Per-Olov Löfroth

The effect of fraction time in intensity modulated radiotherapy : theoretical and experimental evaluation of an optimisation problem.

BACKGROUND AND PURPOSE In intensity modulated radiotherapy (IMRT), the complexity and the number of treatment fields have expanded. This may imply that the delivery time for each fraction becomes prolonged. In a number of IMRT techniques used in the clinic, the delivery time per fraction is usually 10-15 min, sometimes more than 15 min. In studies on human skin, prolonged delivery time is shown to cause significant reduction of radiation effects compared with acute irradiation. In this paper the effect of changes in fraction delivery time was studied by in vitro irradiation of mammalian cells. MATERIAL AND METHODS Chinese hamster fibroblasts (V79-379-A) were used for simulating clinical situations. Most experiments were performed with 2Gy/fraction with 4-h intervals in 40-60 replicates. Each fraction was divided into different subfractions, simulating the delivery of a complicated treatment. The effect of changing the delivery time for each fraction was studied. Parameters for the cell survival curve and repair kinetics were determined experimentally. The same methods were also used for large fraction sizes (8Gy). The validity of the most widely used models in the literature, all derived from linear-quadratic formalism, were tested against the experimental results. RESULTS The effect of prolonging the fraction time for 2-Gy fractions was underestimated by the biological models. The experiments showed that 10-min prolonged delivery time gave a ratio between surviving fractions at 2Gy (S-ratio) of 1.054 with a 95% confidence interval (CI) 1.030-1.080, while the models predicted 1.007 and 1.009. Extending the fraction time to 20 min gave an S-ratio of 1.063 with CI of 1.045-1.080, while the models predicted 1.012 and 1.014. For 8-Gy fractions, there was a good agreement between predications and experimental results. The ratio between surviving fractions at 8Gy is 1.370 with CI of 1.300-1.440, while the models predicated 1.37 and 1.35. CONCLUSIONS The effect of prolonging fraction time at conventional dose/fraction is underestimated by biological models. Prolonging the fraction time will spare tissues with a fast DNA repair. There is a risk for sparing tumours. This should be considered when IMRT technique is implemented in the clinic.

High-precision conformal radiotherapy (HPCRT) of prostate cancer—a new technique for exact positioning of the prostate at the time of treatment

PURPOSE Biopsies taken 2 years after radiotherapy of localized prostate cancer indicate residual tumor cells in 20-60% of cases, and the prognosis for these patients is unfavorable. More precise methods of localization of the prostate are desirable to increase the dose to the prostate tumor and minimize the volume of adjacent sensitive tissues that are currently included in the planning target volume. We have sought a method to more accurately locate the prostate at the time of treatment, allowing a reduction of the volume of rectum and bladder included in the high dose region during dose escalation. METHODS AND RESULTS We have developed a new technique using a special urethral catheter (patent pending), containing markers that can be visualized by the radiotherapy machine for accurate positioning of the prostate. The catheter is used throughout the treatment planning procedure and the isocenter is placed on one of the markers. On the treatment couch the markers are visualized on port-films and with portal imaging immediately before dose delivery. A beam-center-marker on the accelerator makes it possible to adjust the isocenter position to within 1 mm, giving very high precision, independent of external fixation. The technique involves a simple patient setup. The method has been tested in five patients with conventional dose level (70 Gy) and in 24 patients in the first Scandinavian dose escalation study with external beam radiotherapy. No increase in acute side-effects was observed. CONCLUSION With the new high precision conformal radiotherapy (HPCRT) technique we have developed a technique that allows us to increase the dose to the prostate without excessive side effects. The method reduces the uncertainties in prostate localization, is easy to handle, and feasible in routine treatment.

A non-invasive method for fractionated stereotactic irradiation of brain tumors with linear accelerator

A new technique for fractionated stereotactic irradiation of intracranial lesions is described. The treatment is based on a versatile, non-invasive interface for stereotactic localization of the brain target imaged by computed tomography (CT), angiography or magnetic resonance tomography (MRT), and subsequent repetitive stereotactic irradiation of the target using a linear accelerator. The fractionation of the stereotactic irradiation was intended to meet the requirements of the basic principles of radiobiology. The radiophysical evaluation using phantoms, and the clinical results in a small number of patients, demonstrated a good reproducibility between repeated positionings of the target in the isocenter of the accelerator, and a high degree of accuracy in the treatment of brain lesions.

Apoptosis induced by low-dose and low-dose-rate radiation

It has been claimed that external radiation, as a treatment modality for malignant diseases, partly induces apoptosis. It is not known, however, whether therapeutic low‐dose and low‐dose‐rate radiation are able to induce apoptosis.

Hypofractionated Conformal Stereotactic Radiotherapy for Arteriovenous Malformations

OBJECTIVEArteriovenous malformations (AVMs) are congenital vascular lesions that are associated with high morbidity and mortality if left untreated. There are several options for treatment, including radiotherapy. Safe and effective single-fraction radiotherapy for patients with large AVMs has been considered difficult. METHODSBetween December 1986 and June 2001, 36 patients with cerebral AVMs were treated with hypofractionated conformal stereotactic radiotherapy at Umeå University Hospital. Twenty-nine patients have been followed angiographically to date and are reported in this study. RESULTSTwenty-four (83%) of 29 patients (mean AVM volume, 11.5 cm3) underwent complete obliteration of their AVMs. The rates of angiographically verified total obliteration at 2 years after treatment were 56% for AVMs 4 to 10 cm3 and 50% for AVMs larger than 10 cm3. The obliteration rate increased considerably with extended follow-up. Five years after treatment, the obliteration rates were 81% for AVMs 4 to 10 cm3 and 70% for AVMs larger than 10 cm3. CONCLUSIONHypofractionated conformal stereotactic radiotherapy may be an important alternative to single-fraction radiotherapy in patients with large AVMs or AVMs located in eloquent areas, because it allows the administration of a higher radiation dose than is possible to deliver in single-fraction radiosurgery. With our technique of hypofractionated conformal stereotactic radiotherapy, the rate of obliterating AVMs was comparable to that of single-dose radiosurgery, although the volumes of the irradiated AVMs in our study were larger than those reported previously.

Cell Cycle Disturbances and Mitotic Catastrophes in HeLa Hep2 Cells following 2.5 to 10 Gy of Ionizing Radiation

Purpose: Experimental radioimmunotherapy delivering absorbed doses of 2.5 to 10 Gy has been shown to cause growth retardation of tumors. The purpose of this study was to elucidate the sequential molecular and cellular events occurring in HeLa Hep2 cells exposed to such doses. Methods: Dose-response curves, activation of cell cycle checkpoints, and mitotic behavior were investigated in HeLa Hep2 cells following 2.5- to 10-Gy irradiation by carrying out 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, Western blots, fluorescence-activated cell sorting analysis, and immunofluorescence stainings. Terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling staining was used to detect apoptosis. Results: A G2-M arrest was shown by fluorescence-activated cell sorting analysis. p53 and p21 were found to be up-regulated but were not immediately related to the arrest. The G2-M arrest was transient and the cells reentered the cell cycle still containing unrepaired cellular damage. This premature entry caused an increase of anaphase bridges, lagging chromosomal material, and multipolar mitotic spindles as visualized by propidium iodide staining and immunofluorescence staining with α-tubulin and γ-tubulin antibodies. Furthermore, a dose-dependent significant increase in centrosome numbers from 12.6 ± 6.6% to 67 ± 5.3% was identified as well as a dose-dependent increase of polyploid cells from 2.8 ± 1.3% to 17.6 ± 2.1% with the highest absorbed dose of 10 Gy. These disturbances caused the cells to progress into mitotic catastrophe and a fraction of these dying cells showed apoptotic features as displayed by terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling staining 5 to 7 days after irradiation. Conclusion: An absorbed dose of 2.5 to 10 Gy was shown to force HeLa Hep2 cells into mitotic catastrophe and delayed apoptosis. These might be important cell death mechanisms involved in tumor growth retardation following radioimmunotherapy of solid tumors.

Prospective evaluation of urinary and intestinal side effects after BeamCath® stereotactic dose-escalated radiotherapy of prostate cancer

BACKGROUND New data suggest that a higher radiation dose will improve outcome in treatment of localized prostate cancer. External beam radiotherapy (EBRT) may on the other hand induce disturbances in the patients urinary and intestinal function. Since 1997, 195 patients have been treated with a stereotactic boost of 4-8 Gy added to conventional 70 Gy EBRT. Late side effects were prospectively evaluated 3 years after dose-escalated EBRT. METHODS Urinary and intestinal problems were prospectively evaluated with a validated self-assessment questionnaire, the Prostate Cancer Symptom Scale (PCSS). Two hundred and eighty-seven patients completed the questionnaire at the 1 year follow-up, and 153 at 3 years after treatment. Pre-treatment mean age was 66 years. One hundred and sixty-eight patients were treated with the conformal technique and 195 were treated with the dose-escalated stereotactic BeamCath technique. Mean total dose in the conformal group (< or =70 Gy) was 66 Gy (60.8-70.4 Gy). The dose-escalated group consists of three dose levels, 74 Gy (n = 68), 76 Gy (n = 74), and 78 Gy (n = 53). RESULTS Analyzing the whole population 3 years after treatment, urgency and starting problems decreased in comparison to pre-treatment. A minor increase in urinary incontinence was reported 3 years after treatment in comparison to pre-treatment. No increases in other urinary symptoms were reported. Intestinal symptoms were slightly increased during the follow-up period in comparison to pre-treatment. Dose escalation with stereotactic EBRT (74-78 Gy) did not increase gastrointestinal or genitourinary late side effects at 1 year or 3 years in comparison to doses < or =70 Gy. CONCLUSIONS The stereotactic BeamCath EBRT technique facilitates safe dose escalation of patients with prostate cancer.

Planning of radiotherapy for patients with hip prosthesis

The effects of a hip prosthesis on the dose distribution when treating pelvic cancer have been evaluated. A prosthesis of titanium alloy in a water phantom was used as a model. Photon radiation beams with energies of 6, 20, and 50 MV and with a focus phantom distance of 100 cm were directed against the prosthesis. The dose profiles at different depths were measured with the RFA-7 system. The sphere of the prosthesis was inhomogeneous. The dose in a beam behind the prosthesis was reduced with the order of 10-40% and the largest distortion was behind the shaft. Using an opposed four-field technique with the same weight on all the fields, the dose reduction was as large as 7-12% in a string across the target behind the end of the shaft. With 50% weight on the lateral fields, the dose reduction was 4-8% of the average dose. Such an uneven dose distribution may decrease the curability, and a treatment technique not including the prosthesis should be preferred. Finally, a local increase of the dose close to the prosthesis seems to be of limited practical concern even at the highest energies.

Liquid ionization chamber measurements of dose distributions in small 6 MV photon beams

A new liquid ionization chamber (LIC) design optimized for high spatial resolution was used for measurements of dose distributions in radiation fields intended for stereotactic radiosurgery (SRS). This work was mainly focused on the properties of this detector in radiation fields from linear accelerators for clinical radiotherapy (pulsed radiation with dose rates from approximately 0.5 to 5 Gy min-1 and beam diameters down to 8 mm). The narrow beams used in stereotactic radiosurgery require detectors with small sizes in order to provide a good spatial resolution. The LIC is investigated to see whether it can be used as a detector for dose measurements in beams currently used for stereotactic radiosurgery. Its properties are compared with those of silicon diodes. The comparisons include output factor (OF), depth dose and profile measurements in 6 MV photon fields of different sizes. For OF measurements, an NACP air ionization chamber was also used in the comparison. The dependence of the response on the detector orientation in the photon beam is also investigated for the diodes and the LIC. The results suggest that LICs can provide better properties than diodes for measuring dose distributions in narrow photon beams.

Combined castration and fractionated radiotherapy in an experimental prostatic adenocarcinoma

PURPOSE The present study using the Dunning R3327-PAP rat prostatic adenocarcinoma model was designed to study the effect on tumor growth of castration prior to or after irradiation with 20-25 Gy as compared with either irradiation or castration alone. METHODS AND MATERIALS Rats were bilaterally orchidectomized. During the irradiation procedure the nonanesthetized animals were held in a metallic frame with a strong cotton net and they were observed by means of a video camera. The suboptimal irradiation dose was given once daily with a 4-MeV linear accelerator, 4-5 Gy/fraction, during 5 consecutive days. Tumor volumes and rat weights were followed. At the end point of the study the animals were sacrificed and the tumors were morphometrically analyzed. RESULTS The combination of irradiation and castration delayed tumor regrowth better than irradiation alone with the same suboptimal dose. Castration before irradiation delayed tumor regrowth more efficiently than castration after irradiation. However, castration alone delayed tumor regrowth even more effectively than suboptimal irradiation doses combined with castration. CONCLUSIONS In combination with suboptimal irradiation neoadjuvant androgen deprivation was more inhibitory to rat prostatic adenocarcinoma regrowth than adjuvant androgen deprivation. Irradiation with suboptimal doses combined with castration may cause an earlier relapse to androgen-independent tumor growth than castration alone.