Apoptosis, p53, bcl-2, and Ki-67 in invasive bladder carcinoma: possible predictors for response to radiochemotherapy and successful bladder preservation.

PURPOSE: Several groups have reported the value of bladder preservation by a combined treatment protocol, including transurethral resection (TUR-B) and radiochemotherapy (RCT). As more experience is acquired with organ-sparing treatment, patient selection should be optimized. The purpose of this study was to investigate the role of several biologic markers that may predict response to RCT in muscle-invasive bladder carcinoma. METHODS AND MATERIALS: The apoptotic index (AI), Ki-67, p53, and bcl-2 were evaluated by immunohistochemistry on pretreatment biopsies from 70 patients treated for invasive bladder cancer by TUR-B and RCT. Expression of each marker was correlated with initial response, local control, and cancer-specific survival with preserved bladder. An exploratory multivariate analysis was also performed that included clinical and immunohistochemical variables. RESULTS: A high AI (> median = 1.6%) and a high Ki-67 index (> median = 8.8%), but not the p53- and bcl-2 expression, were significantly related to initial complete response (CR) and local control with preserved bladder after 5 years. When the AI and Ki-67 expression were considered simultaneously, the association with initial CR (p < 0. 001), local control (p = 0.0002), and cancer-specific survival with preserved bladder (p = 0.008) was highly significant. In an exploratory multivariate analysis (final model), only AI, Ki-67, and the combined AI/Ki-67 variable retained significance for local control with preserved bladder at 5 years. CONCLUSION: Patients with a high spontaneous AI and a high pretreatment Ki-67 index should be considered preferentially for treatment with RCT, whereas tumors with low proliferation and low levels of apoptosis are less likely to respond to RCT.

Concomitant radiochemotherapy with 5-FU and cisplatin for invasive bladder cancer. Acute toxicity and first results.

PURPOSE: To evaluate acute toxicity and efficacy of simultaneous radiochemotherapy for invasive urothelial cancer of the bladder. PATIENTS AND METHODS: From September 1993 to July 1997, 61 patients with invasive bladder cancer were treated with a transurethral resection (TURB) followed by radiochemotherapy (RCT). Twenty-five received a combination of 5-FU and cisplatin. The prescribed doses were 600 mg/m2 5-FU daily as continuous infusion over 5 days each in the 1st and 5th treatment week and 20 mg/m2 cisplatin daily at the same days as a short infusion. The pelvis was irradiated with 54 Gy, the bladder with 59.4 Gy and the paraaortic nodes in 7 cases with 45 Gy, respectively. Six to 8 weeks after RCT a second TURB was performed for reasons of restaging. RESULTS: Twenty out of 25 patients received at least 80% of the prescribed chemotherapy, in 13 cases the full dose could be given. Gastrointestinal toxicity of Grade I and II occurred in 10 cases, 1 patient developed severe diarrhea (Grade VI). After the 1st course of chemotherapy 7 patients had leuko- or thrombopenia of Grade III. One patient had a leucopenia of Grade IV. After the 2nd course 4 patients developed Grade III leuko- and thrombopenia, 1 of Grade IV. Two Grade II anemia were found. All more severe toxicities and necessary dose reductions were related to radiation of the paraaortic nodes. No life threatening infections, bleedings or cardiotoxicity was found. Restaging TURBs resulted in 22 complete remissions, 1 patient had a de-novo-carcinoma (Tis) at this time, 2 were non-responders (8%). After a median follow-up of 38 months 20 patients are alive (80%). CONCLUSIONS: 1. If irradiation of paraaortic nodes is necessary, 5-FU should not be applied, because the gastrointestinal toxicity is too extensive. In all other cases side effects are tolerable and can be managed by supportive care. 2. The first results are promising and should be evaluated in a prospective study.

Estimation of DNA single-strand breaks by single cells gel electrophoresis in tumor cells.

To estimate the frequency of single-strand breaks on a single cell level the so-called comet-assay (single cell gel electrophoresis) is a well-established technique. We present a modified protocol suitable for testing primary tumors, a kind of tissue very uneasy to be analysed in former single cell gel electrophoresis assays. Tumor cells of 12 studied cases showed a typical dose-rate effect on in vitro irradiation with different X-ray doses, as observed in peripheral blood leukocytes. Interestingly, the repair capability of primary tumor cells was lower than that of peripheral blood leukocytes of the same patients.

Radiotherapy alone or radiochemotherapy with platin derivatives following transurethral resection of the bladder. Organ preservation and survival after treatment of bladder cancer.

PURPOSE: Multivariate analysis of prognostic factors influencing survival and bladder preservation after radiochemotherapy for bladder cancer following transurethral resection of the bladder (TURB). PATIENTS AND METHODS: At the University Hospital of Erlangen 333 patients with bladder cancer were treated with either radiotherapy alone (RT, n = 128) or platin based radiochemotherapy (RCT, n = 205) after TURB between 5/1982 and 5/1996. Two-hundred and eighty-two curative patients, with either muscle invasive or T1-high risk cancer, were analyzed. Median age was 66 years, median follow-up is 7.5 years. Uni- and multivariate analysis was performed for age, grade, R-status after initial TURB, T-category and treatment modality relevant to the endpoints initial response, survival and bladder preservation. RESULTS: Treatment related mortality was below 1%. Complete remissions were achieved at 57%, 70%, and 85% after RT or RCT with carboplatin or cisplatin. This difference was multivariately significant. Further significant prognostic factors were pT-category and R-status. For all patients survival was 59% and 43% after 5 and 10 years. 79% of survivors could keep their own bladder. Five-year survival rates after RT alone, RCT with carboplatin or cisplatin were 47%, 57%, and 69%, respectively. This was univariately significant. The only multivariately significant factor for survival and bladder preservation was the R-status after initial TURB. CONCLUSIONS: Treatment of bladder cancer by TURB and RT/RCT is an alternative to primary cystectomy. The addition of chemotherapy leads to significantly more complete remissions and better survival. Initial TURB is recommended to be as radical as possible.

[The age correction of survival probabilities in cancer studies]. / Die Alterskorrektur von Uberlebenswahrscheinlichkeiten in onkologischen Studien.

PURPOSE: Survival of elder oncological patients may depend on the tumor disease, on reasons not related to the underlying disease or simply on patient's age. Therefore patient' age has to be taken into account if the objective of an oncological study is the disease-related survival. Basically, there are 3 different approaches: multivariate statistical modelling, estimation of disease-related survival after censoring of cases with cause of death not due to the tumor disease, and consideration of demographical data in the general population. PATIENTS AND METHODS: Our paper deals with the age correction using the data from the 1986/88 census in Germany. We have written a computer program based on SPSSWIN, which allows an automated age correction. Using clinical data of radiotherapy after surgical therapy of bladder cancer, we illustrate the method. RESULTS: The estimated 5-year-survival using the age correction was--dependent on patient's age in the sample--10% up to 15% higher than the uncorrected rate. In the whole sample of 333 unselected patients, 5-year-survival was corrected from 47% to 59%. In the normal population adjusted for age- and sex-distribution, the expected survival rate was 80%. CONCLUSIONS: The age correction has substantial influence on survival analysis of male patients elder than 60 years and female patients elder than 70 years. It should therefore be used in oncological studies investigating long-term survival of patients in these age-groups.

Efficacy of radiochemotherapy with platin derivatives compared to radiotherapy alone in organ-sparing treatment of bladder cancer.

PURPOSE: Presently, for muscle-invasive bladder cancer, radical cystectomy is considered to be the standard treatment. Bladder preservation, in the interest of quality of life, is secondary to the primary treatment goal of curing the patient. We present a 14-year multivariate analysis of prognostic factors influencing survival and bladder preservation after transurethral resection of the bladder (TURB) and radiotherapy (RT) +/- chemotherapy. METHODS AND MATERIALS: From May 1982 to May 1996, sequential cohorts of 333 patients with bladder cancer (mean age: 66 years) were treated by either RT alone (128 patients), or with platin-based concomitant radiochemotherapy (RCT, 205 patients) after TURB. Patients (282) with muscle-invasive or T1 high-risk cancers (Grade III, residual tumor after TURB, multifocality, tumor diameter > 5 cm, associated Tis or Ta, multiple recurrences or lymph node metastases), who received a minimal target dose of 45 Gy were selected for analysis (med. follow-up = 7.5 years): after October 1985, 115 patients received cisplatin (25 mg/m2) and 69 patients carboplatin (65 mg/m2) before every treatment fraction (1.8 Gy) on Days 1-5 and 29-33 of conventional fractionated RT. RESULTS: Complete remission rate was 20% (55 of 282 patients) after radical TURB, 57% (56 of 98) after TURB plus postoperative RT, and 80% (145 of 181 patients) after TURB plus RCT (85% after concomitant cisplatin and 70% after RCT plus carboplatin). These differences were significant in multivariate analysis (p = 0.003-0.05). The strongest impact on initial response had T-category (p < 0.0001) and R-status after TURB (p < 0.0003). Cause-specific survival (CSS) was 59 and 43% after 5 and 10 years; 79% of patients survived with preserved bladder. Five-year CSS after RT, RCT-Cis, and RCT-Carbo was 40, 64, and 54%, 10-year CSS 31, 48, and 27%, respectively (p = 0.04-0.045, univariate). R-status after TURB was the only independent prognostic factor for survival and bladder preservation. For relapsed patients after cystectomy, the 5- and 10-year CSS were 40 and 33%. CONCLUSIONS: TURB followed by RT/RCT is an alternative treatment option to primary cystectomy for patients with muscle-invading bladder cancer. Compared to historic controls, the addition of cisplatin or carboplatin leads to significantly more complete remissions and better survival. Survival rates are similar to those achieved by primary cystectomy and possibly even better for selected subjects, such as patients with T3b and T4 tumors. Cystectomy should be restricted to only those patients who fail after RCT.

[Hypoxyradiotherapy: changes in the oxygen partial pressure distribution in the tumor and in the healthy tissue under acute respiratory hypoxia]. / Hypoxie-Radiotherapie: Veränderungen in der Sauerstoffpartialdruckverteilung im Tumor und im gesunden Gewebe unter akuter respiratorischer Hypoxie.

PURPOSE: Based on the oxygen effect a new therapeutic modality has been developed to protect healthy tissues while breathing hypoxic gas mixture during irradiation. MATERIAL AND METHODS: The effect of breathing hypoxic gas mixture (8.1% O2) on pO2 in Yoshida sarcoma and muscle was studied using rats of Wistar strain. Different fractionation schedules were used: 10 x 3 Gy, 6 x 5 Gy and 3 x 10 Gy. Tissue oxygenation was assessed with a polarographic electrode system. RESULTS: The median pO2 in Yoshida sarcoma was 10 mm Hg. 21% of pO2-values were lower than 5 mm Hg. During breathing of hypoxic gas mixture no significant changes in median tumor pO2 or radiobiologic hypoxic values (< or = 5 mm Hg) were recorded. The median pO2 in muscle was 30 mm Hg. During breathing of gas hypoxic mixture a significant decrease of the median to the value 12 mm Hg and an increase of the radiobiologic hypoxic values (p < 0.00001) were observed. The changes of pO2-values were constant independent from fractionation. CONCLUSIONS: Between tumor and healthy tissue exists a significant difference regarding changes in the radiobiologic fraction during breathing of hypoxic gas mixture. This fact explains the experimental and clinical experience, that the breathing hypoxic gas mixture protects the healthy tissue without changes in the radiosensibility of chronic hypoxic tumor tissue.

Use of a three-color chromosome in situ suppression technique for the detection of past radiation exposure.

A three-color chromosome in situ suppression technique and classical cytogenetic analysis were compared for the detection of chromosomal aberrations in blood lymphocytes of 27 patients who had undergone radiation therapies from 1 month to 9 years ago. Depending on the respective regimens of therapy, a high variability was found in the aberration data. Aberration rates depended on the interval between exposure and scoring rather than on the locally applied radiation doses, which were rather uniform among most patients. Chromosome in situ suppression was found to be superior to classical cytogenetics with respect not only to the spectrum of detectable aberrations but also to the uncovering of long-term effects of irradiation. Of particular interest were the relative stability of the frequency of radiation-induced reciprocal translocations and the utility of chromosome in situ suppression to uncover complex rearrangements.

Is chromosome in situ suppression (CISS) hybridization suited as a predictive test for intrinsic radiosensitivity in cancer patients?

Chromosome painting (chromosome in situ suppression hybridization, CISS) analyses were used to control in vitro radiosensitivity of peripheral blood lymphocytes of 70 cancer patients who were assigned to or had just undergone radiation therapy. This technique using three-colour detection of genomic DNA libraries of chromosomes 1, 2, and 4 was shown to uncover reliably radiation-induced chromosome damage in human peripheral blood lymphocytes. The lymphocytes of five out of the 70 cancer patients could be defined as to react hypersensitively to in vitro irradiation. This was particularly underlined not only by the mere increase of aberration rate but also by the quality of the induced abnormalities (e.g. incidence of complex chromosome rearrangements). The same patients were also characterized by extreme radiation reaction in clinical terms. In spite of some confounding factors, based on the presented observations, the CISS-technique can be proposed as a predictive technique for selecting radiosensitive patients and protecting them from undesired side effects of radiotherapy. A simplification of the screening procedure is proposed on the basis of the presented data.

Historical essentials influencing the development of radiooncology in the past 100 years.

An overview of the development in the recent 100 years is given. The work of the most important pioneers is described. Both technical preconditions and radiobiological fundamentals influencing advances in radiotherapy are lined out. It is shown that many modern techniques and therapeutical strategies have their origin in the beginning of radiotherapy and that this is the case for many unsolved problems as well.

[Extended reversible global left ventricular contraction dysfunction with symptomless coronary system as effect of cytostatic therapy with 5-fluorouracil]. / Ausgedehnte reversible globale linksventrikuläre Kontraktionsstörung als Folge einer zytostatischen Therapie mit 5-Fluorouracil bei unauffälligem Koronarsystem.

CASE REPORT: We report on a young female patient suffering from anal-cancer who received simultaneous radiochemotherapy and developed a "hibernating myocardium" during continuous infusion of 5-FU. CONCLUSION: In literature the incidence of cardiac complications caused by 5-FU-therapy is found to be between 1% and 10%. Patients with coronary heart disease have a four-fold higher risk. Possible pathogenic mechanisms are spasm of coronary artery, direct cardiotoxicity, immunological reactions and disturbance of the coagulation system.

Local oxygen supply and blood flow regulation in contracting muscle in dogs and rabbits.

1. Multiwire surface electrodes were used to measure local hydrogen clearance curves and tissues PO2 in the sartorius muscle in dogs under resting conditions and during stimulation of the muscle at 1, 2, 4, 8 and 20 Hz via the femoral nerve. Tissue oxygen supply was assessed by means of PO2 histograms; evaluation of the initial slopes of the hydrogen clearance curves enabled the measurement of capillary blood flow. 2. In a further model, the analysis of hydrogen clearance curves measured in the femoral vein using intravascular needle electrodes in rabbits enabled the distribution of blood flow to be evaluated both under resting conditions and during direct 2 Hz stimulation of the vastus medialis muscle. 3. Increased oxygen consumption, induced by stimulation, caused increases in capillary flow which were not necessarily accompanied by augmentation of femoral artery flow. 4. PO2 histograms provided no evidence of cellular anoxia even at the maximum level of oxygen consumption. 5. A two-compartment distribution of flow was measured under resting conditions, whereas only one compartment could be resolved during 2 Hz stimulation of the vastus medialis muscle in the rabbit experiments. A clear redistribution of flow was observed in the absence of any increase in total flow. 6. A model for oxygen-dependent regulation of capillary blood flow involving high-flow and normal-flow compartments is proposed.