Besonders vielversprechend ist die Kombination mit Gemcitabin und Oxaliplatin (GEMOX), berichtete Dr. Peter Harper, Guy’s and St. Thomas Hospital, London. Beide Substanzen sind bereits als Monotherapie bei verschiedenen Tumoren aktiv; kombiniert zeigen sie aufgrund ihrer unterschiedlichen Ansatzpunkte in der Tumorzelle einen synergistischen Effekt (Tab. 1). Phase-Iund II-Studien sprechen zudem für eine geringe Toxizität der Kombination, die auch von älteren Patienten mit niedrigem Performance-Status gut vertragen wird. Aufgrund positiver Studiendaten gilt GEMOX mittlerweile als neue Hoffnung beim Pankreaskarzinom. Palliative Standardtherapie ist derzeit noch Gemcitabin, mit dem eine 1-Jahres-Überlebensrate von 18% erreicht wird. Die hohe Aktivität von GEMOX bei diesem nur sehr schwer therapierbaren Tumor wurde in einer französischen Phase-II-Studie an 64 Patienten mit lokal fortgeschrittenem (n = 30) oder metastasiertem Pankreaskarzinom (n = 34) deutlich, die Gemcitabin (1000 mg/m2 i.v.) an Tag 1 und Oxaliplatin (100 mg/m2 i.v.) an Tag 2 in zweiwöchigen Zyklen erhielten. Median wurden 9 Therapiezyklen verabreicht, d.h. die Hälfte der Patienten wurde mindestens 18 Wochen lang behandelt. Tumorschrumpfung bei einem Drittel der Patienten

Objective: Immunotherapy, and only immunotherapy, has reproducible, albeit limited efficacy in metastatic renal cell cancer (MRCC). Further improvement is warranted and progress will have to be investigated in randomised clinical trials, because the variable natural history of this disease precludes firm conclusions outside the context of controlled clinical studies. Currently, there is no general accepted standard arm to compare for those randomised clinical protocols. This needs to be established, which is the goal of this project.Materials and Methods: Interferon-alpha (IFN-alpha) or interleukin-2 (IL-2) are registered for the use in MRCC. Taking this regulatory affair into consideration, a systematic literature research using Medline Sources was carried out to identify large controlled clinical studies in MRCC, in which one or both of the registered drugs were involved. Scientific value of the trials was weighed, and the applicability, efficacy, and safety of the control arm was analysed.Results: 13 large controlled studies qualified for this purpose, and a total of 3065 patients were included. IFN-alpha monotherapy, the combination of IFN-alpha and IL-2, and the combination of IFN-alpha, IL-2 and 5-fluorouracil (5-FU) were used as a standard treatment in decreasing frequency, respectively. There is no valid scientific proof that a combination of immunotherapies prolongs survival over monotherapies, but the combination of surgery and immunotherapy leads to a clear survival benefit over immunotherapy alone. IFN-alpha monotherapy has considerable less side effects than IL-2 based regimens.Conclusion: An appealing safety profile, the applicability in an outpatient regimen, the possibility of less stringent selection criteria, and the proven life prolonging effect will make adjuvant monotherapy, in particular IFN-alpha monotherapy, after a tumournephrectomy currently the control-arm of choice in randomised trials for MRCC. (C) 2003 Elsevier Science B.V. All rights reserved.

For many years the prevailing belief was to advocate'radical' nephrectomy via a transperitoneal approach as the standard surgical procedure for renal cell carcinoma (RCC). because the early control of the renal vessels before manipulating the kidney should minimize the likelihood of disseminating tumour cells during surgery. This philosophy was based on retrospective data which were never confirmed in a controlled trial. Since then,evidence has accumulated that some patients maybe better served by an extraperitoneal (translumbar)approach, providing similar oncological efficacy with the added advantage of reduced morbidity. However,these results are again either retrospective or statistically insignificant, and therefore do not allow firm conclusions. Nevertheless, if there is any difference in the possible intraoperative dissemination of tumour, depending on the type of surgical approach, it will be small, requiring analysis in a large randomized multicentre trial. The treatment of choice for disease that is not disseminated is surgery, although the 5-year survival rates for all stages do not exceed 60%, even in contemporary series. Further improvements will probably have to rely on the development of more effective systemic therapy and the application of combined treatments to counter the relatively many patients presenting with advanced stages. Concepts and progress in this field appear to be of major interest for modern uro-oncologists after the advent of immunotherapeutic strategies that require a surgical intervention at some stage of the treatment cascade.

For many years, the prevailing belief was to advocate ‘radical’ nephrectomy via a transperitoneal approach as the standard surgical procedure for renal cell carcinoma (RCC), because the early control of the renal vessels prior to manipulation of the kidney should minimize the likelihood of tumor cell dissemination during the course of the operation. This philosophy was based on retrospective data which were never confirmed in a controlled trial. Since then, evidence kept accumulating that some patients may be better served by an extraperitoneal (translumbar) approach providing similar oncologic efficacy with the additional advantage of reduced morbidity. However, these results are either retrospective again or statistically not significant and, therefore, do not permit firm conclusions. Nevertheless, it is clear that, if there is a difference at all with respect to a possible intra-operative tumor dissemination depending on the type of surgical approach performed, this difference will be small, requiring analysis in a large randomized multicenter trial. Until reliable data from the EORTC trial will become available, it is advisable to act carefully. Small (< 7 cm) unilateral RCCs most likely may safely be approached via a translumbar (intercostal) incision. In patients with a large tumor mass, involvement of the Vena cava, or if local-regional lymph node dissection is desired, it may be preferable to perform a transperitoneal tumornephrectomy.

The aim of this study was to obtain insight into the role of the multidrug resistance (MDR) phenomenon in hormone-independent progressive prostate cancer. Using immunocytochemistry and Western blotting we determined the expression of P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP), glutathione-S-transferase-pi (GST-pi), Bcl-2, Bax, topoisomerase (Topo) I, II alpha and II beta in the human prostate cancer cell lines PC3, TSU-Pr1, DU145 and LNCaP derivatives LNCaP-R, LNCaP-LNO and LNCaP-FGC. Proliferative activity was assessed by immunocytochemistry. MTT assays were used to determine the sensitivity to etoposide, doxorubicin and vinblastin. Pgp was not expressed in any of the cell lines. MRP was variably expressed. GST-pi was expressed in TSU-Pr1, PC3 and DU145. The expression of Bcl-2 was restricted to TSU-Pr1, whereas Bax was found in all cell lines. Topo II alpha was expressed at the highest level in the rapidly proliferating cell lines TSU-Pr1 and DU145. Topo I and II beta were equally expressed. Resistance profiles varied among the cell lines, with TSU-Pr1 being the most sensitive and LNCaP-LNO relatively resistant. Multiple MDR proteins were expressed in prostate cancer cell lines and may well influence response to chemotherapy. Future functional studies, using chemo-selected MDR models, may further help to determine the mechanism or combination of mechanisms underlying the resistance of prostate cancer to chemotherapy.

This paper contains a ‘confirmatory’ phase II study of interferon alpha and cis-retinoic acid in metastatic renal cell carcinoma. The investigation had been instigated by a strongly enthusiastic report from MRSCC (ref. 7) published in 1995. Similar to the results of a later randomised phase III trial from MRSCC (ref. 16) and the interim analysis of an ongoing phase II/III randomised trial from EORTC (30951) [1], this study found predominantly toxicity arising from the combination. Efficacy definitely lacked behind the expectations with 2/24 evaluable patients (2/29 enrolled patients) exhibiting a PR. The question arises whether a protocol alteration contributed to the low efficacy. In the present protocol, treatment was strictly limited to 12 weeks even in patients not being progressive or suffering from significant toxicity. In the large MRSCC series as well as in EORTC 30951 the protocol featured one year targeted treatment duration, with a majority of patients receiving therapy between 5 and 8 months. Given these differences, both protocols are not amenable for direct comparison. However, because of a similar response rate in the present study and the large MRSCC series, the authors may glean some justification for their treatment protocol. Overall, this negative study laudably sets things straight, and may serve as a timely warning against overly enthusiastic reports derived from small numbers of patients. Clearly, new therapies for metastatic renal cell carcinoma should be sought for and the way to go, as stated by the authors, is to participate in controlled clinical trials. G. H. J. Mickisch, Rotterdam