[New data on cytoprotection in radiotherapy].
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Publications and source records attributed to R Sauer.
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Motor effects mediated through adenosine A2A receptors within the caudate-putamen were investigated in rats using bilateral microinfusions of MSX-3 (9 microg in 1 microl per side), a water-soluble phosphate prodrug of the selective A2A receptor antagonist MSX-2. Blockade of striatal A2A receptors produced a significant motor stimulation measured by an enhanced sniffing activity. Furthermore, catalepsy induced by systemic dopamine D1 (0.75 mg/kg SCH23390, i.p.) or dopamine D2 receptor blockade (1.5 mg/kg raclopride, i.p.) was potently reversed. These findings suggest that A2A receptors within the caudate-putamen are tonically activated by endogenous adenosine and that a striatal A2A receptor blockade produces motor stimulant effects, in particular in animals with dopamine hypofunction. The present results support the view that A2A receptor antagonists may be potentially useful therapeutics for the treatment of Parkinson's disease.
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.
OBJECTIVE: To determine the role of transoral laser resection of supraglottic carcinomas. DESIGN: Retrospective unicenter study of the oncologic results of transoral carbon dioxide laser microsurgery for supraglottic carcinomas performed between February 1979 and December 1993. Median follow-up was 37 months. SETTING: University hospital academic tertiary referral center. PATIENTS: We reviewed the medical records of 141 patients (a consecutive sample of 131 men and 10 women; mean age, 60 years) with histologically proven supraglottic carcinomas undergoing transoral laser surgery, possibly in combination with neck dissection or radiotherapy. Stage distribution of patients was as follows: stage I, 23.4%; stage II, 25.5%; stage III, 16.3%; and stage IV, 34.8% (according to the Union Internationale Contre le Cancer staging system). MAIN OUTCOME MEASURES: Recurrence-free survival rates and local and regional recurrence rates. RESULTS: Five-year recurrence-free survival rates were as follows: the whole case load, 65.7%; stage I, 85.0%; stage II, 62.6%; stage III, 74.2%; and stage IV, 45.3%, according to the Union Internationale Contre le Cancer staging system. The local and regional recurrence rates were 16.3% and 9.9%, respectively. CONCLUSIONS: The oncologic results of transoral carbon dioxide laser surgery are satisfying if clean surgical margins (R0 resection) can be reached. In patients in whom tumor-free margins are not achieved (R1 and R2 resection) and transoral revision is not possible, transcervical procedures (partial or total laryngectomy) should be performed. The indication for transoral supraglottic laryngectomy in T3 lesions should be considered with restraint.
The optimal dose and schedule of paclitaxel in combination with irradiation have not been determined yet. The aim of this study was to compare the in vitro cytotoxicity and enhancement of radiation sensitization as a function of single vs. fractionated paclitaxel exposure. A fibroblast cell line (B14) in exponential growth phase was used. The clonogenic assay was applied to determine cell survival. Flow cytometric measurements were performed to study cell cycle DNA distribution. Cytotoxicity of Taxol was examined at concentrations varying from 2 to 50 microM. Single (1 x 0 microM) vs. fractionated (2 microM/day, days 1-5) exposure of Taxol was investigated. The combination of Taxol plus irradiation as single and fractionated treatment was accomplished with 10 microM Taxol on day 1 plus 10 Gy irradiation on day 1 vs. Taxol 2 microM/day, days 1-5, plus irradiation 2 Gy/day, days 1-5. One-, 9-, and 24-hr intervals between end of incubation and irradiation were defined. Control populations demonstrated an average plating efficiency of 93%. Single Taxol exposure showed an average clonogenic survival of 84%. No significant difference between concentrations varying from 2 to 50 microM was observed. Single dose irradiation (1 x 10 Gy) led to clonogenic survival of 3%. Single exposure of Taxol plus single dose irradiation led to clonogenic survival of 4%. Fractionated radiation showed an average clonogenic survival of 41%. Fractionated Taxol treatment led to an average clonogenic survival of 63%. The combination of fractionated Taxol treatment (2 microM/day, days 1-5) plus fractionated irradiation (2 Gy/day, days 1-5) showed an average clonogenic survival of 15%. No significant difference between the chosen intervals was demonstrated. Flow cytometric measurements did not indicate any significant alterations in cell cycle DNA distribution. In conclusion, the data demonstrate a potential beneficial effect by combining fractionated Taxol exposure with fractionated irradiation without evidence for G2/M arrest in DNA analysis.
PURPOSE: This study contained herein assessed long-term results, toxicity, and prognostic variables following combined modality therapy of patients with International Union Against (Cancer Classification T1-4, N0-3, M0 squamous-cell carcinoma of the anal canal. PATIENTS AND METHODS: Between 1985 and 1996, 62 patients completed treatment with combined modality therapy. A median total dose of 50 Gy was given to the primary, perirectal, presacral, and inguinal nodes followed by a local boost in selected cases. 5-Fluorouracil was scheduled as a continuous infusion of 1,000 mg/m2 per 24 hours on days 1 to 5 and 29 to 33 and mitomycin C as a bolus of 10 mg/m2 on days 1 and 29. Routinely processed paraffin-embedded sections were stained using monoclonal antibodies for detection of proliferating cell nuclear antigen and MIB1 (Ki-67) antigen to determine the labeling index. In addition, DNA ploidy was assessed after Feulgen staining. RESULTS: Actuarial cancer-related survival, no evidence of disease survival, and colostomy-free survival rates at five years were 81, 76, and 86 percent, respectively. In univariate analysis, T category (T1/2 vs. T3/4) was predictive for no evidence of disease survival (87 vs. 59 percent; P = 0.03) and colostomy-free survival (94 vs. 73 percent; P = 0.05). N category (N0 vs. N1-3) influenced actuarial cancer-related survival (85 vs. 58 percent; P = 0.002) and no evidence of disease survival (80 vs. 53 percent; P = 0.02). A higher proliferative potential as measured by the MIB1 labeling index was associated with a better colostomy-free survival (90 vs. 50 percent; P = 0.04). In multivariate analysis, actuarial cancer-related survival was only influenced by the N category (P = 0.03) and no evidence of disease survival by N category (P = 0.03) and mitomycin C dose (P = 0.04). Salvage abdominoperineal resection achieved long-term control in only four of seven patients with local failures. CONCLUSION: Treatment with a combination of radiotherapy and chemotherapy is safe and effective for patients with anal canal carcinoma. Abdominoperineal resection is indicated as a salvage procedure in nonresponding and recurrent lesions and may be of benefit in a small subgroup of patients with poor prognostic factors.
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.
PURPOSE: Paclitaxel (Taxol) is a new anticancer agent with a novel mechanism of action. It has demonstrated broad clinical activity in a variety of malignancies. Several aspects of paclitaxel's usage remain to be clarified, including the optimal treatment schedule. Furthermore, the diluent of paclitaxel, Cremophor EL/ethanol, alone has shown to be markedly active in tumor samples. MATERIAL AND METHODS: The in-vitro cytotoxicity of paclitaxel (Taxol) due to single dose (1 x 10 microM/day, day 1 incubation time: 3 h and 15 h) and fractionated exposure (5 x 2 microM/day, day 1 to 5 incubation time: 3 h/day) was evaluated, measuring surviving fraction (clonogenic assay) and DNA distribution (flow cytometric analysis). In the control population, the diluent Cremophor EL/ethanol or a phosphate buffered salt solution (PBS) were applied using identical doses and schedules. A mammalian fibroblast cell line (HyB14FAF28) was used. RESULTS: Fractionated application of paclitaxel (Taxol) produced a significant lower clonogenic survival (0.63) in comparison with single dose exposure for 3 h (0.84) and 15 h (0.82). DNA analysis showed no evidence for a significant difference in DNA distribution of the paclitaxel-specific G2/M phase over a 10-day period. Controls with the diluent Cremophor EL/ethanol showed a clonogenic survival of 0.87 (3 h exposure) and 0.88 (15 h exposure) versus 0.65 after fractionated drug administration (5 x 2 microM/day, day 1 to 5, incubation time: 3 h/day). PBS controls and untreated controls did not show any significant effect. CONCLUSIONS: It seems that clonogenic survival after Taxol exposure of this mammalian fibroblast cell line varies with treatment schedule through a yet unknown process that does not involve G2/M arrest. The results indicate the treatment effects to be mainly based on the diluent combination without any further benefit induced by paclitaxel.
BACKGROUND: Therapy-induced leukopenias with corresponding consequences repeatedly occur in radiotherapy using combined modalities treatment. In radiotherapy, where G-CSF (granulocyte-colony-stimulating-factor) is not licensed, G-CSF has been used successfully under individual circumstances. These results were confirmed in several studies with small patient groups. The aim of this study was to check former results in a larger patient group, to verify postulated side effects and specially to define a cost-effective schedule in the treatment with G-CSF (Neupogen). PATIENTS AND METHODS: In this surveillance trial 50, partially previously treated patients with different malignant tumors were treated with G-CSF. According to the probability of a leucocytosis lower than 1000/mm3, G-CSF (Neuropogen) was already given at leukocyte values lower than 2500/mm3 (500/mm3 bis 2450/mm3). It administered subcutaneously every other day, based on body weight until reaching normal leucocyte levels. RESULTS: In 92% of the patients the increase of leucocytes occurred in the first 24 hours. On average G-CSF was given 4.9 times per patient. Patients without prior therapies or less complex therapies needed less G-CSF applications (3.5 to 5.8 applications). Due to individually varying leucocyte courses the G-CSF therapy was started with leucocyte values between 500/mm3 and 2450/mm3. Patients who were treated with up to 3 G-CSF applications had higher leucocyte levels than those with 4 or more applications (1620/mm3 to 1250/mm3). Leucopenia related infections, therapy interruptions or break-offs did not occur. Besides light "flu like" symptoms in 14% of the patients, no side effects were observed. CONCLUSIONS: When a decrease of leucocyte values lower than 1000/mm3 is expected, the most cost-effective treatment is given when starting the interventional G-CSF administration already at leucocyte values around 1600/mm3. Leucopenias can be treated effectively, with little side effects and in a cost-effective way when G-CSF is given on time.
PURPOSE: Present radiobiological studies for different cell lines in vitro demonstrate the equivalence and efficacy of continuous low-dose-rate brachytherapy (LDR-BT) and pulsed dose rate brachytherapy (PDR-BT) when using small and frequent dose pulses. The aim of this study was to examine monolayer fibroblast cultures in vitro to examine the biological effects of different pulse doses and dose rates under clinically conditions. MATERIAL AND METHODS: B14 cells, Hy B14 FAF 28, peritoneal fibroblasts, were cultured in multi-well plates and exposed to a PDR radiation source at a distance of 9 mm. The following PDR-schemes were compared: dose per pulse: 1 Gy, 2.5 Gy and 5 Gy to a total dose of 5 Gy/5 h (overall time), 10 Gy/10 h, 20 Gy/20 h and 30 Gy/30 h. The pulse duration for the examination of dose rate effects was 20 min, 30 min or 52 min corresponding by dye pulse dose rate of 300 cGy/h, 200 cGy/h or 115 cGy/h. Treatment endpoints were cell measured by dye exclusion test and clonogenic cell survival. RESULTS: Cell survival decreased for pulse doses of 5 Gy compared to 2.5 Gy or 1 Gy per pulse (mean dose rate 200 to 300 cGy/h). No differences were observed with dose rates during irradiation of 300 cGy/h, 200 cGy/h or 115 cGy/h (20 Gy/1 Gy). CONCLUSION: Radiobiological effects of PDR-RT are dependent on the dose per pulse, with differences in biological effects only with a dose per pulse of more than 2.5 Gy, considering the described in-vitro conditions. More examinations with a more pronounced difference in dose rate will be continued for evaluation of dose rate effects.
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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.
BACKGROUND: This study compares 4 classifications in patients with progressive refractory Graves orbitopathy (GO) and examines their prognostic value in long-term follow-up. PATIENTS AND METHODS: From 1984 to 1994, 60 consecutive patients (49 female, 11 male) received 20 Gy (10 x 2 Gy) radiotherapy with 6 MV Linac photons. Ocular symptoms and functional impairment was evaluated according to 4 GO-classification systems: Werner-, modified ATA- and Stanford-Score and Ophthalmopathy-Index (OI) according to Grussendorf. In addition, all patients noted their subjective response on a linear scale (0 to 100%). RESULTS: Improvement was achieved within 1 year after radiotherapy according to the Werner-Score in 28 (47%) patients in > or = 1 symptom category, according to the modified ATA-score in 48 (80%), the Stanford-score in 47 (78%) and the OI-Score in 55 (92%) patients (reduction of > 2 points). The Werner-Score correlated less to the other scores (coefficient r < 0.5) than the other scores among themselves (r approximately 0.9). The ATA-Score improved in the different symptom categories between 47% (stage VI) and 87% (stage V). The OI-Score was reduced by a mean of 6 points. The patients reached a mean subjective improvement of +70 +/- 25%. Acute or chronic side effects were not observed. In multivariate analysis the "male gender" (p = 0.08), a "symptom duration prior to radiotherapy > 1 year" (p = 0.14) and a "high symptom category" (p = 0.11) indicated a negative prognostic trend. CONCLUSIONS: External radiotherapy is effective for severe, progressive GO after pretreatment. A minimum follow-up of at least 12 months and standardized classification and success criteria are required.
BACKGROUND: Radiotherapy of degenerative joint disorders is almost replaced by other treatments, although its efficacy is well known. Compared to orthopedic studies radiotherapy data are lacking long-term analysis and objective reproducible evaluation criteria. PATIENTS AND METHODS: From 1984 to 1994, 85 patients with painful osteoarthritis were treated. The mean follow-up was 4 (1 to 10) years. Seventy-three patients (103 joints) were available for long-term analysis: 17 patients (27 joints) with omarthrosis, 19 (20 joints) with rhizarthrosis, 31 (49 joints) with osteoarthritis of the knee and 6 patients (7 joints) with osteoarthritis of the hip. All patients were intensively pretreated over long time. Mean symptom duration prior to radiotherapy was 4 (1 to 10) years. Orthovoltage or linac photons were applied using some technical modifications depending upon the joint. Two radiotherapy series (6 x 1 Gy, total dose: 12 Gy, 3 weekly fractions) were prescribed. The interval between the 2 series was 6 weeks. The subjective pain profile was assessed prior to and 6 months after radiotherapy and at last follow-up. The classification and assessment of pain symptoms were performed using the Pannewitz score and 5 pain categories and 3 pain grades. Joint edema and effusion were objective response parameters together with special orthopedic scores for each joint. RESULTS: Forty-six (63%) patients (64 joints) achieved a reduction of pain symptoms; 16 of those had a "major pain relief" and 14 "complete pain relief". Large joints--knee and hip--responded better (64% each) than the rhizarthrosis (53%). All pain categories and grades and their combined pain score were significantly reduced. The pain reduction was mostly pronounced for the symptom "pain at rest". The orthopedic score correlated well with the subjective response of the patients. The thumb score improved in 11 (57%) joints, the shoulder score of Constant and Murley [5] in 16 (59%), the Japonese knee score of Sasaki et al. [37] in 33 (67%), the hip score of Harris [12] in 5 (71%) joints. Only 9 of 19 patients which were treated to avoid surgery, had to be operated, and 3 of those received a total arthroplasty of the hip or knee. In multivariate analysis for the endpoint "complete" or "major pain relief" only the criterion "symptom duration > or = 2 years prior to radiotherapy" was an independent negative prognostic parameter (p < 0.05). CONCLUSIONS: Radiotherapy for refractory osteoarthritis is a very effective treatment option for pain reduction compared to other conventional methods. Due to the very low risk of side effects and the low costs, radiotherapy provides an excellent alternative to conventional conservative treatment methods and in case of inoperability.
PURPOSE: The prognosis of patients with pelvic wall recurrences after primary therapy of cervical cancer is bad. In selected patients treated exclusively by surgery as primary therapy the 5-year survival rate was between 5 and 25%. Additionally the combination of operation and radiotherapy (CORT) improved the survival so far. We developed a new concept for the treatment of pelvic wall recurrences. This concept includes the combination of radical surgery, interstitial radiation and chemotheray--CORCT (combined operative- and radiochemotherapy). PATIENTS AND METHODS: After radical surgery, interstitial HDR (Ir-192) brachytherapy in afterloading technique (2.5 Gy, 2 fractions/day in 5 days) was performed. Additionally a chemotherapy with cisplatin 25 mg/m2/day in 5 days and 5-fluorouracil 1000 mg/day in 5 days was applicated. RESULTS: After combined operative- and radiotherapy 3 of 3 patients died after treatment within 8 months (median) because of distant metastases. After additive radiochemotherapy 3 of 4 patients had no evidence of disease (NED) after a follow-up period of 14 (12 to 30) months. CONCLUSION: The first treatment results of the new designed combined operative- and radiochemotherapy concept (CORCT) led us to expect an improvement of the prognosis of patients with recurrences of cervical cancer at the pelvic wall.
BACKGROUND: The Consensus Conference of the German Cancer Society (CAO/AIO/ARO, 1.7.1998) has recently updated recommendations for patients with rectal cancer. Instead of a former reservation regarding the indication of adjuvant therapy for rectal cancer the actual version of the consensus particularly emphasizes the role of postoperative radiochemotherapy for stage-II/III tumors. This article reviews the most recent and ongoing trials of adjuvant and neoadjuvant therapy of rectal cancer. RESULTS: To avoid local recurrence is the most important aspect in the primary treatment of rectal cancer. In some series, e.g. the results of the Surgical Department of the University of Erlangen, a significant correlation between local control and survival was noted. The final results of the Swedish Rectal Cancer Trial with 1168 randomized patients not only confirmed the potential of radiotherapy to reduce local recurrence rate, but also demonstrated a significant survival advantage for patients receiving short-course preoperative radiation therapy. Postoperative combination therapy is usual in the United States and in most European countries since the publication of two randomized trials of the Gastrointestinal Tumor Study Group (GITSG) and the North Central Cancer Treatment Group (NCCTG). The survival advantage resulting from an adjuvant radiotherapy with conventional doses and concurrent fluorouracil-based chemotherapy as compared to surgery alone was recently confirmed in a Norwegian trial. Protracted venous 5-fluorouracil infusion should further improve treatment results. Numerous phase-II studies have demonstrated the efficacy of preoperative radiochemotherapy with high rates of pathological response. Thus, neoadjuvant radiochemotherapy is recommended for patients with locally advanced tumor primarily not amenable to curative surgery. Prospective randomized trials are ongoing to clarify the role of preoperative versus postoperative combined treatment for patients with resectable rectal cancer. CONCLUSION: Radiochemotherapy for rectal cancer is recommended as standard treatment outside clinical trials for stage II/III patients after curative treatment and for patients with T4-tumor prior to surgery. The optimal use of chemotherapy and the sequence of treatment modalities remains to be elucidated.