Quality control of involved field radiotherapy in the HD 13 and HD 14 trials : Report of the radiotherapy panel of the German Hodgkin Study Group (GHSG).

INTRODUCTION: As part of the foundation of the German Hodgkin Study Group (GHSG) in 1978, a central radiotherapy (RT) reference centre was established to evaluate and to improve the quality of treatment. During the study generations, the quality assurance programs (QAP) were continued and adapted to the demands of each study. The purpose of this article is to demonstrate the results of the fifth study generation and to compare them to the previous findings. METHODS: With the start of the fourth GHSG study generation (HD10-12), a central prospective review of all diagnostic images was established to create an individual treatment plan for each early stage study patient. The quality of involved field RT was retrospectively evaluated by an expert panel of radiation oncologists. In the fifth study generation (HD13-15), the retrospective review of radiotherapy performed was refined and the results were compared with the findings of the fourth generation. RESULTS: The expert panel analyzed the RT planning and application of 1037 (28 %) patients (HD13 n = 465, HD14 n = 572). Simulation films were available in 85 % of cases and verification films in 87 %. RT was assessed as major violation in 46 % (HD13 = 38 %, HD14 = 52 %), minor violation in 9 % (HD13 = 9 %, HD14 = 9 %) and according to the protocol in 45 % (HD13 = 52 %, HD14 = 38 %). CONCLUSION: The value for QAP of RT within the GHSG trials is well known. Still there were several protocol violations. In the future, the QAP program has to be adapted to the requirements of "modern RT" in malignant lymphoma.

Nasotracheal intubation with three indirect laryngoscopes assisted by standard or modified Magill forceps.

We assessed the effect of modifying standard Magill forceps on the laryngeal introduction of an Eschmann stylet during nasotracheal intubations with three indirect laryngoscopes (Airtraq™, C-MAC(®) or GlideScope(®)) in patients with predicted difficult intubation. We allocated 50 participants to each laryngoscope. The stylet was advanced by one forceps followed by the other (standard or modified), with each sequence allocated to 25/50 for each laryngoscope. There were no differences in rates of failed tracheal intubation with the allocated laryngoscopes: 6/50, 5/50 and 5/50, respectively. An Eschmann stylet was advanced into the trachea less often with the standard forceps (65% vs 93%, p < 0.0001). Mean (SD) time for stylet advancement was longer with the standard forceps, 38 (30) vs 19 (19) s, p < 0.0001. In conclusion, the modified Magill forceps facilitated nasotracheal intubation, independent of the type of indirect laryngoscope.

[Organ preservation in advanced laryngeal and hypopharyngeal carcinoma by primary radiochemotherapy. Results of a multicenter phase II study]. / Organerhalt beim fortgeschrittenen Larynx- bzw. Hypopharynxkarzinom durch primäre Radiochemotherapie. Ergebnisse einer multizentrischen Phase-II-Studie.

INTRODUCTION: Regarding the promising results of international trials we conducted the first German prospective multicentre phase II trial for organ preservation with primary simultaneous chemoradiation in advanced laryngeal and hypopharyngeal cancer. PATIENTS AND METHODS: 28 of 30 recruited patients suffering from stage II and III (UICC) laryngeal and hypopharyngeal cancer were treated with primary simultaneous chemoradiation within an organ preservation program and monitored in follow-up of one year. Exclusion criteria included tumor infiltration of the laryngeal cartilage, bilateral neck nodes (N2c) and need for flap reconstruction in case of laryngectomy. The protocol included an accelerated concomitant boost chemoradiation (66 Gy) with Carboplatinum (70 mg/m2 1st and 5th week) and a restaging procedure one month after therapy. In case of residual disease, salvage laryngectomy and/or neck dissection were performed. RESULTS: After follow-up of one year 20 of 28 patients (71%) were presented with stable complete remission and functionally preserved larynx. Of these 20 patients 3 developed pulmonary metastases, 1 secondary primary carcinoma of the lung and 3 neck metastases which needed neck dissections. The other patients showed in 4 cases relapsing tumor which was indicated for laryngectomy. One patient needed tracheotomy because of persisting edema and 2 patients died due to tumor progress. One patient died after complications due to salvage surgery. CONCLUSION: The organ preservation protocol was feasible with well tolerated early toxicity. Problems of screening for recurrent disease, salvage surgery and late toxicity should be noted and pronounced in patient information. Further studies should focus on the improvement of patient selection which could be realized by induction Chemotherapy (using new components like taxan) and/or use of prediction factors such as tumor volume and hemoglobin levels.

Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer.

PURPOSE: To demonstrate the efficacy of radiochemotherapy (RCT) as the first choice of treatment for advanced unresectable head-and-neck cancer. To prove an expected benefit of simultaneously given chemotherapy, a two-arm randomized study with hyperfractionated accelerated radiochemotherapy (HF-ACC-RCT) vs. hyperfractionated accelerated radiotherapy (HF-ACC-RT) was initiated. The primary endpoint was 1-year survival with local control (SLC). METHODS AND MATERIALS: Patients with Stage III and IV (UICC) unresectable oro- and hypopharyngeal carcinomas were randomized for HF-ACC-RCT with 2 cycles of 5-FU (600 mg/m(2)/day)/carboplatinum (70 mg/m(2)) on days 1--5 and 29--33 (arm A) or HF-ACC-RT alone (arm B). In both arms, there was a second randomization for testing the effect of prophylactically given G-CSF (263 microg, days 15--19) on mucosal toxicity. Total RT dose in both arms was 69.9 Gy in 38 days, with a concomitant boost regimen (weeks 1--3: 1.8 Gy/day, weeks 4 and 5: b.i.d. RT with 1.8 Gy/1.5 Gy). Between July 1995 and May 1999, 263 patients were randomized (median age 56 years; 96% Stage IV tumors, 4% Stage III tumors). RESULTS: This analysis is based on 240 patients: 113 patients with RCT and 127 patients with RT, qualified for protocol and starting treatment. There were 178 oropharyngeal and 62 hypopharyngeal carcinomas. Treatment was tolerable in both arms, with a higher mucosal toxicity after RCT. Restaging showed comparable nonsignificant different CR + PR rates of 92.4% after RCT and 87.9% after RT (p = 0.29). After a median observed time of 22.3 months, l- and 2-year local-regional control (LRC) rates were 69% and 51% after RCT and 58% and 45% after RT (p = 0.14). There was a significantly better 1-year SLC after RCT (58%) compared with RT (44%, p = 0.05). Patients with oropharyngeal carcinomas showed significantly better SLC after RCT (60%) vs. RT (40%, p = 0.01); the smaller group of hypopharyngeal carcinomas had no statistical benefit of RCT (p = 0.84). For both tumor locations, prophylactically given G-CSF was a poor prognostic factor (Cox regression), and resulted in reduced LRC (log-rank test: +/- G-CSF, p = 0.0072). CONCLUSION: With accelerated radiotherapy, the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to standard fractionated RT. Oropharyngeal carcinomas showed better LRC after HF-ACC-RCT vs. HF-ACC-RT; hypopharyngeal carcinomas did not. Prophylactic G-CSF resulted in an unexpected reduced local control and should be given in radiotherapy regimen only with strong hematologic indication.

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.

Surgical treatment for hypopharynx carcinoma: feasibility, mortality, and results.

This study seeks to evaluate treatment modalities, mortality after surgery, survival, and local control rates for a consecutive cohort of patients with cancer of the hypopharynx treated according to a prospective protocol that favors surgery as an initial approach to the disease. The charts of 228 consecutive patients with previously untreated hypopharyngeal squamous cell carcinoma were reviewed. Outcome measures (overall survival, disease specific survival, and local control) were calculated using the Kaplan-Meier estimator. Of 228 consecutive patients, 136 (59.6%) were found suitable for initial surgical treatment. Of the remaining 92 patients, 18 (7.9%) had nonresectable lymph node metastases, 16 (7.0%) had unresectable primary tumors, 13 (5.7%) refused surgery, and 13 (5.7%) presented distant metastases during initial diagnostic evaluation. Of those who had surgery, 46 had larynx-sparing procedures, 54 had total laryngectomy, and 36 had total laryngo-pharyngectomy. None of the patients who had surgery died postoperatively. Actuarial 5-year overall survival was 27.2% for all 228 patients, 39.5% for the 136 patients with surgical treatment, and 61.1% for the 46 patients who were treated with larynx-sparing procedures.

Radiotherapy of esthesioneuroblastoma.

PURPOSE: Only 3% of all malignant intranasal tumors are esthesioneuroblastomas (ENB). As the tumor is very rare, the number of ENB treated in individual departments is small. In order to evaluate the efficacy of radiotherapy (RT), patients' data of 2 centres were analysed with reference to new reports in literature. METHODS AND MATERIALS: From 1981 to 1998, 17 patients with ENB, 8 men and 9 women aged between 6 and 81 years, were treated in the departments of radiotherapy of the universities of Cologne and Muenster. The tumors were Kadish Stage B in 4/17 patients and Stage C in 13/17 patients. Treatment included incomplete surgery and irradiation in 2/17 patients, adjuvant RT postoperatively in 6/17 patients, definitive RT in 7/17 patients and RT after incomplete surgery of recurrent tumors in 2/17 patients. Postoperatively, the median target dose of EBRT was 56 (range 50-60) Gy; for definitive RT it was 58 (range 40-70) Gy. RESULTS: After a median follow-up period of 86 (range 2-208) months 10/17 patients showed no evidence of disease (NED). There were 6 patients treated with radical complete surgery plus postoperative irradiation and 5 of them were NED. There were 7 patients treated with only irradiation and 3 of those patients were NED. Of 2 patients with incomplete surgery and irradiation there was one patient NED. Of 2 patients with incomplete resection of recurrent tumor who received irradiation, there was one patient NED. 2 of the patients with NED died after 22 and 94 months respectively. 4/17 patients died as a result of local recurrence and 2/17 patients as a result of distant metastases (liver, brain). One patient with a recurrent tumor is alive. Median survival of all 17 patients was 94 months. Progressive disease after definitive RT occurred after a median of 11 months. CONCLUSION: Esthesioneuroblastomas are radiocurable tumors. In correlation to literature a primarily complete tumor resection followed by adjuvant RT (50-60 Gy) offers the best disease free survival.

[Prognostic value of hemoglobin level for primary radiochemotherapy of head-neck carcinomas]. / Prognostischer Stellenwert des Hämoglobinwertes vor primärer Radiochemotherapie von Kopf-Hals-Karzinomen.

The pretherapeutic hemoglobin level (Hb) has been postulated to constitute a prognostic marker for outcome after primary chemoradiation of patients with advanced cancer of the head and neck. However, this hypothesis has not been tested systematically in large study samples. In the years 1992-1997, 125 patients with advanced head and neck cancer (stages III/IV UICC) were treated with primary chemoradiation in two different prospective multicentric trials, 62 patients in trial A (phase II, 1992-1995), and 63 in trial B (phase III, 1995-1997). Beside initial Hb, other pretherapeutic parameters with potential prognostic relevance were assessed and correlated with clinical outcome after 43-months follow-up: total tumor volume (TTV; calculated in initial CT scans), tumor oxygenation (polarographic measurements with Eppendorf histography), TNM, tumor localization, age, and performance status. The evaluation of the clinical end points (progression-free and overall survival and local tumor control) revealed that Hb and TTV were independent parameters with strong predictive character of outcome after primary chemoradiation in both trials (n = 125). Bivariate analysis showed < median (13.5 g/dl) a hazard ratio of 2.1 (P = 0.002) for Hb; and > median (98 ml) a Hazard ratio of 2.0 (P = 0.006) for TTV. Severe anemia (Hb < 10 g/dl) was an adverse factor in three patients. Hypoxia was associated with poorer initial therapeutical response but was not predictive of clinical outcome. Furthermore, tumor oxygenation showed no correlation with Hb. The other parameters examined failed to show prognostic significance. Our results indicate a high prognostic value of initial Hb for outcome after primary chemoradiation in advanced head and neck cancer and imply a therapeutic benefit of Hb substitution or erythropoietin administration. We propose to test this in randomized clinical trials.

External beam radiotherapy for subretinal neovascularization in age-related macular degeneration: is this treatment efficient?

PURPOSE: Control of the natural course of subretinal neovascularization (SRNV) in age-related macular degeneration (AMD) is difficult. Only a subset of patients is suitable for laser coagulation. This prospective study aimed to determine the efficacy and individual benefit of external beam radiotherapy (EBRT). METHODS AND MATERIALS: The prospective trial included 287 patients with subfoveal neovascularization due to AMD which was verified by fluorescein angiography. Patients have been treated between January 1996 and October 1997. All patients received a total dose of 16 Gy in 2-Gy daily fractions with 5-6 MeV photons based on computerized treatment planning in individual head mask fixation. This first analysis is based on 73 patients (50 women, 23 men, median age 74.3 years), with a median follow-up of 13.3 months and a minimum follow-up of 11 months. RESULTS: All patients completed therapy and tolerability was good. First clinical control with second angiography was performed 6 weeks after irradiation, then in 3-month intervals. Eighteen patients with SRNV refusing radiotherapy served as a control group and were matched with 18 irradiated patients. After 7 months median visual acuity (VA) was 20/160 for the irradiated and 20/400 for the untreated patients. One year after radiotherapy final median VA was 20/400 in both groups. CONCLUSION: These results suggest that 16 Gy of conventionally fractionated external beam irradiation slows down the visual loss in exudative AMD for only a few months. Patients' reading vision could not be saved for a long-term run.

External beam radiation in patients suffering from exudative age-related macular degeneration. A matched-pairs study and 1-year clinical follow-up.

BACKGROUND: The aim of this prospective study was to ascertain whether external beam irradiation is effective in patients with subretinal neovascularization (SRN) due to age-related macular degeneration (AMD). METHODS: All patients had subfoveal SRN due to AMD as verified by fluoresceinangiography. Two hundred and eighty-seven patient-eyes were treated by external beam irradiation (total dose of 16 Gy in 2-Gy fractions, 5 times a week) from January 1996. The analysis was restricted to those 73 patients with a minimum follow-up of 11 months. Eighteen patients with subfoveal SRN who refused treatment served as control group (CG). 18 patients of the treatment group (TG) were matched for visual acuity, refraction and extent of SRN. The statistical analysis was performed with the unpaired t-test. RESULTS: The mean age of the CG was 73.9 years (range 66.9-81.3 years) and of the TG 75.6 years (range: 65.7-80.6 years). The median follow-up was 13.5 months (range 11.9-18.4 months) in the CG and 12.9 months (range 11-13.9 months) in the TG. The initial visual acuity (VA) was 20/80 in both groups. After 7 months the follow-up revealed median VA of 20/400 in the CG and 20/160 in the TG (P=0.0335). The final median VA was 20/400 in both groups, with a range from 20/40 to 20/1000 in the CG and from 20/63 to 20/500 in the TG (P=0.2433). The SRN doubled in size during this time in both groups. CONCLUSION: These results suggest that external beam irradiation applied in 2-Gy fractions 5 times a week slows down the visual loss in exudative AMD for a short time. Nevertheless, the patients' reading vision could not be saved in the long term.

Radiation-induced hyposalivation and its treatment with oral pilocarpine.

OBJECTIVE: The aim of this study was to determine the effects of radiation on the secretion of saliva from mucous salivary glands in comparison with serous salivary glands. STUDY DESIGN: The minor salivary glands of the palate were used as an example of mucous glands, while the parotid glands were used as an example of a serous secretion organ. Serial flow rate measurements of the parotid and palatal glands were taken over a period of approximately 9 months in 13 patients who suffered from malignancies of the head and neck region. Twelve patients consented to take part in a second study in which salivary flow was stimulated by oral pilocarpine before and at the conclusion of radiotherapy and 7 months later. Complaints and symptoms were recorded at each time of measurement. RESULTS: After radiotherapy, the secretory performance of the parotid glands dropped off rapidly and irreversibly. Salivary secretion from the palatal glands was not totally diminished as a result of radiation. Clinical complaints and histologic findings indicate a serious alteration of the tissues irradiated; however, residual secretion from the remaining parenchyma of the mucous glands still remains. Pilocarpine produced a clinically significant increase of salivary flow from the palatal glands before and 7 months after radiation. Secretory performance of the parotid glands could not be sufficiently increased by stimulation with pilocarpine after radiotherapy. Clinical side effects and risks for the treatment of symptomatic postradiation xerostomia with pilocarpine were minimal. CONCLUSIONS: These findings emphasize the greater resistance and recoverability of the mucous secreting minor palatal glands in comparison with the serous secreting parotid glands. They also indicate the significant postradiation ability of the mucous secreting glands to be stimulated by pilocarpine.

Linear accelerator radiosurgery for recurrent malignant tumors of the skull base.

The efficacy of linear accelerator-based radiosurgery for patients who have preirradiated recurrent nasopharyngeal carcinomas and unresectable recurrent sarcomas invading the base of skull was assessed. Thirteen patients were treated: 8 patients had carcinomas arising from the nasopharynx (lymphoepithelioma, 4; squamous cell carcinoma, 2; adenoid-cystic, 2); 5 patients had sarcomas (rhabdomyosarcoma, 1; chordoma, 1; chondrosarcoma, 1; hemangiopericytoma, 2). All patients had had repeated tumor resections or irradiation, hindering any further conventional fractionated radiotherapy or surgery. Convergent-beam irradiation was performed with a modified linear accelerator (8-MeV photons). Because of irregular tumor configuration, multiple (up to seven) isocenters had to be used in 10 of 13 patients to match the target volume with the reference isodose (60%-80%). Each isocenter was irradiated with 6 to 10 arcs. The median planning target volume was 33 mL (4-128 mL) and the median dose was 15 Gy (9-24 Gy). Median survival time was 9 months in 8 patients who had recurrent nasopharyngeal carcinomas. Three patients who had complete or partial tumor remission survived 1.5 to 3.5 years. All of the sarcoma patients responded to radiosurgery. After a follow-up of 28 to 67 months, 4 of 5 patients are alive. This investigation demonstrates that radiosurgery is an effective tool in palliative treatment for patients who have recurrent, extensively pretreated nasopharyngeal cancer. Patients who have recurrent sarcomas of the base of skull may be treated for long-term palliation or even for cure.

Risk analysis of LINAC radiosurgery in patients with arteriovenous malformation (AVM).

The purposes of this analysis were the evaluation of the toxicity of stereotactic single dose irradiation in patients with an arteriovenous malformation (AVM) and the comparison of the authors' own results with already existing risk prediction models. Computed-tomography (CT) or magnetic-resonance (MR) images, and clinical data of patients treated with linear accelerator radiosurgery for an AVM were analysed retrospectively. Using the Cox proportional hazards model (1), the relevance of treatment parameters and dose-volume relationships to the occurrence of radiation-induced tissue changes (oedema and localised blood-brain-barrier breakdown) were assessed. The 81 patients selected for analysis had a mean follow-up of 28.9 months (range: 9.0-65.7 months). Radiation-induced tissue changes (22 out of 81 i.e. 27.2%) were documented on CT or MR images 6.3-33.8 months after radiosurgery (median time: 12.8 months). The actuarial risk at 2 years was 32.1% for the development of neuroradiological changes and 20.1% for the development of symptomatic tissue alteration. The coefficient of total volume receiving a minimum dose of 10 Gy (VTREAT10) reached statistical significance in a Cox proportional hazards model. 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.

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.

[Percutaneous and intraluminal radiotherapy and radiochemotherapy in esophageal carcinoma]. / Perkutane und intraluminale Strahlentherapie sowie Radiochemotherapie des Osophaguskarzinoms.

Next to standard external beam radiation therapy, combined treatment schedules of percutaneous and endoluminal radiotherapy as well as simultaneous radiochemotherapy became important over the past ten years, especially for primarily inoperable, advanced carcinomas of the esophagus. Analyzing representative treatment protocols, the following conclusions are evident: the combination of external high-voltage therapy and endoluminal brachytherapy using high-dose afterloading techniques leads to intensified biologically effective tumor doses with increasing tumor control. The simultaneous application for radio- and chemotherapy with 5-fluorouracil, cisplatinum or mitomycin results in a longer median survival compared to irradiation alone, and it is comparable to results in historical controls with radical esophagectomy. Up to now, no reduction of distant metastases was seen after simultaneous radiochemotherapy regimen alone. There is some evidence, that intensified chemotherapy before or after radiochemotherapy might result in improved survival rates and decreased distant metastases.