Roland Guttenberger

Impact of spinal cord repair kinetics on the practice of altered fractionation schedules.

The kinetics of repair of sublethal lesions in the spinal cord was assessed in detail using a rodent model. Experiments were designed to obtain the fractionation sensitivity, alpha/beta, and to quantify the kinetics of repair after a clinically relevant fraction size. Pairs of 2-Gy fractions at intervals ranging from 0 to 24 h were given from Monday through Friday, to cumulative doses of 40-84 Gy. In addition, two groups of animals received 1.5 or 1.2 Gy twice a day at 8-h intervals, 5 days a week, to total doses of 66-90 Gy and 67.2-98.4 Gy, respectively. All irradiations were followed by a top-up dose of 16 Gy. Analysis of the experimental data revealed that a bi-exponential repair model fit the experimental data significantly better than did the mono-exponential model (p = 0.002). The repair half times obtained were 0.7 (0.2-1.3) h and 3.8 (2.6-4.9) h, respectively. The proportion of injury repaired by the longer half time was estimated to be 0.62 (0.37-0.86). The data showed that delivering 2 fractions per day at 6- or 8-h intervals instead of one per day led to a 16.5% (11.8-21.1%) and 13.5% (9.1-17.8%) reduction in the tolerance, respectively. Finally, the results indicated that when incomplete repair between fractions was accounted for, the linear-quadratic (LQ) model was valid in describing fractionation response down to 1.2 Gy per fraction.

Radiation-induced injury to the visual pathway

Radiation-induced injury to the visual pathway was reviewed in a cohort of patients treated for various cancers of the nasal cavity and paranasal sinuses between 1969 and 1985. The study subjects consisted of 219 patients, 137 men and 82 women, in whom detailed records were available on the extent of orbital shielding, treatment plan for estimating doses delivered to various optic structures, and visual acuity follow-up information. There was a wide range in doses administered to various optic structures because patients with different primary lesion types were included and the radiotherapy techniques used varied during this era. The endpoint of the study was visual acuity < 20/100. The Cox proportional hazard model was used to assess the influence of various factors on the latent time to visual impairment and to fit the LQ model to the failure-time data. Actuarial curves showing the proportion of patients with visual impairment as a function of dose and time were generated. Corneal injury occurred in 24 of the 49 patients treated with the 3-field technique without any orbital shielding; variables affecting the incidence of cornea injury were total radiation dose and chemotherapy. Symptomatic retinopathy was diagnosed in 7 of 77 patients who received irradiation to a relatively large retinal surface, but no variables were found to correlate with this complication. Eight patients developed ipsilateral blindness due to optic neuropathy and 11 patients had bilateral visual impairment secondary to chiasm injury. The total radiation dose was identified as the predominant determinant. None of patients receiving a dose of < 50 Gy developed optic neuropathy or chiasm injury.(ABSTRACT TRUNCATED AT 250 WORDS)

MULTIVARIATE ANALYSIS OF PROGNOSTIC FACTORS IN PATIENTS WITH GLIOBLASTOMA

Background: To identify prognostic factors for overall survival in patients with newly diagnosed glioblastoma undergoing radiation therapy. Patients and Methods: From January 1980 to June 2000, we treated 432 consecutive patients with glioblastoma at out institution. 17 patients were excluded from the analysis for various reasons. Mean age of the 415 patients who were included in the study was 59 years (19–81 years), Karnofsky performance status (KPS) was ≥ 70 in 280 patients. 343 patients underwent resection, 72 had a biopsy. Various fractionation schemes were used (conventional fractionation, n = 112; hypofractionation, n = 94; accelerated hyperfractionation, n = 209). Survival probabilities were estimated using the method of Kaplan and Meier. Multivariate analysis was done with a Cox regression model. Results: By July 2001, 406 patients had died. Medial overall survival was 8.2 months. Of ten factors considered in a proportional hazards model stratified for treatment (fractionation scheme and type of surgery), significant variables in a multivariate model were age (50–64 years vs < 50 years [RR 1.35; 95% CI 1.02–1.78], ≥ 65 years vs < 50 years [RR 2.08; 95% CI 1.54–2.81]), performance status (KPS < 70 vs ≥ 70 [RR 1.53; 95% CI 1.23–1.90]), and central tumor location (yes vs no [RR 1.39; 95% CI 1.04–1.87]). Blood hemoglobin (Hb) values were available in 318 patients and serum lactate dehydrogenase (LDH) levels in 234 patients. 89 patients were anemic (Hb men < 13 g/dl, women < 12 g/dl), in 80 patients the LDH level was raised beyond the upper limit of the normal range (> 240 U/l). By including the three significant variables, both parameters had an additional significant effect with an estimated relative risk of about 1.4 in their corresponding subgroups. Conclusion: Besides established prognostic factors, anemia and raised serum LDH levels may negatively influence outcome in glioblastoma patients. Our results from data-dependent modeling have to be confirmed by independent studies.Hintergrund: Die vorliegende Studie untersucht Prognosefaktoren für das Gesamtüberleben bei Patienten, die aufgrund eines neu diagnostizierten Glioblastoms bestrahlt wurden. Patienten und Methodik: Von Januar 1980 bis Juni 2000 wurden 432 Glioblastompatienten an unserer Klinik behandelt. 415 Patienten wurden in die Analyse einbezogen. Das durchschnittliche Alter betrug 59 Jahre (19–81 Jahre), der Karnofsky-Performance-Status (KPS) war bei 280 Patienten ≥ 70. Bei 343 Patienten wurde der Tumor reseziert, bei 72 Patienten biopsiert. Die Strahlentherapie erfolgte konventionell fraktioniert (n = 112), hypofraktioniert (n = 94) oder akzeleriert hyperfraktioniert (n = 209). Die Schätzung der Überlebenswahrscheinlichkeiten erfolgte mit der Methode von Kaplan und Meier. Multivariate Analysen wurden mit einem Regressionsmodell nach Cox durchgeführt. Ergebnisse: Bis Juli 2001 waren 406 Patienten verstorben. Das mediane Gesamtüberleben betrug 8,2 Monate. Von zehn Faktoren, die in einem nach Resektionsstatus und Fraktionierungsschema stratifizierten Proportional-Hazards-Modell untersucht wurden, erwiesen sich als signifikant: Alter (50–64 Jahre vs. < 50 Jahre) [RR 1,35; 95%-CI 1,02–1,78], ≥ 65 Jahre vs. < 50 Jahre [RR 2,08; 95%-CI 1,54–2,81]), Allgemeinzustand (KPS < 70 vs. ≥ 70 [RR 1,53; 95%-CI 1,23–1,90]) und zentraler Tumorsitz (ja vs. nein [RR 1,39; 95%-CI 1,04–1,87]). Werte für Hämoglobin (Hb) und Serum-Lactat-Dehydrogenase (LDH) lagen bei 318 bzw. 234 Patienten vor. 89 Patienten waren anämisch (Hb Männer < 13 g/dl, Frauen < 12 g/dl), bei 80 Patienten war der LDH-Wert erhöht (> 240 U/l). Unter Berücksichtigung der drei signifikanten Variablen übten beide Parameter in den jeweiligen Untergruppen einen zusätzlichen Effekt aus mit einem relativen Risiko von etwa 1,4. Schlussfolgerung: Neben bekannten Prognosefaktoren beeinflussen erniedrigte Hb- und erhöhte LDH-Werte das Überleben bei Patienten mit Glioblastom negativ.

Erythropoietin for patients undergoing radiotherapy: a pilot study

BACKGROUND AND PURPOSE To evaluate the feasibility and efficacy of using recombinant human erythropoietin (rhEPO) to correct decreased hemoglobin levels in patients undergoing radiotherapy and to get an estimate of its influence on the efficacy of radiotherapy. MATERIALS AND METHODS Fifty patients with cancer of the head and neck and the pelvis were randomized before radiotherapy to different rhEPO treatments (none, 3 x 150 U/kg per week i.v., 3 x 300 U/kg per week i.v. and 3 x 150 U/kg per week s.c.). Hematological parameters were evaluated weekly and the locoregional tumor control rates were determined in 38 patients with head and neck cancer. RESULTS rhEPO-treated patients showed a significant increase in their hemoglobin values (0.7 g/100 ml per week). The rhEPO response was comparable for patients with cancer of the head and neck and the pelvis. A delayed recovery was seen when iron deficiency or impaired iron mobilization was present. No serious toxicity was observed. Locoregional tumor control was improved, although not statistically significantly, in those head and neck cancer patients who experienced a rapid rise of hemoglobin. CONCLUSIONS Low hemoglobin levels can be safely and quickly corrected with rhEPO. This may improve the effectiveness of radiotherapy.

Gliosarcoma: a clinical study

BACKGROUND AND PURPOSE Gliosarcomas are rare biphasic neoplasms of the central nervous system composed of a glioblastoma multiforme (GBM) admixed with a sarcomatous component. There are conflicting reports regarding their clinical aggressiveness. Four hundred and twenty-two consecutive patients with GBM were treated at our hospital between 1980 and 1999, among them 12 gliosarcomas. The goal of this study was to examine clinical features, treatment, survival and patterns of failure of gliosarcoma patients and to compare them with the entire group of GBM patients. This comparison was refined by a matched pair analysis with a group of 12 GBM patients selected for age, Karnofsky performance status, resection status, fractionation scheme and total dose (control GBM group). MATERIALS AND METHODS Seven gliosarcoma patients were male, five female, with a median age of 56 years (range 37-76 years). The median tumor size was 4.5 cm (range 3-8 cm). The locations, all supratentorial, included temporal in six, parietal in five, frontal in four and occipital in one patient. All patients underwent tumor resection followed by postoperative radiation therapy. RESULTS Median survival was 11.5 months for the gliosarcoma group, 8.1 months for the entire GBM group (log rank test, P=0.16) and 11.0 months for the control GBM group (log rank test, P=0.36). All gliosarcoma patients had local tumor recurrences and died due to neurologic causes within 19.3 months after radiation therapy. CONCLUSIONS With regard to clinical features, survival and patterns of failure, gliosarcomas and GBM cannot be distinguished clinically. Therefore, the same principles should be applied for the treatment of these tumors.

ANEMIA IS ASSOCIATED WITH DECREASED LOCAL CONTROL OF SURGICALLY TREATED SQUAMOUS CELL CARCINOMAS OF THE GLOTTIC LARYNX

PURPOSE A strong association between hemoglobin levels and tumor control exists in head and neck cancer treated with radiotherapy. This retrospective study has been performed to determine whether or not this association can also be found in the surgical setting. METHODS AND MATERIALS Between January 1970 and December 1990, 258 patients with glottic SCC received conventional surgery only (T1/T2/T3/T4 n = 188/31/37/2, respectively). Locoregional control was calculated by the Kaplan-Meier method. The influence of hemoglobin, T stage, age, gender, performance/nutritional status, and grading was evaluated using a Cox model. RESULTS Five-year locoregional control for T1a/T1b/T2/T3/T4 tumors was 91%/85%/76%/62%/0%, respectively (log-rank test, p < 0.0001). Anemia (male < 13, female < 12 g/dL hemoglobin) was present in 27 patients. It was associated with significantly worse 5-year locoregional control, i.e., 60% vs. 85% (log-rank test, p = 0.003). In multivariate analysis stratified for T stage, two variables were of influence: positive margins (relative risk [RR], 3.8; 95% confidence interval [CI], 1.7-8.4), anemia (RR, 3.0; 95% CI, 1.4-6.2). The largest subgroup consisted of 162 patients characterized by male gender, T1, and complete resection. In this subgroup, the significant variables were T stage (T1b vs. T1a; RR, 3.5; 95% CI, 0.96-12.4) and hemoglobin with a RR of 1.4 (95% CI, 1.0-2.1) per g/dL less analyzed as a continuous variable. CONCLUSION Anemia is associated with a high risk of treatment failure in surgically treated glottic cancer. Hemoglobin levels might be predictive even within the normal range as indicated by subgroup analysis.

Different saliva substitutes for treatment of xerostomia following radiotherapy. A prospective crossover study.

Background and Purpose:Xerostomia is an important chronic side effect of radiotherapy in the head and neck area. The authors investigated the efficacy of different artificial saliva compounds in patients with postirradiation xerostomia.Patients and Methods:In 120 patients with xerostomia after radiotherapy for head and neck cancer, four different saliva substitute compounds (gel, carmellose spray, oil, mucin spray) were tested in a prospective crossover design. Xerostomia at baseline and under treatment with each compound was measured with a questionnaire approved in a pilot trial.Results:All compounds significantly improved xerostomia when compared to baseline situation (p < 0.0001). The gel was rated best, the carmellose spray was rated worst by the patients, but the single compounds did not differ significantly in their effects. In spite of this result, most patients chose the carmellose spray as their favorite compound. This is due to its good taste and easy handling, which play an important role for the acceptance of the products. Big individual differences in the preference of the single compounds were found.Conclusion:For most patients considerable relief from xerostomia can be reached by saliva substitutes. Thus, every patient with xerostomia should be given different artificial saliva compounds for a test period. This will help to find the individually best way to cope with the dry mouth.Hintergrund und Ziel:Eine wichtige chronische Nebenwirkung der Strahlentherapie im Kopf-Hals-Bereich ist die Xerostomie. Die vorliegende Studie untersucht unterschiedliche Speichelersatzprodukte bezüglich ihrer Effektivität auf diese Mundtrockenheit.Patienten und Methodik:An 120 Patienten mit einer Xerostomie nach Bestrahlung im Kopf-Hals-Bereich wurden vier unterschiedliche Speichelersatzprodukte (Gel, Carmellose-Spray, Öl, Mucin-Spray) in einem prospektiven Cross-over-Design getestet. Die Xerostomie vor Beginn der Studie und während der Behandlung mit den einzelnen Präparaten wurde mit einem Fragebogen ermittelt, der in einer Pilotstudie entwickelt worden war.Ergebnisse:Alle Präparate verbesserten im Vergleich mit der Situation vor der Studie die Xerostomie signifikant (p < 0,0001). Das Gel wurde von den Patienten am besten, das Carmellose-Spray am schlechtesten bewertet, doch die verschiedenen Präparate unterschieden sich in ihrem Effekt nicht signifikant. Trotz dieses Ergebnisses wählten die meisten Patienten das Carmellose-Spray als ihr „Lieblingsprodukt“ aus. Dies ist auf seinen guten Geschmack und seine gute Handhabbarkeit zurückzuführen, die für die Akzeptanz der Präparate eine wichtige Rolle spielen. Die Bevorzugung einzelner Produkte war individuell sehr unterschiedlich.Schlussfolgerung:Bei den meisten Patienten kann durch Speichelersatzprodukte eine merkliche Besserung der Xerostomie erreicht werden. Jedem Patienten mit Mundtrockenheit sollten verschiedene dieser Präparate zum Testen zur Verfügung gestellt werden. Dies trägt dazu bei, die individuell beste Möglichkeit der Xerostomiebehandlung herauszufinden.

Different Saliva Substitutes for Treatment of Xerostomia Following Radiotherapy

Background and Purpose:Xerostomia is an important chronic side effect of radiotherapy in the head and neck area. The authors investigated the efficacy of different artificial saliva compounds in patients with postirradiation xerostomia.Patients and Methods:In 120 patients with xerostomia after radiotherapy for head and neck cancer, four different saliva substitute compounds (gel, carmellose spray, oil, mucin spray) were tested in a prospective crossover design. Xerostomia at baseline and under treatment with each compound was measured with a questionnaire approved in a pilot trial.Results:All compounds significantly improved xerostomia when compared to baseline situation (p < 0.0001). The gel was rated best, the carmellose spray was rated worst by the patients, but the single compounds did not differ significantly in their effects. In spite of this result, most patients chose the carmellose spray as their favorite compound. This is due to its good taste and easy handling, which play an important role for the acceptance of the products. Big individual differences in the preference of the single compounds were found.Conclusion:For most patients considerable relief from xerostomia can be reached by saliva substitutes. Thus, every patient with xerostomia should be given different artificial saliva compounds for a test period. This will help to find the individually best way to cope with the dry mouth.Hintergrund und Ziel:Eine wichtige chronische Nebenwirkung der Strahlentherapie im Kopf-Hals-Bereich ist die Xerostomie. Die vorliegende Studie untersucht unterschiedliche Speichelersatzprodukte bezüglich ihrer Effektivität auf diese Mundtrockenheit.Patienten und Methodik:An 120 Patienten mit einer Xerostomie nach Bestrahlung im Kopf-Hals-Bereich wurden vier unterschiedliche Speichelersatzprodukte (Gel, Carmellose-Spray, Öl, Mucin-Spray) in einem prospektiven Cross-over-Design getestet. Die Xerostomie vor Beginn der Studie und während der Behandlung mit den einzelnen Präparaten wurde mit einem Fragebogen ermittelt, der in einer Pilotstudie entwickelt worden war.Ergebnisse:Alle Präparate verbesserten im Vergleich mit der Situation vor der Studie die Xerostomie signifikant (p < 0,0001). Das Gel wurde von den Patienten am besten, das Carmellose-Spray am schlechtesten bewertet, doch die verschiedenen Präparate unterschieden sich in ihrem Effekt nicht signifikant. Trotz dieses Ergebnisses wählten die meisten Patienten das Carmellose-Spray als ihr „Lieblingsprodukt“ aus. Dies ist auf seinen guten Geschmack und seine gute Handhabbarkeit zurückzuführen, die für die Akzeptanz der Präparate eine wichtige Rolle spielen. Die Bevorzugung einzelner Produkte war individuell sehr unterschiedlich.Schlussfolgerung:Bei den meisten Patienten kann durch Speichelersatzprodukte eine merkliche Besserung der Xerostomie erreicht werden. Jedem Patienten mit Mundtrockenheit sollten verschiedene dieser Präparate zum Testen zur Verfügung gestellt werden. Dies trägt dazu bei, die individuell beste Möglichkeit der Xerostomiebehandlung herauszufinden.

Patients with brain metastases: hope for recursive partitioning analysis (RPA) class 3

PURPOSE The objectives of the present study were (a) to validate the prognostic classification derived from recursive partitioning analysis (RPA) of the Radiation Therapy Oncology Group (RTOG); (b) to identify prognostic factors in class 3; (c) to examine the impact of treatment related variables on the prognosis in class 3. PATIENTS AND METHODS Nine hundred and sixteen patients with brain metastases had resection and whole brain radiotherapy (WBRT, n = 257) or WBRT alone (n = 659) at our institution from 1985 to 2000. Patients were grouped into RPA classes 1, 2, and 3 (n = 67, 441, and 408, respectively). RESULTS Median survival of the whole group was 3.4 months. Median survival in classes 1, 2, and 3 was 8.2, 4.9, and 1.8 months, respectively. In class 3, age (<65 years vs. > or =65 years, relative risk (RR) 0.75), status of the primary tumor (controlled vs. uncontrolled, RR 0.86), and the number of brain metastases (single vs. multiple, RR 0.76) were independent prognostic variables. We defined three prognostic subgroups: class 3a (n = 51): age <65 years, controlled primary tumor, single brain metastasis; class 3c (n = 44): age > or =65 years, uncontrolled primary tumor, multiple brain metastases; class 3b (n = 313): all other patients. Median survival in classes 3a, 3b, and 3c was 3.2, 1.9, and 1.2 months, respectively (P < 0.0001). Intra-class comparisons showed that resection followed by WBRT yielded significantly better survival compared with WBRT alone. CONCLUSION Our results validate the RTOG RPA classification for patients with brain metastases. The variables age, status of the primary, and number of brain metastases allow the division of class 3 into prognostic subgroups. Even class 3 patients may benefit from more aggressive treatment strategies.

Accelerated hyperfractionated radiotherapy in 149 patients with glioblastoma multiforme

Between August 1986 and December 1997, 149 patients with glioblastoma were treated postoperatively with 1.5 Gy fractions three times daily to a total dose of 54 Gy with 4-h intervals. Median actuarial survival was 8.8 months. Survival was 31% at 12 months and 4% at 24 months. No severe acute toxicity occurred. Multivariate analysis revealed that only age < or = 60 years and lactate dehydrogenase levels < or = 240 U/l predicted significantly higher survival probabilities.