Influence of different dose rates on cell recovery and RBE at different spatial positions during protracted conformal radiotherapy.

The effect of simultaneous induction and repair of sub-lethal lesions during protracted irradiation is potentially important for conformal irradiation techniques and may influence the relative biological effectiveness (RBE) of different radiation qualities. The importance of repair for 50 kV X rays from a miniaturised X-ray source producing an essentially isotropic dose distribution for intra-operative radiotherapy (IORT) was verified for inactivation of V79 cells in different distances from the source. The experimental data were evaluated in terms of the linear-quadratic model and the generalised Lea-Catcheside time factor. Furthermore, the shape of survival curves for 14 MeV [d(0.25) + T] neutrons at different dose rates implicated a role of repair for fast neutrons. Microdosimetric measurements have previously demonstrated variations in radiation quality between different positions in a therapy phantom for conformal moving-beam therapy with this radiation. Experimental data on the effectiveness for inactivation of V79 cells irradiated at such positions are presented and the influence of repair is analysed.

Spatial variation of radiation quality during moving beam therapy with 14 MeV [d(0.25)+T] neutrons.

In conformal moving beam therapy with fast neutrons, the contributions to dose from the direct beam, scattered radiation and the gamma component vary with the position in the phantom. To determine this variation in radiation quality, microdosimetric measurements of energy deposition spectra were performed at different position in a therapy phantom. Fixed beam irradiation at different incidence angles showed strong changes in the lineal energy spectrum. An increase of slow protons (20 < y < 110 keV.micron-1) and a decrease of fast protons (2 < y < 20 keV.micron-1) was seen for irradiation outside the direct beam. During moving beam irradiation, different positions on the same isodose curves (55% or 35%) showed differences in YD of up to 5%. Variations in the quality parameter, R, determined by applying an empirical biological weighting function, were of similar magnitude. Thus, spatial variations in radiation quality should be taken into account in biological dose planning for moving beam neutron therapy.

Use of neutron therapy in the management of locally advanced nonresectable primary or recurrent rectal cancer.

Inoperable locally advanced or inoperable recurrent rectal cancer is a difficult problem. Tenesmus, discharge, bleeding and pelvic pain are frequently present and often are associated with infiltration of the sacral plexus. The value of radiotherapy in managing such patients is being appreciated, although up to 40% of the treated patients have no symptomatic response. Improvement in tumor response and control has been scored through efforts to overcome the radio resistance of the hypoxic tumor cells by neutron irradiation. This article is an account of the activity of neutron radiotherapy in such patients. Over 350 patients were entered in studies comparing neutrons used alone and neutrons used in a mixed-beam treatment schedule. At present no therapeutic gain for long-lasting survival has been achieved; however, local control and pain improvement seems to be better with neutrons than with photons.

Changes in RBE of 14-MeV (d + T) neutrons for V79 cells irradiated in air and in a phantom: is RBE enhanced near the surface?

PURPOSE: The relative biological effectiveness (RBE) for inactivation of V79 cells was determined as function of dose at the Heidelberg 14-MeV (d + T) neutron therapy facility after irradiation with single doses in air and at different depths in a therapy phantom. Furthermore, to assess the reproducibility of RBE determinations in different experiments we examined the relationship between the interexperimental variation in radiosensitivity towards neutrons with that towards low LET 60Co photons. METHODS: Clonogenic survival of V79 cells was determined using the colony formation assay. The cells were irradiated in suspension in small volumes (1.2 ml) free in air or at defined positions in the perspex phantom. Neutron doses were in the range, Dt = 0.5-4 Gy. 60Co photons were used as reference radiation. RESULTS: The radiosensitivity towards neutrons varied considerably less between individual experiments than that towards photons and also less than RBE. However, the mean sensitivity of different series was relatively constant. RBE increased with decreasing dose per fraction from RBE = 2.3 at 4 Gy to RBE = 3.1 at 0.5 Gy. No significant difference in RBE could be detected between irradiation at 1.6 cm and 9.4 cm depth in the phantom. However, an approximately 20% higher RBE was found for irradiation free in air compared with inside the phantom. Combining the two effects, irradiation with 0.5 Gy free in air yielded an approximately 40% higher RBE than a dose of 2 Gy inside the phantom. CONCLUSION: The measured values of RBE as function of dose per fraction within the phantom is consistent with the energy of the neutron beam. The increased RBE free in air, however, is greater than expected from microdosimetric parameters of the beam and may be due to slow recoil protons produced by interaction of multiply scattered neutrons or to an increased contribution of alpha particles from C(n, alpha) reactions near the surface. An enhanced RBE in subcutaneous layers of skin combined with an increase in RBE at low doses per fraction outside the target volume could potentially have significant consequences for normal tissue reactions in radiotherapy patients treated with fast neutrons.

A variety of fast neutron beams for radiobiological research.

The design and construction of a new fast neutron facility and first dosimetric results obtained from seven neutron beams are presented. The neutrons are produced by bombarding beryllium targets with protons and deuterons from our K = 32 negative ion cyclotron. The dose rate in air 1 m distance from the thick target within a 13 x 13 cm2 field amounts to about 50 cGy/min at 30 microA of 32 MeV protons.

The role of high-dose, single-fraction irradiation in small and large intracranial arteriovenous malformations.

PURPOSE: Radiosurgery with external beam irradiation is an accepted treatment for small intracranial vascular malformations. It has been proven effective and safe for lesions with volumes of less than 4 cc. However, there is only some limited clinical data for malformations of grade 4 and grade 5, according to Spetzler and Martin. METHODS AND MATERIALS: At the Heidelberg radiosurgery facility equipped with a linear accelerator, 212 patients with cerebral arteriovenous malformations have been treated since 1984. Thirty-eight percent of the arteriovenous malformations treated were classified inoperable, 14% grade 5, 19% grade 4, and 29% grades 1-3. Radiation doses between 10 and 29 Gy were applied to the 80% isodose contour. RESULTS: Above a threshold dose of 18 Gy, the overall obliteration rate was 72%. After 3 years, the obliteration rates were 83% with volumes of less than 4.2 cc, 75% with volumes of up to 33.5 cc, and 50% with volumes of up to 113 cc. Of the patients presenting with seizures and paresis, 83% and 56%, respectively, showed improvement, which correlated with the degree of obliteration. After a follow-up period of up to 9 years, the rate of radiation-induced severe late complications was 4.3%. In grade 5 lesions, the risk of side effects was 10%. No serious complications occurred if a maximum dose of less than 25 Gy was applied to treatment volumes of less than 33.5 cc. CONCLUSION: The success of stereotactic high-dose irradiation of arteriovenous malformations depends on the dose applied. The incidence of radiation-induced side effects increased with the applied dose and treatment volumes. From our experience, doses of less than 25 Gy and treatment volumes of up to 33.5 cc are safe and effective. In the future, new techniques of radiosurgery with linear accelerators and dynamically reshaped beams will allow us to apply homogenous dose distributions. Additional use of magnetic resonance angiography for 3D treatment planning will help to identify the nidus more easily.

Fractionated stereotactically guided radiotherapy of head and neck tumors: a report on clinical use of a new system in 195 cases.

Between November 1988 and December 1992, 195 patients with tumors of the head and neck (low grade gliomas, meningiomas, neurinomas, chordomas and miscellaneous) were treated with a newly developed stereotactical system for fractionated, conformal, high-precision radiotherapy. The overall preparation time, including head mask production for fixation, CT, MRI, 3-D treatment planning and stereotactical localisation could be reduced to 4-5 h per patient. The use of MR in the target definition was increased to a mean of about 60%. The medial follow-up time is 22 months. Three different patient groups were selected according to pretreatment. Patients with full high-precision radiotherapy survived in 95% of cases, patients with boost treatment in 86% and patients with preirradiated recurrent disease in 64%. Meningiomas as the largest histology group (n = 62) showed partial response in 27% and complete response in 10% of cases. Progression occurred in two patients. All patients are alive. Acute side-effects were minimal and of the order of 10%, no late complications occurred despite tumor doses ranging up to 72 Gy. High-precision radiotherapy as it is performed in Heidelberg can be regarded as an effective, reliable and tolerable system for selected tumors of the head and neck.

[The relative biological effectiveness (RBE) of fast neutrons on the Dunning rat prostate carcinoma R3327-HI]. / Relative biologische Wirksamkeit (RBW) von schnellen Neutronen auf das Dunning-Rattenprostatakarzinom R3327-HI.

Human prostate tumors are known to be good candidates for neutron therapy. The Dunning rat prostate tumor system R3327 was found in many studies to be an excellent model for human prostate tumors. There is still a paucity of studies on the response of the Dunning tumors to fast neutrons. Tumors of the R3327-HI subline are moderately well differentiated and mucin producing. They show one euploid cell population, a bromodeoxyuridine labelling index of 5%, a potential doubling time of 8.9 days, a volume doubling time of about ten days and a cell loss rate of 10%. Tumors were transplanted s.c. in the distal thigh of Copenhagen rats and treated with 60Co-photons (10, 20, 30, 40 Gy, 45 cGy/min) and 14-MeV-neutrons (8, 10, 12 Gy, 7 to 11 cGy/min). Tumor volumes were measured twice weekly. Growth delay was defined as time in days until the tumors reached twice their treatment volume. Linear regressions on the median growth delays of the different treatment groups were calculated. The ratio of the neutron- and photon-slopes yielded an RBE of 3.1 +/- 0.3. Additionally isoeffect-RBE values between 2.3 and 2.6 were graphically estimated.

[The physical and technical outlook for neutron therapy in Germany]. / Physikalisch-technische Perspektive der Neutronentherapie in Deutschland.

All five fast neutron therapy centres in Germany use low energy cyclotrons or neutron generators and are, therefore, at the low energy end of the 21 neutron therapy facilities presently in use worldwide. The depth dose characteristics are worse than for 60Co gamma rays, the absorbed dose rate is too low and the treatment is technically restricted because of the lack of those modern features like multileaf collimators and full gantry rotation that are available with modern linear accelerators. A survey of the statistical and methodical data on the neutron treatment in Germany is presented. To avoid masking the potential biological benefits of high LET neutron irradiation by the use of suboptimal equipment and to utilise the real therapeutical benefit for specific tumor types, the German neutron therapy centres urgently need modernization of their outdated facilities. Specific recommendations of how to meet the requirements of modern neutron therapy are given.

Long-term follow-up for brain metastases treated by percutaneous stereotactic single high-dose irradiation.

Surgery is considered the treatment of choice for solitary brain lesions, and radiation therapy is indicated for metastases only in vital or sensitive regions that cannot be excised without risk of disabling neurologic defects. In these cases, radiosurgery may be an alternative to conventionally fractionated radiation therapy. At the Heidelberg linear accelerator-based radiosurgery facility, 69 patients were treated for 102 inoperable brain metastases. The primary tumor sites included non-small cell lung carcinoma (n = 24), renal cell carcinoma (n = 14), melanoma (skin) (n = 14), colorectal carcinoma (n = 6), carcinoma of unknown primary (n = 4), and others (n = 7). Eleven patients were treated for relapse after surgery or after conventional whole-brain irradiation. The doses at the isocenter varied from 15-50 Gy (mean, 21.5 Gy). Ten patients with multiple metastases received a planned combination of whole-brain irradiation plus a single boost of 15 Gy. The median survival time for the entire group was 6 months, with a 1-year-survival of 28.3%. Factors associated with significant improvement of survival were brain metastases without other metastatic disease and good response to radiation therapy. Five of 22 patients (22.9%) with metastases located only in the brain survived longer than 2 years. An improvement in neurologic function was found in 81% within a period of 3 months. With imaging techniques, complete remission was found in 20%, partial remission in 35%, stable disease in 40%, and relapse in 5%. The authors concluded that radiosurgery is an effective and safe therapy for brain metastases. It can be applied as primary treatment, as boost in combination with whole-brain irradiation, or as treatment for patients with relapse in a previously irradiated field.

The combined and separate action of neutron radiation and zirconium dioxide on the liver of rats.

To simulate the chronic alpha radiation of Thorotrast, the liver of female Wistar rats was exposed to fractionated neutron irradiation at 14-d intervals (0.2 Gy per fraction) over 2 y to a total dose of 10.0 Gy. Prior to the start of irradiation, one-half of the animals received 120 microL of non-radioactive Zirconotrast (ZrO2), which is comparable to Thorotrast with regard to all other physical and chemical properties. One year after beginning irradiation, the first liver tumor was detected. At the end of the life-span study, the incidence of irradiated animals with liver tumors was about 40%. In the animals treated additionally with ZrO2, the incidence, time of onset, and overall number of liver tumors was nearly equal, indicating that the fractionated neutron irradiation was the exclusive cause of tumor development. The lifelong-deposited ZrO2 colloid had no stimulating effect. Compared to earlier animal studies dealing with Thorotrast, the same histological types of benign and malignant liver tumors were found.

[Stereotactic convergent-beam irradiation: its current prospects based on clinical results]. / Stereotaktische Konvergenzbestrahlung: Aktuelle Perspektiven auf der Grundlage klinischer Ergebnisse.

"Radiosurgery" is the term for a special concept in radiotherapy. It describes a percutaneous, stereotactically guided irradiation delivering a single high dose with collimated narrow beams. The precise stereotactic localization of the target point and a steep dose gradient outside the target volume allow the administration of high doses to a lesion without damage to adjacent normal tissue. Risk of necrosis, due to a dose volume relationship represents the limits of radiosurgery. Units for radiosurgery were designed at Stockholm using multiple external cobalt-60-gamma sources, at Boston operating with protons of a cyclotron, at Berkeley operating with helium ions accelerated by a synchrocyclotron. An attractive alternative to these complicated and expensive facilities is the use of a modified linear accelerator. At the German Cancer Research Center in Heidelberg such a system was developed and has been available for the treatment of patients since 1984. Though, data of over 100,000 patients with vascular malformations and cancer disease are available worldwide, the indication for this therapy is validated only for a minority of entities. In cases of inoperable arteriovenous malformations favourable results in achieving obliteration range between 60% and 100% were obtained. Median survival for solitary brain metastases with controlled, extracerebral tumor diseases were between nine and twelve months. Up to now, advantages of stereotactic irradiation for benign tumor masses could not be proven. Therefore, randomized trials should be initiated in this field, considering decisive improvements in local tumor control with techniques of microsurgery and fractionated, postoperative radiotherapy during the last few years.

Therapy monitoring of presacral recurrences after high-dose irradiation: value of PET, CT, CEA and pain score.

21 patients were followed by positron-emission-tomography (PET) FDG (18Flourdeoxyglucose) uptake, physical examination, CT and CEA levels after combined photon-neutron irradiation for inoperable recurrent rectal carcinoma. In order to evaluate the response to radiotherapy symptomatic relief, CEA levels, decrease of tumor volume measured by CT analysis were correlated with the FDG-uptake. The objective of this study was also to investigate if the level of FDG-uptake prior to radiotherapy or the early decrease after therapy can be used as a prognostic factor. Prior to radiotherapy sacral pain was the predominant symptom. All malignancies showed measurable tumor masses, evaluation of CEA levels and enhanced tracer accumulation of FDG in the PET cross section. The mean FDG-uptake before radiotherapy was 2.3 +/- 1.1 (range 1.1 to 5.0) in 21 patients in contrast to 1.9 +/- 0.7 (range 0.8 bis 4.0) three months after radiotherapy. In six patients FDG concentration values decreased to the range of normal soft tissue, moreover, two of them relapsed after six and 22 months. Elevated FDG-uptake of the sacral bone was noted in PET cross sections in two patients, while there was no evidence of osseous alterations in CT. Normal levels of CEA were achieved in 14 patients and complete or partial pain relief in 20 of 21 patients. A decrease of tumor volume of more than 50% was detected in the follow-up CT scans of three patients but no complete remission was found. The result suggests that enhanced glucose uptake is associated with recurrent rectal cancer. However, enhanced glycolytic activity is related not only to malignant cells but also to all proliferating cells. To distinguish between proliferation, repair, inflammation, and residual viable tumor cells is not possible and may be responsible for an unchanged or elevated FDG-uptake after radiotherapy.

[Comparison of dosimetric properties of 15-MV-photons and 14-MeV-neutrons in external stereotaxic convergence therapy]. / Vergleich der dosimetrischen Eigenschaften von 15-MV-Photonen und 14-MeV-Neutronen bei der externen stereotaktischen Konvergenztherapie.

Dosimetric properties for stereotaxic convergent beam therapy techniques with small field sizes have been investigated as well as for the linear accelerator Mevatron 77 as for the neutron generator KARIN. Additionally we also measured the dose distribution of single plane rotational therapy. As an indication of quality we calculated the V50 ratio as V50 = (F50-F90)/F90 and the corresponding V20 values. For the single plane irradiation there is a considerable difference in dose distribution in favour of photons. V50 (axial) amounts to 1.77 for photons and to 2.7 for neutrons. For the convergential non coplaner arc-therapy using nine plans there is nearly no difference in the high dose region including the 50%-isodose. V50 (axial): 1.16 and 1.6 respectively; (frontal) 1.36 and 1.35 respectively. Regarding to physical dose distributions our results indicate, that 14-MeV neutrons are suitable for high dosed stereotactic single irradiations.

Stereotactic single high dose radiation therapy of benign intracranial meningiomas.

Seventeen patients with intracranial meningiomas were treated with single high dose irradiation at the German Cancer Research Center in Heidelberg. Indications for radiosurgery included unresected tumors, gross disease remaining despite surgery, and recurrences. Therapy was carried out by a technique using multiple non-coplanar arc irradiations from a 15 MeV linear accelerator. This technique coupled with secondary tungsten collimators allowed a high concentration of the dose in the target volume with an extremely steep dose gradient at the field borders. The patients were treated with a single irradiation dose ranging from 10 to 50 Gy (mean of 29 Gy). Four of 17 patients died: one death was tumor-related and not attributable to the treatment, one died of a treatment related complication, and two patients died of intercurrent diseases. The remaining 13 of the 17 patients with a median follow-up time of 40 months have no evidence of tumor relapse. Late severe side effects include five patients with a large area of brain edema, three of which were concurred with tumor necrosis. We conclude from these initial data that single high doses of irradiation concentrated to the tumor volume by stereotaxic methods can achieve local tumor control. It is also clear from these data that the effective therapeutic dose range must be better defined.

[Neutron therapy for adenoid cystic carcinoma]. / Neutronentherapie bei adenoidzystischen Karzinomen. Erste Erfahrungen am DT-Neutronengenerator in Münster mit Literaturübersicht.

In the treatment of adenoid cystic carcinomas, certain situations such as inoperable tumors, macroscopic tumor residues following surgery and recurrences occurring with the previous therapeutic strategies (surgery and/or photon radiotherapy) are afflicted with frequent local recurrences. In these situations the use of radiotherapy with fast neutrons (densely ionizing radiation with high energy transfer) results in absence of recurrences in approx. 70% of the cases, according to data in the literature. The advantage of using neutrons lies in their greater biological effect on slowly growing tumors. In the Hospital for Radiotherapy of the Münster University neutron therapy has been applied since 1986 for these indications using a DT neutron generator (14 MeV). Based on the results obtained in the treatment of 8 patients and a review of the literature, indications for, treatment planning and implementing of neutron therapy is illustrated. Particular consideration is given to CT and MRT. Neutron therapy offers an alternative to previously existing treatment methods for locally advanced adenoid cystic carcinomas or highly differentiated malignomas of the salivary glands. Its effectiveness should be verified by studies involving larger numbers of patients and longer observation periods.

Neutron radiotherapy in adenoidcystic carcinoma: preliminary experience at the Münster neutron facility.

In adenoidcystic carcinoma macroscopic residual disease after surgery, inoperable and recurrent tumors are characterized by relapse rates up to 70% if treated according to conventional treatment strategies including photon radiotherapy. By neutron therapy a tumor control rate of 70% has been reported. At the d,T-generator (14 MeV) in Münster nine patients with adenoidcystic carcinoma of the salivary glands in locally advanced stage have been treated since 1/86. A combined modality schedule (30 Gy photon/5 to 10 Gy neutrons) used in the beginning has been replaced by a definitive neutron therapy (15 Gy) with single fractions of 1.0 to 1.3 Gy in five to six weeks. Treatment planning included CT/MRI as well as computer assisted dose calculations based on a specific software for neutron therapy. The volume reduction by neutron radiotherapy was 82% for advanced disease. Continuous remission was achieved in seven of nine patients in a short follow-up period of medium 15 months (from six to 28 months). The two recurrences occurred at the field edge. Based on this preliminary experience and on a survey of the literature the main issues for neutron therapy in salivary glands tumors in particular adenoidcystic carcinomas are discussed: histology, stage, tumor size, location, surgery, treatment planning and delivery, dose, and side effects. A long term evaluation of neutron therapy within a controlled clinical multicenter trial is proposed.

Quantification of subcutaneous fibrosis after combined photon neutron therapy.

Subcutaneous fibrosis is intensified for neutron therapy compared with photon irradiation. It can be a dose limiting factor. Quantification of subcutaneous fibrosis is possible using CT scans and measuring the tissue density in Hounsfield units. With this technique the time dependent development of fibrosis after neutron irradiation was determined in ten patients, who had been treated for recurrent recto-sigmoidal tumors.

Photon-neutron therapy for recurrent colorectal cancer--follow up and preliminary results.

26 patients with unresectable locally recurrent adenocarcinoma of the rectum were treated with a mixed beam schedule. 40 Gy photons were delivered to the whole pelvis followed by a neutron boost of 6.6 or 10 Gy. Neutron therapy was carried out with a 14 MeV d-t generator (KARIN) using an isocentric are technique. Fluctuation in neutron dose rate during irradiation was monitored by a computer which controlled the gantry speed. All patients were followed clinically by CEA monitoring and CT-scans. In 18 patients positron-emission-tomography (PET) was used to verify the therapeutic efficacy. All patients were symptomatic with severe pain prior to therapy. After a mean follow-up interval of 12.8 months (range six to 26 months), the palliative effect in terms of pain relief was excellent in 22 patients in spite of the poor general condition of most patients and the large tumor extension. In four patients, further pain symptoms developed again after six to nine months due to renewed tumor progression. We observed proctitis at late side effects in one, enteritis in two and a fistula in one patient six to ten months after therapy. Changes in tumor glucose metabolism were monitored by serial PET examinations in all patients. The typical pattern observed by PET was a decrease in the F-18-Deoxyglucose (FDG) accumulation, approximately six weeks after onset of therapy.

[Stereotactically targeted radiotherapy of cerebral arteriovenous malformations]. / Stereotaktisch gezielte Strahlentherapie zerebraler arteriovenöser Gefässmissbildungen.

A report is given about radiotherapy in 41 patients suffering from cerebral vessel anomalies. A modified linear accelerator was used in a moving field technique with multiple pendulum planes to apply single doses between 8 and 28 Gy by means of stereotaxis into the angiographically determined target volume. The medium follow-up is 23 months. The latency of radiogenic effects is between one and two years. Radiological controls with an interval of more than 18 months after therapy are available in 17 out of 41 patients. Angiographic investigation showed complete obliterations of pathological vessels in six out of these patients and partial obliterations in six patients; five patients remained unchanged. There were no acute complications. Seven patients presented neurological deficiencies with a latency of 6 to 12 months, however, in all cases but one they regressed completely. Even taking into consideration the small number of patients and the short time of observation, a comparison with the results of other radiotherapeutical proceedings allows to draw the conclusion that the presented technique of stereotaxic convergent-beam irradiation represents a relatively simple, reliable and, in case of precise indication, efficient method for the therapy of cerebral arteriovenous malformations.