Late complications after radiotherapy for prostate cancer.

BACKGROUND: The aim of the present study was to analyze in detail the time course of the incidence of radiation-induced late effects. For this purpose, unpublished data of patients treated by radiation therapy in Hamburg in the late 1980s were analyzed. Relatively large volumes were exposed to comparatively high doses, thus leading to a high rate of treatment-related side effects. PATIENTS AND METHODS: A total of 180 consecutive patients received radiotherapy for prostate cancer. The median age was 66 years (range 41-88 years). The median of the maximum dose was 77.5 Gy (range 56.3-95 Gy) and overall treatment time was 51 days (range 28-128 days). Endpoints analyzed were late complications of grade 3 or higher, overall and disease-free survival, local tumor control, and distant metastases. Data analysis was actuarial and the log-rank test was used to compare the various subgroups. RESULTS: After 2 years, 80.5 ± 3.2% of the patients were without any complications of grade 3 or higher, and after 5 years a constant level of 70.3 ± 4.0% was approached. When multiple lesions occurred per patient, the later events were disregarded. A total of 66 complications occurred in 42 patients. The percentage of patients being free from late complications, plotted as a function of time after start of radiation therapy, was adequately described by an exponential function and a constant fraction. Complications approached a constant level of 70.3% at a rate of 5.3% per month. This means that patients who will develop a complication do so at exponential kinetics and at a relatively high rate, whereas about 70% of the patients will never experience a late effect even over long observation periods. After subdividing the maximum dose into three equal dose groups of 55 patients each (< 73.3 Gy, 73.3-80 Gy, > 80 Gy), the constant fraction decreased from 85.7 to 72.8% and 52.2%, whereas the incidence rate was 4.3%, 7.7%, and 5.6% per month and, thus, almost independent of radiation dose. CONCLUSION: For a given group of patients, the rate of the incidence of late complications appears to be independent of radiation dose and (from analyzing data in the literature) independent of the grade of lesions, whereas the fraction of patients without late effects depends on both parameters.

[Doubtful evidence for the use of the cholinesterase inhibitor donepezil in patients with dementia--a systematic review]. / Fragliche Evidenz für den Einsatz des Cholinesterasehemmers Donepezil bei Alzheimer-Demenz -- eine systematische Ubersichtsarbeit.

OBJECTIVE: Objective of this systematic review is to determine the level of scientific evidence for the use of Donepezil in Alzheimer's Disease. METHODS: Ten randomised controlled double-blind trials testing Donepezil versus Placebo were identified in MEDLINE and EMBASE. All ten trials were included in this systematic review. Following a detailed catalogue of criteria the methodological standard of the ten trials was assessed. RESULTS: The authors of eight trials postulated statistically significant differences in favour of Donepezil. Unfortunately, the methodological standard of all studies was insufficient. The methodological shortcomings are discussed in detail. CONCLUSION: With regard to severe methodological deficiencies the evidence for the use of Donepezil in moderate to severe Alzheimer's Disease is lacking. But even if the trials had been conducted in a methodologically correct way the clinical relevance of the postulated positive results would have to be questioned.

Time benefit in the assessment of recurrences following fractionated radiotherapy in an experimental tumour system using positron-emission tomography with 18F-fluorodeoxyglucose.

PURPOSE: To determine the sensitivity and specificity of 18F-fluorodeoxyglucose-positron-emission tomography (FDG-PET) in the diagnosis of R1H tumours after fractionated radiotherapy, and the dependency of sensitivity and specificity on time after therapy. In addition, the time benefit of FDG-PET concerning early recognition of recurrences after fractionated radiotherapy was assessed. MATERIAL AND METHODS: Subcutaneously growing rat rhabdomyosarcoma R1H tumours were irradiated by applying total doses of 80 or 85 Gy after reaching a start volume of 0.8 cm3. Twenty animals were treated. Tumour volume was determined twice a week. FDG-PET was performed weekly before, during and for 6 months after therapy using a conventional full-ring whole-body PET scanner. In total, 600 PET results were evaluated qualitatively using a six-scale score. PET results and actual tumour volumes were compared. The sensitivity and specificity of tumour detection by PET was calculated for different times after the onset of therapy. The optimal score for tumour detection and the influence of time after therapy on the quality of PET (time benefit) was evaluated using receiver-operating characteristics. RESULTS: After irradiation, 8/20 tumours (40%) were locally controlled, while 12/20 recurred. In this tumour model, evidence of relapse is assured when a volume of 0.1 cm3 is reached. Sensitivity of tumour diagnosis by PET increases with time, i.e. with the volume of recurrent tumours after the onset of therapy, mounting to > 0.95 after 100 days. Specificities of 0.95-1.0 were determined after therapy, showing no increase with time. Tumour diagnosis by PET is highly accurate when performed 80 days after the start of treatment. On average, tumours were recognized by PET on 31, 62, 74 and 81 days (median) before approaching volumes of 0.2, 0.5, 0.8 or 1.0 cm3, respectively. CONCLUSION: An experimental system was implemented that allows reproducible detection of recurrent R1H tumours after radiotherapy using FDG-PET. The usefulness of PET as a diagnostic test for R1H tumours is very good and a reliable resolution for PET is demonstrated for volumes < 1 cm3. The results indicate that FDG-PET enables early recognition of recurrences after fractionated radiotherapy.

Quantification of late complications after radiation therapy.

BACKGROUND: An increasing number of patients survive cancer after having received radiation therapy. Therefore, the occurrence of late normal tissue complications among long-term survivors is of particular concern. METHODS: Sixty-three patients treated by radical surgery and irradiation for rectal carcinoma were subjected to an unconventional sandwich therapy. Preoperative irradiation was given in four fractions of 5 Gy each applied within 2 or 3 days; postoperative irradiation consisted mostly of 15 x 2 Gy (range, 20-40 Gy). A considerable proportion of these patients developed severe late complications (Radiother Oncol 53 (1999) 177). The data allowed a detailed analysis of complication kinetics, leading to a new model which was tested using data from the literature. RESULTS: Data on late complications were obtained for eight different organs with a follow-up of up to 10 years. For the various organs, the percentage of patients being free from late complications, plotted as a function of time after start of radiation therapy, was adequately described by exponential regression. From the fit, the parameter p(a) was obtained, which is the percentage of patients at risk in a given year of developing a complication in a given organ during that year. The rate p(a) remained about constant with time. Following sandwich therapy, the annual incidence of complications in the bladder, ileum, lymphatic and soft tissue, and ureters was about the same (p(a)=10-14%/year), whereas complications in bone or dermis occurred at lower rates (4.7 or 7.5%/year, respectively). DISCUSSION: Numerous data sets collected from published reports were analyzed in the same way. Many of the data sets studied were from patients in a series where there was a high incidence of late effects. Three types of kinetics for the occurrence of late effects after radiotherapy were identified: Type 1, purely exponential kinetics; Type 2, exponential kinetics, the slope of which decreased exponentially with time; Type 3, curves composed of two components, a fast initial decline followed by an exponential decrease. For each kind of kinetics, provided that the dose distribution is not too heterogeneous, the incidence of late effects appears to occur at exponential or approximately exponential kinetics, even many years after treatment. This implies that a random process might be involved in the occurrence of late radiation sequelae. CONCLUSIONS: There might be a lifelong risk of developing late complications, of which patients and clinicians should be aware. It appears worthwhile to try to identify, in follow-up examinations of patients after radiation therapy, what kind of processes might be involved in triggering subclinical residual injury to develop into a clinically manifest late effect.

[Authorship of scientific publications. Audit of the periodical "Strahlentherapie und Onkologie"]. / Autorenschaft wissenschaftlicher Veröffentlichungen. Analyse der Zeitschrift "Strahlentherapie und Onkologie".

BACKGROUND: The quality of the contributions to "Strahlentherapie und Onkologie" is assessed, aiming for improvement of the journal and consequently its impact factor. MATERIAL AND METHODS: All 164 articles published during 1999 and 2000 in the categories "review", "original article", and "short communication" were analyzed concerning the handling of authorship. RESULT: A median number of five authors and two institutions contribute to one publication. In no case the contribution of individual authors was specified. The proportion of women in radiooncological research is significantly less than their proportion in the German radiooncological society DEGRO (p < 0.0001). There were only eight female senior authors which is also significantly less than expected (p = 0.001). The fraction of female first authors corresponds to their fraction among authors. CONCLUSION: The criteria for authorship of the Deutsche Forschungsgemeinschaft should be regarded for. The contribution of individual authors should be specified. Women appear to be underrepresented in research and in leading positions in radiooncology.

Impact of pulmonary metastases of the R1H-tumour on radiation tolerance of rat lung.

PURPOSE: The aim was to investigate the influence of pulmonary metastases of the rhabdomyosarcoma R1H on the radiation response of the lung of the WAG/Rij rat. MATERIAL AND METHODS: Three groups of animals were investigated: metastases-free animals treated with fractionated irradiation of the lungs; metastases-bearing animals receiving no irradiation; and metastases-bearing animals treated with fractionated irradiation initiated 14, 21 or 28 days after induction of pulmonary metastases of the R1H-tumour by i.v. injection of viable tumour cells. Metastases were thus treated at various well-defined sizes. Total doses of 20-60Gy were applied in fractions of 2 Gy within 11 days. Complication rate and survival time were used as endpoints. RESULTS: About 2 months after onset of irradiation treatment, animals had to be sacrificed because of severe respiratory distress either caused by irradiation-induced lung damage (median 57 days, range 36-77 days), or because of development of lung metastases (65, 20-160 days). A decrease of the ED(50) (dose required to induce lethal lung damage in 50% of irradiated animals) was determined for metastases-bearing animals. This effect increased with metastatic volume. CONCLUSIONS: The results suggest that the presence of tumours in the lung decreased the lung tolerance to radiation. This effect can hardly be explained by a reduction in functional lung volume by metastatic volume.

Impact of treatment acceleration and its timing on the response of the rhabdomyosarcoma R1H of the rat to fractionated irradiation.

BACKGROUND AND PURPOSE: In clinical practice a concomitant boost is usually given as a second daily dose to a reduced field. The question arises which part of treatment should be accelerated to achieve optimal tumor control. An experiment was performed on tumor bearing rats to determine the optimal timing of treatment acceleration for this experimental tumor system. MATERIAL AND METHODS: Rhabdomyosarcoma R1H of the rat were treated applying 30 fractions in an overall treatment time of 40-42 days, up to total doses ranging from 67.5 to 97.5 Gy were administered. For control a standard treatment was given as continuous treatment applying one fraction per day. A boost of five additional fractions was given as a second fraction during 5 days. Three experimental arms received a boost either in the 1st, 4th, or in the last week of treatment. Treatment outcome was assessed using tumor control as endpoint. RESULTS: All experimental arms proved more effective than the standard treatment. Treatment was most effective when the boost was administered in the 1st week of treatment. A TCD37% of 87.1 Gy (95% CI: 82.8 ... 92.7 Gy), 96.5 Gy (89.9 ... 107.1), and 107.3 Gy (97.2 ... 131.0) was determined, when the boost was given in the 1st, 4th, or last week of treatment, respectively. The observed difference between the experimental arms was statistically significant (p = 0.004). CONCLUSIONS: Initially accelerated treatment schedules were found to be more effective for tumor control in an experimental tumor system.

Split-course radiotherapy: where do we stand?

BACKGROUND: Split-course radiotherapy is only rarely applied in curative radiotherapy and there might be a number of arguments to believe that continuous radiotherapy is superior to split-course treatment. In order to point out the evidence current treatment practice is based on, the available randomized trials and some prominent retrospective analyses on split-course radiotherapy were critically assessed. MATERIAL AND METHODS: The analysis of the clinical results was based on published data only. Publications were searched in a Medline database. RESULTS: Assessment of 13 randomized trials, including the data of 2,112 patients, revealed no significant difference between continuous-course and split-course radiotherapy. Astonishingly, the outcome of 77 radiotherapy studies on split-course, most of which are retrospective, seems to depend on the year of publication, suggesting publication bias. CONCLUSIONS: No clinically relevant difference between continuous and split-course radiotherapy could be found. This, of course, does not proof that there are indeed no differences but the data do not allow to draw clear-cut conclusions in favor of or against split-course radiotherapy due to methodological shortcomings of the studies.

Impact of the position of a gap on the response of the R1H-tumor of the rat on fractionated split-course radiotherapy.

BACKGROUND: Gaps are a common feature of clinical radiotherapy. Only little information is available about the influence of the position of a gap on tumor response. MATERIAL AND METHODS: In a rodent tumor model (rhabdomyosarcoma R1H of the rat) three split-course schedules were carried out by inserting a 2-week gap either after the 1st, the 3rd, or the 5th week into a standard schedule of 30 fractions in 6 weeks. For comparison a standard and an accelerated treatment were carried out. RESULT AND CONCLUSION: The position of the gap was found to have a significant influence on the tumor response (p = 0.018).

[Multiple significance tests and their importance in the judging of results. A quality analysis of the journal Strahlentherapie und Onkologie]. / Multiple Signifikanztests und ihre Bedeutung bei der Beurteilung von Resultaten. Qualitätsanalyse der Zeitschrift "Strahlentherapie und Onkologie".

BACKGROUND: The statistical quality of the contributions to "Strahlentherapie und Onkologie" is assessed, aiming for improvement of the journal and consequently its impact factor. MATERIAL AND METHODS: All 181 articles published during 1998 and 1999 in the categories "review", "original contribution", and "short communication" were analyzed concerning the appropriate use of multiple tests. RESULT: One hundred and four publications were excluded from analysis, because they did not contain quantitative data or because no or only 1 statistical test was performed. In 77 publications multiple tests were done which was adequately considered in only 3 of these papers, corresponding to a fraction of 4% (95% CI: 0.8 to 11%). CONCLUSION: Authors, peer reviewers, and editors could contribute to improve the quality of the journal by setting value on correction for multiple tests.

Influence of dose per fraction and overall treatment time on the response of pulmonary micrometastases of the R1H-tumour to fractionated irradiation.

BACKGROUND AND PURPOSE: Macroscopic subcutaneously growing R1H-tumours have been shown to respond almost independently of the dose per fraction when treated under ambient conditions. In addition decelerated repopulation during fractionated irradiation has been shown for this experimental tumour. The aim of the present study was to investigate whether this is also the case for pulmonary micrometastases which are assumed to be fully oxygenated or whether differences in the oxygenation status of the tumour possibly alters its response to fractionation. The influence of the dose per fraction and overall treatment time on the response of micrometastases to fractionated irradiation was studied. MATERIALS AND METHODS: Pulmonary metastases were induced by i.v. injection of viable tumour cells. Treatment was started 14 days later, when metastases reached an average size of four cells. Total doses of 16 to 28 Gy were administered within an overall treatment time of 11 or 25 days, using doses per fraction of 1, 2, or 4 Gy. Tumour response was quantified by metastatic control (MCD(37%)). RESULTS: Fractionation had a significant influence on local control (P=0.009). After application of 1, 2, or 4 Gy and an overall treatment time of 11 days the MCD(37%) was 25.4 (95% C.I.: 21.5-32.0) Gy, 20.7 (17. 0-24.0) Gy, and 18.5 (14.9-21.6) Gy, respectively. When overall treatment time was prolonged to 25 days the MCD(37%) increased to 25. 5 (21.3-33.5) Gy when fractions of 2 Gy where applied, but this difference was not significant (P=0.13). The doubling time of 12.8 days determined for the metastatic clonogenic tumour cells during fractionated irradiation was significantly longer than the 4.1 days observed for untreated metastases (P=0.006). CONCLUSIONS: The results show a strong influence of fractionation on treatment outcome and a decelerated repopulation during fractionated irradiation treatment for well oxygenated pulmonary metastases of the R1H-tumour.

[Confidence intervals and their relevance for the interpretation of results. Audit of the journal "Strahlentherapie und Onkology"]. / Konfidenzintervalle und ihre Bedeutung für die Beurteilung von Resultaten. Qualitätsanalyse der Zeitschrift "Strahlentherapie und Onkologie".

BACKGROUND: The statistical quality of the contributions to "Strahlentherapie und Onkologie" is assessed, aiming for improvement of the journal and consequently its impact factor. MATERIAL AND METHODS: All 181 articles published during 1998 and 1999 in the categories "review", "original contribution", and "short communication" were analysed concerning the appropriate use of confidence intervals. RESULT: Forty-four publications were excluded from analysis, because they did not contain quantitative data or because the quotation of a confidence interval would not have been meaningful for other reasons. Of the remaining 137 publications only 27 presented all relevant results with clearly defined and correctly interpreted confidence intervals. This corresponds to a fraction of 20% (95% CI: 13-28%). CONCLUSION: Authors, peer reviewers, and editors could contribute to improve the quality of the journal by setting value on the documentation of confidence intervals.

[Actuarial analysis of time-failure data and its rrelevance for interpretation of results. Audit of the journal "Strahlentherapie und Onkologie" (Radiotherapy and Oncology)]. / Aktuarische Auswertung von Zeit-Ereignis-Daten und ihre Bedeutung bei der Beurteilung von Resultaten. Qualitätsanalyse der Zeitschrift "Strahlentherapie und Onkologie".

BACKGROUND: The statistical quality of the contributions to "Strahlentherapie und Onkologie" is assessed, aiming for improvement of the journal and consequently its impact factor. MATERIAL AND METHODS: All 181 articles published during 1998 and 1999 in the categories "review", "original contribution", and "short communication" were analyzed concerning actuarial analysis of time-failure data. RESULT: One hundred and twenty-three publications without time-failure data were excluded from analysis. Forty-five of the remaining 58 publications with time-failure data were evaluated actuarially. This corresponds to 78% (95% confidence interval: 64 to 88%) of papers, in which data were adequately analyzed. Complications were reported in 16 of 58 papers, but in only 3 cases actuarially. The number of patients at risk during the course of follow-up was documented adequately in 22 of the 45 publications with actuarial analysis. CONCLUSION: Authors, peer reviewers, and editors could contribute to improve the quality of the journal by setting value on acturial analysis of time-failure data.

[Type two error and its relevance for interpretation of results. Quality audit of the Journal "Strahlentherapie und Onkologie]. / Der Fehler zweiter Art und seine Bedeutung bei der Beurteilung von Resultaten. Qualitätsanalyse der Zeitschrift "Strahlentherapie und Onkologie".

BACKGROUND: The statistical quality of the contributions to "Strahlentherapie und Onkologie" is assessed, aiming for improvement of the journal and consequently its impact factor. MATERIAL AND METHODS: All 181 articles published during 1998 and 1999 in the categories "review", "original contribution", and "short communication" were analyzed concerning the appropriate consideration of Type II error. RESULT: Ninety-nine publications were excluded from analysis for different specified reasons. In none of the remaining 82 clinical publications Type II error was considered. CONCLUSION: Authors, peer reviewers, and editors could contribute to improve the quality of the journal by setting value on adequate consideration of Type II error.

Combined fractionated external beam radiotherapy and low-dose-rate iodine-125 seeds in an experimental tumor system.

BACKGROUND: To quantify the effect of implanted low-dose-rate iodine seeds combined with fractionated external beam radiation on local control rates in an experimental tumor system. MATERIALS AND METHODS: Experiments were done on the rhabdomyosarcoma R1H of the rat transplanted s.c. into the back of male WAG/Raj albino rats. Tumors were irradiated with 200 kVp X-rays with 2 Gy/fraction 5 times weekly. The total dose of the external beam irradiation varied between 60 and 98 Gy for external beam radiotherapy alone and 10 Gy to 82 Gy for combined external beam radiotherapy and iodine seeds. One to 4 iodine seeds with a median activity of 21.05 MBq were permanently implanted 3 days before the start of external radiotherapy or 6 and 7 iodine seeds alone were used. The median tumor volume at the start of treatment was 0.12 cm3. Local tumor control rates were determined and TCD37% values were calculated applying the maximum likelihood method. RESULTS: With increasing number of implanted iodine seeds the TCD37% (of external beam irradiation) decreased. With external beam radiotherapy alone the TCD37% amounted to 103.2 Gy (95% CI, 101.3 to 105.1 Gy) decreasing to (externally applied doses) 69.7 Gy (63.7 to 74.7 Gy) after 1 implanted iodine seed and further to 31.6 Gy (25.6 to 37.6 Gy) after 4 implanted iodine seeds. The effective dose (equivalent to external dose) per iodine seed decreased with increasing number of implanted iodine seeds. One iodine seed gave an effective dose of 33.5 Gy (28.5 to 39.5 Gy) decreasing to 17.9 Gy (16.4 to 19.4 Gy) after 4 iodine seeds. CONCLUSIONS: The combined treatment of tumors with implanted low-dose-rate iodine seeds and external beam irradiation can decrease the total dose of the external beam irradiation and, hence, offer the possibility of considerable dose sparing of normal tissues without compromising local tumor control rates.

Radiation-induced impairment of urinary bladder function in mice: fine structure of the acute response and consequences on late effects.

The time course and dose response of radiation-induced impairment of urinary bladder function in the mouse were assessed after local irradiation with graded single doses. Bladder capacity was defined by transurethral cystometry; a reduction in bladder volume at an intravesical pressure of 10 mmHg by > or =50% of the individual pretreatment control value was considered a positive radiation reaction. Reversible effects of radiation on the urinary bladder were found during the first 30 days postirradiation, followed by a symptom-free latent period and irreversible late changes. Maximum-likelihood analysis revealed that the acute response is composed of two distinct waves from days 1-15 and days 16-30, with mean latent times of 7.1 days [95% confidence interval (5.4, 9.0)] and 23.3 days (21.9, 24.5), respectively, which describe the data significantly better than a single normal distribution (P = 0.0052). The ED50 values (+/- their standard deviation sigma), i.e. the doses at which 50% of the irradiated animals show the > or = 50% reduction in bladder capacity during each of the two intervals, were 21.7 +/- 4.1 and 19.3 +/- 3.9 Gy for the first and the second acute wave, respectively. The ED50 for the late functional effects was 18.7 +/- 2.4 Gy. Multivariate analysis demonstrated (1) that a response during the first acute wave correlated significantly with a reaction in the second acute wave (P = 0.0066), and (2) that a response during the second but not the first acute wave correlated significantly with the development of a late response (P = 0.0008). In conclusion, the present analysis suggests that the radiation response of the urinary bladder of the mouse displays a significant consequential component. However, further studies are required to demonstrate if the frequency of late sequelae can be decreased by an early intervention in the sequence of pathogenic processes.