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  • Adell, Gunnar, 1953-, et al. (författare)
  • Decreased tumor cell proliferation as an indicator of the effect of preoperative radiotherapy of rectal cancer
  • 2001
  • Ingår i: International Journal of Radiation Oncology, Biology, Physics. - 0360-3016 .- 1879-355X. ; 50:3, s. 659-663
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Rectal cancer is a common malignancy, with significant local recurrence and death rates. Preoperative radiotherapy and refined surgical technique can improve local control rates and disease-free survival.PURPOSE: To investigate the relationship between the tumor growth fraction in rectal cancer measured with Ki-67 and the outcome, with and without short-term preoperative radiotherapy.Method: Ki-67 (MIB-1) immunohistochemistry was used to measure tumor cell proliferation in the preoperative biopsy and the surgical specimen.MATERIALS: Specimens from 152 patients from the Southeast Swedish Health Care region were included in the Swedish rectal cancer trial 1987-1990.RESULTS: Tumors with low proliferation treated with preoperative radiotherapy had a significantly reduced recurrence rate. The influence on death from rectal cancer was shown only in the univariate analysis. Preoperative radiotherapy of tumors with high proliferation did not significantly improve local control and disease-free survival. The interaction between Ki-67 status and the benefit of radiotherapy was significant for the reduced recurrence rate (p = 0.03), with a trend toward improved disease-free survival (p = 0.08). In the surgery-alone group, Ki-67 staining did not significantly correlate with local recurrence or survival rates.CONCLUSION: Many Ki-67 stained tumor cells in the preoperative biopsy predicts an increased treatment failure rate after preoperative radiotherapy of rectal cancer.
  • Daşu, Alexandru, et al. (författare)
  • Superfractionation as a potential hypoxic cell radiosensitizer: prediction of an optimum dose per fraction
  • 1999
  • Ingår i: International Journal of Radiation Oncology, Biology, Physics. - 0360-3016 .- 1879-355X. ; 43:5, s. 1083-1094
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: A dose "window of opportunity" has been identified in an earlier modeling study (1) if the inducible repair variant of the LQ model is adopted instead of the pure LQ model, and if all survival curve parameters are equally modified by the presence or absence of oxygen. In this paper we have extended the calculations to consider survival curve parameters from 15 sets of data obtained for cells tested at low doses using clonogenic assays.METHODS AND MATERIALS: A simple computer model has been used to simulate the response of each cell line to various doses per fraction in multifraction schedules, with oxic and hypoxic cells receiving the same fractional dose. We have then used pairs of simulated survival curves to estimate the effective hypoxic protection (OER') as a function of the dose per fraction.RESULTS: The resistance of hypoxic cells is reduced by using smaller doses per fraction than 2 Gy in all these fractionated clinical simulations, whether using a simple LQ model, or the more complex LQ/IR model. If there is no inducible repair, the optimum dose is infinitely low. If there is inducible repair, there is an optimum dose per fraction at which hypoxic protection is minimized. This is usually around 0.5 Gy. It depends on the dose needed to induce repair being higher in hypoxia than in oxygen. The OER' may even go below unity, i.e. hypoxic cells may be more sensitive than oxic cells.CONCLUSIONS: If oxic and hypoxic cells are repeatedly exposed to doses of the same magnitude, as occurs in clinical radiotherapy, the observed hypoxic protection varies with the fractional dose. The OER' is predicted to diminish at lower doses in all cell lines. The loss of hypoxic resistance with superfractionation is predicted to be proportional to the capacity of the cells to induce repair, i.e. their intrinsic radioresistance at a dose of 2 Gy.
  • Denekamp, Juliana, et al. (författare)
  • Hyperfractionation as an effective way of overcoming radioresistance
  • 1998
  • Ingår i: International Journal of Radiation Oncology, Biology, Physics. - 0360-3016 .- 1879-355X. ; 42:4, s. 705-709
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: To model the influence of hypoxic radioprotection in fractionated treatments over a range of fraction sizes. To determine whether there is a "therapeutic window" of dose per fraction where hypoxic radioresistance could be reduced, and if so, where it occurs in different cell lines. MATERIALS AND METHODS: A mathematical model has been used to simulate the response of cells to low doses of radiation, in the region of clinical interest. We have used the inducible repair variant of the linear quadratic (LQ) equation, with a hypersensitive region (alphaS) at low doses that gradually transforms to the accepted "resistance" in the shoulder region (alphaR). It contains two new parameters, the ratio alphaS/alphaR, and D(C). We have accepted that the "induction dose" D(C) is modified by anoxia to the same extent as the other parameters. We have initially modeled using theoretical parameters and then checked the conclusions with 14 sets of published experimental data for cell lines investigated for inducible repair. RESULTS: We have computed the clinical hypoxic protection (OER') as a function of dose per fraction in simulations of clinical fractionated schedules. We have identified a therapeutic window in terms of dose per fraction at about 0.5 Gy, where the OER' is minimized, regardless of the precise cell survival curve parameters. The minimum OER' varies from one cell line to another, falling to about 1.0 if alphaS/alphaR = 6-10 and even far below 1.0 if alphaS/alphaR > or = 20. DISCUSSION: Hyperfractionation using 0.5 Gy fractions may therefore be more effective than oxygen mimetic chemical sensitizers, since it could even make some tumor cells more sensitive than oxic normal tissues. The tumor lines that benefit most from this type of sensitization are those with the highest intrinsic oxic radioresistance, i.e. those with high SF2 values.
  • Rojas, Ana Maria, et al. (författare)
  • Carbogen and nicotinamide as radiosensitisers in a murine mammary carcinoma using conventional and accelerated radiotherapy
  • 1996
  • Ingår i: International Journal of Radiation Oncology, Biology, Physics. - 0360-3016 .- 1879-355X. ; 34:2, s. 357-365
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: To compare the radiosensitivity of mouse tumors treated in air with conventional and accelerated radiotherapy with that of tumors treated in carbogen alone or carbogen combined with nicotinamide. METHODS AND MATERIALS: CaNT mammary tumors were irradiated with either 30 x-ray fractions in 6 weeks or 40 fractions in 26 days in air, carbogen alone, or carbogen combined with 120 mg/kg of nicotinamide (NAM), the latter given intraperitonealy 30 min before each fraction. The response to treatment was assessed using local control, weight loss, and metastasis-free survival. RESULTS: Both carbogen and carbogen plus nicotinamide significantly increased tumor radiosensitivity; enhancement ratios (ERs) in the 6-week regimen were similar to those seen in the accelerated schedule. The majority of the effect was achieved by carbogen alone but the addition of NAM further enhanced tumor radiosensitization (ERs of 1.5 and 1.4 for carbogen in the conventional and accelerated schedule, respectively, were significantly lower than ERs of 1.7 and 1.6 obtained with carbogen plus nicotinamide; p < or = 0.005). Treatment protraction significantly increased radioresistance, especially when tumors were treated under air. An extra 1.5 Gy per day was required in air to counterbalance proliferation; in carbogen alone and carbogen plus nicotinamide a dose loss of 0.9 and 0.6 Gy per day was observed, respectively. Compared with treatments in air alone delivered in 6 weeks, acceleration of treatment combined with carbogen and nicotinamide gave the greatest increase in tumor radiosensitization (ER = 1.9). No toxic side effects and no detrimental changes in body weight were encountered when the sensitizers were administered 30 times (one fraction per day) or 40 times (two fractions per day). In both regimens, the incidence of metastases in mice treated with carbogen or carbogen plus nicotinamide was similar to that seen in animals treated in air. There was, however, a nonsignificant trend of a higher proportion of mice with metastasis in the accelerated schedule compared with the 6-week schedule. CONCLUSIONS: In both conventional and accelerated experimental radiotherapy, carbogen alone or combined with a small clinically relevant dose of NAM were well tolerated, achieved large and significant increases in radiosensitization, and did not affect the incidence of metastases. The sparing of damage, resulting from extending the overall treatment time, was less when the sensitizers were administered than when irradiations were performed in air. The study suggests that clinical radiotherapy regimens, which aim to reduce hypoxic and/or tumor clonogen proliferation, would benefit from the use of carbogen, especially if the gas is combined with nicotinamide and treatment acceleration.
  • Adjeiwaah, Mary, 1980-, et al. (författare)
  • Dosimetric Impact of MRI Distortions : A Study on Head and Neck Cancers
  • 2019
  • Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier. - 0360-3016 .- 1879-355X. ; 103:4, s. 994-1003
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: To evaluate the effect of magnetic resonance (MR) imaging (MRI) geometric distortions on head and neck radiation therapy treatment planning (RTP) for an MRI-only RTP. We also assessed the potential benefits of patient-specific shimming to reduce the magnitude of MR distortions for a 3-T scanner.Methods and Materials: Using an in-house Matlab algorithm, shimming within entire imaging volumes and user-defined regions of interest were simulated. We deformed 21 patient computed tomography (CT) images with MR distortion fields (gradient nonlinearity and patient-induced susceptibility effects) to create distorted CT (dCT) images using bandwidths of 122 and 488 Hz/mm at 3 T. Field parameters from volumetric modulated arc therapy plans initially optimized on dCT data sets were transferred to CT data to compute a new plan. Both plans were compared to determine the impact of distortions on dose distributions.Results: Shimming across entire patient volumes decreased the percentage of voxels with distortions of more than 2 mm from 15.4% to 2.0%. Using the user-defined region of interest (ROI) shimming strategy, (here the Planning target volume (PTV) was the chosen ROI volume) led to increased geometric for volumes outside the PTV, as such voxels within the spinal cord with geometric shifts above 2 mm increased from 11.5% to 32.3%. The worst phantom-measured residual system distortions after 3-dimensional gradient nonlinearity correction within a radial distance of 200 mm from the isocenter was 2.17 mm. For all patients, voxels with distortion shifts of more than 2 mm resulting from patient-induced susceptibility effects were 15.4% and 0.0% using bandwidths of 122 Hz/mm and 488 Hz/mm at 3 T. Dose differences between dCT and CT treatment plans in D-50 at the planning target volume were 0.4% +/- 0.6% and 0.3% +/- 0.5% at 122 and 488 Hz/mm, respectively.Conclusions: The overall effect of MRI geometric distortions on data used for RTP was minimal. Shimming over entire imaging volumes decreased distortions, but user-defined subvolume shimming introduced significant errors in nearby organs and should probably be avoided.
  • Adjeiwaah, Mary, et al. (författare)
  • Quantifying the Effect of 3T Magnetic Resonance Imaging Residual System Distortions and Patient-Induced Susceptibility Distortions on Radiation Therapy Treatment Planning for Prostate Cancer
  • 2018
  • Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier. - 0360-3016 .- 1879-355X. ; 100:2, s. 317-324
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: To investigate the effect of magnetic resonance system- and patient-induced susceptibility distortions from a 3T scanner on dose distributions for prostate cancers.Methods and Materials: Combined displacement fields from the residual system and patient-induced susceptibility distortions were used to distort 17 prostate patient CT images. VMAT dose plans were initially optimized on distorted CT images and the plan parameters transferred to the original patient CT images to calculate a new dose distribution.Results: Maximum residual mean distortions of 3.19 mm at a radial distance of 25 cm and maximum mean patient-induced susceptibility shifts of 5.8 mm were found using the lowest bandwidth of 122 Hz per pixel. There was a dose difference of <0.5% between distorted and undistorted treatment plans. The 90% confidence intervals of the mean difference between the dCT and CT treatment plans were all within an equivalence interval of (−0.5, 0.5) for all investigated plan quality measures.Conclusions: Patient-induced susceptibility distortions at high field strengths in closed bore magnetic resonance scanners are larger than residual system distortions after using vendor-supplied 3-dimensional correction for the delineated regions studied. However, errors in dose due to disturbed patient outline and shifts caused by patient-induced susceptibility effects are below 0.5%.
  • Adra, Jamila, et al. (författare)
  • Distribution of locoregional breast cancer recurrence in relation to postoperative radiation fields and biological subtypes.
  • 2019
  • Ingår i: International journal of radiation oncology, biology, physics. - : Elsevier. - 1879-355X .- 0360-3016. ; 105:2, s. 285-295
  • Tidskriftsartikel (refereegranskat)abstract
    • and purpose: To investigate incidence and location of locoregional recurrence (LRR) in patients who have received postoperative locoregional radiotherapy (LRRT) for primary breast cancer. LRR-position in relation to applied radiotherapy and the primary tumours biological subtype were analysed with the aim to evaluate current target guidelines and RT techniques in relation to tumour biology.Medical records were reviewed for all patients who received postoperative LRRT for primary BC in southwestern Sweden from 2004-2008 (N=923). Patients with LRR as a first event were identified (N=57, distant failure and death were considered competing risks). CT images identifying LRR were used to compare LRR locations to postoperative LRRT fields. LRR risk and distribution were then related to the primary BC biological subtype and to current target guidelines.Cumulative LRR incidence after 10 years was 7.1% (95%CI 5.5-9.1). Fifty-seven of the 923 patients in the cohort developed LRR (30 local recurrences (LR), 30 regional recurrences (RR), of which 3 cases of simultaneous LR/RR). Most cases of LRR developed fully (56%) or partially (26%) within postoperatively irradiated areas. The most common location for out-of-field RR was cranial to RT fields in the supraclavicular fossa. Patients with an ER- (HR 4.6, p<0.001, 95%CI 2.5-8.4) or HER2+ (HR 2.4, p=0.007, 95%CI 1.3-4.7) primary BC presented higher risks of LRR compared to those with ER+ tumours. ER-/HER2+ tumours more frequently recurred in-field (68%) rather than marginal/out-of-field (32%). In addition, 75% of in-field recurrences derived from an ER-/HER+ tumour, compared to 45% of marginal/out-of-field recurrences. A complete pathological response in the axilla after neoadjuvant treatment was associated with a lower degree of LRR risk (p=0.022).Incidence and locations of LRR seems to be related to the primary BC biological subtype. Individualized LRRT according to tumour biology may be applied to improve outcomes.
  • Aksnessaether, Bjorg Y., et al. (författare)
  • In Reply to Sari et al
  • 2020
  • Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier. - 0360-3016 .- 1879-355X. ; 107:2, s. 388-389
  • Tidskriftsartikel (refereegranskat)
  • Aksnessaether, Bjorg Y., et al. (författare)
  • Second Cancers in Patients With Locally Advanced Prostate Cancer Randomized to Lifelong Endocrine Treatment With or Without Radical Radiation Therapy : Long-Term Follow-up of the Scandinavian Prostate Cancer Group-7 Trial
  • 2020
  • Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier. - 0360-3016 .- 1879-355X. ; 106:4, s. 706-714
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Curative radiation therapy (RT) constitutes a cornerstone in prostate cancer (PC) treatment. We present long-term follow-up estimates for second cancer (SC) risk and overall survival (OS) in patients randomized to hormone therapy (ET) alone or combined with 70 Gy prostatic RT in the Scandinavian Prostate Cancer Group-7 (SPCG-7) study. We explored the effect of salvage RT (≥60 Gy to the ET group) and reported causes of death.Methods and Materials: The SPCG-7 study (1996-2002) was a randomized controlled trial that included 875 men with locally advanced nonmetastatic PC. In this analysis, including data from the Norwegian and Swedish Cancer and Cause of Death registries for 651 Norwegian and 209 Swedish study patients, we estimated hazard ratios (HRs) for SC and death, and cumulative incidences of SC.Results: Median follow-up of the 860 (431 ET and 429) ET + RT patients was 12.2 years for SC risk analysis and 12.6 years for the OS analysis. Eighty-three of the Norwegian ET patients received salvage RT, and median time to salvage RT was 5.9 years. We found 125 and 168 SCs in the ET and ET + RT patients, respectively. With ET alone as reference, ET + RT patients had an HR of 1.19 (95% confidence interval [CI], 0.92-1.54) for all SCs and 2.54 (95% CI, 1.14-5.69) for urinary bladder cancer (UBC). The total number of UBC was 31 (23 in ET + RT; 8 in ET), and the vast majority (85%) were superficial. The HR for SC in salvage RT patients was 0.48 (95% CI, 0.24-0.94). Median OS was 12.8 (95% CI, 11.8-13.8) and 15.3 (95%, CI 14.3-16.4) years in the ET and ET + RT groups, respectively. Compared with ET alone, the risk of death was reduced in ET + RT patients (HR, 0.73; 95% CI, 0.62-0.86) and in ET patients receiving salvage RT (HR, 0.44; 95% CI, 0.30-0.65).Conclusions: Although the risk of UBC was increased in PC patients who received RT in addition to ET, this disadvantage is outweighed by the OS benefit of RT confirmed in our study. The risk of SC, and especially UBC, should be discussed with patients and be reflected in follow-up programs.
  • Al-Ubaidi, Firas L. T., et al. (författare)
  • 2012
  • Ingår i: International Journal of Radiation Oncology, Biology, Physics. - 0360-3016 .- 1879-355X. ; 82:3, s. 1243-1248
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Purpose: Neoadjuvant androgen deprivation in combination with radiotherapy of prostate cancer is used to improve radioresponsiveness and local tumor control. Currently, the underlying mechanism is not well understood. Because hypoxia causes resistance to radiotherapy, we wanted to test whether castration affects the degree of hypoxia in prostate cancer. Methods and Materials: In 14 patients with locally advanced prostate cancer, six to 12 prostatic needle core biopsy specimens were taken prior to castration therapy. Bilateral orchidectomy was performed in 7 patients, and 7 were treated with a GnRH-agonist (leuprorelin). After castrationm two to four prostatic core biopsy specimens were taken, and the level of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in cancer was determined by immunofluorescence. Results: Among biopsy specimens taken before castration, strong HIF-1 alpha expression (mean intensity above 30) was shown in 5 patients, weak expression (mean intensity 10-30) in 3 patients, and background levels of HIF-1 alpha (mean intensity 0-10) in 6 patients. Downregulation of HIF-1 alpha expression after castration was observed in all 5 patients with strong HIF-1 alpha precastration expression. HIF-1 alpha expression was also reduced in 2 of 3 patients with weak HIF-1 alpha precastration expression. Conclusions: Our data suggest that neoadjuvant castration decreases tumor cell hypoxia in prostate cancer, which may explain increased radiosensitivity after castration.
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