The German evidence-based guidelines for Hodgkin's lymphoma. Aspects for radiation oncologists.

This report reviews aspects of the German evidence-based guidelines for Hodgkin's lymphoma relevant to radiation oncologists. Stage-adapted treatment is discussed with the focus on radiotherapy. Up-to-date literature citations provide an overview of current recommendations.

Comparing long-term toxicity and efficacy of combined modality treatment including extended- or involved-field radiotherapy in early-stage Hodgkin's lymphoma.

BACKGROUND: To evaluate long-term toxicity and efficacy of a combined modality strategy including extended-field radiotherapy (EF-RT) or involved-field radiotherapy (IF-RT), the German Hodgkin Study Group carried out a follow-up analysis in patients with early unfavorable Hodgkin's lymphoma (HL). PATIENTS AND METHODS: One thousand two hundred and four patients were randomized to four cycles of chemotherapy followed by either 30 Gy EF- or 30 Gy IF-RT (HD8 trial); 532 patients in each treatment arm were eligible. RESULTS: At 10 years, no arm differences were revealed with respect to freedom from treatment failure (FFTF) (79.8% versus 79.7%), progression-free survival (79.8% versus 80.0%), and overall survival (86.4% versus 87.3%). Non-inferiority of IF-RT was demonstrated for the primary end point FFTF (95% confidence interval for hazard ratio 0.72-1.25). Elderly patients had a poorer outcome when treated with EF-RT. So far, 15.0% of patients in arm A and 12.2% in arm B died, mostly due to secondary malignancies (5.3% versus 3.4%) or HL (3.2% versus 3.4%). After EF-RT, there were more secondary malignancies overall (58 versus 45), especially acute myeloid leukemias (11 versus 4). CONCLUSION: Radiotherapy intensity reduction to IF-RT does not result in poorer long-term outcome but is associated with less acute toxicity and might be associated with less secondary malignancies.

Radiotherapy in elderly patients with inoperable esophageal cancer. Is there a benefit?

BACKGROUND: Radiation oncologists increasingly face elderly cancer patients impaired by comorbidities and reduced performance status. As less data are available for this particular group of patients, the aim of the study was to assess the prognosis of inoperable esophageal cancer patients ≥ 70 years undergoing definitive radiotherapy or radiochemotherapy. PATIENTS AND TREATMENT PROTOCOL: Patients aged ≥ 70 with inoperable carcinoma of the esophagus undergoing definitive radio(chemo)therapy between 1995 and 2006 at the University of Cologne were included retrospectively. Maximal total dose of radiotherapy administered was 63 Gy (5 × 1.8 Gy/week). Chemotherapy consisted of cisplatin (20 mg/m(2) on days 1-5 and days 29-33) and 5-fluorouracil (650-1,000 mg/m(2) on days 1-5 and days 29-33). Efficacy was compared with a cohort of 152 patients < 70 years treated with the same protocol during the same time period. RESULTS: A total of 51 patients aged ≥ 70 with inoperable cancer of the esophagus undergoing definitive therapy were identified (stage I/II 23.5%, stage III 56.9%, stage IV 9.8%; squamous cell carcinoma 74.5%, adenocarcinoma 25.5%). While 15 patients (29.4%) received combined radiochemotherapy (RCT), 40 patients (70.6%) were treated with radiotherapy alone (RT). Median progression-free survival (PFS) was 9.5 months; median overall survival (OS) was 13.9 months. Patients treated with RCT had a 2-year OS rate of 53.3% compared with 16.7% for RT patients (p = 0.039). The 2-year OS for clinically lymph node negative patients was 38.5% compared with 21.2% for lymph node positive patients (p = 0.072). Median OS was not significantly different between patients ≥ 70 years versus the patient cohort (n = 152) aged < 70 years (13.9 vs. 7.2 months, p = 0.072) but PFS showed a significant difference (4.9 vs. 9.5 months, p = 0.026) in favor of the > 70 years group. CONCLUSION: Prognosis in elderly patients with inoperable esophageal cancer undergoing definitive radiotherapy/radiochemotherapy is limited, although it is not inferior to patients < 70 years.

Stereotactic LINAC radiosurgery for the treatment of brainstem cavernomas.

BACKGROUND: The management of deep-seated cerebral cavernous malformations (CCMs) is still controversial. Although surgery remains the treatment of choice in patients with recurrent hemorrhage, patients with CCMs located in the brainstem are in many cases not eligible for resection due to high procedure-related morbidity and mortality. We evaluated the long-term outcome of LINAC radiosurgery (LINAC-RS) for the treatment of brainstem CCMs. PATIENTS AND METHODS: Between December 1992 and March 2008, 14 patients (6 men, 8 women) harboring brainstem CCMs underwent LINAC-RS. Pretreatment neuroimaging showed no associated developmental venous angiomas (DVAs) in any of our patients. Prior to treatment, all patients suffered at least from one symptomatic hemorrhage (median 1.8, range 1­3). A median follow-up of 7.1 years (range 2.0­16.8 years) could be obtained in 12 patients. We applied a median tumor surface dose of 13.9 Gy (range 11­18 Gy; median tumor volume 1.6 ml, range 0.4­4.3 ml). RESULTS: Following LINAC-RS, neurological outcome improved in 4 (33.3%) and remained unchanged in 8 patients (66.7%). Rebleeding with subsequent transient neurological status deterioration occurred in 4 patients (33.3%), leading to additional surgical resection in 2 patients (16.7%). The corresponding annual hemorrhage rate was 4.8% (4/82.8 patient­years). Adverse radiation effects (ARE, defined by perilesional hyperintensity on T2-weighted MR images) were revealed in 3 patients (25%), leading to transient neurological deficits in 2 patients (16.7%). There were no procedure-related complications leading to either permanent morbidity or mortality. CONCLUSION: Our results support the role of LINAC-RS as an efficient and safe treatment to significantly reduce the annual hemorrhage rate in patients suffering from brainstem CCMs not eligible to microsurgery. Compared with radiosurgery for arteriovenous malformations (AVMs), the intervention-related morbidity is higher.

Prognostic factors in definitive radiochemotherapy of advanced inoperable esophageal cancer.

The aim of this study was to assess the efficacy and prognostic factors of definitive radiochemotherapy (RCT) for inoperable esophageal cancer. Between 1995 and 2005 all patients with inoperable esophageal cancer that underwent concurrent RCT were included in this retrospective study. Conventional computed tomography-based treatment planning as well as 3D-conformal radiotherapy (RT) was used. Maximum radiotherapy dose was 63 Gy. Chemotherapy consisted of cisplatin (20 mg/m(2) d1-5 and 29-33) and 5-FU (650-1000 mg/m(2) d1-5 and 29-33). Patients not suitable for RCT received radiotherapy alone. Toxicity was measured according to common toxicity criteria (CTC). Two hundred three consecutive patients with inoperable esophageal cancer that received definitive therapy were identified in this time period (160 with squamous cell carcinoma and 43 with adenocarcinoma). The 2-year overall survival probability was 21.2% whereas the progression-free survival at 2 years was 13.8% for all patients. In the univariate analysis, type of histology, T-stage, N-stage, application of chemotherapy, and the radiation dose were significantly correlated with overall/progression-free survival. Moreover, multivariate analysis revealed an independent prognostic impact for N-stage, radiation dose, and concurrent chemotherapy. Definitive RCT is an important palliative treatment option for patients with inoperable esophageal cancer. N-stage, radiation dose, and concurrent chemotherapy are important prognostic factors for survival.

[Multimodality therapy for lung cancer]. / Multimodale Therapie des Lungenkarzinoms.

The primary treatment of lung cancer depends on tumor stage. In case of lung cancer in clinical stage I to IIb and T3N1 surgical treatment is recommended. The use of adjuvant chemotherapy is indicated in stage II and IIIa. In case of limited N2-disease trimodality therapy with chemo- or radiochemotherapy followed by surgery and eventual adjuvant radiotherapy leads to five year survival rate of about 20-40. Non resectable or extended mediastinal lymph node metastases are an indication for definite combined radiochemotherapy. Secondary resection may be evaluated in experienced centers. If the tumor has infiltrated the mediastinum or the upper sulcus (T3/4) or in case of solitary metastasis an individual trimodal treatment plan has to be elaborated. Also for small cell lung cancer surgery combined with chemotherapy can be applied in stage I and II, else and especially in stage III radiochemotherapy should be applied. Additional prophylactic cranial irradiation is used. The majority of lung cancer patients suffers from metastatic disease. The value of systemic chemotherapy is limited with significant, but small improvement in overall survival. Also treatment with the new molecularly targeted drugs does not result in a breakthrough in unselected patient cohorts. Recently, substantial progress could be achieved by personalized treatment approaches for patients harbouring special genetic alterations.

A phase III trial of topotecan and whole brain radiation therapy for patients with CNS-metastases due to lung cancer.

Brain metastases represent an important cause of morbidity in patients with lung cancer and are associated with a mean survival of less than 6 months. Thus, new regimens improving the outcome of these patients are urgently needed. On the basis of promising data raised in a phase I/II trial, we initiated an open, randomised, prospective, multicentric phase III trial, comparing whole brain radiation therapy (WBRT; 20 x 2 Gy) alone with WBRT+topotecan (RCT; 0.4 mg m(-2) day(-1) x 20). A total of 320 patients with CNS-metastases due to SCLC or NSCLC were projected. The primary end point was overall survival, whereas second end points were local response and progression-free survival. However, until the cutoff date of study completion (i.e., a study duration of 34 months), only a total of 96 (RCT:47, WBRT:49) patients had been recruited, and so an analysis was performed at that time point. Although the numbers of grade 3/4 non-haematological toxicities (besides alopecia 115 (RCT/WBRT: 55 out of 60) were evenly distributed, the 25 haematological events occurred mainly in the combined treatment arm (24 out of 1). Local response, evaluated 2 weeks after treatment, was assessable in 44 (RCT/WBRT: 23 out of 21) patients, showing CR in eight (3 out of 5), PR in 17 (11 out of 6), SD in 14 (8 out of 6) and PD in five (1 out of 4) patients (all differences n.s.). Neither OAS (RCT/WBRT: median (days)): 87 out of 95, range 3-752/4-433; HR 1.32; 95% CI (0.83; 2.10)) nor PFS (median (days)): 71 out of 66, range, 3-399/4-228; HR 1.28, 95% CI (0.73; 2.43) differed significantly. On the basis of these results and the slow recruitment, a continuation of the study did not seem reasonable. The available data show no significant advantage for concurrent radiochemotherapy for patients with lung cancer; however, the recruited number of patients is too low to exhibit a small advantage of combined treatment.

The addition of a boost dose on the primary tumour bed after lumpectomy in breast conserving treatment for breast cancer. A summary of the results of EORTC 22881-10882 "boost versus no boost" trial.

PURPOSE: To investigate the impact of the boost dose to the primary tumour bed in the framework of breast conserving therapy on local control, cosmetic results, fibrosis and overall survival for patients with early stage breast cancer. PATIENTS AND METHODS: Five thousand five hundred and sixty-nine patients after lumpectomy followed by whole breast irradiation of 50 Gy were randomised. After a microscopically complete lumpectomy (5318 patients), the boost doses were either 0 or 16 Gy, while after a microscopically incomplete (251 patients) lumpectomy randomisation was between 10 and 26 Gy. The results at a median follow-up of 10 years are presented. RESULTS: At 10 years, the cumulative incidence of local recurrence was 10.2% versus 6.2% for the 0 Gy and the 16 Gy boost groups (p < 0.0001) and 17.5% versus 10.8% for the 10 and 26 Gy boost groups, respectively (p > 0.1). There was no statistically significant interaction per age group but recurrences tended to occur earlier in younger patients. As younger patients had a higher cumulative risk of local relapse by year 10, the magnitude of the absolute 10-year risk reduction achieved with the boost decreased with increasing age. Development of fibrosis was significantly dependent on the boost dose with a 10-year rate for severe fibrosis of 1.6% after 0 Gy, 3.3% after 10 Gy, 4.4% after 16 Gy and 14.4% after 26 Gy, respectively. CONCLUSION: An increase of the dose with 16 Gy improved local control for patients after a complete lumpectomy only. The development of fibrosis was clearly dose dependent. With 10 years median follow-up, no impact of survival was observed.

[A teleradiotherapeutic network for lymphoma patients within the competence network malignant lymphomas]. / Aufbau eines teleradiotherapeutischen Netzwerks für Lymphompatienten im Rahmen des Kompetenznetzes Maligne Lymphome.

PURPOSE: The aim of the subproject "Radiotherapy" within the competence network malignant lymphoma, funded by the Federal German Ministry of Education and Research (BMBF), was to build-up an electronic imaging transfer between five University departments of Radiation Oncology to improve communication between study centers and reference centers. MATERIALS AND METHODS: We describe our experiences with these modern teleradiotherapeutic possibilities, its feasibility within mutticentric clinical trials. RESULTS: Telemedical functions could successfully be integrated into the existing quality asssurance programs of radiotherapy. Since January 2001 more than 700 patients (trials HD10-HD15 of the German Hodgkin Study Group, GHSG) could be assessed after digital transfer via internet, on mobile data carriers or an ISDN-connection in the radiotherapy reference center Cologne. Transfer of digital imaging between participating study centers and the radiotherapy reference center allows immediate or a short-term evaluation of adequacy of treatment fields by expert radiation oncologists before the start of radiotherapy. This improves dialogue and consensus between radiotherapy reference centers and study centers and thus contributes towards high radiotherapy quality for lymphoma patients. CONCLUSION: The long-term aim is to network all those hospitals, institutions and private facilities taking part in the GHSG trials to achieve an integrated system of cooperation. This improves dialogue and consensus between the radiotherapy reference center and the study centers and thus contributes towards high radiotherapy quality for patients with Hodgkin's lymphoma.

Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin's disease: long-term results of a randomized trial of radiotherapy alone.

PURPOSE: To show that radiotherapy (RT) dose to the noninvolved extended field (EF) can be reduced without loss of efficacy in patients with early-stage Hodgkin's disease (HD). PATIENTS AND METHODS: During 1988 to 1994, pathologically staged patients with stage I or II disease who were without risk factors (large mediastinal mass, extranodal lesions, massive splenic disease, elevated erythrocyte sedimentation rate, or three or more involved areas) were recruited from various centers. All patients received 40 Gy total fractionated dose to the involved field areas but were randomly assigned to receive either 40 Gy (arm A) or 30 Gy (arm B) total fractionated dose for the clinically noninvolved EF. No chemotherapy was given. RT films were prospectively reviewed for protocol violations and recurrences retrospectively related to the applied RT. RESULTS: Of 382 recruited patients, 376 were eligible for randomized comparison, 190 in arm A and 186 in arm B. Complete remission was attained in 98% of patients in each arm. With a median follow-up of 86 months, 7-year relapse-free survival (RFS) rates were 78% (arm A) and 83% (arm B) (P =.093). The upper 95% confidence limit for the possible inferiority of arm B in RFS was 4%. Corresponding overall survival rates were 91% (arm A) and 96% (arm B) (P =.16). The most common causes of death (n = 27) were cardiorespiratory disease/pulmonary embolisms (seven), second malignancy (six), and HD (five). Protocol violation was associated with significantly poorer RFS. Nonirradiated nodes were involved in 42 of 52 reviewed relapses, infield areas in 18, marginal areas in 17, and extranodal sites in 16. CONCLUSION: EF-RT alone attains good survival rates in favorable early-stage HD. The 30-Gy dose is adequate for clinically noninvolved areas. Protocol violation worsens the subsequent prognosis. Relapse patterns suggest that systemic therapy can reduce the 20% long-term relapse rate.

Patient population analysis in EORTC trial 22881/10882 on the role of a booster dose in breast-conserving therapy.

The changing composition of the patient population in breast cancer, which has been reported over the last decade, has important consequences for prognosis. In the present trial, an analysis of the population in an EORTC trial (22881/10882) on breast-conserving therapy was conducted. A shift towards earlier stages has been seen stage per stage, therefore better survival and local control rates are likely to be expected in comparison to previously published series. The majority of tumours in this trial were small, with a median clinical size of 2 cm and a median pathological size of 1.5 cm. A substantial number of lesions were detected in a pre-clinical stage (17.8%). Nodal involvement was present in only 19% of all patients and usually in only a low number of nodes (only 4% of all patients had four or more nodes invaded). The median number of nodes examined was 12, the difference between institutions was large. There was a significant correlation between the number of nodes examined, the percentage of patients with positive nodes (P = 0.03) and the percentage of patients with massive axillary invasion (P = 0.003). The correlation between clinical evidence and pathological invasion of the axillary nodes showed that 15% of the clinical examinations were false-negative and 51% were false-positive. Pathological nodal invasion could be clinically predicted in only 31% of patients, and consequently clinical examination of the axilla was a poor predictor of prognosis in this study. Pathological invasion of axillary lymph nodes was better correlated to pathological tumour size than clinical or radiological size.

Carboplatin plus radiation therapy in head and neck cancer.

To determine toxicity and response, escalating dose levels of carboplatin were given simultaneously with accelerated radiation to 36 previously untreated patients with unresectable squamous cell carcinomas of the head and neck (SCCHN) (2 with stage III and 34 with stage IV disease). Twenty-three patients received a total radiation dose of 58.8 Gy with two daily fractions of 2.1 Gy on days 1 through 4 in weeks 1, 2, and 5 and on two additional days in week 6. Simultaneous carboplatin was given intravenously at escalating dose levels: 20 mg/m2 in 3 patients, 30 mg/m2 in 5 patients, 40 mg/m2 in 5 patients, 50 mg/m2 in 6 patients, and 60 mg/m2 in 4 patients. Another 13 patients were treated with an escalated radiation dose of 67.2 Gy, which resulted in 2 more days of radiochemotherapy in week 6. Six patients in this group received 60 mg/m2/d and 7 received 50 mg/m2/d carboplatin. All patients were evaluable for toxicity according to World Health Organization (WHO) criteria and 35 of 36 patients were evaluable for response. Dose-limiting toxicity was myelosuppression with WHO grades 3 and 4 leukopenia in 5 of 6 patients treated with 60 mg/m2 carboplatin and 67.2 Gy. With radiochemotherapy doses of 67.2 Gy and 50 mg/m2, no grade 4 myelosuppression occurred and toxicity was generally tolerable. Independent of the carboplatin dose, mucositis grade 3 or 4 was seen in 12 patients. No other toxicities above WHO grade 2 occurred, except in 2 patients with grade 3 nausea and vomiting. There were 19 complete responses (53%) and 16 partial responses (44%). Our preliminary data suggest that 50 mg/m2 carboplatin together with a total radiation dose of 67.2 Gy might be the best combination for advanced, unresectable SCCHN.

Phase I/II study of simultaneous carboplatin and radiotherapy in unresectable squamous cell carcinoma of the head and neck.

Escalating dose levels of carboplatin together with simultaneous accelerated radiation were administered to 36 previously untreated patients with unresectable carcinomas of the head and neck (two stage III and 34 stage IV disease). Twenty-three patients received a total radiation dose of 58.8 Gy with two daily fractions of 2.1 Gy on days 1 to 4 in weeks 1, 2, and 5 and on another 2 days in week 6. Simultaneous carboplatin was given intravenously in escalating dose levels: 20 mg/m2 in three patients, 30 mg/m2 in five patients, 40 mg/m2 in five patients, 50 mg/m2 in six patients, and 60 mg/m2 in four patients. Another 13 patients were treated with an escalated radiation dose of 67.2 Gy, which led to 2 additional days of chemoradiotherapy in week 6. Six patients in this group received carboplatin 60 mg/m2/d, and seven received 50 mg/m2/d. All patients were evaluable for toxicity according to World Health Organization (WHO) criteria, and 35 of 36 patients were evaluable for response. Dose-limiting toxicity was myelosuppression, with WHO grades 3 and 4 leukopenia in five of six patients treated with carboplatin 60 mg/m2 and 67.2 Gy radiation. In patients treated with carboplatin 50 mg/m2 and 67.2 Gy radiation, no grade 4 myelosuppression developed and toxicity was generally tolerable. Independent of the carboplatin dose, grade 3 or 4 mucositis was seen in 12 patients. No other toxicities above grade 2 occurred. There were 19 complete responses (53%) and 16 partial responses (44%). Comparing these results with our earlier data with sequential chemoradiotherapy (carboplatin/5-fluorouracil followed by conventional radiotherapy) indicated that the higher tumor-clearing rate of simultaneous chemoradiotherapy produced significantly better rates of survival and disease-free response.

Results of high dose 106-ruthenium irradiation of choroidal melanomas.

The favored treatment of intraocular melanomas in Germany is 106-ruthenium eye plaque therapy. The Departments of Radiation Therapy and Ophthalmology (University of Münster) initiated a clinical study in 1981 to reveal the effect of high-dose beta irradiation (15.000 cGy to the apex of the tumor) regarding tumor regression, treatment related side effects, visual acuity, and survival. Sixty-seven patients have been treated since 1981. In 12 patients a second course of irradiation has been performed because of insufficient tumor regression or no change after the first plaque treatment. Sixty-five percent (44/67 pts.) were over 60 years of age. Twenty-four patients had a small tumor (up to 3 mm in height), 20 patients had a medium sized tumor (3.1-5 mm in height), and 22 patients had a large tumor (more than 5.1 mm in height). Fifty-one patients had a follow-up of at least 12 months. A total tumor regression was achieved in 34/51 patients (67%), partial tumor regression occurred in 13/51 patients (25%), and in 4/51 patients (8%) there was no change after the first course. After the second course of 106-ruthenium-irradiation 5 of the 12 patients showed total tumor regression, 3 had partial regression, and in 4 patients only an increase of the tumor echogenity could be assessed by ultrasonography, but no change in height. Visual acuity, which depends mostly on the localization of the tumor, was preserved at pretreatment levels in 72% of the patients. Two patients died with documented metastatic disease, one patient died of myocardial infarction. There was only one enucleation because of neovascular glaucoma.

Pretherapeutic flow cytometric DNA investigations in radiotherapy patients with maxillo-facial carcinomas.

In order to analyze the possible meaning of cellular DNA content and cell cycle phases for the radiosensitivity and the prognosis of human malignant tumors, flow cytometric measurements have been performed in biopsies of 131 patients with histologically proven squamous cell carcinomas of the maxillo-facial region. In two-thirds of the patients (88/131; 67%), aneuploid tumor cell lines have been found, only 33% (43/131) had a diploid DNA distribution pattern. The average DNA index (DI) of the aneuploid carcinomas was 3.4 +/- 0.6 (normal nonmalignant tissue DI = 2.0). The frequency of S-phase cells, which represents the "proliferative activity", was between 4.8 and 63.2%, regardless of the ploidy stages. The aneuploid carcinomas had about twice as many S-phase cells (mean 23.7 +/- 11.8%) than diploid tumors (mean 12.7 +/- 4.8%). Mean survival for patients with diploid carcinoma and aneuploid carcinoma was 12 and 9.5 months, respectively. Concerning the relationship of S-phase frequency and survival times in our material there was a high negative statistical correlation (Spearman-Rank test) in patients with diploid carcinomas. A high S-phase fraction resulted in short survival times. No correlation was found in the aneuploid carcinomas: patients with tumors in high S-phase values in their biopsies showed no difference in prognosis in comparison to tumors with lower S-phase fractions.

Risk analysis of linear accelerator radiosurgery.

PURPOSE: To evaluate the toxicity of stereotactic single-dose irradiation and to compare the own results with already existing risk prediction models. METHODS AND MATERIALS: Computed tomography (CT) or magnetic-resonance (MR) images, and clinical data of 133 consecutive patients treated with linear accelerator radiosurgery were analyzed retrospectively. Using the Cox proportional hazards model the relevance of treatment parameters and dose-volume relationships on the occurrence of radiation-induced tissue changes (edema, localized blood-brain barrier breakdown) were assessed. RESULTS: Sixty-two intraparenchymal lesions (arteriovenous malformation (AVM): 56 patients, meningioma: 6 patients) and 73 skull base tumors were selected for analysis. The median follow-up was 28.1 months (range: 9.0-58.9 months). Radiation-induced tissue changes (32 out of 135, 23.7%) were documented on CT or MR images 3.6-58.7 months after radiosurgery (median time: 17.8 months). The actuarial risk at 2 years for the development of neuroradiological changes was 25.8% for all evaluated patients, 38.4% for intraparenchymal lesions, and 14.6% for skull base tumors. The coefficient: total volume recieving a minimum dose of 10 Gy (VTREAT10) reached statistical significance in a Cox proportional hazards model calculated for all patients, intraparenchymal lesions, and AVMs. In skull base tumors, the volume of normal brain tissue covered by the 10 Gy isodose line (VBRAIN10) was the only significant variable. CONCLUSIONS: These results demonstrate the particular vulnerability of normal brain tissue to single dose irradiation. Optimal conformation of the therapeutic isodose line to the 3D configuration of the target volume may help to reduce side effects.

Radiotherapy for treatment of localized gastrointestinal non-Hodgkin's lymphoma.

BACKGROUND: The study analyses a standardized, risk-adapted radiotherapy for stage IE-IIE primary extranodal lymphoma of the stomach and bowel. METHODS: Sixty eight patients (31 females, 37 males, median age 56 years) were treated from 1987-1992 in 15 centers. Fifty six patients had gastric and 12 patients had bowel lymphomas. Gastric lymphomas (low or intermediate grade stage I-II: 38 patients/high grade stage I: 18 patients) were treated by whole abdominal irradiation (25/30 Gy), booster dose to involved field (30/40 Gy) and additional boost to macroscopic residual lymphoma (40/50 Gy). Surgery consisted of gastrectomy (19 patients), partial gastric resection (30) or biopsy (7). In 8/18 stage II patients, supradiaphragmal irradiation was added. In 10/12 patients with bowel lymphoma, segment resection was performed, two received biopsy only. Radiation doses equalled those used for gastric lymphoma: RESULTS: In 51/56 patients (91%) with gastric lymphoma, the recommended dose for whole abdominal irradiation was given. A total of 40/56 patients (71%) received the required dose to the upper abdominal region, in 22/56 patients (39%) a booster dose for residual disease was applied. Five-year overall survival was 87%, 5-year disease-free survival 84%. Of nine relapses, two were in the gastric stump of low grade patients after reinfection with Helicobacter pylori. Three infield, intraabdominal relapses were observed in intermediate and high grade lymphoma, all other relapses were outfield. Eleven patients experienced late toxicity (bowel obstruction after laparatomy and irradiation, four patients; chronic gastritis, three patients; asymptomatic left kidney atrophy, two patients; asymptomatic hepathopathia, two patients). In bowel lymphoma, 5-year disease-free survival was 65%. CONCLUSION: This study demonstrates the high efficacy of risk-adapted radiotherapy in gastric lymphoma. In low grade gastric lymphoma, whole abdominal irradiation may be reduced in dose or omitted. Total gastrectomy does not improve results and should therefore be avoided if possible.

Computer simulation of cytotoxic and vascular effects of radiosurgery in solid and necrotic brain metastases.

PURPOSE: Solid and necrotic brain tumors respond to radiosurgery, although necrotic lesions often contain a significant proportion of hypoxic cells which cannot become reoxygenated during the short overall treatment time of single dose application. In addition to the direct cytotoxic action, delayed vascular occlusion followed by ischemic tumor cell death could contribute to the effect of radiosurgery. MATERIALS AND METHODS: In order to determine the impact of the two possible effects on tumor response, a 3-dimensional computer simulation was developed and fitted to response data obtained from 90 patients who were treated by LINAC radiosurgery for 1-3 brain metastases with median marginal doses of 20 Gy. Complete response rates were as follows: small, solid lesions (diameter 0.4-1 cm), 52% (12/23); large solid lesions (1.1-5.2 cm), 28% (17/60); large necrotic lesions, 12% (6/50). The 3-dimensional computer model simulated the growth of small solid and large, solid or necrotic tumors situated in a vascularized stroma. Oxygen supply, tumor cell division (cell cycle time 5 days), neovascularization, tumor cell kill by single dose irradiation (linear-quadratic model, alpha/beta=10 Gy, oxygen enhancement ratio 3.0) and time-dependent vascular occlusion (alpha/beta=3 Gy) were modeled by Monte-Carlo simulation techniques. RESULTS: In the presence of neovascularization, solid tumors with a hypoxic fraction of 1-2% developed. Without neoangiogenesis, central necrosis occurred, and tumors had a hypoxic fraction of 20-25%. Assuming a pure cytotoxic effect of radiosurgery, neither the dose-response relationship for the solid lesions of different size nor that for the large lesions with solid or necrotic appearance could be reproduced for any given level of radiosensitivity. This was only possible by introducing a vascular effect that led to the occlusion of >/=99% of the vessels at the border of the target volume within 1 year after irradiation. In the presence of the vascular effect, the apparent radiosensitivity of the tumor cells was increased by 50-100%. Calculations of the dose-equivalent for the vascular effect show that it contributes 19-33% of the overall effect of single dose radiosurgery. CONCLUSION: This simulation study suggests that the therapeutic effect of single radiosurgery in malignant brain tumors cannot be understood without the consideration of vascular effects. The computer model might serve as a basis for exploring new treatment modalities that modify both cytotoxic and vascular effects of radiosurgery.

Emergency stenting of malignant obstruction of the upper airways: long-term follow-up with two types of silicone prostheses.

OBJECTIVE: We evaluated the long-term prognosis of stents placed on an emergency basis in the trachea and its bifurcation for malignant stenosis. METHODS: We retrospectively analyzed all bronchologic treatments of obstructing airway lesions from January 1993 to December 1995. RESULTS: We report on 10 patients with severe malignant "mixed-type" obstruction of the proximal trachea or distal trachea plus both main-stem bronchi. They had far-advanced inoperable tumor (esophageal cancer: n = 4; lung cancer: n = 3; recurrent laryngeal, uvula, and thyroid cancer: n = 1 each). Emergency treatment consisted of a dilating bougie maneuver followed by the insertion of a large one-way (n = 4) or Y-shaped silicone prosthesis (n = 6). After the intervention, there was a long-lasting clinical improvement. Median survival from stent insertion was 8 months for all patients irrespective of tumor type; it was 5 months for patients with lung carcinoma and 8 months for those with esophageal cancer. The results are in accordance with other studies using different therapeutic modalities. Stent exchange was necessary in five patients. Main reasons were continuing tumor growth beyond the proximal and distal boundaries and recurrent productive bronchial infection. Patients died of pneumonia (n = 4), pulmonary lymphatic spread (n = 1), cardiac failure (n = 2), and fatal hemorrhage (n = 1). As of December 1995, three patients were still alive 2, 5, and 8 months after implantation. CONCLUSIONS: As evidenced by clinical efficiency and length of palliation, endoscopic placement of silicone-based one-way and bifurcational prostheses in far-advanced tumor of the central airways is technically feasible and ethically justifiable.