H.-G. Mergenthaler

Prolonged infusion of gemcitabine in stage IV breast cancer: a phase I study.

Gemcitabine is an effective agent in the treatment of metastatic breast cancer. The phosphorylation of gemcitabine into the active gemcitabine triphosphate (dFdCTP) is catalyzed by deoxycytidine kinase. This enzyme is saturated at plasma concentrations achieved after an infusion over 30 min. Therefore accumulation of higher intracellular dFdCTP concentrations, which may result in an enhanced antineoplastic activity, cannot be achieved by higher dosage, but only by prolonged infusion time. The objectives of this phase I trial were to determine the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD) of gemcitabine given as a 6 h i.v. infusion. Patients with metastatic breast cancer were treated with gemcitabine as a 6 h infusion on days 1, 8 and 15 every 4 weeks. The starting dose was 200 mg/m2 with an interindividual escalation in 50 mg/m2 increments. Sixteen patients received 196 doses through three dose levels. All patients were assessable for toxicity, 13 assessable for response. The MTD was 250 mg/m2. DLT was observed at 300 mg/m2 consisting of a reversible elevation of transaminases WHO grade 3 in two patients and cutaneous toxicity grade 3 in one patient. Most common non-hematologic toxicities were mild to moderate and rapidly reversible elevation of liver enzymes in all patients, nausea and vomiting (four patients grade 2, five patients grade 3), and mild alopecia. Hematologic toxicity was mild with neutropenia WHO grade 3 and 4 in only one patient each, and no grade 3 thrombocytopenia. One patient achieved a complete remission and another patient a partial response, for an overall response rate of 15% (two of 13). In addition, seven patients (54%) had stable disease and four (31%) failed to respond to the treatment. We conclude gemcitabine 250 mg/m2 days 1, 8 and 15 every 4 weeks can be safely administered as 6 h infusion. Toxicity, especially myelosuppression, is surprisingly mild. Based on this result a phase II study with 250 mg/m2 administered over 6 h was initiated to determine the efficacy.

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.

The combination of fludarabine and cyclophosphamide results in a high remission rate with moderate toxicity in low-grade non-Hodgkin's lymphomas

We undertook a prospective study to evaluate the role of the combination of fludarabine and cyclophosphamide in patients with low-grade non-Hodgkins lymphoma. Twenty-seven patients with low-grade non-Hodgkins lymphoma were treated with i.v. fludarabine (30 mg/m2) and cyclophosphamide (250 mg/m2) on days 1–3. Cycles were given at 4-week intervals for a maximum of six courses. Fourteen patients (52%) were previously untreated, 13 patients (48%) had been treated with at least one chemotherapy regimen before. Of the 27 patients, 11 (41%) obtained a complete and 13 (48%) a partial remission, thus the overall response rate was 89%. The remission rate in untreated patients was slightly higher than in pretreated patients (93 versus 85%). The toxicity was mild, no treatment-related mortality occurred. Neutropenia was the most common side effect, grade 4 neutropenia of rather short duration was observed in less than 7% of the cycles. At the end of the treatment, the mean CD4+ count was 155/μ l and the mean CD8+ count 204/μ l. Severe infections did not occur. These results show that the combination of fludarabine and cyclophosphamide in the doses used in this study is an effective regimen with manageable toxicity in low-grade non-Hodgkins lymphoma.

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

Gemcitabine and mitoxantrone in metastatic breast cancer: a phase-I-study.

Background: Gemcitabine and mitoxantrone are active agents for the treatment of metastatic breast cancer. Due to different modes of action and a favorable toxicity profile they are suitable for combination therapy. This phase I trial was initiated to determine the optimal doses for the combination in patients with metastatic breast cancer. Secondary objectives included the evaluation of the safety and efficacy of the regimen. Patients and methods: Patients with metastatic breast cancer were treated with gemcitabine (1000–1400 mg/m2) on days 1, 8 and 15 and mitoxantrone (10–14 mg/m2) on day 8. Treatment was repeated every 4 weeks for a maximum of 8 cycles. Doses were assigned at registration according to the escalation scheme. Results: Twenty-six patients received a total of 93 cycles at 5 different dose levels. The maximum tolerated doses were 1200 mg/m2 gemcitabine and 14 mg/m2 mitoxantrone with grade 4 neutropenia being the dose limiting toxicity. Recommended phase II doses, however, are gemcitabine 1200 mg/m2 and mitoxantrone 12 mg/m2 based on a similar median dose intensity and a more favorable toxicity profile. Predominant toxicity was myelosuppression. Most common non-hematological toxicities were nausea, vomiting, alopecia and elevation of liver enzymes. Twenty-one patients were assessable for response. Four patients achieved a partial response accounting for an overall response rate of 19%. In addition, 12 patients (57%) had stable disease and 5 patients (24%) failed to response to the treatment. Median duration of response and duration of clinical benefit were 14 and 9 months, respectively. Conclusion: In this phase I study of gemcitabine and mitoxantrone, the DLT was neutropenia. Recommended phase II doses are gemcitabine 1200 mg/m2 and mitoxantrone 12 mg/m2.

Use of Bisphosphonates in Therapy and Prophylaxis of Cancer-Induced Bone Diseases

The local production of a variety of cytokines by metastatic cells and the bone microenvironment stimulates osteoclast activation and is the crucial event in bone destruction in cancer patients. Skeletal metastases are often associated with pain, pathological fractures, spinal cord compression and hypercalcemia and have a great impact on the quality of life. Bisphosphonates can reduce the bone resorption by inhibition of osteoclast activity. Large randomized clinical trials have shown the efficacy of bisphosphonates in reducing the frequency of skeletal events and pain in patients with multiple myeloma or breast cancer who have established osteolytic bone disease. In most trials, bisphosphonates were given to patients receiving cytotoxic or hormonal treatment. A new approach in bisphosphonate therapy is an earlier administration of the drug before osteolysis appears. Recent results indicate that early intervention with bisphosphonates in adjuvant treatment of high-risk breast cancer may reduce distant metastases and prolong overall survival in certain subgroups of patients. A randomized trial which addresses the role of bisphosphonates in stage I myeloma patients will be initiated by the German Myeloma Study Group.

Grippeschutzimpfung bei Patienten mit malignen Systemkrankheiten – Hintergrund, Empfehlungen und Alternativens

Between April and December, influenza epidemics occur every year. Patients suffering from haematological malignancies, solid tumours as well as metabolic diseases or cardiopulmonary disorders benefit most from influenza vaccination. Immunisation of patients with neoplastic diseases should be performed 1–2 weeks before chemotherapy or at least 4 weeks after chemotherapy. If inoculation is indicated during chemotherapy, a booster vaccination is recommended after 4 weeks. Amantadin, an antiviral compound, provides a chemoprophylaxis in case of Influenza A outbreak and should be given in addition to the inoculation during an epidemic.

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.

Dysproportionaler Riesenwuchs, Flammennävi, Hämangiome, Varizen und Erstdiagnose einer monoklonalen Gammopathie

Über die Koinzidenz einer primären Gammopathie mit einem KTS wird hier erstmals berichtet. Ein kausaler Zusammenhang beider Erkrankungen konnte jedoch nicht nachgewiesen werden. Die Prognose des Patienten ist entsprechend des benignen Charakters des KTS primär durch den weiteren Verlauf der Gammopathie bestimmt. Die Befundkonstellation einer neu aufgetretenen, progredienten zervikalen Raumforderung mit dem Vorliegen einer monoklonalen Gammopathie führte bei einem 43jährigen Patienten zunächst zu der Verdachtsdiagnose einer hämatologischen Systemerkrankung. Die typische Symptomkonstellation von dysproportionalem Riesenwuchs,Flammennävi, Hämangiomen und Lymphangiomen neben venösen Angiodysplasien ohne Beteiligung des arteriellen Schenkels ergab die Diagnose eines Klippel-TrenaunaySyndroms (KTS). Die zervikale Raumforderung konnte nach Extirpation als kavernöses Hämangiom klassifiziert werden. Hinweise auf eine maligne oder sekundäre Genese der Gammopathie fanden sich nicht, so daß hier die Diagnose einer Gammopathie unklarer Signifikanz gestellt wurde.