Björn Zackrisson

The value of pretreatment cell kinetic parameters as predictors for radiotherapy outcome in head and neck cancer: a multicenter analysis.

PURPOSE The aim of this study was to assess the potential of pre-treatment cell kinetic parameters to predict outcome in head and neck cancer patients treated by conventional radiotherapy. MATERIALS AND METHODS Data from 11 different centers were pooled. Inclusion criteria were such that the patients received radiotherapy alone, and that the radiotherapy was given in an overall time of at least 6 weeks with a dose of at least 60 Gy. All patients received a tracer dose of either iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) intravenously prior to treatment and a tumor biopsy was taken several hours later. The cell kinetic parameters labeling index (LI), DNA synthesis time (Ts) and potential doubling time (Tpot) were subsequently calculated from flow cytometry data, obtained on the biopsies using antibodies against I/BrdUrd incorporated into DNA. Each center carried out their own flow cytometry analysis. RESULTS From the 11 centers, a total of 476 patients conforming to the inclusion criteria were analyzed. Median values for overall time and total dose were 49 days and 69 Gy, respectively. Fifty one percent of patients had local recurrences and 53% patients had died, the majority from their disease. Median follow-up was 20 months; being 30 months for surviving patients. Multivariate analysis revealed that T-stage, maximum tumor diameter, differentiation grade, N-stage, tumor localization and overall time correlated with locoregional control, in decreasing order of significance. For the cell kinetic parameters, univariate analysis showed that only LI was significantly associated with local control (P=0.02), with higher values correlating with a worse outcome. Ts showed some evidence that patients with longer values did worse, but this was not significant (P=0.06). Tpot showed no trend (P=0.8). When assessing survival in a univariate analysis, neither LI nor Tpot associated with outcome (P=0.4, 0.4, respectively). Surprisingly, Ts did correlate with survival, with longer values being worse (P=0.02). In the multivariate analysis of local control, LI lost its significance (P=0.16). CONCLUSIONS The only pretreatment kinetic parameter for which some evidence was found for an association with local control (the best end-point for testing the present hypothesis) was LI, not Tpot, and this evidence disappeared in a multivariate analysis. It therefore appears that pretreatment cell kinetic measurements carried out using flow cytometry, only provide a relatively weak predictor of outcome after radiotherapy in head and neck cancer.

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.

DEDICATED MAGNETIC RESONANCE IMAGING IN THE RADIOTHERAPY CLINIC

PURPOSE To introduce a novel technology arrangement in an integrated environment and outline the logistics model needed to incorporate dedicated magnetic resonance (MR) imaging in the radiotherapy workflow. An initial attempt was made to analyze the value and feasibility of MR-only imaging compared to computed tomography (CT) imaging, testing the assumption that MR is a better choice for target and healthy tissue delineation in radiotherapy. METHODS AND MATERIALS A 1.5-T MR unit with a 70-cm-bore size was installed close to a linear accelerator, and a special trolley was developed for transporting patients who were fixated in advance between the MR unit and the accelerator. New MR-based workflow procedures were developed and evaluated. RESULTS MR-only treatment planning has been facilitated, thus avoiding all registration errors between CT and MR scans, but several new aspects of MR imaging must be considered. Electron density information must be obtained by other methods. Generation of digitally reconstructed radiographs (DRR) for x-ray setup verification is not straight forward, and reliable corrections of geometrical distortions must be applied. The feasibility of MR imaging virtual simulation has been demonstrated, but a key challenge to overcome is correct determination of the skeleton, which is often needed for the traditional approach of beam modeling. The trolley solution allows for a highly precise setup for soft tissue tumors without the invasive handling of radiopaque markers. CONCLUSIONS The new logistics model with an integrated MR unit is efficient and will allow for improved tumor definition and geometrical precision without a significant loss of dosimetric accuracy. The most significant development needed is improved bone imaging.

Does electron and proton therapy reduce the risk of radiation induced cancer after spinal irradiation for childhood medulloblastoma? A comparative treatment planning study

Aim The aim of this treatment planning comparison study was to explore different spinal irradiation techniques with respect to the risk of late side-effects, particularly radiation-induced cancer. The radiotherapy techniques compared were conventional photon therapy, intensity modulated x-ray therapy (IMXT), conventional electron therapy, intensity/energy modulated electron therapy (IMET) and proton therapy (IMPT). Material and methods CT images for radiotherapy use from five children, median age 8 and diagnosed with medulloblastoma, were selected for this study. Target volumes and organs at risk were defined in 3-D. Treatment plans using conventional photon therapy, IMXT, conventional electron therapy, IMET and IMPT were set up. The probability of normal tissue complication (NTCP) and the risk of cancer induction were calculated using models with parameters-sets taken from published data for the general population; dose data were taken from dose volume histograms (DVH). Results Similar dose distributions in the targets were achieved with all techniques but the absorbed doses in the organs-at-risk varied significantly between the different techniques. The NTCP models based on available data predicted very low probabilities for side-effects in all cases. However, the effective mean doses outside the target volumes, and thus the predicted risk of cancer induction, varied significantly between the techniques. The highest lifetime risk of secondary cancers was estimated for IMXT (30%). The lowest risk was found with IMPT (4%). The risks associated with conventional photon therapy, electron therapy and IMET were 20%, 21% and 15%, respectively. Conclusion This model study shows that spinal irradiation of young children with photon and electron techniques results in a substantial risk of radiation-induced secondary cancers. Multiple beam IMXT seems to be associated with a particularly high risk of secondary cancer induction. To minimise this risk, IMPT should be the treatment of choice. If proton therapy is not available, advanced electron therapy may provide a better alternative.

p53 Expression and cell proliferation in squamous cell carcinomas of the head and neck

Background. In squamous cell carcinoma of the head and neck (SCCHN), overexpression of the p53 protein has been found in 34‐80% of the tumors studied. No data are available regarding p53 expression versus tumor cell proliferation and prognosis for this tumor type.

Optimized MLC-beam arrangements for tangential breast irradiation

BACKGROUND AND PURPOSE Very large numbers of women are treated with tangential breast irradiation after breast-conserving surgery due to mammary carcinoma. The aim of this study was to improve a conventional treatment plan by modifying the dose intensity in the beams to reduce the absorbed dose outside the planning target volume (PTV) and to reduce the absorbed dose variation inside the PTV diotherapy of mammary carcinoma. MATERIALS AND METHODS Treatment planning was performed both with conventional technique and with a simple intensity modulation technique for 12 consecutive patients. RESULTS In all cases a higher degree of dose conformity was obtained with the dose intensity modulation technique. The relative gain was found to be similar for all patients irrespective of the size of the target volume or the irradiated lung volume. CONCLUSION Simple manual intensity modulation can be used to improve the dose distribution in tangential breast irradiation. With modern accelerators the increased time for this technique is less than 2 min per fraction.

Effects of Sucralfate on Mucositis During and Following Radiotherapy of Malignancies in the Head and Neck Region: A double-blind placebo-controlled study

Radiotherapy of head and neck malignancies is accompanied by oral discomforts, such as epithelitis, pain and functional impairment. This can lead to chronic sequalae with subjective distress such as loss of taste and xerostomia and pronounced decrease in quality of life. Thus, the need to reduce the mucosal damage following radiotherapy is obvious. Therefore, we investigated the possible ability of sucralfate, an aluminium hydroxide complex of sulphated sucrose used in the treatment of gastric ulcer, in preventing oral discomfort in patients treated with curative intent for malignancies in the head and neck region. The study was double-blind, placebo-controlled and randomized and included 50 consecutive patients. The study demonstrated that the proportion of patients with severe mucosal reactions was significantly lower in the sucralfate group than in the placebo group.

Number of patients potentially eligible for proton therapy

A group of Swedish radiation oncologists and hospital physicists have estimated the number of patients in Sweden suitable for proton beam therapy in a facility where one of the principal aims is to facilitate randomized and other studies in which the advantage of protons can be shown and the magnitude of the differences compared with optimally administered conventional radiation treatment, also including intensity-modulated radiation therapy (IMRT) and brachytherapy, can be shown. The estimations have been based on current statistics of tumour incidence in Sweden, number of patients potentially eligible for radiation treatment, scientific support from clinical trials and model dose planning studies and knowledge of the dose-response relations of different tumours together with information on normal tissue complication rates. In Sweden, it is assessed that between 2200 and 2500 patients annually are eligible for proton beam therapy, and that for these patients the potential therapeutic benefit is so great as to justify the additional expense of proton therapy. This constitutes between 14–15% of all irradiated patients annually.

Matching of electron and photon beams with a multi-leaf collimator.

Multi-leaf collimators (MLCs) are offered as an accessory to many accelerators for radiation therapy. However, beam edges generated with these collimators are not as smooth as can be achieved with individually made blocks. The clinical drawbacks and benefits of this ripple were evaluated both for single field treatments and for combined adjacent fields of different beam qualities. In this investigation the MLC-collimated beams of the MM50 racetrack microtron were studied. The distance between the field edge and the 90% isodose was measured at the reference depth for four beam qualities (20 MV photons and 10, 20 and 50 MeV electrons). This distance was found to vary from approximately 6 mm for straight beam edges (i.e., all collimator leaves aligned) to approximately 2 mm from the tip of the leaves for a saw-tooth shaped beam edge. The over- and under-dosage in the joint between combined adjacent fields was found to be typically +/- 10% in small volumes. Improved clinical techniques using adjacent photon and electron fields with the same isocentre and source position (without moving the gantry) have been developed. For treatments of the breast, including the mammary chain, a uniform dose distribution was created with special attention given to the irradiation of the heart and lung outside the target volume. A method for head and neck treatments was optimised to give uniform dose distribution in the joint between the photon and electron fields and a method of treating the mediastinum, including the chest wall in front of the left lung, was analysed with respect to dose uniformity in the tumour and shielding of the lung.

Biological response to radiation therapy.

In an investigation by the Swedish Cancer Society, the present status, critical issues and future aspects and potentials were described by an expert group for each of nine major areas of radiation therapy research. This article deals with biological response to radiation. Separate sections deal with molecular responses to radiation, the stem cell and clonogenic cell concepts and the importance of cell proliferation, cell and tissue responses to doses above and below 1 Gy, respectively, the potential role of intercellular signalling pathways, the so-called bystander effect and radiation biology-based therapy planning and treatment optimization.