German Adjuvant Intergroup Node-positive Study (GAIN): a phase III trial comparing two dose-dense regimens (iddEPC versus ddEC-PwX) in high-risk early breast cancer patients.

BACKGROUND: Dose-dense (dd) regimens are one of the preferred options for the adjuvant treatment of breast cancer patients with intermediate to high risk. The German Adjuvant Intergroup Node-positive trial aimed at optimizing intense dd (idd) strategies by evaluating drug combinations and the addition of capecitabine. PATIENTS AND METHODS: Women (aged 18 years and biologically <65 years) with histologically involved axillary lymph nodes were randomly assigned to receive three courses each of epirubicin (E) 150 mg/m2, paclitaxel (P) 225 mg/m2 and cyclophosphamide (C) 2500 mg/m2 (reduced to 2000 mg/m2 after recruitment of 1200 patients) q2w intravenously (i.v.) (iddEPC-regimen) or ddEC (E 112.5 mg/m2 + C 600 mg/m2, i.v. q2w for 4 cycles) followed by paclitaxel weekly (Pw 67.5 mg/m2 i.v. q8d for 10 weeks) plus capecitabine (X 2000 mg/m2 p.o. days 1-14, q22 for 4 cycles) (ddEC-PwX-regimen). Further randomization assigned patients to ibandronate for 2 years versus observation and to pegfilgrastim day 2 versus 4. RESULTS: From June 2004 to August 2008, 2994 patients were randomized to either iddEPC (N = 1498), or ddEC-PwX (N = 1496) and started treatment. Median age was 50 years; pN1 (37.8%), pN2 (35.3%); pN3 (26.9%); 46.4% were G3 tumors; 76.9% hormone receptor-positive and 22% HER2-positive. After a median follow-up of 74 months, 645 events and 383 deaths were recorded. Hematological adverse events grades 3-4 were more common with iddEPC (P < 0.001), nonhematological with ddEC-PwX (P = 0.04), even if the toxicity profile of the two regimens was different. At 5 years, estimated disease-free survival rates for ddEC-PwX and iddEPC were 81.7% [95% confidence interval (CI) 79.5-83.6] versus 80.2% (95% CI 78.0-82.2). Hazard ratio (HR)=0.95 (95% CI 0.81-1.11, log-rank P = 0.49). Five-year overall survival rates were 89.4% for ddEC-PwX (95% CI 87.7-91.0) and 89.0% for iddEPC (95% CI 87.2-90.6), HR = 0.85 (95% CI 0.69-1.04, log-rank P = 0.10). CONCLUSION: Adding capecitabine to ddEC-Pw did not improve outcome in comparison to iddEPC but increased toxicity and should not be recommended for further use.

Efficacy and patient satisfaction of breast conserving therapy for central breast cancer by the B technique.

PURPOSE: To evaluate the oncologic safety and cosmetic results after breast cancer surgery for central breast cancer by the B technique. METHODS: Seventy women with operable breast cancer located in the central portion of the breast that had received resection surgery with the B technique were recruited. The primary outcome was the oncological safety, quantified as rate of positive resection margins and the cosmetic outcome evaluated by postsurgical self-assessment of the cosmetic outcome via questionnaire. The median follow-up period was 61.4 months (range 7.9-142.6 months). RESULTS: With one exception all patients had T1-2 tumors less than 5 cm in diameter. Most patients had invasive ductal breast cancers (57.1 %), followed by ductal carcinoma-in situ (27.1 %) and invasive lobular breast cancers (8.6 %). The incidence of positive resection margins was 17.1 %. No local tumor recurrence occurred during follow-up; one patient had distant metastases. In total, 80 % of the patients reported that the cosmetic results met or exceeded their expectations. CONCLUSIONS: The B technique is a safe breast conservation surgery for the excision of tumors located in the central portion of the breast and yields a high rate of satisfactory cosmetic results.

Comparative study of surgical margins and cosmetic outcome in lumpectomy versus segmental resection in breast cancer.

OBJECTIVE: The aim of the present retrospective study was to compare two breast-conserving techniques, segmental resection and standard lumpectomy, for the treatment of breast cancer regarding their oncological safety. Quality of life aspects were evaluated by assessing the respective postsurgical cosmetic results. PATIENTS AND METHODS: 190 women with breast cancer located in the superior and lateral quadrant were included in the study. Sixty patients were treated with segmental resection (group 1), whereas 130 underwent standard lumpectomy (group 2). Tumor sizes were determined and excised tissue specimens were analyzed for positive or negative resection margins. Patients were given a 16-item questionnaire for the postsurgical self-assessment of the cosmetic outcome. RESULTS: No statistically significant difference was found concerning the number of positive resection margins between the groups (25 vs. 30%, p = 0.46). Exceptions were ventral margins, which predominated in group 2 (p = 0.016). Group 1 revealed a significantly larger maximum tumor size with negative margins as compared to group 2 (26.6 vs. 17.0 mm). General satisfaction with the cosmetic results was comparable between groups. CONCLUSIONS: Segmental resection surgery, as a method of breast conservation therapy, can be used to treat larger breast lesions as compared to standard lumpectomy.

Significant changes in circulating plasma levels of IGF1 and IGFBP3 after conventional or dose-intensified adjuvant treatment of breast cancer patients with one to three positive lymph nodes.

The insulin-like growth factor 1 (IGF1) and its binding protein IGFBP3 (insulin-like growth factor binding protein 3) play a pivotal role during the growth and development of tissues. The purpose of this study was to evaluate the influence of anthracycline- and taxane-containing adjuvant chemotherapy in breast cancer patients on the circulating plasma levels of IGF1 and its main binding protein, IGFBP3. This investigation was part of a prospective randomized phase III study in which breast cancer patients were treated with either conventional or dose-intensified adjuvant chemotherapy. The factors were quantified in the plasma of 151 patients with a commercially available sandwich enzyme immunoassay. Before therapy, both parameters were within the normal range in most patients (n=145 and n=144). After therapy, both factors had increased significantly by 29% (IGF1) and 19% (IGFBP3), with the highest increase being observed in the dose-intensified group. Correlations with patient and tumor characteristics revealed a relatively higher increase in both parameters in premenopausal patients, patients with lower-grade tumors, more positive lymph nodes, larger tumor volume, and positive hormone receptor status. No correlation was found with the HER2 expression of the tumors.

Primary chemotherapy with doxorubicin and paclitaxel in patients with early breast cancer: final results of a multicenter phase II study.

PURPOSE: To assess the efficacy and safety of primary systemic treatment with doxorubicin and paclitaxel in patients with early breast cancer. PATIENTS AND METHODS: Forty patients with newly diagnosed, histologically confirmed breast cancer (T2, N0-1, M0) received primary chemotherapy with doxorubicin (60 mg/m2) and paclitaxel (200 mg/m2) in 3-week intervals for up to four courses. RESULTS: A total of 151 cycles were administered. The clinical response rate as assessed by sonographic measurement was 70%, and complete remissions of the primary tumor occurred in two patients. Eight patients (20%) had histologically confirmed complete responses. Predominant toxicity was myelosuppression with grade 3/4 neutropenia in 70% of patients. Non-hematological toxicity was generally moderate. Grade 4 non-hematological toxicities were not observed and grade 3 toxicity was reported with alopecia (98%) and stomatitis (10%). CONCLUSIONS: The combination of doxorubicin and paclitaxel is safe and highly active in patients with early breast cancer. The evaluated schedule is suitable for phase III studies.

Intraductal component in invasive breast cancer: analysis of 250 resected surgical specimens.

The presence of an intraductal component together with an invasive carcinoma is known to be associated with a higher rate of local recurrence. The results of reviewing 250 resected surgical specimens from patients with breast cancer are reported. Two-hundred and fifty mastectomy specimens of invasive breast cancer were retrospectively analysed in order to determine intraductal components within the primary tumour as well as additional foci. In addition to the invasive carcinoma, a ductal carcinoma in situ (DCIS) of varying extent was identified in 127 instances. The intraductal components were marginal in 27.6% of the cases, extensive in 61.4%, and predominant in 11.0%. In addition, 21 patients had isolated DCIS only. Such in situ components were more frequently found in the age group younger than 41 years and in premenopausal patients. Seventeen percent of carcinomas associated with an intraductal component were multicentric in location as opposed to only 5% of the breast lesions without an intraductal component. The highest proportion of residual tumour was seen in poorly differentiated invasive carcinomas with DCIS. Intraductal carcinomas with intraductal component tended to have a higher incidence of a positive surgical margin. Small carcinomas with an extensive in situ component require careful surgical management in order to achieve a tumour-free margin.

Adjuvant treatment of breast cancer patients with 1-3 positive lymph nodes: vinorelbine plus epirubicin; vinorelbine plus epirubicin sequential followed up by paclitaxel; epirubicin plus cyclophosphamide; epirubicin plus cyclophosphamide sequential followed up by paclitaxel. A phase II study.

PURPOSE: The efficacy of anthracyclin-containing adjuvant chemotherapy of node-positive breast cancer can be further improved by adding sequential paclitaxel (T). There is also clinical evidence that replacing cyclophosphamide (C) with vinorelbin (V) might further reduce toxicity. In order to assess the safety of these options, we initiated a clinical cohort study of epirubicin/cyclophoshamide and epirubicin/vinorelbine with or without sequential paclitaxel. METHOD: Patients with node-positive (1-3) breast cancer were assigned to open-label epirubicin/vinorelbine (EV), epirubicin/vino-relbine and sequential paclitaxel (EV/T), epirubicin/cyclophosphamide (EC) or epirubicin/cyclophosphamide plus sequential paclitaxel (EC/T) therapy. RESULTS: Fifty four outpatients received a total of 304 chemotherapy cycles. There were significant differences in grade III/IV anemia only between the EV/T and EC/T groups, in favor of the EC/T group (P=0.002). CONCLUSIONS: The safety of paclitaxel is not impaired when given sequentially after administration of the two anthracyclin-containing regimens. The exchange of cyclophosphamide against vinorelbine leads to deteriorating safety of the EC/T regimen.

Non-pegylated liposomal doxorubicin and docetaxel in metastatic breast cancer: final results of a phase II trial.

BACKGROUND: Non-pegylated liposomal doxorubicin (NPLD) has demonstrated equivalent antitumor activity to conventional doxorubicin and a significantly lower risk of cardiotoxicity when given as single agent or in combination with cyclophosphamide, but there is limited experience with the combination of NPLD and taxanes. This phase II study was performed to evaluate the efficacy and safety of the NPLD and docetaxel in patients with metastatic breast cancer. PATIENTS AND METHODS: A total of 51 patients were treated with NPLD (60 mg/m(2)) and docetaxel (75 mg/m(2)) in 3-weeks intervals for up to eight cycles. RESULTS: The overall response rate was 50% and 78% of patients derived a clinical benefit. Median time to progression and overall survival were 10.0 months (95% CI, 6.9-13.1 months) and 25 months (95% CI, 22.1-29.8 months), respectively. Median duration of response was 12.0 months (95% CI 7.1-16.9). The treatment was generally well tolerated and associated with toxicities that were consistent with the known side-effects of the individual agents and of anthracycline/taxane combinations. There were no symptomatic cardiac averse events and mild asymptomatic LVEF changes were reported in five patients. CONCLUSIONS: The combination of NPLD and docetaxel is well tolerated and has high antitumour activity in MBC patients.

[Minimal invasive transvaginal right hemicolectomy: report of the first complex NOS (natural orifice surgery) bowels operation using a hybrid approach]. / Minimalinvasive transvaginale Hemikolektomie rechts: Bericht über die erste komplexe NOS (Natural Orifice Surgery)Darmoperation in Hybridtechnik.

BACKGROUND: Laparoscopic surgery has dramatically changed abdominal surgery by reducing the risk of wound infections, incisional hernias and adhesions. The surgical concept using natural orifices (NOS) may be even less traumatic and so less invasive. PATIENT AND METHODS: This operation was performed in a 66-year-old woman with an adenoma in the ascending colon. Through a 5 mm incision at the umbilicus a pneumoperitoneum was created and a trocar inserted. For the operation a 12 mm trocar and a curved grasper have been inserted in the posterior fornix of the vagina. Because of adhesions an additional 5 mm trocar was necessary. Through this incision the laparoscopic right hemicolectomy with an intracorporal anastomosis was performed. RESULTS: The histology showed an adenoma with 21 lymph nodes. The removal of the specimen through the vagina was without any difficulties. The postoperative course was regular. CONCLUSIONS: This operation is to our knowledge the first right hemicolectomy as a NOS/NOTES-operation in a human patient. It shows that with rigid instruments even complex procedures through natural orifices are feasible.

Quality of care of VLBW neonates: relationship between unit volume and outcome is different between metropolitan and rural regions.

BACKGROUND: Recent studies from predominantly rural areas in Germany show that neonatal outcome of very low birth weight (VLBW) neonates is (on average) inferior with lower NICU (neonatal intensive care unit) volume. However, there are no data available which show that study results of one specific region can be transferred to other areas with possibly different medical infrastructure and needs. AIM: It was investigated whether a systematic difference of treatment quality between smaller (1000-2000 births/year; < or =20 neonatal beds) vs. larger neonatal centres in Berlin (>3000 births/year; >20 neonatal beds) exists. Furthermore, the results are compared to data from a rural region in order to discuss transferability between regions. METHODS: Retrospectively, completely, and for the first time, the data of all centres which treat VLBW neonates (< or =1500 g birth weight) in the city-state of Berlin, Germany, from the years 2003/2004 were reviewed. RESULTS: Our study showed no difference in the treatment quality of smaller vs. larger neonatal units in Berlin. This result differs from those of a study in Baden-Württemberg, a predominantly rural state, with different medical infrastructure than Berlin. CONCLUSION: The present study suggests that regional investigations on the infrastructure vs. treatment outcome are not transferable between areas. Patient volume/unit appears inadequate for predicting the future treatment quality of neonatal departments. Direct quality indicators are stable for the assessed departments and should be preferably used to organize medical infrastructure.

Randomised trial: survival benefit and safety of adjuvant dose-dense chemotherapy for node-positive breast cancer.

We evaluated the survival benefit, safety, feasibility, and tolerability of dose-dense (DD) adjuvant chemotherapy with epirubicin and paclitaxel for women with node-positive primary breast cancer. Randomised patients (n=216) received DD or conventional-schedule (CS) chemotherapy. Dose-dense regimen patients (n=108) received epirubicin 90 mg m-2 plus paclitaxel 175 mg m-2 in four 14-day cycles, then cyclophosphamide 600 mg m-2, methotrexate 40 mg m-2, and fluorouracil 600 mg m-2 (CMF 600/40/600) in three 14-day cycles, plus filgrastim 5 microg kg day-1 as growth support in every cycle. Conventional-schedule regimen patients (n=108) received epirubicin 90 mg m-2 plus cyclophosphamide 600 mg m-2 in four 21-day cycles, then CMF 600/40/600 in three 21-day cycles, plus filgrastim if required. After a median follow-up of 38.4 months, 71 patients (33%) relapsed or died: DD, 33 patients (15 deaths); CS, 38 patients (22 deaths). Dose dense showed a trend for improved disease-free survival (DFS) and overall survival (OS). Four-year rates of DFS and OS were 64 and 85% for DD, and 58 and 75% for CS. All seven cycles were administered to 208 patients (96%). Rates of cycle delay, discontinuation, dose reduction, and adverse events were similar in both groups. Dose-dense sequential chemotherapy with epirubicin/paclitaxel then CMF, supported by filgrastim, is safe and improves survival for patients with node-positive breast cancer.

Primary chemotherapy with gemcitabine as prolonged infusion, non-pegylated liposomal doxorubicin and docetaxel in patients with early breast cancer: final results of a phase II trial.

BACKGROUND: Combinations of anthracyclines, taxanes and gemcitabine have shown high activity in breast cancer. This trial was designed to evaluate a modified combination regimen as primary chemotherapy. Non-pegylated liposomal doxorubicin (NPLD) was used instead of conventional doxorubicin to improve cardiac safety. Gemcitabine was given 72 h after NPLD and docetaxel as a prolonged infusion over 4 h in order to optimize synergistic effects and accumulation of active metabolites. PATIENTS AND METHODS: Forty-four patients with histologically confirmed stage II or III breast cancer were treated with NPLD (60 mg/m(2)) and docetaxel (75 mg/m(2)) on day 1 and gemcitabine as 4-h infusion (350 mg/m(2)) on day 4. Treatment was repeated every 3 weeks for a maximum of six cycles. All patients received prophylactically recombinant granulocyte colony-stimulating factor. Patients with axillary lymph node involvement after primary chemotherapy received adjuvant treatment with cyclophosphamide, methotrexate and fluorouracil. RESULTS: The clinical response rate was 80%, and complete remissions of the primary tumor occurred in 10 patients (25%). Breast conservation surgery was performed in 19 out of 20 patients (95%) with an initial tumor size of less than 3 cm and in 14 patients (70%) with a tumor size

[Obstetrical data of 11,874 deliveries at a university clinic of a developing country]. / Geburtshilfliche Daten von 11,874 Entbindungen unter den Bedingungen einer Universitätsklinik in einem Nationalstaat.

A report a given shout data of 11,874 deliveries and 12,338 childs which was born in 1987 in Central Hospital of Maputo PR of Mozambique. The perinatal mortality smouted to 65% and the maternal mortality 253%. Totally registrated a frequency of 15.2% of cesarean sections and observed in 30 cases a rupture of the uterus. Deliveries have been terminated in 2.8% by vaccum extraction and only in 0.1% by forceps. We observed a twin delivery in 458 cases or in 3.8% and a triplet delivery in 6 time. These data have been discussed in detail.

[Various prognostic aspects in squamous epithelial cervix carcinoma of clinical stage I-III]. / Uber einige Aspekte der Prognose beim Plattenepithelkarzinom der Cervix uteri der klinischen Stadien I-III.

On base of the 5-year healing a report is given about the relationship between prognosis and histological grade of differentiation by epithelial carcinoma of the cervix. For this purpose uniform cases were choses, by which both histological and clinical judgement took place. A near correlation between grade of differtiation and prognosis was found. The 5-year healing amounted by stage I 73.5%, by stage II 56.3%, by stage III 27.5% and by stage IV 0%. Taking all stages of the epithelial carcinoma of the cervix together, the 5-year healing was reached by the differentiated carcinoma in 94% of cases, whereas only 52.4% of the middleripe and 9.2% of the undifferentiated carcinoma were able to reach the same. A near relationship between the biological valence of the tumor and prognosis was found.

[Primary tumor duplicity in cervix cancer in the material of the Berlin University Gynecological Clinic, 1955--1969]. / Uber primäre Tumormultiplizität beim Zervixkarzinom im Material der Universitäts-Frauenklinik der Charite, Berlin, von 1955 bis 1969.

A report is given about the primary event of multiple maligne tumors by patients with carcinoma of the cervix. We found a second maligne tomor in 1.5% of cases. The manifestation was variable. Specially frequent is the coincidence of carcinoma of the cervex and carcimoma of the endometrium. The average age runs up to 62 years. The interval up to the diagnosis of the second tumor amounts 3,8 years. The probability of developing a second maligne tumor declines when the interval becomes longer. The necessity of an interdisciolinary team-work between acters in the follow up care of cancer patients is pointed out.

[Various healing results in adenocarcinoma and squamous-cell carcinoma of the cervix uteri]. / Uber unterschiedliche Heilungsergebnisse beim Adenokarzinom und Plattenepithelkarzinom der Cervix uteri.

An account is given on the difference in prognosis between squamous cell carcinoma and adenocarcinoma of the cervix. -- The 5-year-healing reaches by adenocarcinoma up to 65.3%, by epithelial carcinoma up to 50.1%. -- Possible causes of carcinoma are referred to. Conclusions are pointed out.

[Therapeutic results in uterus sarcoma]. / Behandlungsergebnisse beim Uterussarkom.

Thirty-five cases of uterus sarcoma admitted to the Gynaecological Hospital of Humboldt-Universität zu Berlin, Charité, between 1963 and 1976, are reported in this paper. An account is given of the prognosis of uterus wall and mucous membrane sarcomata, with the authors' findings being compared with data from the literature. The need is emphasised for centralised treatment of the low number of cases.

[Treatment monitoring of patients with uterine cancer with and without progression by free serum amino acids]. / Therapiemonitoring bei Patientinnen mit Korpuskarzinom mit und ohne Progression durch freie Serumaminosäuren.

We determined 10 free serum amino acids by automatic chromatographic analyses in continuous steps in tumour monitoring of 51 patients with cancer of the uterine body. There were 39 patients without and 12 patients with recurrent disease. We found an elevation of aspartic acid, glutaminic acid, tyrosine and phenylalanine in continuous monitoring. Glycine, alanine, valine and leucine have an increased level in pretherapeutic value, too. A monitoring with amino acids in metaphylaxis is possible.

[Incidence of postoperative recurrence (stages Ia-IIb) of squamous cell carcinoma of uterine cervix in correlation with cellular grading (author's transl)]. / Rezidivhäufigkeit in Korrelation zum zellulären Grading bei Plattenepithelkarzinom der Cervix uteri der postoperativen Stadien Ia-IIb.

An account is given in this paper of 251 cases of invasive squamous cell carcinoma of the uterine cervix in postoperative stages Ia to IIb. Tumour recurrence was recorded from 26.6 per cent of the patients. Recurrence rates were 29 per cent in Stage Ib and 57.1 per cent in Stage IIa-b. Incidence of recurrence in these stages was proportionally related to decline in carcinoma differentiation. Recurrence was at its highest within the first three years from primary therapy. Conclusions are drawn for metaphylaxis.

[3-year analysis of gynecologic neoplasms treated at the Central Maputo Hospital]. / Dreijahreanalyse der im Hospital Central Maputo behandelten gynäkologischen Malignome.

Within the time from January 1984 to March 1987 209 patients with female genital neoplasms have been treated in the Hospital Central Maputo in People's Republic of Moçambique. There were nearly 85% cervical carcinomas and about 15% of chorion-carcinomas. Only two cases (0.9%) were endometrial cancers. 80% of the cervical carcinomas were diagnosed in stage III and IV. 31 cases had been operated on radically by abdominal route. Further epidemiological dates are published.