Accelerated versus conventional fractionation. The degree of incomplete repair in human skin with a four-hour-fraction interval studied after postmastectomy irradiation.

A previously presented clinical assay with postoperative irradiation to bilateral parasternal fields in patients with breast cancer was used for a comparison of acute and late reactions in human skin after accelerated and conventional fractionation. Two and 3 fractions per day at 4-hour intervals were compared with one fraction per day. Dose fractions of about 2 Gy were used. Twenty-five fractions were given in 2.5, 1.5 and 5 weeks respectively. The acute reactions were similar regardless if 1, 2 or 3 fractions per day were given, i.e. equal total doses were isoeffective. The repair of intracellular damage was apparently completed within 4 hours. However, this might not be true due to a differential influence of proliferation and redistribution on the effect of different types of fractionation, which makes it difficult to interpret the result and estimate the degree of intracellular repair. The time to the acute peak reaction was shortened by 6 to 7 days with accelerated compared to conventional fractionation, explained by the differences in the dose delivery rates. Consequently, the onset of a compensatory proliferation is earlier after accelerated fractionation. Late reactions were more pronounced after accelerated than after conventional fractionation and 1 X 2.0 Gy/day was found to be equivalent to 2 X 1.80 Gy/day and 3 X 1.65 Gy/day at 4-hour intervals with an equal fraction number for all 3 schedules. Assuming that proliferation is negligible for late responding tissues, we interpret this finding as an expression of the degree of reduced intracellular repair. Finally, we would like to point out that the iso-effect dose relationships between acute and late reactions for accelerated versus conventional fractionation might vary, above all with the cell proliferation kinetics of acutely reacting tissue.

Quality assurance control in the EORTC cooperative group of radiotherapy. 1. Assessment of radiotherapy staff and equipment. European Organization for Research and Treatment of Cancer.

A quality control study was carried out by the EORTC Cooperative Group of Radiotherapy. From January 1982 to December 1984, 17 institutions were visited by a group of "experts" in radiotherapy and radiation physics. The evaluation included three steps: a comparison of megavoltage units, technical and staff environment, and data present in clinical and radiotherapy charts for each center; radiation physics calibration of photon and electron beams; and radiation physics measurements on a stimulated clinical case using an Alderson Rando anatomical phantom. This paper presents the results of Part 1. The results of Parts 2 and 3 will be analyzed in separate papers. Large variations were observed in the number of patients treated per year, per radiotherapist, per radiation physicist and per technician. On average, 400 patients were treated per year per megavoltage unit, but 8/17 centers treated more than 500 patients per unit per year. The number of simulators was suboptimal in 12/17 centers. These observations were summarized by a workload and staff index, and this index shows that in 5/17 centers major problems are present which make it difficult to comply with all the requirements of EORTC protocols. The quality of work-up regarding tumor extension was considered to be satisfactory in all centers. Dental care in patients irradiated to the head and neck was not well organized in 5/17 centers. Interaction between CT scan and dosimetry treatment planning could be improved in most centers and this should be one of the primary objectives of future quality control.

The predictive value of skin telangiectasia for late radiation effects in different normal tissues.

Alterations in the microcirculation and parenchymal cell loss are common phenomena after irradiation of different organs. Whether parenchymal cell loss is a process well dissociated from vasculoconnective damage, or a consequence of this, is much debated. However, comprehensive radiopathological studies have shown that vasculoconnective tissue is an important common target for late effects in various organs. Scoring of skin telangiectasia was used by us as a clinical assay of late tissue effects after different dose schedules. All studies were done prospectively with standardized skin area, field size and radiation quality. The patients were scored regularly up to 10 years. The number of patients at risk for a prescribed score versus time was calculated with the life-table method. The late effects after 5 X 2.0 Gy/wk, in the dose range 40 to 70 Gy and after 2 X 4.0 Gy/wk, in the dose range 40 to 56 Gy have been established. The skin dose is 90% of the referred dose. Dose-response curves, relating the proportion of patients with a certain score at a fixed time and radiation dose and dose-latency curves, relating the latent period for a fixed proportion of patients with a certain score and radiation dose, were constructed. The analysis shows that: ED10/5 yr and ED50/5 yr for 5 X 2.0 Gy/wk is 50 Gy and 65 Gy, respectively, for distinct telangiectasia; The latent period, concerning both a certain frequency and degree of reaction, varies exponentially with dose level; The latent period for 50% of the patients, to obtain a certain score, LP50, is correlated to that for 10%, LP10, with LP50/LP10 = 2.2 +/- 0.2 (S.D.). This correlation is independent of score, total dose, and fractionation; Isoeffective doses for 5 X 2.0 Gy/wk and 2 X 4.0 Gy/wk, determined from the dose-response curves, resulted in the repair exp N between 0.31 and 0.32 and alpha/beta ratio between 2.9 and 3.1 Gy and determined from the dose-latency curves in exp N between 0.30 and 0.32 and alpha/beta ratio between 3.4 and 2.9 Gy. In conclusion, frequent and careful follow-up with registration of normal tissue reactions, until at least 10% of the patients have obtained the prescribed effect, is predictive for the further progression of the late effects. The fractionation characteristics for telangiectasia agree well with those for animal experimental morphological and functional endpoints for late effects in different organs and support the relevance of telangiectasia as a model for predicting late effects.

Local therapy of rhabdomyosarcoma, osteosarcoma and Ewing's sarcoma of children and adolescents.

Local control of the primary tumour is a fundamental requirement for clinical cure. Towards this aim, the primary tumour must be diagnosed early and identified histologically. The size, extension, and spread within the patient must be defined precisely. In planning effective local therapy, additional questions must be answered including resectability, mutilation, sensitivity to radio- and chemotherapy, anticipated morbidity from therapeutic measures, etc. For osteosarcoma there is no reasonable alternative to radical surgery. Because of the 20% local recurrence rate of Ewing's sarcoma following radiotherapy, radical surgical removal of the primary tumour should be attempted whenever possible. For rhabdomyosarcoma, particularly for its embryonal histology, non-radical removal of the primary sarcoma is still compatible with a cure, provided adequate radio- and chemotherapy is also administered. Primary irradiation is indicated in radiosensitive unresectable primary tumours and may convert these into an operable state. Chemotherapy is the domain of prevention and treatment of metastatic disease. It has, however, also a proved effect on primary tumours and, in several recent protocols, precedes local therapy.

Normal tissue reactions to high dose-rate intracavitary irradiation of the vagina with different fractionation schedules and dose levels.

The radiation reactions in the normal tissues of the vagina, rectum and bladder were studied in 166 patients receiving prophylactic vaginal high dose-rate intracavitary irradiation. Most reactions were observed in the vaginal mucosa included in the intracavitary target and only a few in the rectum and bladder in close proximity to the same target. The influence of the total dose, the dose per fraction and the overall treatment time, summarized as the Cumulative Radiation Effect (CRE), correlated well to the rate of reactions after a correction of the formula for late effects.

[Radiotherapy of supraglottic cancers. Report on 84 patients]. / Zur Strahlenbehandlung supraglottischer Karzinome. Bericht über 84 Patienten.

Ten of 84 supraglottic carcinomas were treated by primary surgery, 32 by pre or post operative irradiation and 41 by primary irradiation and salvage surgery if recurrence developed. A comparison of the treatment results between these groups is not possible because of the lack of randomization. After follow up of 4.4 years (range 0,1-19, 7 y) 44% of the patients had died of their primary tumour or complications of treatment, 22.5% had died of intercurrent disease and 11% of other malignancies. The actuarial 5-year survival in the pre/postoperatively irradiated group was 75%, 100% and 67% for Stage I-III respectively. None of the 13 patients in Stage IV survived 5 years. The actuarial 5-year survival for the Stage I-IV irradiated patients was 91%. 67%, 82% and 42%. If possible the primary treatment should preserve the larynx, which is of great importance for the patient's quality of life. With proper selection supraglottic laryngectomy is possible for certain tumours of Stage I and II. For more advanced tumours and those not suitable for partial laryngectomy, well planned curative irradiation should be given with "reducing field" technique allow for salvage surgery for radioresistant tumours or recurrences. A total dose of 62-72 Gy 5 x 2 Gy per week for 6-8 weeks is needed depending on the stage of the tumour. Preoperative irradiation in clearly operable tumours can be given with a short course of 5 x 5 Gy over 5 days as the method of choice. In doubtfully operable tumours conventional preoperative irradiation with 30-40 Gy in 3-4 weeks is preferable.

The influence of irradiation time per treatment session on acute and late skin reactions: a study on human skin.

A comparison of the radiation effect of altering the treatment time per session in fractionated radiotherapy was performed on human skin with 12 MeV electrons. Four fractions of 7.2 Gy were given within 22 days, once a week. The dose per fraction was administered in 4 min and 32 min, respectively. The dose rate was about 2 Gy/min and the prolonged treatment time was achieved by dividing each dose fraction into three equal subfractions with intervals of 14-15 min. Prolongation of the treatment time resulted in a significant reduction of the skin erythema (p less than 0.001), pigmentation (p less than 0.05) and the degree of telangiectasia at 5 years (p less than 0.001). The relative biological effectiveness (RBE) for the prolonged (32 min), in relation to that of the short (4 min) treatment time, RBE4 min/32 min, was 1.09-1.10 for erythema and 1.07-1.12 for telangiectasia. These findings indicate that prolongation of the treatment time per session has to be adjusted for in clinical radiation oncology.

[Radiotherapy of cancer of the vocal cords. Report on 287 patients]. / Zur Strahlenbehandlung des Stimmbandcarcinoms. Bericht über 287 Patienten.

Therapeutic results in 287 glottic and subglottic carcinomas stage I-IV are reported. After primary irradiation and salvage surgery of recurrences the actuarial 10 year-NED probability for tumours with normal mobility of the vocal cords was 78%, for those with impaired mobility it was 60% and for tumours with complete fixation in stage III it was only 27%. The relative actuarial 10 year-survival probability of the same groups were 96%, 82% and 35%. Salvage surgery was performed in 48/51 patients (94%) with radioresistent tumours or recurrences and was successful in 37/48 (77%) of the patients. The larynx could be saved in 162/210 (77%) curative irradiated patients. Primary irradiation can be recommended as the method of choice in glottic carcinoma T 1 + 2. It can be proved also in T3-tumours as alternative to preoperative irradiation and laryngectomy if adequate follow-up is possible, otherwise combined preoperative irradiation and laryngectomy is preferred. Dose levels equivocal to CRE 19 are recommended for curative irradiation of T 1 + 2 N0-tumours. For more advanced tumours T3 + 4 and cervical metastases greater than 3 cm about 10% higher doses are needed. Different fractionation schedules for curative and preoperative irradiation are discussed. A highly significant dose-effect relation was found for dose levels above and below CRE 18.

The influence of fraction size in radiotherapy on the late normal tissue reaction--I: Comparison of the effects of daily and once-a-week fractionation on human skin.

A comparison of the normal tissue reactions to daily and once-a-week fractionation was performed on postoperatively irradiated bilateral parasternal fields in patients with breast cancer. Both schedules resulted in identical acute skin erythema and pigmentation. However, the development of telangiectasia was significantly more pronounced after once-a-week fractionation. These findings imply that the Cumulative Radiation Effect (CRE) formula has to be modified. The slope of the iso-effect dose versus number of fractions was 0.24 for acute skin reactions and estimated to be about 0.34 for late skin reactions at a dose level equivalent to 46 Gy in 2 Gy fractions with conventional fractionation. The beta/alpha ratio was 0.12 Gy-1 for acute and about 0.31 Gy-1 for late effects, for 200 kV X rays.

The influence of fraction size in radiotherapy on the late normal tissue reaction--II: Comparison of the effects of daily and twice-a-week fractionation on human skin.

A comparison of the normal tissue reactions to daily and twice-a-week fractionation over 4 to 6 weeks was performed on postoperatively irradiated parasternal fields in patients with breast cancer. The radiation used was electron beams at 12-13 MeV. We have previously reported that the overall treatment time was of importance for establishment of iso-effect relationships for the acute skin erythema. In this paper we present the degree of telangiectasia after 5 years. Generally, a more pronounced late reaction was found after twice-a-week fractionation than was predicted from the acute reactions. The findings imply that the cumulative radiation effect (CRE) formula has to be modified for both acute and late reactions in certain clinical situations. The main conclusion is that the iso-effect relationship varies significantly over the dose range used in clinical radiotherapy. In the dose range of 30 fractions between 1.6 and 2.1 Gy in 6 weeks, the slope of the curve for iso-effect dose versus number of fractions varies between 0.26 and 0.35, the beta/alpha-ratios between 0.22 and 0.37 Gy-1 and the RBE 2 Fractions/week/5 Fractions/week between 1.97 and 1.82.

The influence of the overall treatment time in radiotherapy on the acute reaction: comparison of the effects of daily and twice-a-week fractionation on human skin.

A comparison of the acute skin erythema and pigmentation after daily fractions of 2 Gy and twice-a-week fractions of 4 Gy was performed on post-operatively irradiated parasternal fields in patients with breast cancer. The radiation quality used was electron beams with an energy of about 12 MeV. The overall treatment time varied between 4 and 6 weeks. The two schedules were also compared for an overall treatment time of 10 weeks, with a rest period of 3 weeks after 4 weeks of irradiation, followed by another 3 weeks of treatment. With 5 to 6 weeks irradiation, daily fractions resulted in a significantly more pronounced skin erythema (p less than 0.05) than twice-a-week fractions, corresponding to about 10% in terms of absorbed dose. With 4 weeks irradiation and split-course therapy, the acute reactions were identical with both schedules. We interpret these findings as indicating a radiation-induced accelerated repopulation of the basal cells in the epidermis, with a fairly abrupt onset after 4 weeks. The higher effect after more frequent fractions of smaller size would be expected from a sensitizing effect of redistribution. In conclusion, the overall treatment time is of importance for establishment of iso-effect relationships for acutely responding tissues. The implication is that different fractionation parameters used in models to predict equivalent radiation effects of different fractionation schedules also vary significantly with the overall treatment time.

Multiple small fractions per day versus conventional fractionation. Comparison of normal tissue reactions and effect on breast carcinoma.

Hyperfractionation (3 fractions of about 1.0 Gy/day) and conventional fractionation were compared in two studies. In the first, the acute skin reactions, erythema and pigmentation, and the development of telangiectasia were analysed on postoperatively irradiated bilateral parasternal fields in patients with breast carcinoma. In the second study, the tumour effect in patients with inoperable breast carcinoma was investigated under conditions of equivalent normal tissue reactions for both fractionation schedules. With hyperfractionation the late-responding normal tissue was spared relative to the acutely responding normal tissue about 5% in absorbed dose. Concerning the therapeutic effect on adenocarcinoma of the breast 3 X 1.0 Gy/day was not better than 1 X 2.4 Gy/day. These daily doses resulted in equivalent late effects as was predicted from the normal tissue study.

[Pre- and postoperative irradiation of the mammary carcinoma]. / Zur prä- und postoperativen Bestrahlung beim Mammakarzinom.

There are different indications for the pre-, per- and postoperative treatment of mammary carcinomas with certain or doubtful operability. Based on clinical examinations, the clinical effect of pre- and postoperative irradiation on the incidence of loco-regional recurrences and distant metastases is explained. The resulting therapy suggestions are discussed. Instead of radical surgery or modified radical surgery in case of subclinical and little carcinomas less than 3 cm, a simple ablation of the tumor with adequate subsequent irradiation is recommended. The therapy results of conservative treatments published hitherto are presented.

[Clinical significance of time dose distribution in radiotherapy]. / Die klinische Bedeutung der zeitlichen Dosisverteilung in der Radiotherapie.

A survey is given of the mathematical and empirical methods allowing to compare different chronological dose distributions; their possibilities and limits are described. The experimental bases of hyper- and superfractionation and the clinical experiences gained hitherto with multiple daily irradiations are communicated; radiotherapy with high individual fractions and long term irradiation are shortly explained. Finally some hints are given for the further development and the practical use of not typical fractionation schemes.

Combined modality therapy of operated astrocytomas grade III and IV. Confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time: a prospective multicenter trial of the Scandinavian Glioblastoma Study Group.

In a controlled, prospective, randomized investigation, started in 1974, 118 patients with supratentorial astrocytoma Grade III--IV were divided into three groups. Groups 1 and 2 received 45 Gy postoperatively to the whole supratentorial brain. Bleomycin in 15-mg doses and a total dose of 180 mg or placebo was given intravenously three times a week, one hour prior to radiotherapy, during weeks 1, 2, 4 and 5. Group 3 received conventional care but no radiotherapy or chemotherapy. Median survival rates of patients were 10.8 months in Groups 1 and 2, and 5.2 months in Groups 3, a statistically significant difference. With regard to performance, the patients in Group 3 deteriorated faster than patients in Groups 1 and 2. Bleomycin had no positive or negative influence on survival.

Design of flattening filters based on intracavitary absorbed dose measurements in external radiation therapy.

A method has been developed for the design of flattening filters on the basis of in-vivo oesophagus measurements of absorbed dose distribution in patients given external radiation therapy. The measurements were made by means of LiF-Teflon thermoluminescent dosimeters, read out by an automatic TL-system. A single filter was designed from the resultant dose distribution of parallel opposing fields. The method was checked clinically and was found to be convenient and reliable. The filters reduced the dose variation along the midline of the patients undergoing upper mantle treatments from about +/- 20% to about +/- 5%. The same limits of variation are believed to exist through the entire mid-plane of the body, though it was not possible to prove this by direct measurements.

Plasma concentrations of misonidazole.

The plasma concentrations of misonidazole doses between 0.6 and 2.0 g/m2 were analyzed in respect to the variation within the same patient and between different patients. Peak plasma levels were observed after 2 hours. The mean plasma levels of misonidazole only at 3 hours were 23.8, 47.0 and 76.5 microgram/ml after misonidazole doses of 0.6, 1.2 and 2.0 g/m2, respectively. The half-life of misonidazole only was found to be 8.2 hours for women and 10.5 for men. Good linearity between plasma levels and drug doses was observed after administration of different single doses to the same patient within the dose range 0.6 to 2.0 g/m2.