Malignant glioma as a secondary malignant neoplasm after radiation therapy for craniopharyngioma: report of a case and review of reported cases.

BACKGROUND: The development of a secondary neoplasm in childhood cancer survivors attains growing importance due to the reported excellent survival and therefore the long exposure to potentially carcinogenic effects of treatment. CASE REPORT: We report a 14-year-old girl in whom a large craniopharyngioma (CP) was diagnosed. After surgery, radiation therapy (RT) was given for residual tumour. Discrete progression necessitated further surgery, resulting in permanent tumour control. Soon after the second surgery hypothalamic-pituitary dysfunction developed together with obesity. Supportive hormone therapy was initiated. Growth hormone (GH) therapy was also given for 15 months. Four years after the diagnosis, a cerebropontine anaplastic astrocytoma WHO grade III was detected, with the main lesion being at the dorsal edge of the irradiated area. The girl died 1 month later from this secondary presumably radiation-induced tumour. Only recently a second child with RT for a CP was diagnosed with malignant glioma in our hospital. CASE REPORTS IN THE LITERATURE: 12 other cases of malignant glioma have been reported after RT for CP. Including our present cases, the mean latency period was 10.7 years (median 9.6 years). However, the shortest latency periods were found in patients who had received GH therapy. In numerous cases, the secondary tumour was seen at the edge of the irradiated volume, and not in the region with the highest absorbed dose. CONCLUSIONS: Therapy-induced secondary gliomas after treatment of CP or other intracranial tumours are rare but dramatic late events with a very poor prognosis. Including our own 2 patients, we reviewed 14 cases of CP with occurrence of a secondary, probably radiation-induced malignant glioma. The short latency periods for patients treated with GH is remarkable. We therefore suspect that GH therapy may accelerate the development of a secondary brain tumour. We are reluctant to recommend GH therapy in conventionally irradiated CP patients. In order to seriously answer the questions about therapy-induced secondary neoplasms, a life-long follow-up is mandatory for all patients who are survivors of childhood cancer.

Radiotherapy of testicular intraepithelial neoplasia (TIN): a novel treatment regimen for a rare disease.

PURPOSE: Testicular intraepithelial neoplasia (TIN) is a consistent precursor of most invasive germ cell tumors, currently treated by radiotherapy with 20 Gy, which destroys TIN but preserves Leydig cells. Nevertheless, analysis has shown dose-dependent dysfunction even with low therapeutic doses of 20 Gy in some cases. Therefore, we tested a dose reduction regimen by delivering smaller fractional doses to enhance the tolerance of Leydig cells. METHODS AND MATERIALS: Between 1993 and 1999, 9 patients were treated for TIN in a prospective multicenter trial. A total dose of 13 Gy was administered in 10 fractions of 1.3 Gy. Hormonal levels of follicle-stimulating hormone, luteinizing hormone, and testosterone were assayed serially. RESULTS: During a median follow-up time of 36 months, no patient showed evidence of local disease. A first postradiation biopsy was obtained 3-12 months after radiotherapy; 5 patients underwent a second biopsy 2-3 years after treatment. All biopsies showed a Sertoli cell-only pattern. Follicle-stimulating hormone levels continued to increase 1 year after radiotherapy, signaling eradicated spermiogenesis. Luteinizing hormone and testosterone remained within the normal range 2 years after radiotherapy. CONCLUSIONS: In the treatment of TIN, there seems to be a dose reduction potential to 13 Gy by lowering single fractional doses, which enhances the therapeutic ratio in favor of the Leydig cells.

Skin markings in external radiotherapy by temporary tattooing with henna: improvement of accuracy and increased patient comfort.

PURPOSE: To guarantee invariable skin markings in patients undergoing a course of external radiotherapy, especially using conformal techniques. Cutaneous markings with henna also increase patient comfort, because washing and showering are allowed. METHODS AND MATERIALS: Henna, a completely natural product, is a skin colorant with a history of 5,000 years. It is applied to the skin in the form of a paste. While drying, henna stains the superficial skin layers for several weeks, and the marked area can be exposed to water arbitrarily. In case of fading of the stain before the end of radiotherapy, the marking procedure can be repeated. From November 1998 until March 2000, we performed skin markings with henna in 158 patients with different tumor sites. The majority of patients received conformal radiotherapy techniques. All patients have been evaluated concerning durability of the markings, the RESULTS: The median durability of henna staining is 23 days (range 12-48 days). On average, two marking procedures (range 1-4) are necessary for a patient treated with curative intent. Although washing and showering are freely permitted, no adverse cutaneous side effects (e.g., erythema, allergic reactions) have been observed. CONCLUSIONS: Skin marking by temporary tattooing with henna increases the accuracy of external radiotherapy. It yields stable and invariable markings for the entire course of radiotherapy and also increases the comfort of patients.

Non-small-cell lung cancer: dose escalation by target splitting with asymmetric collimation.

In order to increase conformation, the target volume is split into a cranial and a caudal part. Both volumes are planned and treated completely independent, using half-collimated fields to prevent over- or under-dosages in the junction plane. In comparison with conventional techniques, the irradiated volume of normal ipsilateral lung tissues at dose levels >or= 65 Gy, >or= 45 Gy, and >or= 20 Gy can be lowered to values of 37%, 49%, and 86%, respectively; other organs at risk, such as the heart and esophagus, can also be significantly spared. From December 1995 to December 1999, 54 non-small-cell lung cancer patients were treated with doses > 80 Gy (mean, 86.3 Gy; range 80.1-94.9 Gy, International Commission on Radiation Units and Measurements). Twenty-two patients were stage I or stage II, and 32 patients were stage III. Fifteen of the 32 stage III patients received chemotherapy before radiotherapy. Only 1 patient showed a transient grade 3 toxicity (pneumonitis), and at the time of this review, no grade 4/5 toxicity has been observed.

[Long-term tumor control and fertility after para-aortic limited radiotherapy of stage I seminoma]. / Langzeittumorkontrolle und Fertilität nach paraaortal limitierter Radiotherapie des Seminoms im Stadium I.

PURPOSE: To review patterns of relapse in a long-term analysis of patients with Stage I seminoma treated by orchidectomy and radiotherapy to the paraaortic lymph nodes only and to follow follicle stimulating hormone (FSH) levels dependent on testicular scatter dose. PATIENTS AND METHODS: From 1980 to 1995, 58 patients with Stage I seminoma received elective radiotherapy to the paraaortic lymph nodes only (Th12 to L4), with a mean total dose of 28.07 Gy (+/- 2.2 SD), using fractional doses between 1.5 and 2 Gy (mean 1.62 Gy +/- 0.083 SD). Since 1989, testicular scatter doses were measured routinely by in-vivo thermoluminescent dosimetry (TLD) in 45 patients. In 26 patients with normal pre-treatment values of FSH, FSH-levels were repeatedly controlled after radiotherapy in order to evaluate any radiation-induced sequelae. RESULTS: During a mean observation period of 69.4 months (range 30 to 210), 2 out of 57 patients (3.5%) developed regional recurrences in the ipsilateral pelvic lymph nodes 14 months and 5 years after radiotherapy, respectively. One patient was lost to follow-up. The relapse-free survival rate at 5 years was 96.5% after radiotherapy alone. After salvage chemotherapy, both relapse-free survival and overall survival rates come to 100%. The mean testicular scatter dose in 45 patients was 0.22 Gy (+/- 0.087 SD). Seven out of 26 patients (26.9%) developed a transient increase of FSH-levels, reaching peak values at 4.2 months and returning to normal ranges within 18 months after radiotherapy. Below 0.2 Gy, no effect on FSH was observed. Testicular scatter doses showed no clear correlation to FSH risings (Figure 1). CONCLUSION: After exclusive paraaortic radiation of Stage I seminoma, even at follow-up periods in excess of 5 years the incidence of pelvic lymph node relapses remains below 4%. However, there seems to be a small potential for the development of late recurrences. With limited radiotherapy, permanent radiation-induced effects on the remaining testicle are very unlikely.

Radiotherapy for lung cancer: target splitting by asymmetric collimation enables reduction of radiation doses to normal tissues and dose escalation.

PURPOSE: This study was performed to develop a method of reducing the radiation doses to normal thoracic tissues, increasing the target dose, especially in the primary radiotherapy of non-small cell lung cancer (NSCLC), and to evaluate acute/subacute toxicity of dose escalation. METHODS AND MATERIALS: From December 1195 to March 1998, the technique of target splitting has been applied to 58 patients. In this period, 30 patients were treated with doses > 80 Gy (ICRU-specification, mean 85.1 Gy, range 80. 1-90.2 Gy). The target volume is split into a cranial part (e.g., upper mediastinum) and a caudal part (e.g., primary tumor and middle mediastinum). Both volumes are planned and treated independently, using conformal irradiation techniques for both parts with half-collimated fields to prevent over- or underdosage in the junction plane. After fine-adjustment of the jaws, a verification film, exposed in a polymethylmethacrylate (PMMA) phantom, demonstrates the homogeneity of dose in the entire target volume. For comparison with conventional techniques, planning to identical doses is performed for 5 patients. Dose-volume histograms (DHVs) for normal lung tissue are presented for both methods. RESULTS: The irradiated volume of normal tissue of the ipsilateral lung can be lowered at dose levels > or = 65, > or =45 Gy, and > or = 20 Gy to values of 37% (range 25-54%), 49% (range 46-54%), and 86% (range 55-117%), respectively. Other organs at risk, such as heart or esophagus, can also be spared significantly. Only 1 patient showed a transient grade 3 toxicity (pneumonitis), and there where no grade 4 acute/subacute side-effects. Two patients with Stage III A central tumors in close proximity to the large vessels died due to a pulmonary hemorrhage 2 and 4 months after therapy, respectively. No patient developed esophagitis. Antimycotic prophylaxis for esophagitis and posttherapeutic steroid prophylaxis for pneumonitis for several weeks were routinely used. CONCLUSION: The technique of target splitting by asymmetric collimation helps to increase conformation, and thus enhances the sparing of normal tissues. It can be used whenever there is a marked difference in the shape of the planning target volume (PTV) in a cranio-caudal direction. This technique can principally be handled with 2D-planning systems, because it is coplanar. We consider target splitting as an important tool for dose escalation in the primary radiotherapy of NSCLC, that should also be used for other lung cancer patients necessitating moderate doses only.

Oral Anticoagulation in patients with gynecological cancer and radiotherapy: a retrospective analysis of 132 patients.

Venous thromboembolism is reported to be a leading cause of death and morbidity after surgery and during radiotherapy for gynecologic malignancies. This study was performed to evaluate the incidence of thromboembolism as well as the benefit and risk of its prophylaxis with coumarin in this patient selection. Between 1988 and 1992, 132 patients with gynecologic malignancies underwent postoperative or primary radiotherapy (53 patients without prior surgery). Heparin (5000 IU t.i.d., s.c.) was administered perioperatively, and coumarin (International normalized ratio = INR target 2.0-3.5) was given to all patients during radiotherapy. Daily visits for inspection of the legs and for possible symptoms and signs of thromboembolism were performed. In case of diagnostic doubts, impedance plethysmography and phlebography for diagnosis of venous thrombosis, and lung scanning for diagnosis of pulmonary embolism were performed. Among the 132 patients, 9 (6.8%) developed deep venous thrombosis of the renal vein and of the inferior caval vein occurred in one additional patient. Pulmonary embolism was detected in 5 patients (3.8%). All thromboembolic events were without lethal outcome. Bleeding episodes were observed in 7 patients (5.3%); in two of them a major bleeding led to cessation of coumarin administration. The prophylaxis of thromboembolism in gynecologic oncology with coumarin seems to be effective, safe and inexpensive.

[100 years radiotherapy. On the birth of a new specialty]. / 100 Jahre Strahlentherapie. Zur Geburt eines neuen Faches.

Radiotherapy was founded as a new scientific specialty by the Viennese physician Leopold Freund 100 years ago. Freund provided the world's first scientific proof of the biological effectiveness of x-rays and performed the first successful treatment with these new rays on a 5-year old girl suffering from a huge nevus pigmentosus pilosus (hairy nevus) on her back. Before Freund's historical three experimental x-ray treatments (the first of these began on November 24, 1896, in Vienna) there had been earlier attempts and suggestions to apply x-rays therapeutically during 1896. However, none of these previous therapeutic attempts was successful. Also, there was no scientific proof of the biological effectiveness of x-rays among the therapeutic attempts which preceded Freund's fundamental x-ray treatments. Modern radiotherapy and radiation oncology contribute towards nearly one half of all cancer cures. Two thirds of cancer patients need the help of radiation oncology, and this scientific specialty is, thus, the most frequently used treatment modality in the management of tumor patients.

Endocrine profiles after radiotherapy in stage I seminoma: impact of two different radiation treatment modalities.

BACKGROUND AND PURPOSE: In patients with stage I seminoma treated with elective lymph node irradiation, testicular scatter doses are often thought to be responsible for later disturbances in fertility. We studied the influence of radiation field extensions and testicular doses on hormonal function. MATERIALS AND METHODS: FSH (follicle stimulating hormone) and LH (luteinizing hormone) were evaluated before radiotherapy (RT) and by serial analyses after treatment for 4 years. Twenty-three patients were irradiated by hockey stick fields with a mean dose of 31.9 Gy (+/-4.7 SD) and a mean scatter dose of 54 8 cGy (+/-16.6 SD). Twenty-one patients received limited RT to the paraaortic nodes with 28.1 Gy (+/-2.4 SD). The mean testicular dose was only 25 cGy (+/-7.8 SD). All patients had normal pre-treatment hormonal values. RESULTS: Six months after the end of RT, mean FSH values were significantly elevated in the hockey stick group (P = 0.032), returning to normal after 3 years. The increase in LH was also significant, but stayed within normal ranges. Limited RT resulted in a minimal, dose-dependent increase of FSH; no changes in LH were noted. CONCLUSIONS: In patients with a normal hormonal status after semicastration, FSH is a reliable monitor for transient radiation-induced effects. To avoid treatment-related disturbances in spermatogenesis, scatter doses should be reduced to less than 20 cGy.

Inauguration of radiotherapy as a new scientific speciality by Leopold Freund 100 years ago.

There is an increasing acceptance and knowledge of the fact that the inauguration of radiotherapy as a new scientific speciality was performed by Leopold Freund 100 years ago. With a clear and logical rationale, Freund provided the first scientific proof of the biological effectiveness of X-rays on a 5-year-old patient and performed the world's first successful treatment with X-rays. Before Freund's historical experimental treatments, which started in Vienna on November 24th, 1896, there were several suggestions and attempts at the therapeutic use of X-rays, however none of these mostly one-of-a-kind attempts was successful, and there was no scientific proof of a therapeutic effectiveness of X-rays in these previous experiments.

The history and evolution of radiotherapy and radiation oncology in Austria.

Austria has a longstanding and eventful history in the field of radiotherapy and radiation oncology. The founder of radiotherapy, Leopold Freund, began his well-documented first therapeutic irradiation on November 24, 1896, in Vienna. He also wrote the first textbook of radiotherapy in 1903. Further outstanding Viennese pioneers in the field of radiotherapy, radiobiology, radiation physics, and diagnostic radiology include Gottwald Schwarz, Robert Kienböck, and Guido Holzknecht. Because many of the leading Austrian radiologists had to emigrate in 1938, irreparable damage occurred at that time for the medical speciality of radiology. After World War II, the recovery in the field of radiotherapy and radiation oncology started in Austria in the early sixties. Eleven radiotherapy centers have been established since that time, and an independent society for radio-oncology, radiobiology, and medical radiophysics was founded in 1984. Finally, in March 1994, radiotherapy-radio-oncology became a separate clinical specialty.

Quality assurance in breast cancer brachytherapy: geographic miss in the interstitial boost treatment of the tumor bed.

PURPOSE: To assess the role of geographic misses in the interstitial boost treatment of breast cancer patients and to evaluate methods of optimizing breast implants in design, performance, and dosimetry. METHODS AND MATERIALS: During lumpectomy, the tumor excision sites of 89 patients were marked by five hemoclips. Postoperative radiographs demonstrated the clips' positions with respect to the extension of the surgical cavity, which was demarcated by air and hematoseroma. Twenty-seven selected patients received interstitial boosts to the tumor bed. The implant was first designed according to the clinical assumptions of the tumor bed's topography and then compared with the radiological findings. Prior to brachytherapy, the planning of the implant's dimension and the needle guidance was performed under simulator control. Dose distributions were first calculated following the Paris System and then electively optimized for the target volume by changing source positions and dwell times. RESULTS: Compared to clinical estimations, the radiological determination of the tumor bed's location revealed an overall potential of topographic errors of 51.8% (14 out of 27 patients), rising up to 78.5% in patients with large adipose breasts (11 out of 13 patients). This observation was due to a high mobility of the tissue, leading to varying tumor site projections at the time of mammography, surgery, and brachytherapy. In all patients, the presimulation of the implant resulted in an adequate coverage of the target volume. In 17 of the 27 treated patients, dose distributions were modified to achieve a higher dose delivery in zones where a higher residual tumor load was expected (boost-in-boost). CONCLUSION: Breast implants have a high potential of geographic misses that can be avoided by intraoperative clip demarcation. The delineation of the tumor bed allows for dose reports actually referring to the target volume and not to the implant system to be obtained. In addition, modern afterloading techniques offer possibilities of individual dose planning with regard to high risk subvolumes within the implanted tissue.

Inadequacy of conventional computerized tomography scans for treatment planning of tangential breast (chest wall) fields.

The use of transverse tomography treatment-planning scans, which have to be taken in the exact treatment position of the patients, is essential for precision radiotherapy of breast cancer. Transverse tomography scans give all necessary informations for an optimal isodose distribution within the target volume for the individual patient, and maximal sparing of normal tissues (e.g. lung) is achieved. The exact topography of internal mammary nodes may also be incorporated in the planning scan with the help of lymphoscintigraphy. Conventional computerized tomography (CT) scanners have too small gantry openings (50-70 cm) to allow for proper positioning of the patients under treatment conditions. Using such treatment-planning scans for patients in the actual treatment position would cause an underdosage in excess of 5% within the target volume, when 60Co fields are used. Also, a much larger volume of normal tissues (mainly lung) would unnecessarily be irradiated. Treatment-planning scans obtained by TAT (transverse analog tomography) do not have the crucial positioning problems of conventional CT scanners and enable the precise transformation of a valid isodose distribution to each patient. In addition, positioning wedges (with adjustable wedge angles) may be placed under the patient to achieve the optimal treatment position. A useful alternative of TAT scanning for precise treatment planning of patients with breast cancer would be a CT scanner with a wide enough gantry opening to allow for any patient positioning under actual treatment conditions.

Local control and outcome of patients irradiated for isolated chest wall recurrences of breast cancer.

Between January 1970 and December 1978, 149 breast cancer patients with isolated chest wall recurrences developing after initial curative treatment (mastectomy with or without postoperative irradiation) were referred to the University Clinic for Radiotherapy and Radiobiology of Vienna. Following radiotherapy, survival was analysed in 134 patients with regard to the amount of disease in the chest wall at the time of treatment and local tumour control. Patients with "subclinical" disease (after excision of solitary recurrences) had a median survival time of 55 and 50 months for controlled and uncontrolled disease in the entire chest wall, respectively. The corresponding survival times for patients with "macroscopic" chest wall disease was 36 and 25 months, respectively. Local tumour control within the irradiated field was 69% for patients with subclinical disease and 49% for patients with macroscopic tumour manifestation. Freedom from tumours in the entire chest wall could be achieved in 41% of patients with subclinical and 24% of patients with macroscopic disease. The 5-year survival rate for patients with subclinical disease, with tumour control in the entire chest wall is 53%. Of all 134 patients, 22% survived 5 years from the time of local recurrence.

Iodine-125-seed implantation combined with external radiotherapy under potentially curative intention in patients with advanced stage-C prostatic cancer.

We report on 18 patients, aged 43-77 years, with clinical stage-C adenocarcinoma of the prostate, primarily treated by pelvic lymphadenectomy and 125I-seed implantation. After lymphadenectomy, the staging assessment differed from the preoperative diagnosis as follows: 4 patients were classified as stage C; 6 as D1, and 8 as D2 (distant nodal metastases). The 4 patients, classified postoperatively as stage C, received no further treatment. 11 patients with a postoperative classification of stage D had additional external beam radiation to the pelvic and paraaortic lymph nodes with shielding of the implanted prostatic region. In addition, 8 of these 11 patients had hormonal therapy. The remaining 3 patients have been treated by combining interstitial irradiation with preoperative external beam radiotherapy; postoperative irradiation was supplemented when the lymph nodes were positive.

Misonidazole and irradiation in the treatment of high-grade astrocytomas: further report of the Vienna Study Group.

A randomized study investigating the value of misonidazole in patients irradiated for grade III and IV supratentorial astrocytomas was started in June 1977. With a minimum follow-up time of 6 months, 45 patients who completed therapy are available for analysis. All patients received the same radiation treatment (66.5 Gy in 31 fractions over 7.5 weeks, field size reduction after 45 Gy). In the first, second and eighth week, a 4 Gy tumor dose was given on Monday and Thursday. Misonidazole was given 4 hours before irradiation to 18 randomized patients on those 6 treatment days (2.1-2.7 g/m2 per treatment day). Daily tumor doses of 1.7 Gy were administered Monday through Friday from the third until the seventh week. Median survival for patients treated with misonidazole is 13.8 months; for those treated by irradiation alone it was 9.8 months. The corresponding 1 year survival rates are 64 and 25%, respectively. Survival plots indicate some advantage for the patients treated with misonidazole, however statistically there is no significant difference observed (p greater than 0.08). There are no significant differences in Karnofsky performance status, sex and in histological grade or in age distribution between the groups. However, the type of surgery (complete or subtotal) influenced survival markedly: patients with complete surgery lived significantly longer (p less than 0.0009). Neurotoxic side effects of misonidazole were minimal.

[Clinical course of patients with isolated chest wall recurrences of breast cancer]. / Der klinische Verlauf von Patientinnen mit isolierten Brustwandrezidiven eines Mammakarzinoms.

A retrospective study was done of 149 patients with isolated chestwall recurrences of breast cancer. All patients received chestwall irradiation for the recurrence. The absolute survival for the patients at five years from the onset of chestwall recurrence was 28,4%. The amount of chestwall disease at the time of irradiation for the recurrence (subclinical versus macroscopic) as well as the time interval between mastectomy and recurrence were found to be prognostically significant factors. For patients with subclinical chestwall disease and a time interval to recurrence of at least two years the survival rate at five years was 53,8%. As about 80% of all patients with chestwall recurrences ultimately developed distant metastases, the importance of elective postoperative irradiation as part of the initial curative management of breast cancer is stressed.

[Radiosensitization of hypoxic tumor cells with special reference to head and neck cancers]. / Die Strahlensensibilisierung hypoxischer Tumorzellen unter besonderer Berücksichtigung der Karzinome des Kopf-Hals-Bereichs.

The radioresistance of hypoxic tumour cells may be the cause of recurrences in some clinical situations. In nearly all biological systems radiosensitivity is increased by a factor of 2 to 3 in the presence of oxygen. During a course of curative radiotherapy the process of reoxygenation occurs in most tumours. With the use of electron-affinic radiosensitizers of hypoxic cells the possibility exists to eliminate the disadvantage of insufficient reoxygenation of hypoxic cells. The current status of clinical studies using misonidazole in the treatment of head and neck carcinomas is discussed.