Stefan Wellek

Advanced Bladder Cancer (Stages pT3b, pT4a, pN1 and pN2): Improved Survival after Radical Cystectomy and 3 Adjuvant Cycles of Chemotherapy. Results of a Controlled Prospective Study

A total of 49 bladder cancer patients with tumor stages pT3b, pT4a and/or pelvic lymph node involvement without microscopic or macroscopic evidence of residual tumor was randomized into 2 comparative groups: the chemotherapy group was to receive 3 adjuvant cycles of methotrexate, vinblastine and cisplatin plus doxorubicin (M-VAC) or epirubicin (M-VEC) after radical cystectomy. The control group received no additional treatment. The protocol was activated in May 1987. Patient recruitment was concluded in December 1990 because an interim analysis of the 49 randomized patients revealed a significant prognostic advantage in favor of 26 patients randomized to the chemotherapy group compared to 23 in the control group (p = 0.0015, log rank test for relapse-free survival curves). Of the 26 patients randomized for adjuvant chemotherapy 18 were treated with M-VAC or M-VEC (3 cycles in 16 patients and 2 cycles in 2). Of the remaining 8 patients 7 refused chemotherapy before or during cycle 1 and 1 received chemotherapy without cisplatin because of impaired renal function. An update of the patients in August 1991 revealed a further increase in the prognostic difference between the 2 trial arms (p = 0.0012). Of 18 patients who received treatment with M-VAC or M-VEC only 3 have had tumor progression to date compared to 18 of 23 patients in the control group. Further statistical analysis of the data was performed on the basis of Coxs regression model, incorporating various criteria as explanatory variables, including patient sex and age, pT stage and number of involved lymph nodes. This multivariate analysis revealed a significant decrease in the risk of tumor recurrence (p = 0.0007, 2-sided) after adjuvant chemotherapy. The number of lymph nodes involved was also of prognostic significance (p = 0.0028, 1-sided). The results indicate that the survival time after radical cystectomy can be prolonged considerably by adjuvant polychemotherapy in cases of locally advanced bladder carcinoma. Fortunately, all of these conclusions are not affected by switching from an intent-to-treat analysis to an analysis of the therapy actually performed. The p values obtained from the latter are 0.0005 (log rank test) and 0.0001 (Cox model with the same set of additional regressors).

Adjuvant polychemotherapy of nonorgan-confined bladder cancer after radical cystectomy revisited : long-term results of a controlled prospective study and further clinical experience

A total of 83 patients with nonorgan-confined bladder cancer with or without lymph node metastases (tumor stages pT3b, pT4a and/or pN1, pN2) was evaluated in November 1993 for relapse-free and overall survival. All patients underwent radical cystectomy between 1987 and 1991, 38 underwent adjuvant polychemotherapy with methotrexate, vinblastine and cisplatin plus doxorubicin (M-VAC) or epirubicin (M-VEC). Of the 83 patients 49 had entered a prospective randomized trial comparing adjuvant to no adjuvant treatment. The protocol was activated in May 1987. Patient recruitment was concluded in December 1990 because an interim analysis of the 49 randomized patients revealed a significant prognostic advantage in favor of the 26 patients randomized to the chemotherapy group compared to 23 in the control group (p = 0.0015, log-rank test for relapse-free survival curves). Preliminary data were published in 1992. Of the 26 patients randomized for adjuvant chemotherapy 18 were treated with M-VAC or M-VEC, 7 refused chemotherapy before or during cycle 1 and 1 received chemotherapy without cisplatin because of impaired renal function. The update of patient followup obtained in November 1993 continues to demonstrate a significant improvement in progression-free survival in favor of patients randomized for adjuvant chemotherapy (p = 0.0005). Followup of patients living free of disease ranged from 38 to 78 months. In a second analysis of actual treatment, the total collective of 83 patients treated from 1987 to 1991 was reviewed: 38 who had actually undergone adjuvant M-VAC/M-VEC (18 during the prospective trial and 20 in 1991 as the routinely recommended therapy) were compared with 45 without adjuvant M-VAC/M-VEC (7 refused to participate in the adjuvant trial, 8 randomized for but did not undergo adjuvant M-VAC/M-VEC, 23 belonged to the control group of the trial, and 7 underwent cystectomy in 1991 and remained without adjuvant treatment). This analysis again revealed a significant prognostic advantage in favor of the patients treated with adjuvant M-VAC/M-VEC. We conclude that adjuvant chemotherapy with M-VAC/M-VEC leads to a significant prolongation of relapse-free survival and to an improvement of the definitive cure rates after radical cystectomy for locally advanced transitional cell carcinoma of the bladder.

Prognostic value of DNA analysis in colorectal carcinoma

Background. Reported experiences regarding the prognostic significance of DNA content in colorectal carcinoma have been a matter of controversy.

Factors influencing survival after resection of pancreatic cancer : a DNA analysis and a histomorphologic study

Background. The influence of DNA content on prognosis in stomach cancer has been investigated rarely, and the results are controversial.

[PREFERE - the German prostatic cancer study: questions and claims surrounding study initiation in January 2013].

The PREFERE study is a multicenter randomized study of patients with low or early intermediate risk for prostatic cancer. The four treatment options, radical prostatectomy, percutaneous irradiation therapy, permanent seed implantation and active surveillance recommended by the German S3 guidelines and international guidelines will be tested and compared with respect to effectiveness and potential side effects. Over a period of 4 years a total of 7,600 patients are to be recruited and assigned to 1 of these 4 therapy forms according to personal preference (by possible exclusion of 1 or 2 therapy options) in a 2-4 arm study design by randomization.

Multivariate Equivalence Tests for Use in Pharmaceutical Development

Statistical equivalence analyses are well-established parts of many studies in the biomedical sciences. Also in pharmaceutical development and manufacturing equivalence testing methods are required in order to statistically establish similarities between machines, process components, or complete processes. This article presents a choice of multivariate equivalence testing procedures for normally distributed data as generalizations of existing univariate methods. In all derived methods, variability is interpreted as nuisance parameter. The use of the proposed methods in pharmaceutical development is demonstrated with a comparative analysis of dissolution profiles.

DNA image cytometry in stomach carcinoma. Its relation to histomorphologic parameters and its influence on prognosis

Background. The influence of DNA content on the prognosis in stomach cancer is controversial.

A nonparametric model for product-limit estimation under right censoring and left truncation

The object of this paper is the generalization of the product-limit estimator (PLE) to the case of survival data subject to both right censoring and left truncation. From a practical point of view the problem admits a straightforward solution: The usual Kaplan-Meier formula may be adapted by simply eliminating from the risk set to be assigned to any given point t on the time axis, all items entering observation later than t. The model which we propose is a natural generalization of the well known random censorship model, giving a precise mathematical meaning to the intuitive notion of a noninformative left truncation mechanism. In our analysis of the asymptotic behaviour of the PLE under this model, the ”classical” approach via empirical processes of i.i.d. random variables is used. The main results derived in this way are strong uniform consistency, and asymptotic normality of the generalized PLE on any compact interval in which the probability of being at risk of failure is bounded away from zero. The p...

Vorschläge zur Reformulierung der statistischen Definition von Bioäquivalenz

Gegen das herkommliche, nur die Erwartungswerte berucksichtigende Bioaquivalenzkriterium last sich der Einwand mangelnder Relevanz fur den Emzelfall geltend machen. Beide zur Behebung dieses Mangels vorgeschlagenen Ansatze betrachten als primar interessierende Grose die Wahrscheinlichkeit eines Ereignisses, das die individuelle Reaktion gegenuber der Test (T) — und der Referenzformulierung (R) eines gegebenen Wirkstoffs beschreibt. Ansatz (I) fuhrt auf einen einfachen Binomialtest mit der Anzahl von Probanden, bei denen der individuell beobachtete Bioverfugbarkeitsquotient im Sinne des 80–120%-Kriteriums akzeptabel ist. Der Test ist gleichmasg bester unter allen verteilungsfreien Tests zur Entscheidung zwischen den zugehorigen Hypothesen. Ansatz(II) formuliert die Alternativhypothese, das die Wahrscheinlichkeit, mit der T die schlechtere Bioverfugbarkeit ergibt als R, nahe bei 1/2 liegt. Unter der Annahme lognormalverteilter Bioverfugbarkeitsquotienten ist diese Hypothese gleichbedeutend mit der Aussage, das der standardisierte Erwartungswert einer Normal verteilung, aus der eine einzelne Stichprobe gezogen wird, in einem engen, zu 0 symmetrischen Intervall liegt. Hierfur existiert ebenfalls ein optimaler (namlich gleichmasg bester invarianter) Test, den man als ”verbundenen t-Test auf Aquivalenz” bezeichnen kann. Zu der Losung nach Ansatz (II) existiert eine Zweistichproben-Version. Diese eignet sich fur die Auswertung von Bioaquivalenzstudien, in denen die Applikationsreihenfolge der Formulierungen im Zweiperioden-Cross-over einen erkennbaren Einflus auf das Ergebnis der Bioverfugbarkeitsprufung hat.

Equivalence Testing With Particle Size Distribution Data: Methods and Applications in the Development of Inhalative Drugs

ABSTRACT Key criteria of the quality of inhalative drugs are assessed in experiments generating so-called particle size distributions as data. Many experiments of that kind are carried out to demonstrate that necessary modifications to whatever part of the manufacturing process do not substantially change basic characteristics of an inhalable drug product. The equivalence testing procedures we derive for that purpose rely on different models accommodating the specific structure of such data and on different ways of specifying the region of nonrelevant differences. For each hypotheses formulation, three different tests are derived (two parametric and one asymptotically distribution-free procedures) and compared in terms of level and power. The results support the conclusion that the asymptotically distribution-free procedure exhibits surprisingly favorable properties. Supplementary materials for this article are available online.