Long-term outcomes of a randomized, open-label, phase II study comparing cabazitaxel versus paclitaxel as neoadjuvant treatment in patients with triple-negative or luminal B/HER2-negative breast cancer (GENEVIEVE).

BACKGROUND: The GENEVIEVE study, comparing neoadjuvant cabazitaxel versus paclitaxel in triple-negative breast cancer (TNBC) and luminal B/human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC), previously reported significant differences in pathological complete response (pCR) rates. Effects on long-term outcome are unknown. PATIENTS AND METHODS: GENEVIEVE randomized patients with cT2-3, any cN or cT1, cN+/pNSLN+, centrally confirmed TNBC or luminal B/HER2-negative BC (latter defined as estrogen/progesterone receptor-positive and >14% Ki-67-stained cells) to receive either cabazitaxel 25 mg/m2 q3w for four cycles or paclitaxel 80 mg/m2 weekly for 12 weeks. Anthracycline-containing chemotherapy was allowed in case of histologically proven invasive residuals as neoadjuvant treatment or after surgery as adjuvant treatment. Here we report the secondary endpoints invasive disease-free survival (iDFS), distant disease-free survival (DDFS), and overall survival (OS). RESULTS: Of the 333 patients randomized, 74.7% and 83.2% completed treatment in the cabazitaxel and paclitaxel arms, respectively. After a median follow-up of 89.3 months (interquartile range 68.8-97.3 months), 80 iDFS events (43 after cabazitaxel and 37 after paclitaxel) and 47 deaths (23 after cabazitaxel and 24 after paclitaxel) were reported. IDFS rates were not significantly different between the cabazitaxel and paclitaxel arms after a 3-year (83.6% versus 85.0%) and 5-year follow-up (76.2% versus 78.3%) [hazard ratio (HR) = 1.27, 95% confidence interval 0.82-1.96, P = 0.294], respectively. DDFS rates at 3 years (88.6% versus 87.8%) and 5 years (82.1% versus 82.8%) for cabazitaxel and paclitaxel were comparable (HR = 1.15, P = 0.573). Similarly, OS rates at 3 years (91.6% versus 91.8%) and 5 years (89.2% versus 86.8%) showed no significant differences (HR = 1.05, P = 0.872). Subgroup analysis for TNBC and luminal B/HER2-negative BCs indicated no significant variations in 3- or 5-year iDFS, DDFS, or OS. CONCLUSIONS: The significant differences in pCR rates observed in both treatment arms did not significantly impact long-term outcomes for patients treated with cabazitaxel versus paclitaxel in the GENEVIEVE trial.

Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study).

BACKGROUND: The efficacy and toxicity of olaparib as combination therapy in early breast cancer (BC) patients with homologous recombinant deficiency (HRD) [score high and/or germline (g) or tumour (t) BRCA1/2 mutation] is not well described. GeparOLA (ClinicalTrials.gov, NCT02789332) investigated olaparib in combination with paclitaxel in HER2-negative early BC with HRD. PATIENTS AND METHODS: Patients with untreated primary HER2-negative cT2-cT4a-d or cT1c with either cN+ or pNSLN+ or cT1c and triple-negative breast cancer (TNBC) or cT1c and Ki-67>20% BC with HRD were randomised either to paclitaxel (P) 80 mg/m2 weekly plus olaparib (O) 100 mg twice daily for 12 weeks or P plus carboplatinum (Cb) area under the curve 2 weekly for 12 weeks, both followed by epirubicin/cyclophosphamide (EC). Stratification factors were hormone receptor (HR) status (HR+ versus HR-) and age (<40 versus ≥40 years). The primary endpoint was pathological complete response (pCR; ypT0/is ypN0). A two-sided one-group χ2-test was planned to exclude a pCR rate of ≤55% in the PO-EC arm. Secondary end points were other pCR definitions, breast conservation rate, clinical/imaging response, tolerability and safety. RESULTS: A total of 107 patients were randomised between September 2016 and July 2018; 106 (PO N = 69; PCb N = 37) started treatment. Median age was 47.0 years (range 25.0-71.0); 36.2% had cT1, 61.0% cT2, 2.9% cT3, and 31.8% cN-positive tumours; grade 3 tumours: 86.8%; Ki-67>20%: 89.6%; TNBC: 72.6%; confirmed gBRCA1/2 mutation: 56.2%. The pCR rate with PO was 55.1% [90% confidence interval (CI) 44.5% to 65.3%] versus PCb 48.6% (90% CI 34.3% to 63.2%). Analysis for the stratified subgroups showed higher pCR rates with PO in the cohorts of patients <40 years and HR+ patients. CONCLUSION: GeparOLA could not exclude a pCR rate of ≤55% in the PO arm. PO was significantly better tolerated and the combination merits further evaluation.

Sorafenib in combination with docetaxel as first-line therapy for HER2-negative metastatic breast cancer: Final results of the randomized, double-blind, placebo-controlled phase II MADONNA study.

BACKGROUND: This multicenter, double-blind phase II study assessed the antitumor activity and toxicity profile of docetaxel with the antiangiogenic multikinase inhibitor sorafenib or matching placebo as a first-line treatment in patients with metastatic or locally advanced HER2-negative breast cancer. PATIENTS AND METHODS: Patients were randomized 1:1 to receive docetaxel 100 mg/m2 on day 1 every 3 weeks in combination with sorafenib 400 mg bid or placebo on days 2-18 of each cycle until tumor progression, or unacceptable toxicity. Sorafenib/placebo could be continued at the investigator's discretion if docetaxel was stopped due to toxicity. Primary endpoint was progression free survival (PFS). RESULTS: From October 2008 to December 2013, 102 patients were randomized; 98 patients were evaluable. The trial was prematurely terminated due to slow accrual. Due to increased toxicity the dose of docetaxel was reduced to 75 mg/m2 and an increasing sorafenib dosing schedule was implemented as part of a protocol amendment. The addition of sorafenib to docetaxel did not improve PFS (8.2 vs. 7.3 months for docetaxel/placebo; HR 0.84, log rank p = 0.43), but led to higher rates of early treatment discontinuation. There were no statistically significant differences between sorafenib dosing schedules. CONCLUSIONS: Addition of sorafenib to taxane-based first-line chemotherapy in patients with metastatic breast cancer failed to improve PFS and resulted in increased toxicity.

Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response-final results from GeparSixto.

Background: In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD). Patients and methods: Patients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA). Results: A significantly better DFS (hazard ratio 0.56, 95% CI 0.34-0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) [odds ratio (OR) 2.60, 95% CI 1.26-5.37, P = 0.008]. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46-9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17-1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23-1.04, P = 0.059). Conclusions: The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.

[Retrieval of a migrated plastic stent in a 51-year-old man]. / Bergung eines migrierten Doppel-Pigtail-Stents bei einem 51-jährigen Patienten.

BACKGROUND: Endosonographically guided transgastric drainage is the first-line interventional therapy of walled-off necrosis and symptomatic pancreatic pseudocysts in necrotizing pancreatitis. Plastic stents or lumen apposing metal stents are commonly used. A possible complication of endoscopic therapy is stent migration. CASE REPORT: We report upon a 51-year-old man who presented with acute necrotizing pancreatitis. Transgastric necrosectomy was performed and 5 transmural double-pigtail stents (DPS) were left in situ to drain the residual retroperitoneal cavity. The patient recovered and 4 stents were endoscopically removed 5 weeks later on an outpatient basis, whereas the fifth stent was suspected to have passed spontaneously via the natural route. The asymptomatic patient presented 3 months later for follow-up computed tomography. The necrosis had healed but one DPS was seen beyond the gastric wall near the kidney. Transmural access to the stent could be achieved by an endosonographically guided puncture toward the proximal portion of the stent followed by placement of a hydrophilic guidewire alongside the stent. A new gastrostomy was created by using a 6F cystotome followed by wire-guided dilation with a 12 mm balloon. The stent could then be grasped with transmurally inserted rat-tooth forceps and repositioned across the gastrostomy site. The patient was given prophylactic antibiotics. After removal of the stent, the patient could be discharged. CONCLUSION: Herein, we present the successful endosonographically guided transmural removal of a retroperitoneally migrated plastic stent. Of note, in our patient we had to rely completely on endosonography and radiography for localization and targeting of the stent, since the former necrotic cavity had meanwhile completely healed.

Topotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or pegylated liposomal doxorubicin plus carboplatin (PLDC): a randomized phase III trial of the NOGGO-AGO-Study Group-AGO Austria and GEICO-ENGOT-GCIG intergroup study (HECTOR).

BACKGROUND: Randomized, phase III trial to evaluate safety and efficacy of topotecan and carboplatin (TC) compared with standard platinum-based combinations in platinum-sensitive recurrent ovarian cancer (ROC). PATIENTS AND METHODS: Patients were randomly assigned in a 1:1 ratio to the experimental TC arm (topotecan 0.75 mg/m2/ days 1-3 and carboplatin AUC 5 on day 3 every 3 weeks) or to one of the standard regimes [(PC) paclitaxel plus carboplatin; (GC) gemcitabine plus carboplatin; (PLDC) pegylated liposomal doxorubicin and carboplatin] which could be chosen by individual preference but before randomization. The primary end point was progression-free survival (PFS) after 12 months. Overall survival (OS), response rate, toxicity, quality of life and treatment preference regarding standard treatment were defined as secondary end points. RESULTS: A total of 550 patients were recruited. The PFS rate after 12 months was 37.0% for TC compared with 40.2% in the standard combinations (P = 0.470). The overall response rate was 73.1% for TC versus 75.1% for standard combinations (P = 0.149). After a median follow-up of 20 months, the median PFS was 10 months [95% confidence interval (CI) 9.4-10.6] and did not differ between both arms (P = 0.414). The median OS was 25 months in the TC arm versus 31 months in the standard arm (95% CI: 22.4-27.6 resp. 26.0-36.0; P = 0.163). Severe hematologic toxicities (grade 3/4) were rare in the experimental arm (P < 0.001), with 17.4% leucopenia, 27.8% neutropenia and 15.9% thrombopenia. CONCLUSION: The combination of carboplatin and topotecan was well tolerated with significant lower rates of severe hematological toxicities but did not improve PFS or OS in platinum-sensitive relapsed ovarian cancer compared with established standard regimens.

Argon plasma coagulation of gastric inlet patches for the treatment of globus sensation: it is an effective therapy in the long term.

AIM: To determine the long-term effect of argon plasma coagulation (APC) of gastric inlet patches in the cervical esophagus for patients suffering from globus sensation. METHODS: We intended to follow up all patients between 2004 and 2011 (n = 49) who received argon plasma ablation of gastric inlet patches for globus sensation at our clinic. Symptoms were assessed by a visual analogue scale (VAS) in 31 of 49 patients. Follow-up endoscopy of the upper gastrointestinal tract was performed to confirm residual or relapsed cervical inlet patches. RESULTS: After a median period of 27 months, APC was assessed as a successful therapy in 23 of 31 patients (74%). VAS scores decreased significantly from 7.6 to 4.0 in the long term. Twenty-two of 31 patients were willing to undergo follow-up endoscopy. Endoscopy revealed recurrent/residual gastric inlet patches after APC in 11 of 22 cases. These patients suffered from a significant relapse of symptoms in the postinterventional period (p < 0.001). CONCLUSION: This retrospective study indicates that APC of gastric inlet patches for the treatment of globus sensation might be a sufficient therapy option. Recurrences or residual heterotopic gastric mucosa are possible and seem to be associated with a relapse of symptoms. Therefore, endoscopic follow-up and retreatment might be necessary if globus sensation is not sufficiently eliminated.

[Endoscopic and percutaneous intervention in the long-term treatment of benign biliary stenosis. A 71-year-old patient with cholestasis following radiotherapy]. / Endoskopische und perkutane Interventionen in der Langzeitbehandlung benigner Gallengangstenosen : 71-jähriger Patient mit Cholestase nach Radiatio.

Benign biliary stenosis can have various causes and requires differentiation from disorders caused by malignant disease. Treatment of benign stenosis is often difficult and includes treatment modalities such as endoscopic, percutaneous or surgical interventions. Exact knowledge of the etiology and localization of the stenosis is essential when selecting the appropriate method of treatment. Here we present the case of a 71-year-old patient admitted to our hospital with cholangitis 13 years after undergoing radiotherapy of the renal bed due to hypernephroma of the right kidney. The patient was diagnosed with common bile duct stenosis due to the secondary effects of radiation, which is rarely reported in the literature. Our case covers a total treatment period of 15 years, enabling us to also discuss a viable sequence of treatment modalities in the treatment of benign bile duct stenosis.

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.

Biweekly pegylated liposomal doxorubicin in patients with relapsed ovarian cancer: results of a multicenter phase-II trial.

BACKGROUND: The obvious benefit of pegylated liposomal doxorubicin (PLD) for tumour control in recurrent ovarian cancer is frequently offset by severe palmar-plantar erythrodysesthesia (PPE). There is evidence that dose reduction from 50 to 40 mg/m(2) reduces the incidence of PPE without compromising cytotoxic activity. We set out to investigate whether biweekly application further improves the therapeutic index of PLD. PATIENTS AND METHODS: Patients with recurrent ovarian cancer after surgery and adjuvant chemotherapy with platinum and taxane compounds were eligible to participate in this multi-institutional phase II study. PLD was administered at a dose of 20 mg/m(2) every two weeks. Eligible patients had ECOG performance status of < or =2, and sufficient organ function. We employed an optimized two-stage design to test the hypothesis that biweekly application of PLD reduces the frequency of grade III and IV PPE from 25% to 10%. Response and survival were addressed descriptively. RESULTS: Between October 2001 and February 2004, 64 patients with median age of 59 (range 38-81) years were recruited onto this trial. We evaluated 553 (median 7, range 1-25) courses of PLD treatment. Most patients were in their third or fourth line of chemotherapy. PPE was noted in 30 patients (47.6%), but only three participants progressed to grade 3 severity (4.7%, 95% confidence interval 1.0-13.1%). Partial response, stable disease, and tumour progression were observed in 5, 13, and 24 patients, respectively. Median overall and progression-free survival were 18.2 (range, 1.4-34.0) and 4.3 (range 0.5-22.3) months. CONCLUSIONS: Biweekly PLD may reduce the incidence of PPE while retaining efficacy in relapsed ovarian cancer. Our data support the need for a randomized trial to strengthen these assumptions.

A phase II study of topotecan plus gemcitabine in the treatment of patients with relapsed ovarian cancer after failure of first-line chemotherapy.

BACKGROUND: Second-line chemotherapy for patients with ovarian cancer who failed platinum and paclitaxel treatment remains a therapeutic challenge. We investigated the toxicity profile and therapeutic efficacy of a novel combination regimen, topotecan plus gemcitabine, in a clinical phase II study. PATIENTS AND METHODS: Women with relapsed epithelial ovarian cancer after platinum and paclitaxel treatment were eligible to participate in this trial. Topotecan was given at an initial dose of 0.5 mg/m(2) daily (days 1-5), combined with gemcitabine 800 mg/m(2) and 600 mg/m(2) on days 1 and 8, respectively. Precluding good tolerability, this protocol facilitated subsequent dose increases of topotecan up to 1.0 mg/m(2). The primary objective was to determine the dose-limiting toxicity, whereas secondary objectives comprised measurable and CA-125 response rates, disease-free and overall survival. RESULTS: The twenty-one patients (median age 57 years, range 37-70 years) who were allocated to this trial received a total of 94 courses of chemotherapy. Median follow-up was 20.5 months. Topotecan dosage could be escalated to 0.75 mg/m(2) in nine patients and 1 mg/m(2) in another two patients. Dose reduction was not necessary in any case. There were no episodes of neutropenic fever, sepsis or chemotherapy-related fatalities. Only one patient developed CTC grade 4 leukopenia after the first treatment cycle, whereas three patients showed grade 3/4 anaemia. Five patients experienced thrombocytopenia grade 4 without clinical sequelae. Non-hematological toxicities were mild and rare. Eleven patients could be evaluated for clinical tumour response, with three complete, and four partial remissions. Two patients each had stable and progressive diseases. The median progression-free survival rate was 8.8 months [95% confidence interval (CI) 6.3-13.4 months]. The median overall survival rate was 21.1 months (95% CI 14.8-22.1 months). CONCLUSIONS: Topotecan combined with gemcitabine has a favourable toxicity profile and encouraging efficacy in patients with recurrent ovarian cancer.

[First manifestation of choriocarcinoma in a 24-year-old patient in the form of hemiparesis]. / Erstmanifestation eines Chorionkarzinoms bei einer 24 jährigen Patientin in Form einer Hemiparese.

We report on a case of a 24 years old woman with a high risk metastatic choriocarcinoma. The last pregnancy and delivery was 15 months ago. As a first symptom a complete paralysis of the upper right extremity was found. In the following a rapid progression of the disease with severe multiple cerebral and retroperitoneal bleedings was seen. Among chemotherapy and intensive care treatment the HCG-titre decreased quickly and the bleedings stopped but no change in the neurological condition was observed.

[Multiple liver abscesses in long-term intrauterine device]. / Multiple Leberabszesse bei langliegendem IUP.

We report on two cases of multiple hepatic abscesses caused by sever pelvic inflammatory disease secondary to intrauterine device. Such complication have previously been reported only twice. The course of the diseases were non-specifically for a long time. As causative agent we isolated Klebsiella pneumoniae in the first case and in the other Fusobacterium necroforum. The patients were cured with combined operative and medical therapy.

Transvaginal gamete intra-fallopian transfer and embryo intra-fallopian transfer.

This study describes the conduct and results of a recently developed technique for transvaginal catheterization of the Fallopian tube in order to transfer gametes or early embryos. Transvaginal gamete intra-Fallopian transfer (TV-GIFT) was performed in 46 patients after stimulation with human menopausal gonadotrophin (HMG) and human chorionic gonadotrophin (HCG) and transvaginal oocyte retrieval. This resulted in 11 (23.9%) pregnancies. Eight patients delivered healthy children, including one set of twins. Two patients had abortions at 8 and 11 weeks of gestation and one had an ectopic pregnancy. In a first series of 11 women, oocytes were fertilized in vitro and a maximum of three embryos at the 2- to 8-cell stages were transferred into one tube. Three of the 11 cycles with tubal embryo-stage transfer' (TV-TEST) resulted in clinical pregnancy.

[Severe hydrops fetalis in a first trimester pregnancy with Ulrich-Turner syndrome]. / Schwere hydropische Entwicklung der Schwangerschaft im ersten Trimenon bei Ulrich-Turner-Syndrom.

We report about a case of abundant hydropic evolution of a fetus in the first trimester of gestation. Already in the 8th week of gestation we diagnosed the first references of failure with transvaginal ultrasound. In the following three weeks we observed the progression of the hydrops. The genetic research of fetal tissue after induced abortion show the karyotype 45 X0.