Ingemar Näslund

Stereotactic High Dose Fraction Radiation Therapy of Extracranial Tumors Using An Accelerator: Clinical experience of the first thirty-one patients

A stereotactic body frame with a fixation device has been developed for stereotactic radiation therapy of extracranial targets, a precision localization and positioning system in analogy with the stereotactic head frames used for intracranial targets. Results of the first 42 treated tumors in 31 patients are presented. Most of the patients had solitary tumors in liver, lung or retroperitoneal space. Clinical target volumes ranged from 2 to 622 cm3 (mean 78 cm3) and minimum doses to the planning target volumes (PTV) of 7.7-30 Gy/fraction (mean 14.2 Gy) were given on 1-4 occasions to a total minimum dose to the PTVs of 7.7-45 Gy (mean 30.2 Gy) to the periphery of the PTV and total mean doses to the PTVs of 8-66 Gy (mean 41 Gy). The central part of the tumor was usually given about 50% higher dose compared to that of the periphery of the PTV by a planned inhomogeneous dose distribution. Some of the patients received stereotactic radiation therapy concomitantly to more than one target, in others new metastases were also treated which appeared during the follow-up period. We observed a local rate of no progressive disease of 80% during a follow-up period of 1.5-38 months. Fifty percent of the tumors decreased in size or disappeared.

STEREOTACTIC RADIOTHERAPY OF MALIGNANCIES IN THE ABDOMEN Methodological aspects

A method for stereotactic high-dose radiotherapy of malignancies in the abdomen has been developed. A stereotactic frame for the body has been developed and a method for fixation of the patient in the frame is described. The reproducibility in the stereotactic system of tumours in the liver and the lung was found to be within 5-8 mm for 90% of the patient set-ups. The diaphragmatic movements were reduced to 5-10 mm, by applying a pressure on the abdomen. An analytical method is used to calculate dose distributions for a continuum of beams in an isocentric treatment technique. The advantage of a heterogeneous target dose is demonstrated and proposed for the present application. A non-coplanar treatment technique, using eight individually shaped beams is proposed and has been used for patient treatments. The dose distribution for a patient with a metastasis in the liver is shown as well as dose volume histograms for the target and the liver.

Extracellular 8-oxo-dG as a sensitive parameter for oxidative stress in vivo and in vitro

8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG) is one of the mutagenic base modifications produced in DNA by the reaction of reactive oxygen species. The biological significance of 8-oxo-dG is shown by the existence of repair pathways that are able to recognize and remove this lesion from both DNA and the nucleotide pool. The final outcome of these evolutionarily conserved repair mechanisms in man is excretion of 8-oxo-dG/8-oxo-Gua from the intracellular to extracellular milieu including the blood plasma and urine. The aim of this investigation was to establish dose response relations for radiation-induced appearance of extracellular 8-oxo-dG in cellular model systems. Here we report on excretion of 8-oxo-dG after in vitro irradiation of whole blood and isolated lymphocytes with clinically relevant doses. We find that this excretion is dependent on dose and individual repair capacity, and that it saturates above doses of 0.5–1 Gy of gamma radiation. Our data also suggest that the nucleotide pool is a significant target that contributes to the levels of extracellular 8-oxo-dG; hence the mutagenic target for oxidative stress is not limited to the DNA molecule only. We conclude that extracellular 8-oxo-dG levels after in vitro irradiation have a potential to be used as a sensitive marker for oxidative stress.

Electrochemical treatment of tumours

The electrochemical treatment (EChT) of tumours implies that tumour tissue is treated with a continuous direct current through two or more electrodes placed in or near the tumour. The treatment offers considerable promise of a safe, simple and relatively noninvasive anti-tumour therapy for treatment of localised malignant as well as benign tumours. Although more than 10,000 patients have been treated in China during the past 10 years, EChT has not yet been universally accepted. The reason for this is the lack of essential preclinical studies and controlled clinical trials. Uncertainties regarding the destruction mechanism of EChT also hinder the development of an optimised and reliable dose-planning methodology. This article reviews the collected Chinese and occidental experiences of the electrochemical treatment of tumours, alone and in combination with other therapies. The current knowledge of the destruction mechanism underlying EChT is presented along with different approaches towards a dose planning methodology. In addition, we discuss our view of different important parameters that have to be accounted for, if clinical trials are to be initiated outside of China.

Effects of information supply on satisfaction with information and quality of life in cancer patients receiving curative radiation therapy

In order to test the efficacy of various information inputs, 210 consecutive cancer patients were randomized to one of three information conditions before the start of curative radiation treatment: (1) standard information plus group and repeated individual information (n=70), (2) standard information plus brochure (n=70), and (3) standard information only (n=70). Patients completed questions regarding satisfaction with information, anxiety, depression, subjective distress and quality of life at inclusion, and 1h before the start of the radiation therapy treatment (approximately 4 weeks later). Patients receiving standard information plus group and repeated individual information were significantly more satisfied with the information than were patients in the remaining two groups. There were no differences with respect to any of the other outcome measures. This study has shown that the nurses group and individual information was of significant importance in preparing the patients for the procedure of receiving radiation therapy.

Dose distributions in SBRT of lung tumors: Comparison between two different treatment planning algorithms and Monte-Carlo simulation including breathing motions

In stereotactic body radiotherapy (SBRT) of lung tumors, dosimetric problems arise from: 1) the limited accuracy in the dose calculation algorithms in treatment planning systems, and 2) the motions with the respiration of the tumor during treatment. Longitudinal dose distributions have been calculated with Monte Carlo simulation (MC), a pencil beam algorithm (PB) and a collapsed cone algorithm (CC) for two spherical lung tumors (2 cm and 5 cm diameter) in lung tissue, in a phantom situation. Respiratory motions were included by a convolution method, which was validated. In the static situation, the PB significantly overestimates the dose, relative to MC, while the CC gives a relatively accurate estimate. Four different respiratory motion patterns were included in the dose calculation with the MC. A “narrowing” of the longitudinal dose profile of up to 20 mm (at about 90% dose level) is seen relative the static dose profile calculated with the PB.

Hyperfractionated Radiotherapy of Bladder Cancer: A ten-year follow-up of a randomized clinical trial

One hundred and sixty-eight patients with invasive bladder cancer, T2-T4, were randomized to one of two treatments; hyperfractionation with 1 Gy 3 times a day to a total of 84 Gy or conventional treatment 2 Gy once a day to a total of 64 Gy. Both treatments were given over 8 weeks with a rest interval of 2 weeks in the middle of the treatment period. The present report included all patients after a follow-up period of at least 10 years. The survival benefit from hyperfractionation previously reported after 5 years is still evident after 10 years. The effect was detectable in all three subsets (T2, T3 and T4) and in the pooled data. However, it only reached statistical significance in the T3 subset and in the total pooled data set. Local control was also assessed by cystoscopy and cytology on bladder washouts. An improvement in local control was seen at all follow-up intervals and at all times out to 10 years but the differences were not statistically significant due to the falling number of patients available for assessment. Complications in the bowel requiring surgical treatment were more common in the hyperfractionated group but the difference was not significant since this group consisted of a greater number of patients alive and therefore at risk. This trial showed that the benefit of the hyperfractionated schedule persisted over a 10-year follow-up period, both for local control and survival.

Stereotactic Radiotherapy of Extracranial Targets

Abstract A method for Stereotactic Radiotherapy of extracranial targets was developed. The localisation modality is similar to that of intracranial stereotaxy. The patient is immobilized in a body-frame with vacuum pillows. The method is in clinical use.

Radiation-induced stress response in peripheral blood of breast cancer patients differs between patients with severe acute skin reactions and patients with no side effects to radiotherapy

The aim of the study was to compare the radiation-induced oxidative stress response in blood samples from breast cancer patients that developed severe acute skin reactions during the radiotherapy, with the response in blood samples from patients with no side effects. Peripheral blood was collected from 12 breast cancer patients showing no early skin reactions after radiotherapy (RTOG grade 0) and from 14 breast cancer patients who developed acute severe skin reactions (RTOG grade 3-4). Whole blood was irradiated with 0, 5 and 2000mGy γ-radiation and serum was isolated. The biomarker for oxidative stress, 8-oxo-dG, was analyzed in the serum by a modified ELISA. While a significant radiation-induced increase of serum 8-oxo-dG levels was observed in serum of the RTOG 0 patients, no increase was seen in serum of the RTOG 3-4 patients. The radiation induced increase in serum 8-oxo-dG levels after 5mGy did not differ significantly from the increase observed for 2000mGy in the RTOG 3-4 cohort, thus no dose response relation was observed. A receiver operating characteristic (ROC) value of 0.97 was obtained from the radiation-induced increase in 8-oxo-dG indicating that the assay could be used to identify patients with severe acute adverse reactions to radiotherapy. The results show that samples of whole blood from patients, classified as highly radiosensitive (RTOG 3-4) based on their skin reactions to radiotherapy, differ significantly in their oxidative stress response to ionizing radiation compared to samples of whole blood from patients with no skin reactions (RTOG 0). Extracellular 8-oxo-dG is primarily a biomarker of nucleotide damage and the results indicate that the patients with severe acute skin reactions differ in their cellular response to ionizing radiation at the level of induction of oxidative stress or at the level of repair or both.

Development of light ion therapy at the Karolinska Hospital and Institute

Recent developments in radiation therapy have made it possible to optimize the high dose region to cover almost any target volume and shape at the same time as the dose level to adjacent organs at risk is acceptable. Further implementations of IMRT (Intensity Modulated Radiation Therapy), and inverse treatment planning using already available technologies but also foreseeable improved design of therapy accelerators delivering electron- and photon beams, will bring these advances to the benefit of a broad population of cancer patients. Protons will therefore generally not be needed since in most situations the improvement will be insignificant or moderate due to the large lateral penumbra with deep proton therapy. A further step would be to use He-ions, which have only half the penumbra width of protons and still a fairly low-LET in the spread-out Bragg peak. There is however still a group of patients that cannot be helped by these advances as the tumor might be radioresistant for the presently utilized low ionization density beam qualities. The ultimate step in the therapy development process should therefore be to optimize the beam quality for each tumor-normal tissue situation. To facilitate beam quality optimization light ions are needed. It is argued that in many radioresistant tumors a dose-mean LET of 25-50 eV/nm in the target would be optimum as then tumor cells will be lost in the highest proportion through apoptotic cell kill and the superficial tissues will still be irradiated with a fairly low LET. Light ions using Li, Be, B, and C would then be the ideal choice. In this paper a light ion facility is outlined for the Karolinska University Hospital facilitating both dose distribution and beam quality optimization.