R. Kath

Oral naloxone reverses opioid-associated constipation.

Abstract Opioid‐related constipation is one of the most frequent side effects of chronic pain treatment. Enteral administration of naloxone blocks opioid action at the intestinal receptor level but has low systemic bioavailability due to marked hepatic first‐pass metabolism. The aim of this study was to examine the effects of oral naloxone on opioid‐associated constipation in an intraindividually controlled manner. Twenty‐two chronic pain patients with oral opioid treatment and constipation were enrolled in this study. Constipation was defined as lack of laxation and/or necessity of laxative therapy in at least 3 out of 6 days. Laxation and laxative use were monitored for the first 6 days without intervention (‘control period’). Then, oral naloxone was started and titrated individually between 3×3 to 3×12 mg/day depending on laxation and withdrawal symptoms. After the 4‐day titration period, patients were observed for further 6 days (‘naloxone period’). The Wilcoxon signed rank test was used to compare number of days with laxation and laxative therapy in the two study periods. Of the 22 patients studied, five patients did not reach the ‘naloxone period’ due to death, operation, systemic opioid withdrawal symptoms, or therapy‐resistant vomiting. In the 6 day ‘naloxone’ compared to the ‘control period’, the mean number of days with laxation increased from 2.1 to 3.5 (P<0.01) and the number of days with laxative medication decreased from 6 to 3.8 (P<0.01). The mean naloxone dose in the ‘naloxone period’ was 17.5 mg/day. The mean pain intensity did not differ between these two periods. Moderate side effects of short duration were observed in four patients following naloxone single dose administrations between 6 and 20 mg, resulting in yawning, sweating, and shivering. Most of the patients reported mild or moderate abdominal propulsions and/or abdominal cramps shortly after naloxone administration. All side effects terminated after 0.5–6 h. This controlled study demonstrates that orally administered naloxone improves symptoms of opioid associated constipation and reduces laxative use. To prevent systemic withdrawal signs, therapy should be started with low doses and patients carefully monitored during titration.

Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia

Abstract Bendamustine, an alkylating agent without cross-resistance to cyclophosphamide is active in a variety of lymphoproliferative and other malignancies. In an open phase-II study we treated 23 patients with a median age of 62 years at study entry (43–86 years) with advanced, refractory or relapsed (Rai stage III n=9, Rai stage IV n=14) chronic lymphocytic leukemia (CLL) with bendamustine. At study entry, only 13 patients were chemotherapy-naive. The treatment schedule with bendamustine was as follows: for patients up to 70 years 60 mg/m2 for 5 days, for patients over 70 years 50 mg/m2 for 5 days, repetition at day 29. Remission criteria were used according to Cheson et al. (1996). All patients were evaluable for toxicity and 20 for response. An objective remission was achieved in 15/20 patients (75%), including six patients with complete remission (CR). Three of the complete responders had no chemotherapy prior to bendamustine. No change (NC) occurred in 5/20 patients (25%). Median overall survival after bendamustine treatment is 13.6 months (1–46 months) and 16.6. months (1–46 months) in patients responding to bendamustine. In total, 74 courses of bendamustine were applied. Therapy-related anemia and thrombocytopenia were rare. However, WHO grade III/IV leukocytopenia occurred in 38/74 cycles (51%), resulting in treatment-related mortality in 3/23 patients (13%). These patients were severely immunocompromised due to pretreatment or the underlying disease. As a corollary of the study, a general prophylactic antibiotic treatment (trimethoprim/sulfamerazine) was instituted. A general feature was the decline of the CD4/CD8 ratio: mean before therapy: 1.36; after two courses: 0.98; after four courses: 0.6, as documented in all patients who received at least two courses of bendamustine (n=12). All evaluable patients showed a decline in the CD4/8 ratio. However, this decline was not clearly related to an increased risk of infectious episodes. We observed mainly cutaneous allergic reactions (three WHO grade I; one WHO grade II) leading to a cessation of bendamustine treatment in 4/23 patients (18%). Bendamustine is highly effective in advanced or refractory CLL. In multiple pretreated or otherwise severely immunocompromised patients bendamustine might lead to additional immunosuppression with subsequent infectious complications.

Gastric cancer in very young adults: apropos four patients and a review of the literature.

Abstract Whether gastric cancer in young adults differs from gastric cancer in older patients has been a controversial issue. It has long been suspected that young patients with gastric cancer have different biological features with a more aggressive course of disease and a poorer prognosis than older patients. This, however, has not been firmly substantiated. We report on the clinical course of four patients (three female and one male) with locally advanced (n  =  1) or metastasized (n  =  3) non-resectable gastric cancer diagnosed under the age of 29 years (23, 25, 27, 28 years). Prior to diagnosis, all three women had recently been pregnant (1–22 months). Diagnosis was endoscopically biopsy-proven and staging work-up was performed by primary explorative surgery (n  =  1), laparoscopy and explorative surgery (n  =  1) or CAT scan and ultrasound (n  =  2). The delay between initial symptoms and diagnosis was 8–22 weeks (median, 10 weeks). The histology was signet-ring cell (n  =  2) or undifferentiated (n = 2) gastric cancer. All patients had the diffuse type of gastric cancer according to Lauren. Patients were treated with the FLAP polychemotherapy regimen consisting of leucovorin, 5-fluorouracil, doxorubicin and cisplatinum, as previously reported. The best response after chemotherapy was partial in two patients. Two patients showed progressive disease. Secondary surgery was performed in three responding patients (one of them responded only locally). One patient achieved no evidence of disease after complete tumor resection (R0). In two patients surgery was palliative (R2/exploration). Three patients died 6, 4 and 8 months after diagnosis. One patient is still alive. In our series, very young adults with gastric cancer had adverse clinical and pathological features. In accordance with other reports, we observed a predominance of female patients and a possible association with recent pregnancies. Though the delay between the first symptoms and diagnosis in our patients was no different from that reported for older patients, special emphasis should be given to prompt referral and diagnostic investigations, ensuring the diagnosis of gastric cancer early in the course of disease.

Severe non-haematological toxicity after treatment with gemcitabine.

Abstract The authors report that 4 out of a series of 56 patients (7.1%) treated with gemcitabine developed an unexplained non-cardiogenic pulmonary distress syndrome most likely related to gemcitabine. One further patient developed ventricular arrhythmia immediately after gemcitabine exposure, leading to cardiac arrest. Between 1995 and 1998 56 patients with locally advanced or metastatic carcinoma were treated with gemcitabine. The patients suffered from breast cancer (n = 17), pancreatic cancer (n = 17), lung cancer (n = 12), cancer of unknown primary (n = 5), ovarian cancer (n = 2), oral cavity cancer (n = 2) and cancer of the bladder (n = 1). Their median age was 55 years, and there were 33 female and 23 male patients. Fifteen patients had been pretreated with radiation therapy: 2 had received radiation therapy involving the mediastinum as treatment for non-small-cell lung cancer and cancer of unknown origin respectively, 11 patients had had prior neoadjuvant or adjuvant radiation therapy of the chest wall for breast cancer and 2 patients had received radiation therapy for head/neck cancer. All patients received gemcitabine on days 1, 8 and 15 and this was repeated on day 29 at a dose of 1000 mg/m2 as a 30-min infusion in 250 ml isotonic NaCl. In 4 patients gemcitabine treatment was combined with cisplatinum, in 7 patients with a somatostatin analogue and in 1 patient with epirubicin. All other patients received gemcitabine as a single agent. We assume that the pulmonary or cardiac toxicity of 5 patients was related to gemcitabine. In 3 patients re-exposure resulted in repeated toxicity. One patient did not receive gemcitabine again because of the life-threatening nature of the primary response. Two patients had received prior radiation to the mediastinum with 62 Gy and 50 Gy respectively, 3 years and 1 year before gemcitabine application. In our experience pulmonary toxicity after gemcitabine treatment is more common than initially anticipated. Gemcitabine should be used with caution in patients who have received prior radiation to the mediastinum.

BRCA1 mutations in German breast‐cancer families

We analyzed germline mutations of the BRCAI gene in 20 German breast/ovarian‐cancer families. BRCAI mutations co‐segregating with breast‐cancer susceptibility were identified in 3 of these families. All mutations were found to generate a premature stop codon leading to the synthesis of truncated BRCAI proteins of different length. Nine polymorphisms were detected in BRCAI, 4 of which have not been described previously. Analysis of familial tumors for LOH revealed that only the disease‐related allele of BRCAI was present.

BRCA1 mutations and phenotype

More than 100 mutations have been described for the breast-cancer-susceptibility geneBRCA1. The paper describes phenotypical aspects of three selected mutations located at the beginning, in the middle, and at the end of the gene. A remarkable decrease of the age of diagnosis of the mammary carcinoma is observed with increasing length of the putative gene product, combined with greater severity of the disease.

Oncological Resource Allocation in Germany

Background: Oncology is a resource-intensive medical discipline where, so far, effectiveness rather than efficiency of a treatment has stood in the foreground. The aim of our study was, therefore, to determine the resource allocation and to assess the efficiency of oncology in Germany for the period of 2002–2004. Materials and Methods: With the aid of the official German Health Report, the expenditures for health in 2004 and the gain in years of life according to ICD 10 disease categories were analyzed. Based on the incremental costs and years of life gained, the cost calculation per year of life gained was made. Results: Malignant neoplasms appear in 5th place in health expenditures at a cost of 15 billion 1. With costs per year of life gained of 140,750 1, malignant neoplasms range ahead of respiratory diseases (52,500 1)digestive diseases (27,455 1), and injuries (14,538 1). Costs involving malignant neoplasm per year of life gained range between 39,000 1(malignancies of the lip, oral cavity, and the pharynx), and 126,000 1(digestive organ cancer). Conclusion: In Germany, oncology incurs higher costs per year of life gained as compared to several other diseases. Also, in malignant neoplasm considerable differences can be observed regarding resource allocation and efficiency.

Zerebrale Metastasen bei kolorektalen Karzinomen

ZusammenfassungHintergrund: Die Überlebenszeit nach Auftreten zerebraler Metastasen bei kolorektalen Karzinomen wird aufgrund der bisher vorliegenden Literatur meist als äußerst gering eingeschätzt. Dies führt dazu, dass Patienten, wenn überhaupt, hoch palliativen Therapiekonzepten zugeführt und aus Studienprotokollen im Allgemeinen ausgeschlossen werden. Jedoch gibt es zunehmend Berichte über Krankheitsverläufe, bei denen durch Anwendung moderner multimodaler Therapiekonzepte ein Überleben erreicht werden kann, das dem anderer Metastasierungslokalisationen bei Patienten mit kolorektalen Karzinomen entspricht. Patienten und Methoden: In unserer Klinik wurden zwischen November 1996 und Oktober 2000 113 Patienten mit metastasiertem kolorektalen Karzinom behandelt. Bei 13 Patienten wurden durch CT- und/oder MRT-Untersuchungen zerebrale Metastasen nachgewiesen. Anhand dieser 13 Patienten wird der heterogene Verlauf nach Diagnose der zerebralen Metastasierung kolorektaler Karzinome dargestellt. Ergebnisse: Die mittlere Überlebenszeit beträgt derzeit 9,0 Monate (Spanne 1–40 Monate), fünf Patienten leben mit Krankheitszeichen. Zwischen Resektion des kolorektalen Karzinoms und Diagnose der zerebralen Metastasen lagen durchschnittlich 26,5 Monate. Lediglich bei einer Patientin erfolgte die Exstirpation einer parietal gelegenen Metastase vor Kenntnis des Primärtumors. Die Gruppe der neurochirurgisch operierten sieben Patienten erreichte bisher eine Überlebenszeit von 10,4 Monaten bei vier noch lebenden Patienten. Zwei Patienten, bei denen eine Ganzhirnbestrahlung durchgeführt wurde, lebten jeweils 3 Monate. Ein Patient weist nach stereotaktischer Bestrahlung die in dieser Untersuchung ermittelte, bislang längste Überlebenszeit von 40 Monaten auf. Bei den drei Patienten, die lediglich supportiven Maßnahmen zugeführt wurden, lag die Überlebenszeit unter 1 Monat. Schlussfolgerungen: Bei unseren Patienten mit zerebralen Metastasen von kolorektalen Karzinomen zeigte sich ein heterogener klinischer Verlauf. Die Überlebenszeit der Patienten ist durch multimodale Therapiekonzepte quantitativ und qualitativ beeinflussbar. Mehrjährige Langzeitverläufe stellen keine Seltenheit dar. Dies ist in Übereinstimmung mit neueren Literaturangaben.AbstractBackground: Patients with brain metastases from colorectal cancer are supposed to have the lowest median survival compared to other locations of metastases from this cancer. Patients with brain metastases usually receive highly palliative treatment and are excluded from studies investigating new therapeutic concepts. However, there appears to be a subgroup of patients with brain metastases originating from colorectal cancer who have a median survival comparable to that of other metastatic sites. Patients and Methods: Between November 1996 and October 2000, 13 out of 113 patients from our clinic with colorectal cancer had brain metastases (11.5%). We describe their heterogeneous clinical course and present a review of the literature. Results: The median survival time after the diagnosis of brain metastases was 9.0 months for all patients, less than 1 month for three patients who received only supportive care, 40 months for a patient who was treated with radiosurgical resection, 3 months for two patients who received whole brain radiation, and 10.4 months for seven patients who underwent surgical resection. The median interval between the diagnosis of primary cancer and the diagnosis of brain metastases was 26.5 months (2–84). In one case brain metastasis was the initial manifestation of colorectal cancer. Five patients are still alive with a survival time between 6–40 months. Conclusion: The clinical course of our 13 patients varified significantly. Thus, patients with brain metastases of colorectal cancer may profit from modern multimodal therapeutic concepts. A therapeutic nihilism should be avoided.

Premenopausal breast cancer: chemotherapy and endocrine therapy.

Modern treatment of premenopausal breast cancer is based on well-established prognostic and predictive factors for disease outcome such as nodal status, hormone receptor expression, tumour size, tumour grading and patient age. The development of strategies according to such individual risk profiles has resulted in significant improvements both in overall and disease-free survival. An abundant number of new prognostic and predictive factors in addition to those already mentioned may help to increase our understanding of the biology of breast cancer and to individualise therapy in premenopausal patients. Although less than 10% of patients directly benefit, it is estimated that approximately each year the life of more than 4000 women in Germany will be saved or prolonged by adjuvant treatment. Whether dose intensive modifications and new antineoplastic drugs can improve disease outcome will be clarified when ongoing studies have increased observation time.At present, hormone ablation via surgical, radiotherapeutical or drug-induced castration in addition to selective estrogen response modifiers (SERM), such as tamoxifen, with or without chemotherapy remains the cornerstone of adjuvant treatment in premenopausal patients with breast cancer. In advanced disease, new highly effective hormonal and other target-oriented antineoplastic agents with few adverse effects have been recently introduced. However, overall survival in metastatic disease remains poor, even when intensive or high-dose chemotherapy is used. Special attention must be given to longer follow up and potential toxic long-term adverse effects of therapy when new regimens are applied in clinical trials.

Theneu oncogene product in serum and tissue of patients with metastatic gastrointestinal carcinomas

We report on our experience investigating the serum levels of the soluble domain of p185 and theneu protein expression in the corresponding tumour tissue in patients with advanced gastrointestinal carcinomas. The study included 32 patients who were treated with palliative chemotherapy. The serum levels of theneu protein were investigated by immunosorbent assay techniques. We used the alkaline phosphatase/anti-(alkaline phosphatase) method for investigating the corresponding tumour tissue immunohistochemically. Increased serumneu protein levels were found in 8 of 22 (36%) patients with colorectal carcinomas and in 2 patients with advanced abdominal adenocarcinoma of unknown primary. All other patients with advanced gastrointestinal cancers were serum-neu-protein-negative. All serum-neu-protein-positive patients with colorectal carcinomas showed also an elevatedneu protein expression. The extent of serumneu protein expression corresponded to the clinical course and the tumour marker CA 19–9. The serumneu protein may be useful for monitoring patients with advanced colorectal carcinomas, particularly in cases of immunohistochemicalneu-protein-positive primary tumours.