[History of German radiation oncology]. / Geschichte der deutschen Radioonkologie.

An overview of the development of radiotherapy especially in Germany, from its beginning until today, is given, including the difficulties during and after the two world wars. Technical progress is described as well as the organization and structure of radiology and especially radiotherapy.

Management of carcinoma of the bladder.

Carcinoma of the bladder (CaB) is a common tumor of the genitourinary tract. In the United States in 1997, CaB was second in frequency of occurrence and third in mortality among genitourinary tumors. This tumor has a well-documented history of environmental and industrial causative factors. The strongest etiologic risk factors include the use of tobacco, which is thought to be responsible for half of the CaB diagnosed in men in the United States, and some arylamines. In the past 30 years, there has been major improvement in the survival of patients with this disease. Multiple factors were responsible for this accomplishment and they include: 1) better understanding of the natural history of CaB, 2) development of immunohistochemical analysis helpful in defining prognostic factors, 3) improved imaging and nonimaging diagnostic modalities helpful in making earlier diagnosis and better defining the true anatomical extent of the tumor, 4) development of more effective therapy for carcinoma in situ, 5) major improvement in surgical techniques resulting in better treatment outcomes, and 6) the wide use of adjuvant chemotherapy. Major stress has been placed on the quality of life of patients treated for CaB. Quality of life was improved by optimizing surgical, radiation, and medical treatment techniques. The two most important factors producing this quality-of-life improvement include: 1) the use of organ-preserving therapy in properly selected patients that involves the use of a multimodality therapeutic approach with transurethral resection, radiation therapy, and chemotherapy; and 2) the ability to treat selected men and women with radical cystectomy followed by orthotopic reconstruction that allows patients nearly physiologic voiding. Current research efforts are directed toward better patient selection for appropriate therapy which is expected to increase patient survival and improve quality of life. Of particular importance in the selection of this optimal therapy in patients with CaB is a wide application in the clinical practice of important recent advances in molecular genetics.

High-dose radiation therapy alone for inoperable non-small cell lung cancer--experience with prolonged overall treatment times.

The purpose of this study as to determine the impact of overall treatment time on long-term survival after high-dose radiation therapy alone for inoperable non-small cell lung cancer (NSCLC). Between 1978 and 1990, 229 patients with stage I-III disease and Karnofsky Performance Scores of 80-100 received a conventionally fractionated total dose of 70 Gy through a split-course technique. After a first treatment course of 40 or 50 Gy, a restaging was performed and only patients without any contraindications, such as newly diagnosed distant metastases or serious deterioration of performance status, were given a second course. In 83% of patients this break lasted for 4-6 weeks. Overall treatment time ranged between 7 and 24 weeks (median 12 weeks). Median follow-up time was 6.6 years (range 4.0-9.3 years). Actuarial overall survival rates at 2 and 5 years were 28% and 7% respectively. Complete radiological tumor response was observed in 31% of patients, and was found to be the strongest positive predictor of survival with 2- and 5-year rates of 50% and 12% respectively compared with 17% and 4% for patients without complete response. Treatment duration was not found to be a significant prognostic factor in univariate or multivariate analysis. For overall treatment times of 7-11 weeks (n = 50), 12 weeks (n = 79) and > 12 weeks (n = 100), 5-year survival was 4%, 6%, and 8%, respectively (p = 0.6). To conclude, in our experience and in contrast to other studies, prolonged overall treatment times in radiation therapy alone for inoperable NSCLC had no negative impact on long-term survival. It is hypothesized that accelerated tumor cell repopulation is absent in a significant number of these patients with the time-factor playing no apparent role for outcome of treatment.

[One hundred years of radiotherapy. Historical origins and development of fractionated irradiation in German speaking countries]. / Ein Jahrhundert Strahlentherapie. Geschichtliche Ursprünge und Entwicklung der fraktionierten Bestrahlung im deutschsprachigen Raum.

This review studies the historical development of fractionated X-ray therapy in the German speaking countries until World War II. Fractionated treatments appear to have their origin already in the first attempts of fractionation performed by Freund in 1896. In the following, fractionated treatments could not compete with the so-called single dose or intensive radiation treatment in Germany. However, until the 1920s there were repeated sporadic attempts of various motifs to distribute the radiation doses over a prolonged period of time. Only with the end of the 1920s the conditions for a rise of fractionated irradiation were favourable, mainly due the fiasco of the intensive treatments and their subsequent decline. The impulse for this rise, however, came from France where Coutard had developed an individual empirical treatment regimen with great clinical success. This technique and its modifications and developments spread over Europe and America fast. In spite of the similarities between the various fractionation methods used during the first decades of the century, review of the radiological literature of that time fails to show any logical scientific connection of these methods, but rather there was a mix and overlap of irradiation attempts of various motivations. Thus, radiation therapy, and thereby the current standard fractionation scheme of 1.8 to 2 Gy per fraction 5 times per week, obviously did not grow out of a scientific basis, but originated from individual observation of patients and empirical experience.

Is the time interval between surgery and radiotherapy important in operable nonsmall cell lung cancer? A retrospective analysis of 340 cases.

PURPOSE: To evaluate the influence of prognostic factors in postoperative radiotherapy of NSCLC with special emphasis on the time interval between surgery and start of radiotherapy. METHODS AND MATERIALS: Between January 1976 and December 1993, 340 cases were treated and retrospectively analyzed meeting the following criteria: complete follow-up; complete staging information including pathological confirmation of resection status; maximum interval between surgery (SX) and radiotherapy (RT) of 12 weeks (median 36 days, range 18 to 84 days); minimum dose of 50 Gy (R0), and maximum dose of 70 Gy (R2). Two hundred thirty patients (68%) had N2 disease; 228 patients were completely resected (R0). One hundred six (31%) had adenocarcinoma, 172 (51%) squamous cell carcinoma. RESULTS: In univariate analysis, Karnofsky performance status (90+ >60-80%; p = 0.019 log rank), resection status stratified for nodal disease (R+

[Combined breast-preserving surgery, chemotherapy and radiotherapy in the treatment of breast carcinoma. Effect of the interval between surgery and the beginning of radiotherapy]. / Kombinierte brusterhaltende Chirurgie, Chemotherapie und Strahlentherapie bei der Behandlung des Mammakarzinoms. Der Einfluss des Intervalls zwischen Operation und Bestrahlungsbeginn.

BACKGROUND: The timing of breast conserving surgery, chemotherapy, and radiotherapy in breast cancer treatment has become the subject of increasing interest over the last years. PATIENTS AND METHOD: Seventy-four patients who underwent postoperative radiotherapy at our institution between 1985 and 1992 form the basis of this study. Median follow-up time was 5 years. Seventy-three percent of patients were pre- or perimenopausal. Almost all patients (91%) were UICC-stage II. Axillary lymph nodes were positive in 95% of cases. Complete gross resection was achieved in all patients, and in 65% final pathological margins were free of invasive or intraductal carcinoma. Postoperatively, 70% of patients received 6 cycles of polychemotherapy (predominantly CMF) before onset of irradiation. The radiation dose was in almost all cases 60 Gy including 10 Gy boost. RESULTS: Five years after start of treatment overall survival, disease-free survival, and local recurrence rates were 86% (95%-confidence limits, 76 to 93%), 73% (61 to 83%), and 8% (3 to 16%), respectively. For disease-free survival, the only significant prognostic factor was the number of involved lymph nodes: 0 to 3 = 86%, > or = 4 = 40% (p < 0.0001). The interval between surgery and radiation (< or = versus > 20 weeks) had no significant influence on disease-free survival or local tumor control. In contrast, there was a trend of increased regional and distant failure with shortening of the interval due to the delivery of less than 6 cycles chemotherapy before the onset of radiotherapy. CONCLUSIONS: In our experience, there was no negative impact of a delay of radiotherapy in order to deliver full course chemotherapy before initiation of radiotherapy. However, the low statistical power of this analysis due to the small number of patients must be considered. it appears possible that a less intense chemotherapy before starting radiation treatment correlates with enhanced distant failure and subsequently decreased disease-free survival rates. Therefore, for patients at increased risk for distant metastasis, we prefer to give 6 cycles polychemotherapy before irradiation.

[Radiotherapy in northern Germany: data on radio-oncology from 6 Bundesländer]. / Strahlentherapie in Norddeutschland: Daten zur Radioonkologie aus sechs Bundesländern.

BACKGROUND: Facts and figures about German radio-oncologic centers are scarcely available. A first glance was made possible by the accumulation of data published by the German Röntgen Society ("Abteilungen und Praxen für Strahlentherapie in der Bundesrepublik Deutschland, 1994"[4]). Detailed and up-to-date information is difficult to collect from the whole Federal Republic. Therefore, a regional data-base limited to the 6 northern German states was created in order to get correct, detailed and current facts and figures from radio-oncologic departments of this region. PATIENTS AND METHOD: Traditionally there was a close cooperation between the Röntgen Society of Northern Germany and the Society of "Niedersachsen" and "Sachsen-Anhalt". Therefore, hospital departments and free standing office-type facilities in radio-oncology from 6 states have put together a regional North German data-base. Detailed questionnaires were sent out in order to get data on heads of departments, professional staff, technical equipment, workload, diagnoses and training facilities. The collected data were distributed to all participating centers for confidential individual analysis. This paper reports the data collected. RESULTS: The survey 1995/96 had an unexpected return. Thirty-six from 38 centers in a region with 17.36 million inhabitants in 6 states (21.3% of Germany) took part. There were 73 megavolt machines and 31 afterloading facilities. Two hundred and forty physicians, 110 physicists, and 350 radiographers were working in radio-oncology; and there were 852 hospital beds specifically assigned to radio-oncology for the care of in-patients. In 1995, 32,000 patients were treated with 37,000 series, 570,000 treatment visits and 1,600,000 radiation fields. The average patient got 1.2 series, 18 treatment visits and 50 fields. Equipment-wise, an average department runs a mean of 2 megavolt machines and 1 afterloading facility. The corresponding data for 1 megavolt machine were 3.5 physicians, 1.6 physicists, 5 radiographers and 13 hospital beds. There was 1 machine for 240,000 inhabitants. The average workload of a megavolt machine was 439 patients a year with 513 series, 7,813 treatment visits and 21,845 radiation fields. CONCLUSIONS: A regional data-base for radio-oncology is being described. It is demonstrated that it is possible to get detailed and current data by this method. It provides transparent data on equipment, personnel and workload in radio-oncology. It should set an example for other regions to collect their data in the same fashion, and then compile all such data for the whole country to identify and correct potential deficiencies for improvement of care.

Radiation oncology: historical development in Germany.

In the first period after the discovery of x-rays by Roentgen until World War II, German radiotherapy made major contributions to the development of the specialty. During the Nazi regime and World War II, German doctors were separated from international developments, and after the war the technical standard was poor. It took German radiotherapy a relatively long time to return to international standards again. Because of the difficulties caused by the war, mistakes were made in placing too much emphasis on technical, physical, and biological questions in the publications of the 1960s and 1970s, while in other countries clinical research was promoted. An exception is the work of K. Musshoff (47, 48) from Freiburg. His treatment results in Hodgkin's disease were known and acknowledged internationally. Because of a variety of reasons, it was and is difficult to perform prospective randomized trials in Germany even today. In addition, the turn to the English language in medicine made it difficult for publications written in German to be popular outside of Germany. Therefore, today German journals publish abstracts in English, too. In the meantime, the clinical and technical standard as well as scientific work in German radiotherapy are comparable again to the international level, especially relative to the United States, Great Britain, France, and the Scandinavian countries.

Innovations in brachytherapy in gynecologic oncology.

With the discovery of radium by Curie in 1898, researchers recognized that this unique radionuclide had specific biologic properties that were applicable to treating patients with cancer. In the beginning, the radium sources were placed within cavities as independent sources and, when needles were available, implanted into tissues. The first combination of brachytherapy, technologies with external-beam radiation therapy was reported by Wright at the Memorial Sloan-Kettering Cancer Center in New York in 1914 in the treatment of a patient with cervical cancer. Next, there was a rapid implementation of brachytherapy in the treatment of cancer by intracavitary placement of radionuclides, interstitial implantation technologies, and systemic administrations. With the development of new radionuclides, including cesium-137, cobalt-60, iridium-192, iodine-125, palladium-103, ruthenium-109, strontium-90, iodine-131, and californium-225, which had varying types of radiation emissions appropriate when properly selected in treatment of cancer, there was a rapid development of innovative technologies to treat all malignancies, especially gynecologic cancer. The evolution of events brought forth new applicators and techniques that allowed for better distribution of the radiation dosage within the tumor being treated, safer use of radionuclides, and the development of computer programs allowing for varying source applications and dose distributions within the volume implanted.

Small cell lung cancer with and without superior vena cava syndrome: a multivariate analysis of prognostic factors in 408 cases.

PURPOSE: Patients with small cell lung cancer (SCLC) and superior vena cava syndrome (SVCS) are widely believed to have a grave prognosis. The purpose of this study was to determine the prognosis of patients with SCLC and SVCS as compared to SCLC without SVCS. METHODS AND MATERIALS: A retrospective analysis of 408 cases of SCLC +/- SVCS was performed. Three- hundred and sixty showed no clinical signs of SVCS and 43 (11%) had SVCS; in 5 patients no adequate information was available about clinical signs of SVCS. All patients were classified as limited disease cases. About 98% received chemotherapy usually as the first treatment followed by radiotherapy. A median total dose of 46 Gy (range 30 to 70 Gy) was given at 2.0 Gy per fraction five times weekly. A prophylactic cranial irradiation was applied if a complete remission was achieved after chemotherapy or after 30 Gy of irradiation. Kaplan-Meier survival curves are shown and comparisons were made by the log-rank and the Gehan/Wilcoxon test. To adjust for prognostic factors, a proportional hazards analysis was done. RESULTS: Patients without SVCS had 5-year survival rates ( +/- SE) and a median survival time (MST; 95% confidence intervals) of 11% +/- 2% and 13.7 months (12.7-14.5) in UICC Stage I to III; in Stage III the figures were 9% +/- 2% and 12.6 months (11.2-13.7). In comparison, SCLC with SVCS had 5-year survival rates of 15% +/- 7% and MST of 16.1 months (13.8-20.5). The difference was significant in univariate analysis (Stage II disease: p = 0.008 by the log-rank test). In a multivariate analysis of all patients, Stage (Stage I + II > III; p = 0.0003), SVCS (yes > no; p = 0.005), and Karnofsky performance status ( < or = 70 < 80-100%; p = 0.008) were of significant importance. CONCLUSIONS: SVCS is a favorable prognostic sign in SCLC. The treatment should be curatively intended.

Prognostic factors in high-grade malignant glioma. A multivariate analysis of 76 cases with postoperative radiotherapy.

PURPOSE: Patients with malignant gliomas have a limited survival prognosis. We retrospectively analyzed data of malignant glioma patients with the aim of defining prognostic factors on which individualized treatment strategies might be built on. PATIENTS AND METHODS: Seventy-six patients with primary malignant glioma (51 glioblastoma multiforme, 20 anaplastic astrocytoma, 4 anaplastic oligo-astrocytoma, 1 anaplastic glioma) were postoperatively irradiated with 5 and 8 Me V photons, 2 Gy per fraction to a median total dose of 60 Gy (range 50 to 70 Gy). RESULTS: The youngest quartile of patients (up to 45 years) had the highest 3-year survival rates (mean +/- SE: 15 +/- 8%) and median survival time (17.9 months, 95% confidence interval: 9.2, 24.2 months) as compared to the oldest quartile (> 61 years) with no 3-year survivor and a median survival time of 9.7 months (7.2, 12.3 months). The middle quartiles (46 to 61 years) showed intermediate results. The difference between the youngest and oldest quartile (p = 0.01) and the middle quartile versus the oldest quartile (p = 0.04) was significant. In univariate analysis, tumor size (p = 0.04 for -30 mm vs > 50 mm) was of importance. In multivariate analysis only age of the patient reached statistical significance (p = 0.03). As compared to the youngest quartile of patients, the oldest quartile had a relative risk of 2.1 (95% confidence interval: 0.9, 5.1) of dying from the disease; the age group of 46 to 61 years had a relative risk of 2.0 (0.9, 4.3). CONCLUSIONS: Age of the patient is the most important factor for survival prognosis favouring younger age (< or = 45 years). The possible implications for radiation therapy are discussed.

[The radiotherapy of inoperable non-small-cell bronchial carcinoma. A retrospective analysis of 427 cases]. / Strahlentherapie des inoperablen nichtkleinzelligen Bronchialkarzinoms. Eine retrospektive Analyse von 427 Fällen.

BACKGROUND: The influence of tumor and patient characteristics on survival as well as acute normal tissue toxicity was retrospectively analyzed. PATIENTS AND METHODS: 427 patients with inoperable non-small cell lung cancer were retrospectively analyzed. Two thirds received a total dose of at least 70 Gy, and one third was irradiated with 60 to 66 Gy (2.0 to 2.5 Gy per fraction; split-course technique). 92% had a Karnofsky performance index of > or = 80%. Kaplan-Meier survival curves were generated and comparisons were made by the log-rank test. Prognostic factors were adjusted for by a proportional hazards analysis. RESULTS: Five-year survival rates (+/- SE) and the median survival times (95% confidence interval) were 2 +/- 2% and 11.1 months (9.1 ... 14.5) after 60 to 66 Gy; 8 +/- 2% and 14.9 months (13.3 ... 16.5) after 70+ Gy. The difference was significant in univariate (p = 0.0013) and multivariate analysis (p = 0.0006). Tumor stage (p = 0.0029: I + II > III; IIIA > IIIB) and gender (p = 0.0387: female > male patients) reached significance in multivariate analysis. Acute pneumonitis and esophagitis were observed in 11% and 9% of cases. CONCLUSIONS: Inoperable non-small cell lung cancer stage I to IIIA should be treated in a curative intention with total doses of about 70 Gy. This is feasible with acceptable normal tissue toxicity. Stage IIIB patients have a particular bad prognosis and should only be treated palliatively.

Inoperable non-small cell lung cancer: a retrospective analysis of 427 patients treated with high-dose radiotherapy.

PURPOSE: The influence of patient and treatment characteristics on survival as well as normal tissue toxicity were retrospectively analyzed. METHODS AND MATERIALS: Four hundred twenty seven patients with unresectable non-small cell lung cancer received at least 60 Gy and two-thirds were treated with 70 Gy. RESULTS: Five-year survival rates and median survival time (95% confidence interval) were 2 +/- 2% (mean +/- s.e.) and 11.1 months (9.1-14.5) after 60-66 Gy (median 60 Gy); 8 +/- 2% and 14.9 months (13.3-16.5) after > or = 70 Gy (p = 0.0013). Stage I-II patients had significantly higher survival rates as compared to Stage III patients (p = 0.0015). Within the subgroup of Stage III patients those with Stage IIIA had significantly higher survival rates than Stage IIIB (p = 0.0167). Female patients achieved 5-year survival rates after 70 Gy of 15 +/- 7% as compared to only 7 +/- 2% of their male counterparts. Chemotherapy, histology, Karnofsky status, and age had no influence on survival after univariate and multivariate analysis. Nine percent and 11% of the patients suffered from moderate to severe pneumonitis and esophagitis. CONCLUSION: High-dose radiotherapy of unresectable non-small cell lung cancer with total doses > 60 Gy conventionally fractionated is feasible. With doses of > or = 70 Gy significantly higher survival rates were achieved as compared to 60-66 Gy. Normal tissue toxicity was acceptable. For Stage IIIB patients, however, treatment results are disappointingly low even after 70 Gy with no 5-year survivor.

[High dose intensity with COP-BLAM in Hodgkin's disease with unfavorable risk factors]. / Hohe Dosisintensität durch COPBlAM beim Morbus Hodgkin mit ungünstigen Risikofaktoren.

Thirty three patients with unfavourable risk factors suffering from Hodgkin's disease received COPBlAM polychemotherapy as first treatment in a phase-II study between 3/86 and 2/89. The median cumulative relative dose intensity (RDI) of 0.97, calculated as a measure for the given amount of cytostatics per time, was very high. Fourteen patients (43%) achieved a complete remission (CR); 11 (33%) additional cases were categorized as far-reaching remission (FRR) due to small residual tumors in the regions of originally large tumor masses, 7 (21%) as partial remission (PR), and one case (3%) as progression. As the small residual tumors of the patients grouped as FRR did not shrink during the following radiotherapy (RT), these cases were also classified as complete responders retrospectively. Thus, after chemotherapy 76% CR resulted. After completion of RT 91% of the patients have achieved a CR. The progress-free survival probability and the survival probability were 83% and 86% respectively after 45 months.

[Bronchial cancer: radiation therapy]. / Bronchuskarzinom: Strahlentherapie.

Postoperative radiotherapy as a routine procedure has failed to show any benefit in prospective randomized studies. Local failure was diminished, but survival rates remained unchanged, probably because of radiation complications. By improvement of radiation techniques, however, reduction of single doses and total dose and focusing postoperative irradiation of lung cancer to high risk cases (N2, T4) survival rates with postoperative irradiation are about 20% after 5 years. The results of 191 treated patients are demonstrated.

[Theoretical aspects of injector ventilation from a clinical point of view]. / Theoretische Aspekte der Injektorbeatmung aus klinischer Sicht.

Basing on Sander's inject-ventilation and Venturi's principle problems of the jet-ventilation with free-jet and injector-ventilation with jet-pump-effect are discussed, and theoretical aspects of the own method are presented.