BackgroundDose-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 methodsWomen (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.ResultsFrom 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).ConclusionAdding capecitabine to ddEC-Pw did not improve outcome in comparison to iddEPC but increased toxicity and should not be recommended for further use.

Aim: In locally advanced breast cancer pts (≥pN2), adjuvant iddETC resulted in superior disease-free (DFS) and overall survival (OS) compared to conventionally dosed EC > Tq3w (AGO-ETC; Möbus JCO 2010). In the GAIN trial, iddETC was compared to a 4-drug dose-dense regimen with capecitabine (ddEC > TwX). Using the GAIN data, here we want to confirm the iddETC-results of the AGO-ETC trial with regard to DFS, OS, and toxicity.

To evaluate the oncologic safety and cosmetic results after breast cancer surgery for central breast cancer by the B technique.

624 Background: Combinations of trastuzumab and anthracyclines in HER2-positive breast cancer are highly active but associated with a high incidence of cardiotoxicity. The risk of cardiac damage can be significantly reduced through liposomal encapsulation of anthracyclines. This phase I/II study was initiated to evaluate the combination of non-pegylated liposomal doxorubicin (NPLD), paclitaxel and lapatinib as primary treatment for patients with early stage, HER2-positive primary breast cancer. Methods: Patients with newly diagnosed HER2-positive (IHC 3+ or FISH+) early stage (T1c N1-2 or T2 N0-2) breast cancer were treated with NPLD (60mg/m2; day 1), paclitaxel (175mg/m2, day 1) and lapatinib (750-1500 mg orally daily) in 3-week intervals for up to 6 cycles. The primary endpoints were dose-limiting toxicities (DLT) and pathological complete response (pCR). Secondary endpoints include safety, incidence of cardiac events, and clinical response. Exploratory endpoints include molecular markers for sensitivity or resistance to chemotherapy and/or lapatinib evaluated. Results: A total of 84 patients have been included to date.No DLTs were observed and the maximum tolerated doses were NPLD 60mg/m2, paclitaxel 175mg/m2 and lapatinib 1500mg. Recommended phase 2 doses (P2D) were NPLD 60mg/m2, paclitaxel 175mg/m2 and lapatinib 1250mg. The treatment was generally well tolerated and associated with toxicities that were consistent with the known side-effects of the individual agents. No cardiac event has been observed to date. Preliminary efficacy data confirm a pCR breast rate of 41.7% and pCR rate in breast and lymph nodes of 37.5%, in 24 evaluable patients treated at ≥P2D. Conclusions: The combination of NPLD, paclitaxel and lapatinib is well tolerated and has high antitumour activity in patients with HER2-positive primary breast cancer. The phase II part of the study is ongoing and updated results will be presented.

Abstract Background: Several studies showed that pathologic complete response (pCR) is a surrogate for disease free survival (DFS) and overall survival (OS). Combinations of trastuzumab and anthracyclines in HER2-positive breast cancer are highly active but associated with a high incidence of cardiotoxicity. The risk of cardiac damage can be significantly reduced through liposomal encapsulation of anthracyclines. This phase I/II study was initiated to evaluate the combination of non-pegylated liposomal doxorubicin (NPLD), paclitaxel and lapatinib as primary treatment for patients with early stage, HER2-positive primary breast cancer. Patients and Methods: Patients with newly diagnosed HER2-positive (IHC 3+ or FISH+) early stage (T1c N1-2 or T2 N0-2) breast cancer were treated with NPLD (60mg/m2; day 1), paclitaxel (175mg/m2, day 1) and lapatinib (750–1500 mg orally daily) in 3-week intervals for up to 6 cycles. The primary endpoints were dose-limiting toxicities (DLT) and pathological complete response (pCR). Secondary endpoints include safety, incidence of cardiac events, and clinical response. Exploratory endpoints include molecular markers for sensitivity or resistance to chemotherapy and/or lapatinib evaluated. Results: A total of 84 patients have been included. No dose-limiting toxicity were observed and the maximum tolerated doses were NPLD 60mg/m2, paclitaxel 175mg/m2 and lapatinib 1500mg. Recommended phase 2 doses (P2D) were NPLD 60mg/m2, paclitaxel 175mg/m2 and lapatinib 1250mg. The treatment was generally well tolerated and associated with toxicities that were consistent with the known side-effects of the individual agents. No cardiac event has been observed to date. Preliminary efficacy data confirm a pCR breast rate of 41.7% and pCR rate in breast and lymph nodes of 37.5%, in 32 evaluable patients treated at ≥P2D. Conclusions: The combination of NPLD, paclitaxel and lapatinib is well tolerated and has high antitumor activity in patients with HER2-positive primary breast cancer. Updated results of all 84 patients will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-05.

Abstract Background: We previously showed that intense dose-dense (idd) epirubicin (E), paclitaxel (T), cyclophosphamide (C) results in a superior DFS and OS compared to conventionally dosed EC-T in pts with primary breast cancer (PBC) and ≥4 involved lymph nodes (LN) (Möbus et al JCO 2010). In the GAIN study, the intense dose-dense strategy has been further investigated as well as the adjuvant application of ibandronate (I). We here report on the planned interim efficacy analysis after 50% (N>401) of the required events have occurred. Methods: A prospective, multi-center, controlled, non-blinded, randomized phase III trial investigating ETC (E: 150 mg/m2, T:225 mg/m2, C:2500–2000 mg/m2, i.v. day 1, q15 for 3 cycles each: A1); or EC→TX (E: 112.5 mg/m2 + C: 600 mg/m2, i.v. day 1, q 15 for 4 cycles→T: 67.5 mg/m2 i.v. day 1, q 8 for 10 weeks + X: 2000 mg/m2 p. o. day 1–14, q 22 for 4 cycles: A2). Pts were further randomized in a 2:1 ratio to receive ibandronate: 50 mg/day p.o. for 2 years (B1) or observation (B2). Pts received a primary prophylaxis with either epoetin β or darbepoetin α and pegfilgrastim during ETC or EC. After recruitment of 1500 pts prophylactic ciprofloxacin was implemented and the dose of C was reduced to 2000 mg/m2. Eligibility: Females ≥18 and <65 years, histologically confirmed LN positive uni- or bilateral PBC; adequate surgery, ≥1 pos.LN; ECOG ≤2; written informed consent. Primary objective:compare DFS A1 vs. A2 and B1 vs.B2. Secondary objectives: OS, safety, incidence of secondary primaries, and EFS in subgroups of hormone sensitivity and number of pos. LN between arms; assessment of compliance; determine prognostic factors. 3000 pts with 801 events were needed to show an increase of 5-year DFS from 75% to 79% for pts receiving EC→TX and 728 events to show an increase of 5-year DFS from 75% to 79.5% for pts receiving I, assuming a drop-out rate of 5%, α=0.05 (two-sided)and 1-β =80%. An interim analysis for both primary objectives was planned after 50% of the expected events occurred. Safety results have been reported previously (Möbus et al. SABCS 2009). Results: 3023 patients were randomized between 06/2004 and 08/2008.1512 received ETC and 1511 EC→TX. 29pts never started therapy, 14 in ETC, 15 in EC→TX. Median follow-up is 38.7 months. Median age was 50 years; pN1 (37.7%), pN2 (35.4%); pN3 (26.9%); 77.4% had ductal invasive carcinoma, 46.6% were grade 3; 76.7% had hormone receptor-positive tumors, 22% were HER2−positive. 405 events have occurred by 12.05.2011.380pts relapsed and 25pts. died w/o relapse. The interim futility boundary for chemotherapy was not crossed. For the ibandronate question the futility boundary was reached. There was no difference in DFS and OS between the patients with and without ibandronate (DFS log-rank p=0.593; HR 1.059; 95%CI 0.861−1.301; OS log-rank p=0.801 HR 0.961; 95% CI 0.705−1.31). Conclusion: The GAIN study demonstrated that adjuvant ibandronate does neither improve DFS nor OS in primary node positive breast cancer after treatment with dose-intensified chemotherapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S2-4.

Eine Gigantomastie in der Schwangerschaft, ist ein seltenes aber potentiell komplikationsträchtiges Krankheitsbild. Sie ist charakterisiert durch ein überdurchschnittliches Brustwachstum mit möglichen Folgen von Gewebsnekrosen, Ulzerationen, Infektionen und Blutungen. Schon 1648 beschrieb Palmuth ein überdimensionales Wachstum der graviden Mammae. Die Prävalenz der schwangerschaftsassoziierten Gigantomastie wird mit einer Häufigkeit von 1:28000 und 1:118000 Geburten angegeben. Aus den Fallbeispielen lassen sich Behandlungskonzepte von der Notfall Indikation einer Ablatio mammae bis zur elektiven Versorgung im Langzeitverlauf ableiten, wobei dies nach den Literaturbeispielen bei nur 40% der Patientinnen möglich war. Mit unserer Behandlungsstrategie möchten wir einen optimierten Behandlungsablauf einer komplikationslosen Gingatomastie in der Schwangerschaft skizzieren.

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.

Abstract Background: There is a paucity on toxicity (tox) data in elderly patients (pts) above 65 years (yrs) treated with anthracycline containing standard chemotherapy (ct) for primary breast cancer. We investigated the tox of standard anthracycline based regimen (AC/EC) and compared those with alternatives like dose-dense monotherapies and combinations (Edd; ADdd), intensified combinations (Canadian FEC) and taxane/anthracycline combinations (TAC) in various age groups. Patients and methods: In this pooled analysis, individual pts data from 4 German randomized trials (n= 4775) were evaluated regarding tox and compliance. Docetaxel/doxorubicin/cyclophosphamide (75/500/500mg/m2) 3qw (A=TAC), 5-fluorouracil/epirubicin (500/60mg/m2) iv d1+8 followed by cyclophosphamide (75mg/m2) po d1-14 q4w (B=cFEC), doxorubicin (epirubicin)/cyclophosphamide (60(90)/600mg/m2) q3w followed by docetaxel (100mg/m2) or paclitaxel (175mg/m2) q3w (C= AC/EC-D/p), doxorubicin/docetaxel (50/75mg/m2) q2w (D= AD dose dense(dd)) and epirubicin-paclitaxel q2w (120/175 mg/m2) (E= sequence dd) were given. Only the anthracycline containing cycles were investigated. A descriptive analysis was performed on compliance and (non-) hematological tox. Pts were grouped according to their age: < 60yrs [1], 60-64 yrs [2] and >64yrs [3]. Primary G-CSF support was given in A, D, E. Results: 73.6% were <60 yrs, 15.8% were 60-64 and 10.6% were > 64. A total of 22,306 anthracycline containing cycles were administered, of those 74.6% were given to [1], 15.2% to [2] and 10.0 % to [3]. 41.6% of the pts received TAC; 11.5% cFEC; 29.2% AC/EC-D/P; 8.2% ADoc dd and 9.5% Edd-Pdd. The incidence of febrile neutropenia (FN) did not significantly differ between the 3 age groups (overall A:10.0%; B:2.9%; C:1.0%; D:4.7%) apart from E with 0.9% ([1]0%; [2]6.4%; [3]0% P<0.001). FN in pts >64 was lower in B (2.4%) than in A (14.4%) and D (5.1%). Diarrhea grade 3+4 increased with age to 8.2% for [3] under TAC (p= 0.01) and mucositis grade 3+4 under E to 12% for >64 (P<0.001). Conclusion: In total, range and intensity of tox increased with age. Neutropenia did significantly increase with age in standard regimen but not in the dd groups Rate of dose reduction increased with age in A ([1] 6.1%; [2]6.5%; [3] 11.5; p=0.02) and B ([1]15.7%; [2]26.9%; [3]39.3%; p< 0.001). Similar significant results were observed for discontinuations and hospitalizations in A, B, D. Neutropenia grade 3+4 in [3] was 77% with cFEC, vs 55%with TAC (with primary G-CSF). Leucopenia Grade 3+4 in % (D, E). The severity of the non-hematotox differed between age groups and regimen. Monotherapies and sequential regimen seem more favorable in elderly pts. cFEC without G-CSF is not an option in pts >64. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-09.

Rationale: Die B-Plastik ist eine OP-Methode der brusterhaltenden Therapie zur Resektion eines Mammakarzinoms oder dessen Vorstufen mit zentralem Sitz, bei der nach Resektion des Tumor mit der darüberliegenden Mamille eine onkoplastische Deckung des Defekts erfolgt. Eine Untersuchung bezüglich der Wertigkeit dieser Methode gibt es derzeit nicht. Ziel dieser retrospektiven Studie ist die Evaluierung der Tumorschnittränder, der Rate von Zweitoperationen und der Patientenzufriedenheit nach der B-Plastik im Vergleich zur Segmentresektion. Methode: Retrospektiv wurden 70 bzw. 60 Patientinnen mit einer B-Plastik oder Segmentresektion (mit Haut, T-Schnitt) hinsichtlich der Tumorschnittränder, der Nachresektionsrate und der Patientenzufriedenheit analysiert. Die zwei Patientengruppen wurden jeweils in drei Kliniken im Zeitraum von 9/1998 bis 9/2007 behandelt. Zur Erfassung der Patientenzufriedenheit erfolgte eine Befragung nach mindestens einem halben Jahr der Primärtherapie. Ergebnisse: Ein schnittrandbildendes Karzinom/DCIS lag in der Gruppe der B-Plastik in 12(17,1%) und der Gruppe der Segmentresektionen in 15(25%) der Fälle vor (p=0,28). Zweitoperationen wurden bei 10 (14,3%) Patientinnen mit B-Plastik und 12(20%) Patientinnen mit Segmentresektion durchgeführt (p=0,48). Das kosmetische Ergebnis der operierten Brust wurde durch die Patientinnen mit einer B-Plastik bzw. Segmentresektion in 90% und 94% der Fälle mit sehr gut bis gut beurteilt. Diskussion: Die B-Plastik ist hinsichtlich der tumorfreien Resektionsränder und der Rate von Zweitoperationen eine sichere OP-Technik. Die Patientenzufriedenheit bzgl. des kosmetischen Ergebnisses war in beiden Gruppen sehr hoch.

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.

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.

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.

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 μ g 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.

Due to improved life expectancy and the increase in incidence of breast cancer in old age, ever more older women are developing this disease. Although there is only limited evidence-based data from randomized trials on the treatment, older patients are still under-represented in clinical studies, and currently there is no clear consensus on chemotherapy treatment for older women with breast cancer. Adjuvant therapy strategies, in particular, suffer from a lack of uniform standards and reflect a generally less aggressive treatment. Recently published studies have shown that older women suffering from breast cancer can also profit from a treatment based on therapeutic standards and consensus guidelines. In spite of developments in adjuvant chemotherapy using increased amounts of therapeutic agent to improve survival, many older patients receive instead reduced quantities of chemotherapeutic agent. Thus, the questions arise, whether undertreatment of older patients with breast cancer can lead to a poorer outcome or whether new therapy strategies (e.g., dose-intensive chemotherapy) can be used with older patients. A common reason for dose reductions is neutropenia, but studies have shown that it is manageable by using granulocyte colony-stimulating factors (G-CSFs). In this review, the current status of clinical research in the area of adjuvant treatment and the necessity for clinical studies that take into account the special therapeutic requirements of older women are discussed.