[External beam irradiation of head and neck cancer]. / Perkutane Strahlentherapie maligner Tumore im Kopf-Hals-Bereich.

Ionising rays are employed in percutaneous radiation of head and neck tumours. Radiation reduces cell division in the target tissue. The individual parameters of the radiation procedure are determined within the framework of the interdisciplinarily conceived treatment. Tumour control probability depends on tumour-specific factors and on the dosage as well as on the treatment period. The macroscopic and microscopic extend of the tumour area determines the target volume and dosage of the radiation. Conformal radiation is the standard procedure in primary radiation treatment. The anticipated side effects influence the therapy concept and the radiation parameters. Long-term aftercare of the tumour patient is imperative.

Evidence for radiosensitizing by gliotoxin in HL-60 cells: implications for a role of NF-kappaB independent mechanisms.

Radioresistance markedly impairs the efficacy of tumor radiotherapy and may involve antiapoptotic signal transduction pathways that prevent radiation-induced cell death. A common cellular response to genotoxic stress induced by radiation is the activation of the nuclear factor kappa B (NF-kappaB). NF-kappaB activation in turn can lead to an inhibition of radiation-induced apoptotic cell death. Thus, inhibition of NF-kappaB activation is commonly regarded as an important strategy to abolish radioresistance. Among other compounds, the fungal metabolite gliotoxin (GT) has been reported to be a highly selective inhibitor of NF-kappaB activation. Indeed, low doses of GT were sufficient to significantly enhance radiation-induced apoptosis in HL-60 cells. However, this effect turned out to be largely independent of NF-kappaB activation since radiation of HL-60 cells with clinically relevant doses of radiation induced only a marginal increase in NF-kappaB activity, and selective inhibition of NF-kappaB by SN50 did not result in a marked enhancement of GT-induced apoptosis. GT induced activation of JNKs, cytochrome c release from the mitochondria and potently stimulated the caspase cascade inducing cleavage of caspases -9, -8, -7 and -3. Furthermore, cleavage of the antiapoptotic protein X-linked IAP and downregulation of the G2/M-specific IAP-family member survivin were observed during GT-induced apoptosis. Finally, the radiation-induced G2/M arrest was markedly reduced in GT-treated cells most likely due to the rapid induction of apoptosis. Our data demonstrate that various other pathways apart from the NF-kappaB signaling complex can sensitize tumor cells to radiation and propose a novel mechanism for radiosensitization by GT, the interference with the G2/M checkpoint that is important for repair of radiation-induced DNA damage in p53-deficient tumor cells.

[Prostatectomy, brachytherapy, percutaneous irradiation. Which method helps your patients the most?]. / Prostatektomie, Brachytherapie, perkutane Bestrahlung. Welches Verfahren hilft Ihrem Patienten am besten?

For the treatment of cancer of the prostate that has not yet metastasized, several therapeutic options that promise lasting local tumour control are now available: Among the surgical options, radical retropubic prostatectomy is most commonly employed. The basic radiotherapeutic options are interstitial and external beam irradiation, or a combination of the two. The choice of the most suitable therapeutic approach is determined by the extent of the tumor, and the side effects that are acceptable to the patient.

Cell cycle and growth response of CHO cells to X-irradiation: threshold-free repair at low doses.

PURPOSE: To test the hypothesis of a threshold for induced repair of DNA damage (IR) and, secondarily, of hyperradiosensitivity (HRS) to low-dose X-irradiation. METHODS AND MATERIALS: Exponentially growing Chinese hamster ovary cells (CHO) were X-irradiated with doses from 0.2 to 8 Gy. Survival data were established by conventional colony-forming assay and flow-cytometric population counting. The early cell cycle response to radiation was studied based on DNA-profiles and bromodeoxyuridine pulse-labeling experiments. RESULTS: Colony-forming data were consistent with HRS. However, these data were of low statistic significance. Population counting provided highly reproducible survival curves that were in perfect accord with the linear-quadratic (LQ) model. The dominant cell cycle reaction was a dose-dependent delay of G2 M and late S-phase. CONCLUSION: There was no evidence for a threshold of IR and for low-dose HRS in X-irradiated CHO cells. It is suggested that DNA damage repair activity is constitutively expressed during S-phase and is additionally induced in a dose-dependent and threshold-free manner in late S-phase and G2. The resulting survival is precisely described by the LQ model.

Radiation treatment related factors influencing outcome in vulvar cancer patients.

The objective of this research is to identify the impact of radiation treatment factors on survival in vulvar cancer patients. We performed a follow-up study on 60 women with squamous cell carcinoma of the vulva treated at the Department of Radiotherapy of the University of Ulm from 1980 to 1997. The follow-up time ranged from 0.5 to 17 years (mean 6.5 years). The irradiated volume included vulva and regional lymph nodes. The influence of treatment factors (tumor resection versus no tumor resection, treatment time, dose) on overall and disease-free survival was examined. In addition, applied doses were corrected for treatment time using the extended alpha/beta-model for calculating the biologically effective doses. The applied dose was 48.1 +/- 13.2 Gy (median: 50 Gy). Treatment time was 40.4 +/- 19.4 days (median: 38 days). 34/60 patients underwent surgery with complete resection of macroscopic tumor. 26 of 60 patients were resected incompletely or only a biopsy was taken. In univariate analysis prognostic factors influencing overall and disease-free survival were, along with T- and N-stage, treatment time, and biologically effective dose. In multivariate analysis, biologically effective dose was the only significant factor. We conclude that biologically effective dose and treatment time are important treatment factors influencing overall and disease-free survival vulvar cancer patients.

Comparative analysis of apoptosis in HL60 detected by annexin-V and fluorescein-diacetate.

BACKGROUND: Our aim was to compare and evaluate apoptosis formation as detected by propidium-iodide (PI)/annexin-V or PI/fluorescein-diacetate (FDA) as dose-response parameters in a human promyelocytic leukemia cell line, HL60. METHODS: In exponentially growing HL60 cells, apoptosis was induced by ionizing radiation, hyperthermia, topotecan, and cytosine beta-D-arabinofuranoside. At 4 consecutive days following induction, apoptosis was detected by double-labelling, either with PI/annexin-V or PI/FDA. Forward and side scatter, red (PI), and green (FDA or annexin-V) fluorescence were measured by flow cytometry. RESULTS: While light scatter discriminated between morphologically damaged and undamaged cells, fluorescence differentiated vital, apoptotic, and dead cells. Equal proportions of these three subpopulations were detected by both staining techniques. Occasionally, early and mature apoptoses were identified as distinct clusters. During the 4-day observation period, no pronounced maxima of the apoptotic fractions were obtained with either treatment modality. The gradual increases usually showed a delay of 1-2 days. CONCLUSIONS: FDA and annexin-V are equally suitable for detecting apoptosis. Separation improves with time after induction, indicating that, with respect to test specificity, mature apoptoses are superior to early stages. However, the sensitivity towards low rates of apoptosis after weak induction appears limited with both staining procedures.

[Effect of therapy on survival of patients with pancreatic carcinoma]. / Der Einfluss der Therapie auf das Uberleben von Patienten mit Pankreaskarzinom. Eine Analyse von Einzelfaktoren.

PURPOSE: To identify the impact of treatment factors on overall survival in patients with pancreatic carcinoma. PATIENTS AND METHODS: We performed a follow-up study on 38 patients with adenocarcinoma of the pancreas treated from 1984 to 1998. 18/38 patients were resected. Irradiated volume included the primary tumor (or tumor bed) and regional lymph nodes. Thirty-seven patients received in addition chemotherapy consisting of mitoxantrone, 5-fluorouracil and cis-platin, either i.v. (14/38) or i.a. (23/38). The influence of treatment related factors on the overall survival was tested. Biologically effective dose was calculated by the linear-quadratic model (alpha/beta = 25 Gy) and by losing 0.85 Gy per day starting accelerated repopulation at day 28. RESULTS: Treatment factors influencing overall survival were resection (p = 0.02), overall treatment time (p = 0.03) and biologically effective dose (p < 0.002). Total dose and kind of chemotherapy had no significant influence. Treatment volume had a negative correlation (r = -0.5, p = 0.06) with overall survival, without any correlation between tumor size, tumor stage, and treatment volume. In multivariate analysis only biologically effective dose remained significant (p = 0.02). CONCLUSIONS: Among with surgery, biologically effective dose strongly influences overall survival in patients treated for pancreatic carcinoma. Treatment volume should be kept as small as possible and all efforts should be made to avoid treatment splits in radiation therapy.

Differential proliferation dependence of alpha and beta damage in X-irradiated Chinese hamster cells.

PURPOSE: To determine quantitatively the influence of altering proliferation rates on clonal survival of asynchronously growing Chinese hamster (CHO) cells after X-irradiation and to evaluate the related contribution of alpha and beta damage. MATERIAL AND METHODS: Cell cycle distributions at the time of X-irradiation of CHO cells were assessed by flow cytometry. Clonal radiation survival was established by colony forming assay. Survival data were fitted to the linear-quadratic model and analyzed on the basis of the mean inactivation dose, D. RESULTS: Increased S-phases were associated with increased resistance to X-rays. Radiosensitivity as expressed by D differed by a factor of 1.6 between the most sensitive and the most resistant populations. Separately analyzing the alpha and beta coefficients of survival curves revealed that the proliferation dependent effect was correlated only with beta. The major determinant of D was alpha, but its substantial interexperimental variations were independent of the cell cycle. CONCLUSIONS: Due to altering cell cycle distributions, considerable changes of radiosensitivity can occur. They can in part be understood as a consequence of S-phase dependent alterations of DNA damage repair. Reasons for the changes of a damage dependent lethality remain to be discovered by further research.

[Radiotherapy for tumor pain. Long-term freedom from pain with minimal side-effects]. / Strahlen gegen Tumorschmerzen. Langanhaltende Schmerzfreiheit bei geringen Nebenwirkungen.

Radiotherapy may be the treatment of choice in patients suffering pain from early-stage cancer and is used in curative intent. In addition, it is often used for palliative treatment in advanced tumor disease, when, thanks to local regression of the tumor, pain relief may be long-term and achieved with only mild or moderate side effects.

20 MHz ultrasonic imaging for quantitative assessment and documentation of early and late postradiation skin reactions in breast cancer patients.

BACKGROUND AND PURPOSE: In dermatology high resolution ultrasonic systems proved to be valuable in following up genuine and experimental inflammatory dermatoses. The opportunities of 20 MHz ultrasonic imaging for quantitative assessment of early and late postradiation skin reactions are investigated. MATERIAL AND METHODS: Between April and November 1996, 96 high resolution ultrasound examinations of the skin in 29 patients treated for breast cancer at the University of Ulm were analyzed. Total doses between 46 and 60 Gy were applied. The time interval between the completion of radiotherapy and ultrasonic examination was < or =3 months in 18 patients and 6-135 months in 11 patients. For examinations we used a digital high resolution ultrasonic system with a ceramic 20 MHz transducer. Irradiated and non-irradiated skin were compared. RESULTS: A change of thickness and texture of the dermis depending on the time interval between the completion of radiotherapy and ultrasonic examination and on the administered radiation dose was found. There were significant differences between irradiated and non-irradiated skin regarding the dermal thickness in early (P < 0.001) as well as in late (P = 0.0018) reactions. Echogenicity of the upper and lower corium of irradiated skin decreased in early and late reaction. In upper corium the greatest reduction of signal intensity occurred in early reactions (P = 0.0001). Early reactions of the lower corium differed significantly from late changes (P = 0.001). Discrepancies between visible skin reactions described by examining physicians and ultrasonically proven changes were obvious mainly in late reactions. CONCLUSIONS: There are specific textures of early and late postradiation skin reactions in comparison to non-irradiated skin. High resolution digital 20 MHz ultrasound is non-invasive and quantitative, and in contrast to physical examination, an easy reproducible method for assessing and documenting early and late skin reaction during and after radiation therapy treatment.

Stable radiobiological features in a genetically unstable glioblastoma cell line.

In a human glioblastoma (grade IV) cell line, A7, the change in chromosome number, growth characteristics, radiosensitivity and DNA-repair capacity were determined during continuous culture over approximately 1300 generations. The median chromosome number fell from 101 to 85 while a remarkable variability was retained. The net population doubling time shortened from 21 to 16 h but no alterations were detected either in radiosensitivity or DNA-repair capacity, as measured by colony and plasmid-reconstitution assays respectively. Reviewing radiosensitivity data from the literature, it is considered that the relative radioresistance of glioblastomas might be inherited from the normal tissue from which they are derived.

Quality assurance by specification and achievement of goals in palliative cancer treatment.

As the goals of palliative cancer treatments have not always been clearly specified, this paper describes how frequently the goals of palliative cancer treatment can be specified according to a given definition and how frequently those specified goals can be achieved. The clinical problems of 171 cancer patients were discussed in the Interdisciplinary Oncologic Conference (IOC) of the Cancer Centre University of Ulm (CCUU) and recommendations concerning further diagnostic treatments and/or therapy were provided. These recommendations had been documented and analysed retrospectively. The goals were classified as either cure or palliation or further investigation. If the goal was palliation, it was investigated whether or not the goal was specified as either alleviation of existing problems or prevention of impending problems. The achievement of the specified goals was assessed. Palliation was the goal of treatment in 119 (71%) of the 168 evaluable recommendations. In 83 of the 119 cases (70%), immediate treatment was recommended. The goal was specified in 57 (69%) of the 83 recommendations and could be realized in 24 of 57 specified cases (42%). Patients in this group survived longer (p < 0.01) than patients in whom the goals could not be achieved. Impending problems could be prevented more often (p = 0.001) in 14 out of 18 cases, while existing problems could be alleviated in only 10 out of 34 cases. It is concluded that specification of the goals of palliation is necessary because it is impossible to decide if a goal of treatment could be achieved or not unless the goal of treatment has been defined (as existing/impending problem). The prevention of impending problems could be investigated in prospectively controlled clinical trials.

Effect of pH and moderate hyperthermia on doxorubicin, epirubicin and aclacinomycin A cytotoxicity for Chinese hamster ovary cells.

The influence of extracellular pH on the cytotoxicity of the anthracyclines doxorubicin, epirubicin, and aclacinomycin A was examined at 37 degrees C and 41 degrees C in tissue culture. Chinese hamster ovary (CHO) cells were exposed for a total of 24 h to anthracyclines at doses ranging between 0.12 and 0.69 nmol/ml at pH 7.4, 6.7, and 6.4 and at 37 degrees C. Temperature elevation to 41 degrees C was carried out for 3 h after the initiation of the drug treatment. Doxorubicin and epirubicin were about equally cytotoxic in the pH range examined at both temperatures. Aclacinomycin A demonstrated a higher cytotoxicity at pH 7.4 and 37 degrees C only at low doses. At low pH, however, aclacinomycin A was increasingly more effective with increasing dose as compared with doxorubicin and epirubicin. At 41 degrees C and at higher doses aclacinomycin A was even less cytotoxic than doxorubicin or epirubicin. Doxorubicin and epirubicin were less effective at lower pH. However, aclacinomycin A at doses of greater than 0.25 nmol/ml was more cytotoxic at low pH. Moderate hyperthermia did not increase the cytotoxicity of the three drugs at low pH, except for aclacinomycin A at doses of less than 0.25 nmol/ml. At pH 7.4, aclacinomycin A was even less effective at the elevated temperature. At doses of greater than 0.25 nmol/ml, moderate hyperthermia decreased the cytotoxicity of aclacinomycin A at low pH.

[ Radiotherapy method in the treatment of medulloblastoma]. / Die Strahlentherapie Technic bei der Behandlung des Medulloblastoms.

The extension of the irradiated treatment volume beyond the primary site has produced permanent control in the majority of patients with medulloblastoma. Available technical procedures are described to reduce or prevent side effects and complications. The complexity of high precision radiotherapy, however, requires stringent quality control, particularly if the effectiveness of additional treatment modalities are examined.

Technique and dosimetry of total body irradiations at Ulm.

At the University of Ulm total body irradiation before bone marrow transplantation is given in nine fractions within three days. A total dose of 13 Gy is applied via four fields with 8-MV X-rays. Dose to the lung is limited to 10.5 Gy by means of individually shaped blocks. The homogeneity of dose distributions is improved by the use of compensators for the lower extremities and boli in the head and neck region. Dosimetric data for treatment planning are measured by an ionization chamber and thermoluminescence dosimeters in water and perspex phantoms. In vivo measurements of dose distributions (ionization chamber, TLD) during each fraction allow modifications of compensators and boli in the case of deviations from calculated data.

[Role of radiotherapy in malignant testicular tumors]. / Die Rolle der Strahlentherapie bei malignen Hodentumoren.

Early stages of seminoma are well treated by radiotherapy alone. In advanced stages modern combination chemotherapy allows to achieve improved results. In embryonal carcinomas and teratomas the management by radiotherapy is controversial. For the primary treatment of lymphomas of the testis, radiotherapy should be restricted to early stages.

pH-induced modification of BCNU toxicity on glial cells.

A dose-response relationship for the dependence of the cytotoxic activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) on extracellular pH has been established. The hypothesis, that the integral dose of the rapidly degrading BCNU determines cytotoxicity, has been examined. Human glial cells exhibited lower survival rates for BCNU exposure at pH 6.5 and pH 6.7, compared to pH 7.4. This effect can be explained by the more rapid decay of BCNU at pH 7.4, leading to a lower integral dose. However, the determination of BCNU decay constants for different pH values and calculation of the integral exposure dose reveal that tolerance to BCNU is increased with decreasing pH.