Diana Lüftner

Serum HER‐2/neu and relative resistance to trastuzumab‐based therapy in patients with metastatic breast cancer

Previous reports based on small patient numbers suggested that changes in serum HER‐2/neu levels may predict response or lack of response to trastuzumab‐based therapies in metastatic breast cancer (MBC). The objectives of this study were to pool data from 307 patients with MBC from 7 medical institutions to validate that the serum HER‐2/neu profile predicts patient resistance to trastuzumab and to establish a clinically relevant cutoff.

Serum HER-2/neu in the management of breast cancer patients.

The clinical role of HER-2/neu, a 185 kD epithelial transmembranous protein, has evolved after the approval of the anti-HER-2/neu targeted monoclonal antibody trastuzumab (Herceptin) for the therapy of metastatic breast cancer. The extracellular domain of HER-2/neu undergoes proteolytic cleavage from the full-length protein by metalloproteases, and is shed into the blood as a circulating antigen. While HER-2/neu gene amplification and/or protein overexpression are detected in approximately 25% of primary breast cancers, serum HER-2/neu levels are elevated beyond the upper limit of normal in 50 to 60% of stage IV breast cancer patients. HER-2/neu in serum can be detected by enzyme immunoassays (manual and automated versions). It has been shown to have prognostic and predictive information in breast cancer patients. Monitoring for recurrence by serum HER-2/neu reaches a high sensitivity for HER-2/neu positive tumors. Longitudinal follow-up of patients during any kind of systemic therapy allows for monitoring of the therapeutic success. When utilized in these applications, serum HER-2/neu testing is complementary to HER-2/neu tissue results and to the determination of classical tumor markers such as CA 15-3, CA 27.29 and CEA, which are not targeted by specific forms of systemic therapy.

Gemcitabine for palliative treatment in metastatic breast cancer

Abstract Gemcitabine is one of the recently developed drugs with a high efficacy in various malignant tumours and a mild toxicity profile. As monochemotherapy in metastatic breast cancer, gemcitabine yielded response rates up to 46% as first- and second-line treatment. Neutropenia is the clinically most relevant unwanted effect. Haematological and nonhaematological toxicities are mild, making dose reductions, delays of treatment or withdrawal from treatment very rare. The first phase I and phase II studies of gemcitabine in combination with anthracyclines have shown a good toxicity profile and promising remission rates. Phase I experiences with long-time infusion schedules reveal good feasibility and high patient acceptance.

Gemcitabine plus dose-escalated epirubicin in advanced breast cancer: results of a phase I study

Gemcitabine has shown single-agent activity in metastatic breast cancer. Epirubicin is also widely used for the adjuvant and treatment of metastatic breast cancer. The toxicity profiles and modes of action are different which provides a good rationale for studying both drugs in combination. In a phase I study gemcitabine at a fixed dose of 1000 mg/m2 on days 1, 8, 15 of a 28 day cycle was combined with escalated weekly doses of epirubicin starting with an initial dose of 10 mg/m2. Patients had stage IV metastatic disease without previous chemotherapy except as adjuvant treatment. Nineteen patients were included in the study which defined the maximum tolerated dose (MTD) of epirubicin at 20 mg/m2. Myelosuppression was the dose limiting toxicity with leucopenia WHO grade 3 and 4 in 40.0% and 20.0%, neutropenia WHO grade 3 and 4 without neutropenic fever in 20.0% and 40.0% and thrombocytopenia WHO grade 4 in 20.0%. At the epirubicin 15 mg/m2 dose level, leucopenia (11.1% WHO grade 3) and neutropenia (12.5 and 37.5% WHO grade 3 and 4) were reported. Symptomatic toxicity was generally mild: nausea/vomiting in about 20% of patients (WHO grade 3 or 4) on both 15 and 20 mg/m2 epirubicin dose levels. Alopecia WHO grade 3 and 4 was seen in 2 patients at MTD. Four of 19 evaluable patients had a partial response. We conclude that the combination of gemcitabine and epirubicin is well tolerated and has promising activity. A phase II study is underway with gemcitabine 1000 mg/m2 and epirubicin 15 mg/m2 on days 1, 8 and 15 of a 28 day cycle.

Effect of the tyrosine kinase inhibitor lapatinib on CUB-domain containing protein (CDCP1)-mediated breast cancer cell survival and migration

The surface receptor CUB domain-containing protein 1 (CDCP1) is highly expressed in several adenocarcinomas and speculated to participate in anchorage-independent cell survival and cell motility. Tyrosine kinase phosphorylation seems to be crucial for intracellular signaling of CDCP1. Lapatinib, a tyrosine kinase inhibitor (TKI), is approved for treatment of HER-2/neu overexpressing metastatic breast cancer and functions by preventing autophosphorylation following HER-2/neu receptor activation. This study aimed to investigate the effect of CDCP1 expression on anchorage-independent growth and cell motility of breast cancer cells. Moreover, studies were performed to examine if lapatinib provided any beneficial effect on HER-2/neu((+)/-)/CDCP1(+) breast cancer cell lines. In our studies, we affirmed that CDCP1 prevents cells from undergoing apoptosis when cultured in the absence of cell-substratum anchorage and that migratory and invasive properties of these cells were decreased when CDCP1 was down-regulated. However, only HER-2/neu(+), but not HER-2/neu((+)/-) cells showed decreased proliferation and invasion and an enhanced level of apoptosis towards loss of anchorage when treated with lapatinib. Therefore, we conclude that CDCP1 might be involved in regulating adhesion and motility of breast cancer cells but that lapatinib has no effect on tyrosine kinases regulating CDCP1. Nonetheless, other TKIs might offer therapeutic approaches for CDCP1-targeted breast cancer therapy and should be studied considering this aspect.

Prescription pattern of aromatase inhibitors in the adjuvant setting in Germany : Final results of a survey among German breast cancer specialists

Einleitung: Das Verschreibungsverhalten zur adjuanten Therapie mit Aromatasehemmern (AI) ist nicht bekannt auch angesichts der Tatsache, dass die Einzelsubstanzen eingeschränkt oder noch nicht zugelassen sind. Wir führten eine Umfrage unter den Mitgliedern der Deutschen Gesellschaft für Senologie durch. Methoden: Insgesamt wurden 1,233 Briefe (Fragebogen und die letzten Abstracts der 3 Studien aus Vollpublikationen) verschickt, die Antworten waren anonymisiert. Alle Fragen sollten getrennt nach Privatpatienten (PP) und Kassenpatienten (KP), beantwortet werden. Ergebnisse: Die Fragebögen wurden überwiegend von Gynäkologen (82,4%) ausgefüllt. Insgesamt waren im Jahr 2003 >16 000 Mammakarzinompatientinnen behandelt worden. Adjuvante AI wurden von 69,4% der Ärzte in bis zu 25% der KP bevorzugt, 5,6% der Kollegen behandelten sogar >50% ihrer Patientinnen, wobei allerdings 10,3% der Ärzte mehr als 50% ihrer PP mit einem AI behandelten. Unter der Hypothese von uneingeschränkten Zulassungsbedingungen würden 44,5% der Ärzte >50% ihrer Patientinnen mit AI behandeln. Die Umstellung auf einen AI nach 2-3 Jahren Tamoxifen wurde bei 22% der KP und bei 36% der PP gewählt. Die erweiterte adjuvante Therapie mit einem AI nach 5 Jahren Tamoxifen wurde bei 26% der KP und 35%

CHEMOTHERAPY AND CHEMO-RADIOTHERAPY OF ADVANCED PANCREATIC CARCINOMA

Until recently, 5-Fluorouracil (5-FU) monochemotherapy had to be considered the standard in advanced pancreatic carcinoma although neither remission rates nor increases in median survival time have be

Catheter occlusion by calcium carbonate: a well-known problem persists in spite of better knowledge.

Accessible online at: www.karger.com/onk Fax +49 761 4 52 07 14 E-mail Information@Karger.de www.karger.com developed a catheter blockade due to formation of calcium carbonate (calcite) [3]. The time from initiation of therapy to catheter obstruction ranged from 8 to 24 weeks. After the encouraging clinical results of the ‘Ardalan’ schedule, the original regimen was modified by other groups to avoid the inconvencience of two i.v. infusions which led to the development of the ‘AIO’ variant, i.e. the prior administration of a 2-h infusion of calcium folinate followed by the 24-h infusion of 5-FU via a portable infusion pump. This mode of application represented a compromise between the need for one i.v. device only and the pharmacological rationale of parallel toxification of 5-FU by folinic acid. However, keeping in mind the half lives of folinic acid with approximately 7 hours and 5FU with a few minutes, this compromise a priori renounces optimal toxification of 5-FU, especially towards the end of the 24-h infusion. In the first quarter of 2002, the initially restricted approval for calcium folinate was extended and then permitted the mixture of calcium folinate with 5-FU. The basis for this extension was the in vitro compatibility without any loss of drug by complex formation for 48 h in a mixture of calcium folinate (4 mg/ml) and 5-FU (20 mg/ml) as demonstrated by high performance liquid chromatography (HPLC). These data were integrated into the summary of producer characteristics (SPC) of several suppliers without any further in vivo confirmation at that time. Based on this presumably valid recommendation, Bruch and Esser started biomodulated, high-dose 5-FU therapy in a patient with stage IV rectal cancer and administered a mixture of calcium folinate and 5-FU over a period of 24 h once a week via a port-a-cath as described in a case report in this volume [4]. During the course of this therapy, the patient developed port occlusion and needed port explantation. The thorough work-up of the occluding firm material from inside the lumen of the removed catheter revealed calcium carbonate as reason for the obstruction. The time to development of The so-called ‘AIO’ regimen with high-dose 5-FU (5-fluorouracil) and calcium folinate is a standard regimen in the treatment of advanced colorectal cancer. In this well-known combination therapy, the 2-h infusion of calcium folinate (500 mg/m2) precedes the 24-h continuous infusion with high-dose 5-FU (2,600 mg/m2). The basis for this schedule was given by the clinical study done by Ardalan and co-workers in the year 1991 [1]. In the original regimen, 5-FU and calcium folinate were administered simultaneously via a central venous device, generally a Hickman catheter or a port-a-cath® system. Why are calcium folinate and 5-FU applied sequentially in the AIO-regimen although the original data were produced with a mixed infusion? To answer this question we have to look back to the early times of treatment of metastatic colorectal cancer with calcium folinate and high-dose 5-FU. First pre-clinical studies had been done on human colon cancer xenografts comparing different infusion schedules of calcium folinate. By comparing i.v. bolus, 4-h infusion and 24-h infusion schedules of fixed doses of calcium folinate and 5-FU, variations of reduced folate levels in human colon cancer xenografts depending on the duration of infusion could be demonstrated [2]. Interestingly, the most pronounced increases of intratumoral folate levels were seen after the 24-h infusion. Based on these data, Ardalan and co-workers started their clinical study with 5-FU and calcium folinate mixed together in a continuous infusion over 24 h [1]. By using this new schedule they reached a remarkable response rate accompanied by a survival time of more than 22 months and moderate toxicity. Unfortunately, it became evident that many catheters were obstructed by crystal formation after a certain number of cycles. As a consequence, Ardalan et al. changed the mode of administration and furthermore used two separate venous accesses to avoid catheter occlusion. Four years later, Ardalan reported in full length that 11 of the 22 treated patients had Catheter Occlusion By Calcium Carbonate: A Well-Known Problem Persists in Spite of Better Knowledge

Fortschritte in der zytostatischen und supportiven Therapie des Pankreaskarzinoms

Obwohl in den letzten Jahren sowohl die diagnostischen als auch die therapeutischen Möglichkeiten beim Pankreaskarzinom deutlich erweitert werden konnten, bleibt die Prognose dieser Erkrankung außerordentlich schlecht. Unverändert besteht der seltene, kurative Ansatz in der radikalen Tumorresektion im frühen Kankheitsstadium. Palliative Therapieverfahren konnten bislang weder die Remissionsrate noch das mittlere Überleben klinisch relevant verbessern. Dennoch hat sich zunehmend ein Wandel in der Haltung gegenüber der zytostatischen Therapie des fortgeschrittenen Tumorleidens eingestellt: Seitdem gezeigt werden konnte, daß durch Chemotherapie im Vergleich zur besten supportiven Therapie die Lebensqualität verbessert bzw. länger eine gute Lebensqualität aufrechterhalten werden kann, sollte Patienten mit metastasiertem oder lokal fortgeschrittenem Pankreaskarzinom eine zytostatische Therapie angeraten werden. Bei der Beurteilung des therapeutischen Nutzens muß die Linderung krankheitsassoziierter Symptome als patientenorientierter Maßstab besonders hoch gewertet werden, da Remissionen selten erreicht werden und kaum mit einem Überlebensvorteil verbunden sind. Somit kommt es zu einer Deckung des Therapieziels von zytostatischer Behandlung und supportiven Maßnahmen der Schmerztherapie und interventionellen Onkologie.

Dokumentationsprogramme in der Onkologie – Oncodoc

In der Onkologie ist eine exakte Dokumentation für die strategisch richtige Therapieführung des Patienten und die Qualitätssicherung des medizinischen Handelns unersetzlich geworden. Daher wird auch vom Gesetzgeber eine Basisdokumentation für Erkrankungen aus dem onkologischen Formenkreis zum Aufbau eines Krebsregisters gefordert. Bundesweit anerkannte Empfehlungen hierfür liegen mittlerweile vor [1]. Anforderungen an die Tumordokumentation