours
· Patients with operable stage IIIA disease should be offered chemotherapy. They should receive adjuvant chemotherapy following surgery, or primary chemotherapy followed by locoregional management.
· Chemotherapy should contain an anthracycline. Acceptable regimens are 6 cycles of FAC, CAF, CEF or FEC. Taxanes are under intense investigation.
Inoperable tumours
· Patients with stage IIIB or IIIC disease, including those with inflammatory breast cancer and those with isolated ipsilateral internal mammary or supraclavicular lymph-node involvement, should be treated with primary anthracycline-based chemotherapy.
· Acceptable chemotherapy regimens are FAC, CAF, CEF or FEC. Taxanes are under intense investigation.
· Patients with stage IIIB or IIIC disease who respond to primary chemotherapy should be treated until the response plateaus or to a maximum of 6 cycles (minimum 4 cycles). Patients with stage IIIB disease should then undergo definitive surgery and irradiation. The locoregional management of patients with stage IIIC disease who respond to chemotherapy should be individualized. In patients with stage IIIB or IIIC disease who achieve maximum response with fewer than 6 cycles, further adjuvant chemotherapy can be given following surgery and irradiation. Patients whose tumours do not respond to primary chemotherapy can be treated with taxane chemotherapy or can proceed directly to irradiation followed by modified radical mastectomy, if feasible.
Systemic therapy: hormonal therapy
Operable and inoperable tumours
· Tamoxifen for 5 years should be recommended to pre- and postmenopausal women whose tumours are hormone responsive.
Locoregional management
Operable tumours
· Patients with stage IIIA disease should receive both modified radical mastectomy (MRM) and locoregional radiotherapy if feasible. They may be managed with MRM followed by chemotherapy and locoregional radiotherapy, or chemotherapy first followed by MRM and locoregional radiotherapy. Breast-conserving surgery is currently not a standard approach.
· Locoregional radiotherapy should be delivered to the chest wall and to the supraclavicular and axillary nodes. The role of internal mammary irradiation is unclear.
Inoperable tumours
· Patients with stage IIIB disease who respond to chemotherapy should receive surgery plus locoregional radiotherapy.
· The locoregional management of patients with stage IIIC disease who respond to chemotherapy is unclear and should be individualized.
· Patients whose disease remains inoperable following chemotherapy should receive locoregional radiotherapy with subsequent surgery, if feasible.
Validation
The authors' original text was revised by members of the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. Subsequently, feedback was provided by 9 oncologists from across Canada. The final document was approved by the steering committee.
Sponsor
The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer was convened by Health Canada.
Completion date
December 2003.
doi:10.1503/cmaj.1030944
PMCID: PMC359433  PMID: 15023926
4.  Differential Expression of Cytokines in Breast Cancer Patients Receiving Different Chemotherapies: Implications for Cognitive Impairment Research 
Supportive Care in Cancer  2011;20(4):831-839.
Purpose
In many neurodegenerative diseases abnormal concentrations of cytokines and chemokines affect neuronal integrity leading to cognitive impairments; altered levels of these molecules could also play a role in cancer- and cancer-treatment related cognitive difficulties. Patients receiving doxorubicin-based (with cyclophosphamide, or cyclophosphamide plus fluorouracil; AC/CAF) chemotherapy or cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy report experiencing cognitive difficulties; because these regimens work by different modes of action, it is possible that they differentially affect cytokine levels.
Methods
This secondary study examined the relationships between cytokine levels (i.e., IL-6, IL-8, and MCP-1) and type of chemotherapy among 54 early-stage breast cancer patients receiving AC/CAF or CMF. Cytokine levels were assessed at two time-points: prior to on-study chemotherapy cycle 2 (Cycle 2) and after 2 consecutive chemotherapy cycles (prior to on-study cycle 4; Cycle 4).
Main Results
Analyses of variance using Cycle 2 levels as a covariate (ANCOVA) were used to determine differences between chemotherapy groups. Levels of IL-6, IL-8, and MCP-1 increased in the AC/CAF group and decreased in the CMF group; the only significant between-group change was in IL-6 (p<0.05).
Conclusions
These preliminary results suggest that AC/CAF chemotherapy is more cytokine inducing than CMF; future studies should explore the distinct inflammatory responses elicited by different chemotherapy regimens.
doi:10.1007/s00520-011-1158-0
PMCID: PMC3218259  PMID: 21533812
chemotherapy; cytokines; cancer; cognitive impairment; immune response
5.  Manganese Superoxide Dismutase and Breast Cancer Recurrence: A Danish Clinical Registry-Based Case-Control Study, and a Meta-Analysis 
PLoS ONE  2014;9(1):e87450.
Background
Manganese superoxide dismutase (MnSOD) inhibits oxidative damage and cancer therapy effectiveness. A polymorphism in its encoding gene (SOD2: Val16Ala rs4880) may confer poorer breast cancer survival, but data are inconsistent. We examined the association of SOD2 genotype and breast cancer recurrence (BCR) among patients treated with cyclophosphamide-based chemotherapy (Cyclo). We compared our findings with published studies using meta-analyses.
Methods
We conducted a population-based case-control study of BCR among women in Jutland, Denmark. Subjects were diagnosed with non-metastatic breast cancer from 1990–2001, received adjuvant Cyclo, and were registered in the Danish Breast Cancer Cooperative Group. We identified 118 patients with BCR and 213 matched breast cancer controls. We genotyped SOD2 and used conditional logistic regression to compute the odds ratio (OR) and associated 95% confidence intervals (95% CI) of BCR. We used random-effects meta-analytic models to evaluate the association of SOD2 polymorphisms and BCR.
Results
The frequency of the SOD2-Ala allele was 70% in cases versus 71% in controls; 40% versus 44% were heterozygotes, and 30% versus 25% were homozygotes, respectively. Heterozygote and homozygote carriers of the Ala allele had no increased rate of BCR (OR = 1.1, 95%CI = 0.65, 2.0, and OR = 0.87, 95%CI = 0.47, 1.6, respectively). Five studies informed the meta-analytic models; summary estimates associating BCR for homozygote, or any inheritance of the variant Ala allele were 1.18 (95%CI = 0.74, 1.88), and 1.18, (95%CI = 0.91, 1.54), respectively.
Conclusion
Our findings do not suggest that MnSOD enzymatic activity, as measured by SOD2 genotype, affects rates of BCR among patients treated with Cyclo.
doi:10.1371/journal.pone.0087450
PMCID: PMC3909115  PMID: 24498107
6.  Effect on Antioxidant Levels in Patients of Breast Carcinoma during Neoadjuvant Chemotherapy and Mastectomy 
Background:
Breast cancer is the most common cancer in Indian women. The aim of this study was to assess the levels of red blood cell (RBC) superoxide dismutase (r-SOD), RBC catalase (r-CAT), RBC glutathione peroxidase (r-GPx) and the ferric reducing ability of plasma (FRAP) in advanced breast cancer patients post mastectomy before and after chemotherapy.
Methods:
Female breast cancer patients between 27 and 65 years of age who were admitted to the Department of Surgery of the All India Institute of Medical Sciences in New Delhi were enrolled in the study. This study included two arms: a control group of healthy age-matched females (n=20) and patients undergoing treatment with a combination of the anticancer drugs cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) (n=55), No treatment was given to the control group. The CAF group received CAF treatment at weeks 0, 3, and 6, then surgery at week 9 followed by CAF treatment at weeks 12, 15, and 18. A three-week drug-free interval was included between each cycle of drug treatment. Blood samples were collected from control subjects and from patients in the CAF group before administration of drugs at week zero to establish a baseline, again weeks 12 and 18, and once more at the end of the 26-week treatment. Blood samples collected from the control subjects and CAF patients were analysed to determine levels of the endogenous antioxidants, r-SOD, r-CAT, r-GPx, and FRAP.
Results:
Levels of r-SOD, r-CAT, r-GPx, and FRAP in CAF-treated patients at 12, 18, and 26 weeks were significantly decreased (P<0.001) in comparison to the baseline levels observed at week zero.
Conclusion:
The results from the present study show that a change in the enzyme antioxidant systems in patients after chemotherapy and mastectomy causes an overall decrease in antioxidant levels. Chemotherapeutic agents induce oxidative stress that damages many cellular targets.
PMCID: PMC3216162  PMID: 22135534
antineoplastic combined chemotherapy protocols; antioxidants; breast neoplasms; medical sciences
7.  Viscum album L. extracts in breast and gynaecological cancers: a systematic review of clinical and preclinical research 
Background
Viscum album L. extracts (VAE, European mistletoe) are a widely used medicinal plant extract in gynaecological and breast-cancer treatment.
Methods
Systematic review to evaluate clinical studies and preclinical research on the therapeutic effectiveness and biological effects of VAE on gynaecological and breast cancer. Search of databases, reference lists and expert consultations. Criteria-based assessment of methodological study quality.
Results
19 randomized (RCT), 16 non-randomized (non-RCT) controlled studies, and 11 single-arm cohort studies were identified that investigated VAE treatment of breast or gynaecological cancer. They included 2420, 6399 and 1130 patients respectively. 8 RCTs and 8 non-RCTs were embedded in the same large epidemiological cohort study. 9 RCTs and 13 non-RCTs assessed survival; 12 reported a statistically significant benefit, the others either a trend or no difference. 3 RCTs and 6 non-RCTs assessed tumour behaviour (remission or time to relapse); 3 reported statistically significant benefit, the others either a trend, no difference or mixed results. Quality of life (QoL) and tolerability of chemotherapy, radiotherapy or surgery was assessed in 15 RCTs and 9 non-RCTs. 21 reported a statistically significant positive result, the others either a trend, no difference, or mixed results. Methodological quality of the studies differed substantially; some had major limitations, especially RCTs on survival and tumour behaviour had very small sample sizes. Some recent studies, however, especially on QoL were reasonably well conducted. Single-arm cohort studies investigated tumour behaviour, QoL, pharmacokinetics and safety of VAE. Tumour remission was observed after high dosage and local application. VAE application was well tolerated. 34 animal experiments investigated VAE and isolated or recombinant compounds in various breast and gynaecological cancer models in mice and rats. VAE showed increase of survival and tumour remission especially in mice, while application in rats as well as application of VAE compounds had mixed results. In vitro VAE and its compounds have strong cytotoxic effects on cancer cells.
Conclusion
VAE shows some positive effects in breast and gynaecological cancer. More research into clinical efficacy is warranted.
doi:10.1186/1756-9966-28-79
PMCID: PMC2711058  PMID: 19519890
8.  Cognitive function in older women with breast cancer treated with standard chemotherapy and capecitabine on Cancer and Leukemia Group B 49907 
Cognitive changes in older women receiving chemotherapy are poorly understood. We examined self-reported cognitive function for older women who received adjuvant chemotherapy on Cancer and Leukemia Group B (CALGB) 49907. CALGB 49907 randomized 633 women aged ≥65 with stage I–III breast cancer to standard adjuvant chemotherapy (cyclophosphamide–methotrexate–5-fluoro-uracil or doxorubicin–cyclophosphamide) versus capecitabine. We examined self-reported cognitive function in 297 women (CALGB 361002) who enrolled on the quality of life substudy and had no gross impairment on cognitive screening. Women were evaluated using an 18-item instrument at six time points (baseline through 24 months). At each time point for each patient, we calculated a cognitive function score (CFS) defined as the mean response of items 1–18 and defined impairment as a score >1.5 standard deviations above the overall average baseline score. Differences in scores by patient characteristics were evaluated using a Kruskal–Wallis test. A linear mixed-effects model was used to assess CFSs by treatment over time. Among 297 women, the median age was 71.5 (range 65–85) and 73 % had performance status of 0. Baseline depression and fatigue were reported in 6 and 14 % of patients, respectively. The average CFS at baseline was 2.08 (corresponding to “normal ability”), and baseline cognitive function did not differ by treatment regimen (p = 0.350). Over 24 months, women reported minimal changes at each time point and insignificant differences by treatment arm were observed. In a healthy group of older women, chemotherapy was not associated with longitudinal changes in self-reported cognitive function.
doi:10.1007/s10549-013-2562-6
PMCID: PMC3920483  PMID: 23681403
Cognitive function; Older women; Breast cancer; Age
9.  Interaction of standardized mistletoe (Viscum album) extracts with chemotherapeutic drugs regarding cytostatic and cytotoxic effects in vitro 
Background
Given the importance of complementary and alternative medicine (CAM) to cancer patients, there is an increasing need to learn more about possible interactions between CAM and anticancer drugs. Mistletoe (Viscum album L.) belongs to the medicinal herbs that are used as supportive care during chemotherapy. In the in vitro study presented here the effect of standardized mistletoe preparations on the cytostatic and cytotoxic activity of several common conventional chemotherapeutic drugs was investigated using different cancer cell lines.
Methods
Human breast carcinoma cell lines HCC1937 and HCC1143 were treated with doxorubicin hydrochloride, pancreas adenocarcinoma cell line PA-TU-8902 with gemcitabine hydrochloride, prostate carcinoma cell line DU145 with docetaxel and mitoxantrone hydrochloride and lung carcinoma cell line NCI-H460 was treated with docetaxel and cisplatin. Each dose of the respective chemotherapeutic drug was combined with Viscum album extract (VAE) in clinically relevant concentrations and proliferation and apoptosis were measured.
Results
VAE did not inhibit chemotherapy induced cytostasis and cytotoxicity in any of our experimental settings. At higher concentrations VAE showed an additive inhibitory effect.
Conclusions
Our in vitro results suggest that no risk of safety by herb drug interactions has to be expected from the exposition of cancer cells to chemotherapeutic drugs and VAE simultaneously.
doi:10.1186/1472-6882-14-6
PMCID: PMC3893555  PMID: 24397864
Mistletoe (Viscum album L.); Iscador; Chemotherapy; Drug interactions; Cytostasis; Cytotoxicity
10.  Psychological impact of adjuvant chemotherapy in the first two years after mastectomy. 
Psychological symptoms were assessed over two years in a randomised trial of three forms of treatment given to women after mastectomy for stage II breast cancer. The treatments were: three weeks' radiotherapy; one year's adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil; and radiotherapy followed by chemotherapy. Analysis of the results on an intention to treat basis showed no substantial differences in depression or anxiety among groups at one, three, or six months after the operation. At 13 months, however, patients who had been allocated chemotherapy had significantly more symptoms, especially depression, than control patients treated with radiotherapy alone. Conditioned reflex nausea and vomiting increased considerably during the second six months of chemotherapy and persisted for up to a year afterwards. The psychological morbidity of adjuvant chemotherapy could be substantially reduced if courses of treatment were restricted to about six months.
PMCID: PMC1342107  PMID: 3535990
11.  Mammostrat® as a tool to stratify breast cancer patients at risk of recurrence during endocrine therapy 
Introduction
Patients with early-stage breast cancer, treated with endocrine therapy, have approximately 90% 5-year disease-free survival. However, for patients at higher risk of relapse despite endocrine therapy, additional adjuvant therapy, such as chemotherapy, may be indicated. The challenge is to prospectively identify such patients. The Mammostrat® test uses five immunohistochemical markers to stratify patients on tamoxifen therapy into risk groups to inform treatment decisions. We tested the efficacy of this panel in a mixed population of cases treated in a single center with breast-conserving surgery and long-term follow-up.
Methods
Tissue microarrays from a consecutive series (1981 to 1998) of 1,812 women managed by wide local excision and postoperative radiotherapy were collected following appropriate ethical review. Of 1,390 cases stained, 197 received no adjuvant hormonal or chemotherapy, 1,044 received tamoxifen only, and 149 received a combination of hormonal therapy and chemotherapy. Median age at diagnosis was 57, 71% were postmenopausal, 23.9% were node-positive and median tumor size was 1.5 cm. Samples were stained using triplicate 0.6 mm2 tissue microarray cores, and positivity for p53, HTF9C, CEACAM5, NDRG1 and SLC7A5 was assessed. Each case was assigned a Mammostrat® risk score, and distant recurrence-free survival (DRFS), relapse-free survival (RFS) and overall survival (OS) were analyzed by marker positivity and risk score.
Results
Increased Mammostrat® scores were significantly associated with reduced DRFS, RFS and OS in estrogen receptor (ER)-positive breast cancer (P < 0.00001). In multivariate analyses the risk score was independent of conventional risk factors for DRFS, RFS and OS (P < 0.05). In node-negative, tamoxifen-treated patients, 10-year recurrence rates were 7.6 ± 1.5% in the low-risk group versus 20.0 ± 4.4% in the high-risk group. Further, exploratory analyses revealed associations with outcome in both ER-negative and untreated patients.
Conclusions
This is the fifth independent study providing evidence that Mammostrat® can act as an independent prognostic tool for ER-positive, tamoxifen-treated breast cancer. In addition, this study revealed for the first time a possible association with outcome regardless of node status and ER-negative tumors. When viewed in the context of previous results, these data provide further support for this antibody panel as an aid to patient management in early-stage breast cancer.
doi:10.1186/bcr2604
PMCID: PMC2949634  PMID: 20615243
12.  Ki-67 biomarker in breast cancer of Indian women 
Background:
Biological markers that reliably predict clinical or pathological response to primary systemic therapy early during a course of chemotherapy may have considerable clinical potential.
Aims:
Aims of study to evaluated changes in Ki-67 (MIB-1) labeling index and apoptotic index (AI) before, during, and after neoadjuvant anthracycline chemotherapy in breast cancer in Indian women.
Materials and Methods:
Breast cancer tissues were collected from Grant Medical College and Sir J.J. Group of Hospitals, Mumbai, India. Twenty-seven patients receiving neoadjuvant FEC (5-fluorouracil, epirubicin, and cyclophosphamide) chemotherapy for operable breast cancer underwent repeat core biopsy after 21 days of treatment.
Results:
The objective clinical response rate was 56%. Eight patients (31%) achieved a pathological response by histopathological criteria; two patients had a near-complete pathological response. Increased day-21 AI was a statistically significant predictor of pathological response (p = 0.049). A strong trend for predicting pathological response was seen with higher Ki-67 indices at day 21 and AI at surgery (p = 0.06 and 0.06, respectively).
Conclusion:
The clinical utility of early changes in biological marker expression during chemotherapy remains unclear. Until further prospectively validated evidence confirming the reliability of predictive biomarkers is available, clinical decision-making should not be based upon individual biological tumor biomarker profiles.
doi:10.4297/najms.2011.3119
PMCID: PMC3336898  PMID: 22540077
Ki-67 (MIB-1); breast cancer; prognostic factor; proliferative labeling index; apoptotic index; chemotherapy; primary systemic therapy
13.  The combination of radiotherapy, adjuvant chemotherapy (cyclophosphamide-doxorubicin-ftorafur) and tamoxifen in stage II breast cancer. Long-term follow-up results of a randomised trial. 
British Journal of Cancer  1992;66(6):1171-1176.
Two hundred patients with node positive stage II breast cancer were randomised to four groups after radical mastectomy and axillary evacuation: (1) Postoperative radiotherapy, (2) Adjuvant chemotherapy with eight courses of CAFt (cyclophosphamide 500 mg m-2 + doxorubicin 40 mg/m-2 + ftorafur 20 mg kg-1 orally day 1-14) every fourth week, (3) Postoperative radiotherapy and adjuvant chemotherapy and (4) postoperative radiation, adjuvant chemotherapy and tamoxifen 40 mg daily for 2 years. Thirty-two per cent of the patients discontinued treatment due to GI-toxicity, while 26% required dose reductions due to leukopenia. Radiation pneumonitis was more frequent after the combination of postoperative radiotherapy with chemotherapy. There was a better relapse-free survival in the groups receiving chemotherapy compared to radiotherapy alone (P = 0.05), which was highly significant in a multivariate Cox analysis (P = 0.004). No significant survival differences were seen. Tamoxifen had no clear overall effect but there were better relapse-free (P = 0.04) and overall (P = 0.004) survival with tamoxifen in estrogen receptor positive patients, while estrogen receptor negative patients had a somewhat poorer survival (P = 0.07) after tamoxifen. Local control was better (NS) after the combination (93%) radiotherapy and chemotherapy compared to either treatment alone (76% with radiotherapy and 74% with chemotherapy at 5 years).
PMCID: PMC1978025  PMID: 1457360
14.  Pneumonitis and pulmonary fibrosis in a patient receiving adjuvant docetaxel and cyclophosphamide for stage 3 breast cancer: a case report and literature review 
Introduction
Pulmonary toxicities associated with chemotherapeutic agents utilized as adjuvant therapy in patients with breast cancer are distinctly uncommon. The chemotherapy regimen of docetaxel/cyclophosphamide has a more favorable therapeutic index compared to anthracycline-based regimens due to a significantly lower incidence of heart failure and leukemia. Consequently, docetaxel/cyclophosphamide is the preferred adjuvant chemotherapy of choice in older women or in women where anthracyclines may be contraindicated. Pulmonary complications in patients with breast cancer receiving taxane-based adjuvant chemotherapy in the absence of radiation are distinctly uncommon. Here, we report the case of a patient receiving adjuvant docetaxel/cyclophosphamide who developed rapid-onset, biopsy-proven interstitial pneumonitis.
Case presentation
A 72-year-old Hispanic woman was diagnosed as having stage 3 hormone-receptor positive, human epidermal growth factor receptor 2/neu negative, invasive breast cancer. Due to the estimated 10-year risk of recurrence of approximately 80 percent, a decision was made to treat our patient with adjuvant chemotherapy. Due to her age and increased risk of cardiac toxicity with anthracycline-based chemotherapy regimens, our patient was treated with docetaxel/cyclophosphamide chemotherapy for a total of four planned cycles. However, approximately two weeks after receiving the third cycle of chemotherapy, our patient developed rapidly progressive dyspnea, and a non-productive cough and went to the emergency room at an outside medical facility. She was found to have mild hypoxemia, and new onset of peripheral, subpleural fibrotic changes not present on pre-treatment scans. A thorascopic-guided wedge biopsy of the lung tissue revealed subacute interstitial pneumonitis. Our patient made a rapid clinical recovery after treatment with corticosteroids.
Conclusions
Interstitial pneumonitis is a rare complication of docetaxel/cyclophosphamide chemotherapy that carries a high mortality rate. The only way to make a definitive diagnosis is with a wedge biopsy of the lung, which should be performed when feasible. Our patient’s case illustrates that no therapeutic intervention is without its intrinsic and unanticipated risks, and interstitial pneumonitis should be discussed as a potential side effect with all patients prior to administering docetaxel/cyclophosphamide chemotherapy.
doi:10.1186/1752-1947-6-413
PMCID: PMC3533898  PMID: 23198815
15.  Uncaria tomentosa—Adjuvant Treatment for Breast Cancer: Clinical Trial 
Breast cancer is the most frequent neoplasm affecting women worldwide. Some of the recommended treatments involve chemotherapy whose toxic effects include leukopenia and neutropenia. This study assessed the effectiveness of Uncaria tomentosa (Ut) in reducing the adverse effects of chemotherapy through a randomized clinical trial. Patients with Invasive Ductal Carcinoma—Stage II, who underwent a treatment regimen known as FAC (Fluorouracil, Doxorubicin, Cyclophosphamide), were divided into two groups: the UtCa received chemotherapy plus 300 mg dry Ut extract per day and the Ca group that only received chemotherapy and served as the control experiment. Blood samples were collected before each one of the six chemotherapy cycles and blood counts, immunological parameters, antioxidant enzymes, and oxidative stress were analyzed. Uncaria tomentosa reduced the neutropenia caused by chemotherapy and was also able to restore cellular DNA damage. We concluded that Ut is an effective adjuvant treatment for breast cancer.
doi:10.1155/2012/676984
PMCID: PMC3395261  PMID: 22811748
16.  Breast Cancer during Pregnancy: An Interdisciplinary Approach in Our Institution 
Breast Care  2012;7(4):311-314.
Background
Breast cancer is the most common cancer diagnosed during pregnancy.
Case Report
We report on a case of a 26-year-old woman who was diagnosed with right-sided breast cancer in her 15th week of gestation. We discussed possible treatment scenarios and the patient opted for neoadjuvant therapy with taxanes and anthracyclines during pregnancy, followed by delivery and then followed by surgery, antibody therapy, and radiotherapy. The patient received neoadjuvant chemotherapy with paclitaxel 80 mg/m2 weekly for 12 cycles, followed by 4 cycles of epirubicin and cyclophosphamide (90/600 mg/m2) every 3 weeks. Complete clinical response was seen after preoperative chemotherapy. After delivery of a healthy child at 40 weeks of gestation, she received breast-conserving surgery and axillary dissection. Anti-HER2 antibody treatment with trastuzumab was started concomitantly with adjuvant radiotherapy. Endocrine treatment with a gonadotropin-releasing hormone (GnRH) analog and tamoxifen for 5 years was planned to be started after radiotherapy.
Conclusion
Treatment of breast cancer during pregnancy requires an interdisciplinary approach and careful consideration of the patient's stage of disease, the gestational age, and the preferences of the patient and her family.
doi:10.1159/000341383
PMCID: PMC3515786  PMID: 23904834
Pregnancy-associated breast cancer; Outcome of pregnancy; Neoadjuvant chemotherapy; Interdisciplinary care
17.  The optimal sequence of radiotherapy and chemotherapy in adjuvant treatment of breast cancer 
Background
The optimal time sequences for chemotherapy and radiation therapy after breast surgery for patients with breast cancer remains unknown. Most of published studies were done for early breast cancer patients. However, in Egypt advanced stages were the common presentation. This retrospective analysis aimed to assess the optimum sequence for our population.
Methods
267 eligible patients planned to receive adjuvant chemotherapy [FAC] and radiotherapy. Majority of patients (87.6%) underwent modified radical mastectomy while, 12.4% had conservative surgery.
We divided the patients into 3 groups according to the sequence of chemotherapy and radiotherapy. Sixty-seven patients (25.1%) received postoperative radiotherapy before chemotherapy [group A]. One hundred and fifty patients (56.2%) were treated in a sandwich scheme (group B), which means that 3 chemotherapy cycles were given prior to radiotherapy followed by 3 further chemotherapy cycles. A group of 50 patients (18.7%) was treated sequentially (group C), which means that radiotherapy was supplied after finishing the last chemotherapy cycle. Patients' characteristics are balanced between different groups.
Results
Disease free survival was estimated at 2.5 years, and it was 83.5%, 82.3% and 80% for patient receiving radiation before chemotherapy [group A], sandwich [group B] and after finishing chemotherapy [group C] respectively (p > 0.5). Grade 2 pneumonitis, which necessitates treatment with steroid, was detected in 3.4% of our patients, while grade 2 radiation dermatitis was 17.6%. There are no clinical significant differences between different groups regarded pulmonary or skin toxicities.
Conclusion
Regarding disease free survival and treatment toxicities, in our study, we did not find any significant difference between the different radiotherapy and chemotherapy sequences.
doi:10.1186/1755-7682-4-35
PMCID: PMC3206410  PMID: 21999819
breast cancer; chemotherapy; radiotherapy; sequence
18.  Quality of life and quality-adjusted survival (Q-TWiST) in patients receiving dose-intensive or standard dose chemotherapy for high-risk primary breast cancer 
British Journal of Cancer  2007;98(1):25-33.
Quality of life (QL) is an important consideration when comparing adjuvant therapies for early breast cancer, especially if they differ substantially in toxicity. We evaluated QL and Q-TWiST among patients randomised to adjuvant dose-intensive epirubicin and cyclophosphamide administered with filgrastim and progenitor cell support (DI-EC) or standard-dose anthracycline-based chemotherapy (SD-CT). We estimated the duration of chemotherapy toxicity (TOX), time without disease symptoms and toxicity (TWiST), and time following relapse (REL). Patients scored QL indicators. Mean durations for the three transition times were weighted with patient reported utilities to obtain mean Q-TWiST. Patients receiving DI-EC reported worse QL during TOX, especially treatment burden (month 3: P<0.01), but a faster recovery 3 months following chemotherapy than patients receiving SD-CT, for example, less coping effort (P<0.01). Average Q-TWiST was 1.8 months longer for patients receiving DI-EC (95% CI, −2.5 to 6.1). Q-TWiST favoured DI-EC for most values of utilities attached to TOX and REL. Despite greater initial toxicity, quality-adjusted survival was similar or better with dose-intensive treatment as compared to standard treatment. Thus, QL considerations should not be prohibitive if future intensive therapies show superior efficacy.
doi:10.1038/sj.bjc.6604092
PMCID: PMC2359705  PMID: 18043579
breast cancer; adjuvant chemotherapy; quality of life; adaptation; quality-adjusted survival
19.  Incidence of taxane-induced pain and distress in patients receiving chemotherapy for early-stage breast cancer: a retrospective, outcomes-based survey 
Current Oncology  2010;17(4):42-47.
Introduction
With the widespread use of sequential anthracycline/taxane–based chemotherapy for early-stage breast cancer, clinicians are becoming rapidly aware of toxicities associated with those regimens. Despite the low incidence reported in the literature of significant arthralgia and myalgia with those regimens, it is clinically evident that a substantial proportion of patients develop such toxicities. We performed a pilot study to investigate the extent of this problem.
Patients and Methods
Patients who had received prior adjuvant or neoadjuvant chemotherapy [doxorubicin–cyclophosphamide followed by paclitaxel (ac-t), doxorubicin–cyclophosphamide followed by docetaxel (ac-d), or 5-fluourouracil–epirubicin–cyclophosphamide followed by docetaxel (fec-d)] completed a retrospective outcomes-based survey. The survey utilized the Functional Assessment of Cancer Therapy–Taxane Scale, the Memorial Symptom Assessment Scale, and a modified Brief Pain Inventory.
Results
Interviews were conducted with 82 patients. Interviewees had received ac-t (43%), fec-d (43%), and ac-d (14%). Pain as a side effect of either the anthracycline or the taxane chemotherapy was reported by 87% of patients. Most of the patients (79%) indicated that their worst pain occurred during the taxane component of treatment. Compared with paclitaxel, docetaxel was reported to cause more pain. Narcotics for pain management were required by 35 of 82 patients (43%).
Conclusions
A significant number of patients receiving sequential anthracycline/taxane–based chemotherapy for early-stage breast cancer experience pain, particularly during the taxane component. Prospective patient-reported outcome assessments are needed to help individualize treatment interventions and to improve symptom management in this population.
PMCID: PMC2913828  PMID: 20697513
Breast cancer; taxanes; anthracyclines; toxicities
20.  Evaluation of host quality of life and immune function in breast cancer patients treated with combination of adjuvant chemotherapy and oral administration of Lentinula edodes mycelia extract 
OncoTargets and therapy  2013;6:853-859.
Purpose
Anthracycline-based chemotherapies for breast cancer are well known to have adverse effects and can also negatively affect host immune function. There is therefore a necessity for an adjuvant that maintains the quality of life (QOL) and immune function of cancer patients receiving anthracycline-based chemotherapies.
Patients and methods
The present study investigated the effectiveness of the concomitant use of Lentinula edodes mycelia extract (LEM), an oral immunomodulator, with FEC75 (5-fluorouracil + epirubicin + cyclophosphamide) therapy on host QOL and immune function in breast cancer patients with nodal metastases. Ten breast cancer patients with nodal metastases receiving surgery were enrolled in this study. Treatment with 5-fluorouracil (500 mg/m2), epirubicin (75 mg/m2), and cyclophosphamide (500 mg/m2) was performed every 21 days for two courses, and LEM (1800 mg/day by mouth) was administered during the second course.
Results
In the first course, hematological toxicity was observed and host QOL and immune function were exacerbated. In the second course, however, the number of white blood cells and lymphocytes did not decrease and host QOL was maintained. Furthermore, the cytotoxic activities of natural killer (NK) and lymphokine-activated killer cells and the proportion of activated NK and NK T-cells in lymphocytes were maintained in the second course.
Conclusion
It has been suggested that the concomitant use of LEM with FEC75 therapy can maintain host QOL and immune function, and offer important implications for an application of LEM as a useful oral adjuvant to anthracycline-based chemotherapies.
doi:10.2147/OTT.S44169
PMCID: PMC3711972  PMID: 23874107
clinical study; breast cancer; anthracycline; Lentinula edodes; immunity; quality of life
21.  Estimation of the cost of treatment by chemotherapy for early breast cancer in Morocco 
Background
Breast cancer is the first cancer in women both in incidence and mortality. The treatment of breast cancer benefited from the progress of chemotherapy and targeted therapies, but there was a parallel increase in treatment costs. Despite a relatively high incidence of many sites of cancer, so far, there is no national register for this disease in Morocco.
The main goal of this paper is to estimate the total cost of chemotherapy in the early stages of breast cancer due to its frequency and the chances of patients being cured. This study provides health decision-makers with a first estimate of costs and the opportunity to achieve the optimal use of available data to estimate the needs of antimitotics and trastuzumab in Morocco.
Method
We start by evaluating the individual cost according to the therapeutic sub-groups, namely:
1. Patients needing chemotherapy with only anthracycline-based therapy.
2. Patients needing chemotherapy with both anthracycline and taxane but without trastuzumab.
3. Patients needing trastuzumab in addition to chemotherapy.
For each sub-group, the protocol of treatment is described, and the individual costs per unit, and for the whole cycle, are evaluated.
Then we estimate the number of women suffering from breast cancer on the basis of two data bases available in Morocco.
Finally, we calculate the total annual cost of treatment of breast cancer in Morocco.
Results
The total cost of breast cancer in Morocco is given in Moroccan dirhams (MAD), the US dollar at the current exchange rate (MAD 10 = USD 1.30) and in international dollars or purchasing power parity (MAD 10 = PPP 1.95).
The cost of a therapy with trastuzumab is 8.4 times the cost of a sequential chemotherapy combining anthracycline and taxane, and nearly 60 times the cost of chemotherapy based on anthracycline alone.
Globally, between USD 13.3 million and USD 28.6 million need to be devoted every year by the Moroccan health authorities to treat women with localized breast cancer in keeping with international recommendations.
Discussion
According to our estimation methods, the complete cost of adjuvant chemotherapy including trastuzumab will range from 1.3 to 2.4% of the global budget of the Moroccan Health Department (MAD 9.8 billion or USD 1.274 billion). Unfortunately, only one-third of the Moroccan population has healthcare insurance whereas for each patient the treatment with chemotherapy alone costs 1.15 times the annual minimum income (MAD 23,710 or USD 3,082), and treatment requiring both chemotherapy and trastuzumab costs 9.76 times the annual minimum income. For the tumour over expressing HER2Neu, we need to treat 25 women in order to save (cure) one woman: the calculated cost for one life saved is USD 663,000. The question is, is it cost-effective for an emerging country?
Conclusion
In this paper we aimed at evaluating the total cost of chemotherapy in the early stages of breast cancer in order to provide health decision-makers with a first estimation and a good opportunity for the optimal use of available data for the needs of antimitotics and trastuzumab in Morocco. Different protocols were considered and the individual cost of the whole treatment was given according to therapies using anthracycline alone, sequential chemotherapy combining anthracycline and taxane, and sequential chemotherapy with trastuzumab. According to our estimations, Moroccan health authorities need to devote between USD 13.3 million and USD 28.6 million every year in order to treat women suffering from localized breast cancer in ways consistent with international recommended standards.
doi:10.1186/1478-7547-8-16
PMCID: PMC2942794  PMID: 20828417
22.  Survival of cancer patients treated with mistletoe extract (Iscador): a systematic literature review 
BMC Cancer  2009;9:451.
Background
In Europe, extracts from Viscum album (VA-E), the European white-berry mistletoe, are widely used to treat patients with cancer.
Methods
We searched several databases such as Cochrane, EMBASE, NCCAM, NLM, DIMDI, CAMbase, and Medline. Inclusion criteria were controlled clinical studies on parameters associated with survival in cancer patients treated with Iscador. Outcome data were extracted as they were given in the publication, and expressed as hazard ratios (HR), their logarithm, and the respective standard errors using standard formulas.
Results
We found 49 publications on the clinical effects of Iscador usage on survival of cancer patients which met our criteria. Among them, 41 studies and strata provided enough data to extract hazard ratios (HR) and their standard errors (Iscador versus no extra treatment). The majority of studies reported positive effects in favour of the Iscador application. Heterogeneity of study results was moderate (I2 = 38.3%, p < 0.0001). The funnel plots were considerably skewed, indicating a publication bias, a notion which is corroborated by statistical means (AC = -1.3, CI: -1.9 to -0.6, p <= 0.0001). A random effect meta-analysis estimated the overall hazard ratio at HR = 0.59 (CI: 0.53 to 0.66, p < 0.0001). Randomized studies showed less effects than non-randomized studies (ratio of HRs: 1.24, CI: 0.79 to 1.92, p = 0.35), and matched-pair studies gave significantly better results than others (ratio of HRs: 0.33; CI: 0.17 to 0.65, p = 0.0012).
Conclusions
Pooled analysis of clinical studies suggests that adjuvant treatment of cancer patients with the mistletoe extract Iscador is associated with a better survival. Despite obvious limitations, and strong hints for a publication bias which limits the evidence found in this meta-analysis, one can not ignore the fact that studies with positive effects of VA-E on survival of cancer patients are accumulating. Future studies evaluating the effects of Iscador should focus on a transparent design and description of endpoints in order to provide greater insight into a treatment often being depreciated as ineffective, but highly valued by cancer patients.
doi:10.1186/1471-2407-9-451
PMCID: PMC2804713  PMID: 20021637
23.  Course of Fatigue in Women Receiving Chemotherapy and/or Radiotherapy for Early Stage Breast Cancer 
Although much has been learned about the complication of fatigue during breast cancer treatment, the possibility that there are differences across treatment modalities in breast cancer patients’ experience of fatigue has not yet been established. In this study, fatigue was assessed in 134 women receiving chemotherapy and radiotherapy or radiotherapy only for early stage breast cancer. Comparisons of fatigue during initial treatment indicated that women who received chemotherapy reported greater fatigue severity and disruptiveness than women receiving radiotherapy. Women not pre-treated with chemotherapy experienced increased fatigue over the course of radiotherapy. Results confirmed predictions that fatigue in women with early stage breast cancer differs as a function of the type of treatment and sequencing of treatment. Findings indicating increases in fatigue during radiotherapy only among women not pretreated with chemotherapy suggest a response shift, or a change in internal standards, in women’s perceptions of fatigue as a function of prior chemotherapy treatment.
doi:10.1016/j.jpainsymman.2004.01.012
PMCID: PMC2398710  PMID: 15471655
Fatigue; breast cancer; chemotherapy; radiotherapy
24.  Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial 
Lancet  2009;373(9676):1681-1692.
Summary
Background
Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment. The UK TACT study (CRUK01/001) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with standard chemotherapy of similar duration.
Methods
In this multicentre, open-label, phase III, randomised controlled trial, 4162 women (aged >18 years) with node-positive or high-risk node-negative operable early breast cancer were randomly assigned by computer-generated permuted block randomisation to receive FEC (fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2 at 3-weekly intervals) for four cycles followed by docetaxel (100 mg/m2 at 3-weekly intervals) for four cycles (n=2073) or control (n=2089). For the control regimen, centres chose either FEC for eight cycles (n=1265) or epirubicin (100 mg/m2 at 3-weekly intervals) for four cycles followed by CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 at 4-weekly intervals) for four cycles (n=824). The primary endpoint was disease-free survival. Analysis was by intention to treat (ITT). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN79718493.
Findings
All randomised patients were included in the ITT population. With a median follow-up of 62 months, disease-free survival events were seen in 517 of 2073 patients in the experimental group compared with 539 of 2089 controls (hazard ratio [HR] 0·95, 95% CI 0·85–1·08; p=0·44). 75·6% (95% CI 73·7–77·5) of patients in the experimental group and 74·3% (72·3–76·2) of controls were alive and disease-free at 5 years. The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group (p<0·0001); the most frequent events were neutropenia (937 events vs 797 events), leucopenia (507 vs 362), and lethargy (456 vs 272).
Interpretation
This study did not show any overall gain from the addition of docetaxel to standard anthracycline chemotherapy. Exploration of predictive biomarker-defined subgroups might have the potential to better target the use of taxane-based therapy.
Funding
Cancer Research UK (CRUK 01/001), Sanofi-Aventis, Pfizer, and Roche.
doi:10.1016/S0140-6736(09)60740-6
PMCID: PMC2687939  PMID: 19447249
25.  Chemotherapy versus chemotherapy plus irradiation in limited small cell lung cancer. Results of a controlled trial with 5 years follow-up. 
British Journal of Cancer  1986;54(1):7-17.
One hundred and forty-five patients with limited stage small cell lung cancer were included in a randomized trial to evaluate the effect of chemotherapy with or without chest irradiation. Seventy-six patients were allotted chemotherapy alone while 69 patients received the same chemotherapy plus radiotherapy, 40 Gy in split-course, administered in weeks 6 and 10 after the initiation of chemotherapy. The chemotherapy consisted of lomustine, cyclophosphamide, vincristine and methotrexate. Patients treated with chemotherapy alone survived for a median of 52 weeks compared to 44 weeks in patients receiving the combined regimen (P = 0.055). After exclusion of five early deaths and one patient refusing the irradiation plus 14 completely resected patients, the remaining 65 patients receiving chemotherapy alone and the 60 patients treated with chemotherapy plus radiotherapy were included in a new analysis. The difference in survival duration which could be ascribed to treatment with or without chest irradiation thereby diminished (P = 0.24). Eighteen months' disease-free survival was obtained in 9.2% of the 65 patients and in 9.8% of the 60 patients. The complete remission rates were 37% and 46%, respectively, (P = 0.33) and the median durations of complete remission were 40 weeks and 52 weeks (P = 0.67). Treatment failure of the primary tumour occurred in 85% of patients treated with chemotherapy alone in contrast to 61% of patients receiving the combined regimen (P = 0.005). Seventy-nine of these patients underwent autopsy at which no residual chest disease was observed in 17% and 37%, respectively (P = 0.045). The combined regimen was more toxic than chemotherapy alone resulting in significantly greater dose reductions and more pronounced thrombocytopenia. Lung and pericardial fibrosis was responsible for four deaths among the complete responders in the radiotherapy group. The combined regimen thus tended to be more efficacious with respect to tumour control at the expense, however, of increased toxicity which per se, eliminated a potential improvement of the overall therapeutical results.
PMCID: PMC2001661  PMID: 3015184

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