Horst Sack

Early results of the EORTC randomized clinical trial on multiple fractions per day (MFD) and misonidazole in advanced head and neck cancer.

From Feb. 1981 to Oct. 1984, a randomized clinical trial was carried out in the EORTC Radiotherapy Group, comparing classical radiotherapy 70 Gy/7 weeks to MFD (3 X 1.6 Gy/day for 10 days, 3 weeks rest, followed by a boost to 67.2 or 72 Gy), with or without Misonidazole (1 g/m2 every irradiation day, total 12 to 14 g/m2) in advanced head and neck cancer (all T3 and T4, all N2, N3 and N1 greater than 3 cm). A total of 523 patients were entered in the study. At the time of analysis (4/85), the median follow-up time was 64 weeks. No significant differences in survival or locoregional control could be demonstrated between the three treatment arms at this time. Whereas early mucosal reactions were heavier in the MFD-arms, no differences in late effects (fibrosis, edema, xerostomy) were found between the three treatment arms. Five patients (all MFD + Misonidazole) died with local complications (edema, necrosis). All five had cancer of the laryngopharynx and 3 of them died from a hemorrhage. Factors affecting prognosis were tumor site, tumor stage, nodal status, and histological differentiation.

Postoperative radiotherapy of spinal and intracranial ependymomas: analysis of prognostic factors

PURPOSE Postoperative radiation therapy adds significantly to disease control and survival of patients with ependymoma. However, much controversy exists about the radiation treatment policy. We report the long-term results of a cohort of 56 patients with primary intracranial and spinal ependymomas. Special effort has been taken to define prognostic indicators as a basis for future treatment strategies. PATIENTS AND METHODS Between November 1963 and May 1995, 56 patients with histological proven ependymoma were referred to our clinic for further treatment following surgery. Thirty patients had a high grading tumor and 26 had low grade tumors. Seventeen patients had supratentorial tumors and 24 had infratentorial tumors. Fifteen patients suffered from localized spinal tumors. RESULTS The mean survival time for all patients was 77 months. Five- and 10-year survival probabilities were 60 and 51%, respectively. The mean progression free survival (PFS) probability for all patients was 67 months with corresponding 5- and 10-year PFS probabilities of 53 and 39%, respectively. On univariate analysis initial performance status, age and tumor grade were significant for survival probability. Concerning PFS radiation dose was significant with improved survival with doses > 45 Gy. On multivariate analysis, tumor grade and initial performance status proved to be the only independent prognostic factors. CONCLUSIONS Tumor grade, age, initial performance status and radiation dose are significant factors for the clinical course of patients and have to be taken into account for the urgently needed prospective trials.

Local recurrences of soft tissue sarcomas in adults: a restrospective analysis of prognostic factors in 102 cases after surgery and radiation therapy

Between 1974 and 1990, 102 adult patients (age 18-86 years) with the diagnosis of a soft tissue sarcoma (STS) were treated with photons and/or electrons in combination with surgery. The total doses in the initial treatment volume (second order target volume) was 40-50 Gy. For the coning down volume (first order target volume) the median total dose was 59 Gy (range 45-72 Gy). A total of 18% (18/102) local failures was observed. In multivariate analysis, prognostic factors for the occurrence of a local failure were identified as follows: treatment of a primary or recurrent STS (P = 0.02), total dose (P = 0.025) and tumour grade (P = 0.05). Mode of surgery, tumour size (trunk versus extremity), pre- or postoperative radiotherapy, combined chemotherapy and tumour size (T1 versus T2) had no significant impact on the local relapse-free survival. These data give further evidence that combined surgery and radiotherapy is an effective modality in treatment of soft tissue sarcomas.

Impact of anemia prevention by recombinant human erythropoietin on the sensitivity of xenografted glioblastomas to fractionated irradiation.

Background:Pronounced oxygen deficiency in tumors which might be caused by a diminished oxygen transport capacity of the blood (e. g., in anemia) reduces the efficacy of ionizing radiation. The aim of this study was to analyze whether anemia prevention by recombinant human erythropoietin (rHuEPO) affects the radiosensitivity of human glioblastoma xenografts during fractionated irradiation.Material and Methods:Anemia was induced by total body irradiation (TBI, 2 × 4 Gy) of mice prior to tumor implantation into the subcutis of the hind leg. In one experimental group, the development of anemia was prevented by rHuEPO (750 U/kg s.c.) given three times weekly starting 10 days prior to TBI. 13 days after tumor implantation (tumor volume approx. 40 mm3), fractionated irradiation (4 × 7 Gy, one daily fraction) of the glioblastomas was performed resulting in a growth delay with subsequent regrowth of the tumors.Results:Compared to nonanemic control animals (hemoglobin concentration cHb = 14.7 g/dl), the growth delay in anemic mice (cHb = 9.9 g/dl) was significantly shorter (49 ± 5 days vs. 79 ± 4 days to reach four times the initial tumor volume) upon fractionated radiation. The prevention of anemia by rHuEPO treatment (cHb = 13.3 g/dl) resulted in a significantly prolonged growth delay (61 ± 5 days) compared to the anemia group, even though the growth inhibition found in control animals was not completely achieved.Conclusions:These data indicate that moderate anemia significantly reduces the efficacy of radiotherapy. Prevention of anemia with rHuEPO partially restores the radiosensitivity of xenografted glioblastomas to fractionated irradiation.Hintergrund:Ein ausgeprägter Sauerstoffmangel im Tumorgewebe, der durch eine Verminderung der O2-Transportkapazität des Blutes (z. B. bei Anämie) verursacht sein kann, schränkt die Wirksamkeit ionisierender Strahlen ein. Ziel der Studie war, den Einfluss einer Anämieprävention mit rekombinantem humanem Erythropoietin (rHuEPO) auf die Strahlensensibilität von humanen xenotransplantierten Glioblastomen bei fraktionierter Bestrahlung zu untersuchen.Material und Methodik:In Mäusen wurde eine Anämie durch Ganzkörperbestrahlung (TBI, 2 × 4 Gy) unmittelbar vor Tumorimplantation in die Subkutis des Hinterlaufs erzeugt. Ein Teil der Versuchstiere erhielt zur Anämieprävention rHuEPO (750 U/kg s.c., dreimal wöchentlich, beginnend 10 Tage vor TBI). 13 Tage nach Implantation (Tumorvolumen ca. 40 mm3) wurden die Glioblastome fraktioniert bestrahlt (4 × 7 Gy, tägliche Fraktion), was zu einer Wachstumsverzögerung mit anschließendem Nachwachsen der Tumoren führte.Ergebnisse:Im Vergleich zu nichtanämischen Kontrolltieren (Hämoglobinkonzentration cHb = 14,7 g/dl) war die Wachstumsverzögerung durch fraktionierte Bestrahlung in anämischen Mäusen (cHb = 9,9 g/dl) signifikant kürzer (49 ± 5 Tage vs. 79 ± 4 Tage bis zum Erreichen des vierfachen Tumorvolumens). Die Anämieprävention mit rHuEPO (cHb = 13,3 g/dl) führte wieder zu einer signifikanten Zunahme der Wachstumsverzögerung (61 ± 5 Tage) im Vergleich zur Anämiegruppe, wobei jedoch die Wachstumshemmung bei den Kontrolltieren nicht vollständig erreicht wurde.Schlussfolgerungen:Die Ergebnisse der Untersuchung belegen, dass eine moderate Anämie die Effektivität einer Bestrahlung signifikant verschlechtert. Eine Anämieprävention mit rHuEPO erhöht die Sensitivität von Glioblastomen gegenüber fraktionierter Bestrahlung wieder, ohne jedoch die Wachstumshemmung von nichtanämischen Kontrolltieren zu erzielen.

Induction Chemotherapy followed by Concurrent Chemotherapy and High-Dose Radiotherapy for Locally Advanced Squamous Cell Carcinoma of the Cervical Oesophagus

The efficacy and toxicity of combined radiochemotherapy for locally advanced squamous cell carcinomas of the cervical oesophagus was evaluated retrospectively. Induction chemotherapy consisted of three courses of 5-fluorouracil (5-FU), leucovorin, etoposide and cisplatin (FLEP) or two courses weekly six times of 5-FU and leucovorin combined with biweekly cisplatin. This induction regimen was followed by high-dose external beam radiotherapy up to 60–66 Gy and concurrent chemotherapy with cisplatin and etoposide. Median follow-up of the recruited 17 patients was 37 months (13–73 months). Long-term survival was 24% at 2 and 3 years. The probabilities of locoregional tumour recurrences and distant metastases as sites of first relapse were 67 and 39% at 2 years. Acute and late toxicity of this schedule was moderate. The protocol offers a definitive chance of long-term survival for patients with locally advanced carcinomas of the cervical oesophagus, but local in-field recurrences remain the predominant risk after treatment. Intensification of the regimen seems possible because no dose-limiting late toxicities were observed.

Evaluation of Time, Attendance of Medical Staff, and Resources During Radiotherapy for Head and Neck Cancer Patients

Introduction:A number of national and international societies have published recommendations regarding the required equipment and manpower that is assumed to be necessary to treat a specific number of patients with radiotherapy. None of these recommendations were based on actual time measurements needed for specific radiotherapy procedures. The German Society of Radiation Oncology (DEGRO) was interested in substantiating their recommendations by prospective evaluations of all important core procedures of radiotherapy in the most frequent cancer treated by radiotherapy. The results of the examinations of radiotherapy in head and neck cancer (HNC) patients are presented in this manuscript.Patients and Methods:Four radiation therapy centers (University of Jena, University of Erlangen, University of Düsseldorf and the community hospital of Neuruppin) participated in this prospective study. Working time of the different occupational groups and room occupancies for the core procedures of radiotherapy in HNC were prospectively documented during a 4-month period and subsequently statistically analyzed.Results:The time needed per patient varied considerably between individual patients and between centers for all evaluated procedures. Room occupancy, presence of technicians, and overall medical staff times were 21 min, 26 min, and 42 min, respec-tively, for planning CT with i.v. contrast medium (n = 79), and 23 min, 44 min, and 51 min respectively, for planning CT without contrast medium (n = 45). Definition of the target volume (n = 91) was the most time consuming procedure for the physicians taking 1 h 45 min on average. Medical physicists spent a mean time of 3 h 8 min on physical treatment planning (n = 97) and 1 h 8 min on authorization of the treatment plan (n = 71). Treatment simulations (n = 185) required an average room occupancy of 23 min, and a mean technicians presence of 47 min. The mean room occupancy (n = 84) was 24 min for the first radiotherapy including portal imaging associated with a mean presence of the technicians of 53 min. For routine radiotherapy sessions (n = 2,012) and routine radiotherapy sessions including portal imaging (n = 407), mean room occupancies were 13 min and 16 min, respectively. The presence of increasing number of technicians was significantly associated with shorter room occupancy. IMRT including portal imaging (n = 213) required an average room occupancy of 24 min and a mean technician time of 48 min.Conclusion:The data presented here allow an estimate of the required machine time and manpower needed for the core procedures of radiotherapy in an average head and neck cancer patient treated with a specific number of fractions. However, one has to be aware that a number of necessary and time consuming activities were not evaluated in the present study.ZusammenfassungFragestellung:Internationale Gesellschaften haben Empfehlungen für die erforderliche technische Ausrüstung und für die Anzahl von Mitarbeitern zur Behandlung von Tumorpatienten in der Strahlentherapie veröffentlicht. Keine dieser Empfehlungen basiert auf durchgeführten Messungen für die einzelnen Behandlungsabschnitte in der Strahlentherapie, sondern sind Schätzwerte. Die Deutsche Gesellschaft für Radioonkologie will ihre Empfehlungen durch prospektive Auswertungen aller wichtigen Abläufe in der Strahlentherapie bei den häufigsten Tumorentitäten untermauern. Ziel dieser Untersuchung war es, die erforderlichen Ressourcen bei der strahlentherapeutischen Behandlung von Kopf- und Halstumoren zu evaluieren.Methodik:Vier Strahlentherapie-Zentren (Universität Jena, Universität Erlangen, Universität Düsseldorf und das Städtische Krankenhaus Neuruppin) nahmen an dieser prospektiven Studie teil. Die Arbeitszeit der verschiedenen Berufsgruppen sowie die Raumbelegung bei der Planung und Durchführung der Strahlentherapie wurde prospektiv während eines Zeitraumes von 4 Monaten dokumentiert und statistisch ausgewertet.Ergebnis:Die Zeit für die einzelne Abschnitte der Behandlung variierte erheblich zwischen den einzelnen Patienten und den Behandlungszentren. Für ein CT mit Kontrastmittel (n = 79) wurden im Durchschnitt 21 Minuten für die Raumbelegungszeit benötigt. 26 Minuten benötigten die medizinisch-technischen Angestellten für die Durchführung des CTs und 42 Minuten das gesamte medizinische Personal. Für ein CT ohne Kontrastmittel (n = 45) betrug die Raumbelegungszeit 23 Minuten, 44 Minuten benötigten die m.-t. Assistenten (MTA) und 51 Minuten das gesamte medizinische Personal. Die Definition des Zielvolumens (n = 91) war das zeitaufwendigste Verfahren für das ärztliche Personal und dauerte 1 h 45 min. Die Medizin-physiker brauchten 3 h 8 min für die physikalische Bestrahlungsplanung (n = 97). Die Verifikation der Pläne durch die Ärz-te (n = 71) betrug 1h 8 min. Die Simulationen von Kopf-Hals-Tumorpatienten (n = 185) erforderten eine durchschnittliche Raumbelegungszeit von 23 min, und der Zeitaufwand für die MTA betrug 47 min. Die mittlere Raumbelegung (n = 84) betrug 24 min für die ersten Strahlentherapie einschließlich der Verifikationsaufnahme. Der zeitliche Aufwand betrug für eine MTA 53 min. Für die routinemäßige Bestrahlung von Kopf-Hals-Tumoren ohne Verifikationsaufnahme (n = 2012) waren 13 Minuten erforderlich, mit Verifikationsaufnahmen (n = 407) 16 min. Die Anwesenheit von mehreren MTAs korrelierte signifikant mit einer kürzeren Raumbelegungszeit (p < 0,05). Die intensitätsmodulierte Radiotherapie mit Verifikation (n = 213) erforderte eine durchschnittliche Raumbelegungszeit von 24 min mit der Anwesenheit einer MTA von 48 min.Schlussfolgerung:Die Untersuchung ermöglicht die Abschätzung des durchschnittlichen Personal- und Ressourcenbedarf für die Kernprozeduren einer Strahlentherapie bei Patienten mit Kopf-Hals-Tumoren, die mit einer bestimmten Anzahl von Fraktionen behandelt werden. Dabei ist zu beachten, dass eine Reihe von erforderlichen und zeitaufwendigen Tätigkeiten in der Studie nicht evaluiert wurden.

Blood flow and steady state temperatures in deep-seated tumors and normal tissues

Blood flow related data obtained in different deep-seated tumors and adjacent normal tissues were analyzed in 28 patients who were treated with combined regional hyperthermia and radiation for recurrent or metastatic tumors. The evaluation of blood flow related data has been made using the thermal clearance/thermal cooling coefficient technique and dynamic computed tomography. With both methods significant differences in global perfusion have been observed between tumor center and tumor periphery, between tumor and normal tissue (deep muscle and fat tissue), and between tumor entities. Washout rates or thermal cooling coefficient values, as well as the enhancement of contrast material over baseline (expressed in delta Hounsfield Units), correlated significantly with the achieved steady state temperatures for different tissue categories (i.e., tumor center, tumor periphery, different tumor entities, normal tissue). Thermal cooling coefficient values higher than 63000-83000 W/m3-K (washout rates higher than 15-20 ml/100 g-min) or values of enhancement of contrast material higher than delta 20-25 HU coincide with a limitation in achieving therapeutic temperatures higher than 40 degrees C.

Hyperthermia in eccentrically located pelvic tumors: Excessive heating of the perineal fat and normal tissue temperatures

Regional hyperthermia in deep-seated tumors can be limited by excessive heating of normal tissues, usually associated with pain or local discomfort. In this report, 57 hyperthermia treatments in 8 patients with locally advanced presacral recurrences of colorectal cancer were analyzed with respect to normal tissue temperatures, especially with respect to the perineal fat temperature. In 27 treatments, 1 to 2 catheters had been inserted from the perineal region through a large part of the perirectal and presacral fat into the tumor, so that temperature profiles of the perineal fat could be obtained. The mean maximum temperature (+/- SD) of the vagina, rectum, bladder, muscle tissue, and perineal fat was 40.8 +/- 1.2 degrees C, 40.9 +/- 1.6 degrees C, 40.5 +/- 1.6 degrees C, 39.8 +/- 0.7 degrees C, and 42.6 +/- 1.1 degrees C, respectively. The mean maximum systemic temperature (+/- SD) was 37.7 +/- 0.7 degrees C. In 42% of the treatments, the temperature in the perineal fat ranged between 43 and 46 degrees C and was treatment-limiting. In conclusion, overheating of the perineal fat is a problem in the treatment of eccentrically located tumors of the presacral region when relatively high temperatures in the tumor will be maintained for longer time periods.

Radiosensitivity, repair capacity, and stem cell fraction in human soft tissue tumors: An in vitro study using multicellular spheroids and the colony assay

Radiation doses necessary to control 50% of spheroids (SCD50) were determined for five human soft tissue tumor lines after single dose and fractionated irradiation. Spheroids with 1000-1500 cells were used throughout. A similar number of cells per spheroid resulted in different sized spheroids for the respective cell lines. The parameters alpha, beta, and the number of regenerating cellular units per spheroid (SRU) were estimated from the spheroid control data using a direct fit according to the linear quadratic model assuming Poisson statistics. The number of spheroid regenerating cellular units was also determined from the growth delay at doses required for 10% spheroid control. In addition, alpha, beta, and the fraction of clonogenic cells of the five cell lines were obtained from a soft agar colony forming assay. The most precise parameter for radiation sensitivity was the SCD50, with a coefficient of variation smaller than 5%. SCD50 values ranged from 5.9 to 11.0 Gy for the five soft tissue tumor lines. Two of the five cell lines showed significantly higher alpha values and lower calculated survival fractions after 2 Gy (SF2) in the soft agar clonogenic assay than in the spheroid control assay. This points to a resistance-enhancing effect in the spheroid system. Whereas the fractions of SRU from the number of cells per spheroid, estimated from the spheroid control and growth delay assays, agreed well, no significant correlation existed between the fraction of SRU and the fraction of clonogenic cells in the soft agar colony forming assay. The alpha/beta ratios as a descriptive measure of the fractionation sensitivity of the tumor cell spheroids in the spheroid control assay corresponded well with those derived from the dose-cell survival data using a soft agar colony forming assay. Two of the five cell lines showed high fractionation sensitivities with alpha/beta values smaller than 5 Gy while those of the remaining three ranged from 7.8 to 10.8 Gy. Spheroids are structurally more similar to in vivo tumors than monolayer cultures. From the observed lack of correlation in the radiosensitivity parameters alpha and SF2 as well as in the fraction of SRU or clonogenic cells obtained from the spheroid control assay or the colony forming assay, one would expect even greater differences between results from colony forming assays and the radiosensitivity of in vivo tumors, at least for human soft tissue sarcomas.

Radioresponsiveness of human glioma, sarcoma, and breast cancer spheroids depends on tumor differentiation☆

Abstract Purpose: Differences in the intrinsic radiosensitivity within and between different tumor classes have been noticed for human tumor cell lines using the clonogenic assay. By far, most of the cell lines studied up to now were derived from poorly differentiated tumors. In this study, the influence of tumor differentiation on the radiation doses necessary to control 50% of small oxic spheroids (SCD 50 ) was determined. Evidence of a distinct dependence of radioresponsiveness on tumor progression provides a background for an investigation of the underlying mechanisms. Methods and Materials: Spheroids were aggregated from 1000–1500 cells in agarose coated 24 multi-well plates. Their diameters ranged from 156 to 405 μm, depending on the cell line. Spheroids were irradiated with graded 60 Co single doses using spheroid control as end point and a minimum follow-up period of 3 months. Results: Cell lines from three low grade gliomas and 10 malignant gliomas were studied in the spheroid control assay. The group mean SCD 50 values were 6.1 ± 1.6 Gy and 13.1 ± 3.3 Gy, respectively. Four cell lines from grade 2 soft tissue sarcomas had a mean SCD 50 value of 6.2 ± 0.5 Gy and one undifferentiated sarcoma line of 11.0 Gy. Three well-differentiated breast cancer lines expressed the cell adhesion molecule E-cadherin, had an epitheloid morphology in monolayer culture, were estrogen receptor positive or contact inhibited in multicellular spheroids. Two undifferentiated breast cancer lines had a fibroblastoid morphology and were marker negative. The mean SCD 50 value of the former was 10.5 ± 1.0 Gy while that of the undifferentiated lines was 14.8 ± 2.8 Gy. Analysis of variance revealed a significant effect of the tumor type as well as the grade of dedifferentiation on the SCD 50 after irradiation with one fraction or 2Gy/fraction. The surviving fractions at 2 Gy (SF2), obtained from the spheroid control rates after different fractionation schedules by approximation of the linear quadratic model assuming Poisson statistics were significantly dependent on tumor type ( p = 0.001, ANOVA F-test) but not on tumor differentiation ( p = 0.27). The αβ ratios did not depend on tumor type ( p = 0.08, ANOVA F-Test) but significantly increased with the grade of tumor cell dedifferentiation ( p = 0.03). Conclusion: The spheroid model is suitable for measuring the radioresponsiveness of differentiated cell lines with very low colony forming efficiencies. Tumor cell differentiation is an important factor for the radioresponsiveness and recovery capacity of human tumor cells.