Clinical, molecular- and cytogenetic analysis of a case of severe radio-sensitivity.

In radiotherapy the normal tissue reaction is often a limiting factor for radiation treatment. Still there is no screening method, which predicts normal tissue reaction on radiotherapy, especially in comparison to tumor tissue, and therefore allows tailoring of the radiation dose to each patient. Here, we present a case of severe radiation-related side effects. We applied classical cytogenetic techniques (Giemsa-banding and staining of centromeric regions), the comet assay as well as multicolor fluorescence in situ hybridization on peripheral blood lymphocytes of this patient in order to determine the radio-sensitivity on the DNA level and to correlate these findings with the clinical outcome. Our investigations revealed abnormalities on chromosome 9, deficiencies in the DNA-repair capacity after radiation exposure and a high number of radiation induced chromosomal aberrations. A detected high amount of residual damage two or three hours after radiation exposure and repair as well as the high number of chromosomal aberrations (ChAs) suggests a correlation between repair capacity and radiation induced ChAs. We concluded that the detected abnormalities might serve as a genetic basis for the radio-sensitive phenotype of this patient. Taken together this report strengthens the idea that intensive DNA genomic analysis of individual patients can serve as the basis for more favourable treatment of cancer patients.

Reduction of the dose to the lens in prophylactic cranial irradiation: a comparison of three different treatment techniques and two different beam qualities.

Three treatment techniques using two beam qualities have been compared on the basis of dose to the lens in prophylactic cranial irradiation. The dose to the lens and the globe was measured with thermoluminescent crystals in an anthropomorphic phantom and calculated by a computer-assisted planning system. A comparison was made of large field and small field techniques using 60Co and 8 MV photons. Modifications to the basic techniques studied included angulation of the gantry, angulation of the couch, and placement of an additional eye block close to the surface. The dose to the lens could be reduced to four percent of the midplane dose by applying the small-field technique combined with the use of 8 MV energy photons, by placing an additional block close to the surface, and by five degree occipitally angling the gantry, as well as rotating the treatment couch to account for the divergence of the beam. The use of 60Co produced an underdosage of the posterior segment of the globe in angled treatment techniques.

Busulfan/cyclophosphamide plus bone marrow transplantation is not sufficient to eradicate the malignant clone in juvenile chronic myelogenous leukemia.

Bone marrow transplantation plays an essential role in the successful treatment of both juvenile and adult chronic myelogenous leukemia. Recently, it has been reported that conditioning with high doses of busulfan can successfully replace total body irradiation (TBI), in patients with acute myelogenous leukemia as well as adult chronic myelogenous leukemia. We report here the case of a 29-month-old boy with juvenile chronic myelogenous leukemia (JCML) transplanted with HLA-identical bone marrow after conditioning with busulfan, etoposide and cyclophosphamide. Successful engraftment was followed by early relapse on day 67. A second HLA-identical transplant was performed following myeloablative treatment with TBI. Engraftment was once again successful and the patient remains free of disease more than 24 months after transplantation. We conclude that busulfan is insufficient in eradicating JCML and that TBI is required prior to transplantation.

Intraluminal irradiation in the treatment of malignant airway obstruction.

A group of 79 patients with non-resectable lung carcinomas (T1, 1; T2, 13; T3, 34; T4, 19; recurrence, 12) underwent endobronchial iridium-192 high-dose rate afterloading therapy (5 Gy/session total dose: 5-25 Gy, mean 11.6 Gy). In 39 cases the fair general condition and absence of metastases allowed external-beam irradiation (EBR) to be administered (50-70 Gy total dose; 2gy/day), starting 1 week after the brachytherapy session. In nine cases with superior vena cava syndrome, EBR (30 Gy total dose; 3 Gy/day) was administered concomitantly. Improvement in symptoms of respiratory obstruction was noted in 87% of our patients. The mean duration of palliation was 17.1 weeks in the group without and 34.7 weeks in that with additional EBR. The median survival time was 6 months without and 13 months with additional EBR. In T4 cases EBR had no impact on the 1-year survival (30.8% vs 24.4%, P > 0.05). The rate of severe complications was 7%, without significant differences between cases with or without EBR.

Results of irradiation treatment in patients with non-resectable oesophageal cancer.

Forty-eight patients with non-resectable cancer of the oesophagus and oesophagogastric junction (Group A: Stage I/II, 32; Group B: Stage III/IV, 16) underwent intraluminal Iridium-192 high dose-rate afterloading therapy (5-7 Gy/session, total dose: 5-21 Gy, mean: 12.4 Gy) and external beam irradiation (Karnofsky > or = 80% 50-60 Gy/2 Gy per day; Karnofsky 60-79%: 30 Gy/3 Gy per day). Durable satisfactory palliation (intake of at least semi-solid food) was demonstrated in 96% of patients. The mean survival for group A was 19.1 months and that for group B, 6.9 months, with a 12-month survival rate of 66% (group A) and 0% (group B) (P < 0.001). Local tumour response and complication rate were significantly dose-related with a predicted response rate of 70.5%, and a complication rate of 50% at ERD 129.3 Gy.

Iridium-192 high dose rate brachytherapy combined with external beam irradiation in non-resectable oesophageal cancer.

Forty-eight patients with non-resectable cancer of the oesophagus and oesophagogastric junction (group A: Stage I/II: n = 32; group B: Stage III/IV: n = 16) underwent intralumenal iridium-192 high dose-rate afterloading brachytherapy (5-7 Gy/session, total dose 5-21 Gy, mean 12.4 Gy) and external beam irradiation (Karnofsky > or = 80%: 50-60 Gy/2 Gy per day; Karnofsky 60%-79%: 30 Gy/3 per day). Prolonged satisfactory palliation (intake of at least semi-solid food) was demonstrated in 96% of patients. The mean survival for group A was 19.1 months and that for group B 6.9 months, with a 12-month survival rate of 66% for group A and 0% for group B (P < 0.001). Local tumour response and complication rate were significantly dose related with a predicted response rate of 70.5% and a complication rate of 50% at extrapolated response dose (ERD) 129.3 GY3 (Gy at alpha/beta = 3).

[Metallic mesh endoprosthesis and intraluminal high dose rate 192Ir brachytherapy in the palliative treatment of malignant bile duct obstruction. Initial results]. / Metallgeflecht-Endoprothese und intraluminare High-dose-rate-192Iridium-Brachytherapie zur palliativen Behandlung maligner Gallengangsobstruktionen. Erste Erfahrungen.

Since December 1989, 9 patients with inoperable malignant biliary tract obstruction were treated palliatively by a combined modality treatment consisting of placement of a permanent biliary endoprosthesis followed by intraluminal high dose-rate 192Ir brachytherapy. A dose of 10 Gy was delivered in a hyperfractionated schedule at the point of reference in a distance of 7.5 mm of centre of the source. External small field radiotherapy (50.4 Gy, 1.8 Gy per day, 5 fractions per week) was also given in six cases (M/O, Karnofsky greater than 60%). In 9/9 cases an unrestrained bile flow and an interruption of pruritus was achieved, in 78% (7/9) of cases the duration of palliation was as long as the survival time (median survival time 7.5 months).

[Endocrinologic function following cranial irradiation in acute lymphoblastic leukemia in childhood]. / Endokrinologische Funktion nach Schädelbestrahlung bei akuter lymphoblastischer Leukämie im Kindesalter.

Endocrinological function was evaluated in 31 children after successful treatment of acute lymphoblastic leukaemia. All patients had received combination chemotherapy and 12-24Gy of cranial irradiation according to the German therapy protocols BFM-81, BFM-83 and BFM-86. Height, weight, bone age and pubertal development, as well as hypothalamic-pituitary function were measured. Long-term linear growth was unaffected in all patients. However, 9 patients showed subnormal serum growth hormone levels in response to pharmacological stimulation of the pituitary. All patients had normal levels of T3 and T4, but one patient showed an increased response of thyrotropin to thyrotropin releasing hormone. All prepubertal and postpubertal children demonstrated appropriate secretion of follicle-stimulation hormone (FSH) and luteinizing hormone (LH) after stimulation with LH-releasing hormone (LH-RH). 3 pubertal girls showed adequate oestradiol levels, but abnormally high levels of gonadotropins in response to LH-RH. Sexual development was normal in two of them, but the third had a late menarche and irregular menses. The significance of these findings is discussed in the context of recommendations possibly to further reduce or completely delete prophylactic cranial irradiation.

[Breast cancer in the man: a report of 30 patients]. / Das Mammakarzinom des Mannes: Ein Bericht über 30 Patienten.

A retrospective review of male patients suffering from breast cancer seen over an 18-year period was carried out at the Department of Clinical Oncology of the University Hospital of Graz. Thirty evaluable cases were analysed. Eight patients had Stage I, 11 had Stage II, 8 had Stage III, and 3 had Stage IV disease. Local control was achieved in the majority, 29/30 (97%), by either surgery alone or combined surgery and radiation therapy. Local recurrence developed in 2 (7%) patients. Further 7 (23%) patients developed distant metastases and were treated in accordance with policies developed for the appropriate stage of the disease in females, with hormonal manipulation for hormone receptor-positive and -unknown patients and chemotherapy for hormone receptor-negative patients. The corrected five-year survival (Kaplan-Meier) is 83% for the entire group, 100% for patients with Stage I disease, 86% in Stage II, and 67% in Stage III and IV disease, respectively. This corresponds well with the results in recently published series. Stage of disease at initial presentation was a significant factor determining survival in our investigation. Our own data as well as recent data from literature suggest that with respect to TNM Stages in mammary carcinoma, there is no prognostic difference between men and women. To what extent improved local control by adequate local therapy or systemic adjuvant treatment modalities may improve overall survival remains to be discussed.

Surgical and non-surgical treatment of cancer of the oesophagus and the oesophagogastric junction: results of 200 consecutive cases.

200 consecutive, unselected patients with cancer of the oesophagus or the oesophagogastric junction (89 squamous, 110 adenocarcinoma or undifferentiated, 1 oat cell) between 1984 and 1987 were reviewed. Resection with postoperative adjuvant irradiation in the cases of squamous cell cancer, was carried out in 51 patients and non-surgical treatment [57 combined dilation and Nd-YAG-laser, 64 iridium 192 high-dose rate brachytherapy with or without 60 Gy external beam irradiation (EBR); 28 endoprostheses] was performed in the remaining 149 patients. The overall 5 year-survival rate was 9.2% (resections: 17.9%, non-resected: 5.2%). Resected nodal negative T1 or T2 patients had the best prognosis (45.8% 5-year survival). The median survival following dilation and laser was 3.4 months for all T-stages. Endoprostheses yielded a median survival of 1.7 months. Intracavitary brachytherapy gave the best palliative result with 6.5 months median survival, whereby only T1 and T2 patients benefitted from additional EBR. Histological subtype, age, sex or tumour localization did not influence survival. Multivariate analysis showed that in M0 patients the choice of treatment had a significant impact on prognosis.

[Evaluation of irradiation techniques in breast carcinoma using dose-volume histograms. Comparison of the heart and lung exposure]. / Die Beurteilung von Bestrahlungstechniken beim Mammakarzinom mit Hilfe von Dosis-Volumen-Histogrammen. Eine Gegenüberstellung der Herz- und Lungenbelastung.

For irradiation of the internal mammary lymph nodes (IMN), together with irradiation of the breast the commonly used treatment techniques are of three types: 1. two tangential opposed fields, 2. three field plans with a separate "straight on" IMN-field, or 3. with a separate "angled" IMN-field. To determine lung and heart volumes and doses for these techniques, dose-volume-histograms in 30 patients were analyzed. The optimum dose distribution was achieved with the "angled" field technique and an appropriate combination of electrons and 60Co gamma radiation for the IMN-field. (The beam mixture used was 40% 60Co beam and 60% electron beam.) The least possible dose to the lung was obtained with the "straight-on" field technique and the least possible dose to the heart with the separate "angled" IMN-field technique.

Intraoperative radiation therapy, endotracheal hyperthermia and IR-192-brachytherapy in patients with advanced thyroid cancer.

Tracheal stenosis due to infiltrative nonresectable thyroid cancer causes severe reduction in life quality. Palliative therapy, apart from tracheostomy is--up to now--intraluminal and/or external radiation. Good tumor control is achieved by local hyperthermia. A combined modality treatment (CMT) consisting of surgery, brachytherapy and intraoperative radiation, eventually combined with intraluminal NdYg-Laser-desobliteration was performed. An intraoperative radiation therapy (IORT)-protocol was designed for poorly differentiated non-anaplastic thyroid carcinoma. Out of 155 cases of differentiated thyroid tumors, 12 showed marked vascular and/or capsular invasion. Five entered the study (3 primarily local invasive tumors, 2 local recurring). IORT was administered after tumor surgery (4-10 Gy) and combined with postoperative percutaneous irradiation. The tumor control rate in the thyroid bed is 5/5, 1/5 developed mediastinal nodes, 1/5 with primary mediastinal tumor extend shows tumor progression. No specific complications occurred.

Synchronous radiochemotherapy in unfavorable brain tumors of children and young adults.

The prognosis of patients with incompletely resected malignant brain tumors is almost fatal. In an attempt to improve the outcome of children and young adults with unfavorable brain tumors an intensive multimodal therapeutic strategy was developed combining simultaneous (hyper)fractionated external beam irradiation and conventional adjuvant chemotherapy after initial surgery. 17 patients aged between 2.10 and 25.11 years were entered into the study. 16/17 patients were treated according to the German/Austrian Pediatric Brain Tumor Study Group multicenter trial HIT '91. They are not protocol patients of this HIT '91 trial. Induction chemotherapy consisted of 2 courses of ifosfamide (3 g/m2/d) on days 1-3, etoposide (150 mg/m2/d) on days 4-6, methotrexate (5 g/m2) on days 15 and 22, cisplatin (40 mg/m2/d) and cytarabine (400 mg/m2/d) on days 29-31. Three weeks after the last dose of cisplatin/cytarabine the second course of chemotherapy was started. The last patient entered into the study received a modified therapy containing ifosfamide, cisplatin and etoposide. Synchronously at a median of 12 days after initiation of chemotherapy 12/17 patients received local radiotherapy (6000-7040 cGy) to the brain and 5/17 patients craniospinal irradiation (3520 cGy with a tumor boost of 1400-2000 cGy). 4-6 weeks after completion of the second course of chemotherapy maintenance therapy was started with carmustine (CCNU) (75 mg/m2) and carboplatin (400 mg/m2) each on day 1 and vincristine (1.5 mg/m2) on day 1, 8, 15. This course was repeated eight times every six weeks. 9/17 patients are alive at a median follow-up of 25 months (range 5-50) with 4 complete remissions, 2 partial remissions and 1 stable disease lasting 42+ months. Two patients, who initially had stable disease, progressed, but are still alive at 31+ and 41+ months after diagnosis. Median progression-free survival and median overall survival is 19 and 36 months, respectively. Hematologic and methotrexate-induced toxicity were severe and resulted in one therapy-related death. However, radiotherapy concomitant to chemotherapy appears to be an effective method of treatment for brain tumors with poor prognosis, though toxicity is severe in some cases.

[Treatment of primary cancer of the fallopian tube]. / Die Behandlung des primären Karzinoms der Tuba Fallopii.

33 patients treated since 1970 at the Medical School of the University of Graz, were classified using the FIGO system for ovarian carcinoma, fourteen were in stage I, 8 stage II, 8 stage III and 3 stage IV. In 17 patients, surgery consisted of total abdominal or vaginal hysterectomy with bilateral salpingo-oophorectomy; 12 patients underwent additional pelvic +/- paraaortic lymph node extirpation and in 4 the tumour excision was incomplete. Treatment in 6 patients was surgery alone (2/stage I, 4 with advanced disease) (Group A). Adjuvant radiotherapy was performed in 14 patients (Group B); the remaining patients were treated with single (2/13) or multiple agent chemotherapy (11/13) (Group C). The 3-year survival rate was 55% for stage I, 42% for stage II; 10/11 of the stage III/IV patients died within 26 months. The 4-year actuarial survival rate for group B was 68%, for group C 11%. There was no difference between the short-time results of stage II tumours when comparing radiotherapy against chemotherapy. The tumour progression rate was 60%, indicating the need for radical surgery as well as for more aggressive adjuvant treatment. Surgery alone is recommended for stage I disease confined to the mucosa. More advanced disease (extension to the serosa, stage Ic, stage II) requires whole abdominal irradiation with a boost to the pelvic lymph nodes. For stage III/IV tumours a multi-modality treatment is recommended. Chemotherapy (cis-platinum, cyclophosphamide) for recurrent disease resulted in remission in some cases.

Primary fallopian tube carcinoma--a retrospective survey of 51 cases. Austrian Cooperative Study Group for Fallopian Tube Carcinoma.

OBJECTIVE: To evaluate retrospectively the importance of invasion beyond the basement membrane on overall survival in Fallopian tube carcinoma and its influence on the necessity of postoperative adjuvant therapy (stage 0 vs. stage I). DESIGN: In a nationwide analysis the data of 51 patients were evaluated. The participating departments provided the study center with histologic specimens. A re-staging was done according to the FIGO-classification for Fallopian tube carcinomas. Stage 0 patients received no further postoperative therapy, in stage I patients were divided in 2 groups to evaluate the impact of postoperative adjuvant therapy (chemotherapy vs. irradiation). RESULTS: Patients of stage 0 had a significantly better prognosis than patients of stage I (p = 0.035). Stage I patients treated by irradiation showed a significantly better prognosis than patients treated by chemotherapy (p = 0.017). CONCLUSION: Tumour penetration through the basement membrane causes prognosis to deteriorate significantly (5-year survival rate about 50% in stage I). Postoperative therapy is thus indicated with stage I disease. Irradiation seems to give better results than chemotherapy.

Evaluation of adjuvant therapy after surgery for primary carcinoma of the fallopian tube.

OBJECTIVE: To evaluate the impact of postoperative therapy (chemotherapy vs. irradiation) on overall survival. DESIGN: A nationwide retrospective analysis. SETTING: Hanusch-Krankenhaus, Department of Gynaecology, SUBJECTS: 115 patients with histologically proved primary carcinoma of the Fallopian tube: 49 received six treatment cycles of a cis-platinum regimen (group I), 24 patients were treated by full irradiation using 50 Gray minimum (group II). The two groups had a similar distribution of stage I and II; in the more advanced stages chemotherapy was the predominant method of treatment. RESULTS: The five-year survival rate was 53% for women receiving irradiation as against 27% for those given cis-platinum. If the analysis was restricted to those patients with comparable stage I and stage II lesions, the p-value (0.07) was of borderline significance. There was no advantage in adding abdominal to pelvic irradiation (P = 0.62). CONCLUSIONS: Stage I and stage II carcinoma is probably better treated postoperatively by radiotherapy than chemotherapy. Chemotherapy may have more therapeutic potential in patients with more advanced lesions.

[The photon therapy of subfoveal choroidal neovascularization in age-dependent macular degeneration. The results of a prospective study in 40 patients]. / Photonentherapie der subfovealen choroidalen Neovaskularisation bei altersabhängiger Makuladegeneration. Ergebnisse einer prospektiven Studie an 40 Patienten.

AIM: To determine the effect of external beam radiotherapy on subfoveal choroidal neovascularization in age-related macular degeneration. PATIENTS AND METHODS: Between September 1995 and July 1996, 40 patients (9 males and 31 females; mean age 74 years, range 61 to 83 years) were included in a prospective study. Eight patients had classic, well-defined neovascularisations, 32 patients had occult lesions. Complete ophthalmic investigations included visual acuity contrast sensitivity as well as fluorescein and indocyanine green angiographic examinations prior to treatment and 1, 3, 6, and 12 months after radiotherapy. External beam radiotherapy (8-MV photons) was delivered with a total dose of 14.4 Gy in 8 fractions of 1.8 Gy per day (Figures 1 and 2). The field size averaged 5.5 x 4.5 cm. RESULTS: No treatment related morbidity during or after treatment was obtained. After 6 months follow-up the visual acuity was improved in 2 (5%) patients and maintained at pretreatment level in 17 (42%) patients. However, 12 months post treatment a stable situation was found in 6 (15%) patients and a decrease in visual acuity in 34 (85%) patients (Table 1). The central visual fields deteriorated significantly from 16.5 decibel (dB) to 12.4 dB. The enlargement of exudates and neovascular membranes increased 5- to 7-fold. At 12 months after treatment, 3 (7.5%) patients stated that they had improved vision subjectively, 12 (30%) patients had no change and 25 (62.5%) patients suffered from subjective decrease in visual acuity. CONCLUSIONS: Using a total dose of 14.4 Gy/1.8 Gy no difference concerning visual acuity and exudative changes in comparison to the natural history on age-related macular degeneration was obtained after 12 months. However, the results of multicenter studies are to be awaited.

Ocular sequelae of multimodal therapy of hematologic malignancies in children.

We retrospectively analyzed the ocular findings after polychemotherapy including intrathecal methotrexate, systemic corticosteroids, and prophylactic cranial irradiation in children with acute lymphoblastic leukemia (n = 16) and non-Hodgkin's lymphoma (n = 2). After a median surveillance time of 4.1 years, asymptomatic ocular abnormalities were observed in 83% of the patients: 7/18 had a decreased tear formation, 5/17 had an opacity of the vitreous body, and 13/18 had an opacity of the lens. It was not possible to determine retrospectively which therapy caused a particular effect. A comparison of the 2 irradiation techniques (with and without blocking of the lacrimal glands) showed that in 5/7 children who developed a reduced eye secretion, the lacrimal glands are within the treatment volume. Therefore, the reduced eye secretion is most likely radiation-induced. Whereas the opacities of the vitreous body were caused by thrombopenia and bleeding during the course of disease, corticoid therapy might have contributed to the lens opacities.

Follow-up and quality of survival of 67 consecutive children with CNS tumors.

We report the findings at follow-up in 67 consecutive children with central nervous system tumors treated over a 5-year-period at a single institution. The diagnoses were supratentorial astrocytoma (n = 12), cerebellar astrocytoma (n = 10), ependymoma (n = 9), medulloblastoma (n = 9), brain stem glioma (n = 6), optic pathway glioma (n = 5), and others (n = 16). The survival rates were 83% for supratentorial astrocytomas at a median of 46.5 months, 90% for cerebellar astrocytomas and 55% for ependymomas at 40 months, respectively, 55% for medulloblastomas at 22 months, 33% for brain stem gliomas at 23 months, and 80% for optic pathway gliomas at 49 months. With regard to neurological sequelae, 13 patients were treated for epilepsy, 13 patients had mild to moderate neurological deficits, and 4 patients were severely disabled. Seventeen of 37 tested patients performed below average on formal neuropsychometric testing, one-fourth attended special education courses, and at least one-fourth suffered from behavioral and adjustment problems.