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Background and Purpose: Doses to the coronary arteries in breast cancer (BC) radiotherapy (RT) have been suggested to be a risk predictor of long-term cardiac toxicity after BC treatment. We investigated the dose-risk relationships between near maximum doses (Dmax) to the right coronary artery (RCA) and left anterior descending coronary artery (LAD) and ischemic heart disease (IHD) mortality after BC RT., Patients and Methods: In a cohort of 2,813 women diagnosed with BC between 1958 and 1992 with a follow-up of at least 10 years, we identified 134 cases of death due to IHD 10-19 years after BC diagnosis. For each case, one control was selected within the cohort matched for age at diagnosis. 3D-volume and 3D-dose reconstructions were obtained from individual RT charts. We estimated the Dmax to the RCA and the LAD and the mean heart dose (MHD). We performed conditional logistic regression analysis comparing piecewise spline transformation and simple linear modeling for best fit., Results: There was a linear dose-risk relationship for both the Dmax to the RCA (odds ratio [OR]/Gray [Gy] 1.03 [1.01-1.05]) and the LAD (OR/Gy 1.04 [1.02-1.06]) in a multivariable model. For MHD there was a linear dose-risk relationship (1,14 OR/Gy [1.08-1.19]. For all relationships, simple linear modelling was superior to spline transformations., Interpretation: Doses to both the RCA and LAD are independent risk predictors of long-term cardiotoxicity after RT for BC In addition to the LAD, the RCA should be regarded as an organ at risk in RT planning.

During fractionated radiotherapy, epithelial cell populations are thought to decrease initially, followed by accelerated repopulation to compensate cell loss. However, previous findings in skin with daily 1.1 Gy dose fractions indicate continued and increasing cell depletion. Here we investigated epidermal keratinocyte response with daily 2 Gy fractions as well as accelerated and hypofractionation. Epidermal interfollicular melanocytes were also assessed. Skin-punch biopsies were collected from breast cancer patients before, during and after mastectomy radiotherapy to the thoracic wall with daily 2 Gy fractions for 5 weeks. In addition, 2.4 Gy radiotherapy four times per week and 4 Gy fractions twice per week for 5 weeks, and two times 2 Gy daily for 2.5 weeks, were used. Basal keratinocyte density of the interfollicular epidermis was determined and immunostainings of keratinocytes for DNA double-strand break (DSB) foci, growth arrest, apoptosis and mitosis were quantified. In addition, interfollicular melanocytes were counted. Initially minimal keratinocyte loss was observed followed by pronounced depletion during the second half of treatment and full recovery at 2 weeks post treatment. DSB foci per cell peaked towards the end of treatment. p21-stained cell counts increased during radiotherapy, especially the second half. Apoptotic frequency was low throughout radiotherapy but increased at treatment end. Mitotic cell count was significantly suppressed throughout radiotherapy and did not recover during weekend treatment gaps, but increased more than threefold compared to unexposed skin 2 weeks post-radiotherapy. The number of melanocytes remained constant over the study period. Germinal keratinocyte loss rate increased gradually during daily 2 Gy fractions for 5 weeks, and similarly for hypofractionation. DSB foci number after 2 Gy irradiation revealed an initial radioresistance followed by increasing radiosensitivity. Growth arrest mediated by p21 strongly suggests that cells within or recruited into the cell cycle during treatment are at high risk of loss and do not contribute significantly to repopulation. It is possible that quiescent (G 0 ) cells at treatment completion accounted for the accelerated post-treatment repopulation. Recent knowledge of epidermal tissue regeneration and cell cycle progression during genotoxic and mitogen stress allows for a credible explanation of the current finding. Melanocytes were radioresistant regarding cell depletion.

Background and Purpose: Previously we reported that hyper-radiosensitivity (HRS) was evidenced by quantifying DNA double strand break (DSB) foci in epidermis biopsies collected after delivering radiotherapeutic one and five dose fractions. The aim of this study was to determine whether HRS was preserved throughout a 7-week radiotherapy treatment, and also to examine the rate of foci decline and foci persistence between dose fractions., Materials and Methods: 42 patients with prostate cancer received 7-week fractionated radiotherapy treatment (RT) with daily dose fractions of 0.05-1.10Gy to the skin. Before RT, and at several times throughout treatment, skin biopsies (n=452) were collected at 30min, and 2, 3, 24, and 72h after dose fractions. DSB-foci markers, γH2AX and 53BP1, were labelled in epidermal keratinocytes with immunofluorescence and immunohistochemical staining. Foci were counted both with digital image analysis and manually., Results: HRS in keratinocytes was evidenced by the dose-response relationships of DSB foci, observed throughout the treatment course, independent of sampling time and quantification method. Foci observed at 24h after dose fractions indicated considerable DSB persistence. Accordingly, foci significantly accumulated after 5 consecutive dose fractions. For doses below 0.3Gy, persistent foci could be observed even at 72h after damage induction. A comparison of γH2AX and 53BP1 quantifications in double-stained biopsies showed similar HRS dose-response relationships., Conclusions: These results represented the first evidence of preserved HRS, assessed by γH2AX- and 53BP1-labelled DSB foci, throughout a 7-week treatment course with daily repeated subtherapeutic dose fractions., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: This report contains the mature five-year data from the Swedish ARTSCAN trial including information on the influence of p16 positivity (p16+) for oropharyngeal cancers., Material and Methods: Patients with previously untreated squamous cell carcinoma without distant metastases of the oral cavity, oropharynx, larynx (except T1-2, N0 glottic cancers) and hypopharynx were included. Patients were randomised between accelerated fractionation (AF) (1.1Gy+2Gy per day, 5days/week for 4.5weeks, total dose 68Gy) and conventional fractionation (CF) (2Gy per day, 5days/week for 7weeks, total dose 68Gy). Human papillomavirus (HPV)-associated p16-expression was assessed retrospectively in tumour tissues from patients with oropharyngeal carcinoma., Results: There was no significant difference in loco-regional control (LRC) between AF and CF (log-rank test p=0.75). LRC at 5years was 65.5% for AF and 64.9% for CF. Overall survival (OS) was similar in both arms (p=0.99). The estimated cancer specific survival (CSS) at 5years was 62.2% (AF) and 63.3% (CF) (p=0.99). 206 specimens were analysed for p16 with 153 specimens (74%) identified as p16+. P16 status did not discriminate for response to AF vs. CF with regard to LRC, OS or CSS. Patients with p16+ tumours had a statistically significant better overall prognosis compared with p16- tumours., Conclusion: This update confirms the results of the 2-year report. We failed to identify a positive effect resulting from AF with regards to LRC, OS and CSS. The addition of information on the HPV-associated p16 overexpression did not explain this lack of effect., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To identify volume and dose predictors of paresthesia after irradiation of the brachial plexus among women treated for breast cancer., Methods and Materials: The women had breast surgery with axillary dissection, followed by radiation therapy with (n=192) or without irradiation (n=509) of the supraclavicular lymph nodes (SCLNs). The breast area was treated to 50 Gy in 2.0-Gy fractions, and 192 of the women also had 46 to 50 Gy to the SCLNs. We delineated the brachial plexus on 3-dimensional dose-planning computerized tomography. Three to eight years after radiation therapy the women answered a questionnaire. Irradiated volumes and doses were calculated and related to the occurrence of paresthesia in the hand., Results: After treatment with axillary dissection with radiation therapy to the SCLNs 20% of the women reported paresthesia, compared with 13% after axillary dissection without radiation therapy, resulting in a relative risk (RR) of 1.47 (95% confidence interval [CI] 1.02-2.11). Paresthesia was reported by 25% after radiation therapy to the SCLNs with a V40 Gy ≥ 13.5 cm(3), compared with 13% without radiation therapy, RR 1.83 (95% CI 1.13-2.95). Women having a maximum dose to the brachial plexus of ≥55.0 Gy had a 25% occurrence of paresthesia, with RR 1.86 (95% CI 0.68-5.07, not significant)., Conclusion: Our results indicate that there is a correlation between larger irradiated volumes of the brachial plexus and an increased risk of reported paresthesia among women treated for breast cancer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: When evaluating late toxicity after combined external beam radiation therapy (EBRT) and high-dose rate brachytherapy (HDR BT) prostate cancer treatments, it is important that the composite dose distribution is taken into account. This can be challenging if organ-at-risk (OAR) dose data are incomplete, i.e. due to a limited ultrasound imaging field-of-view in the HDR BT procedure. This work proposes a method that provides estimates of composite OAR doses for such situations., Material and Methods: Original EBRT, simulated HDR BT, and composite dose-volume histograms (DVHs) for 10 pelvic OARs in 30 prostate cancer cases were used for method implementation and evaluation (EBRT: 25×2.0 Gy+BT: 2×10.0 Gy). The proposed method used information from the EBRT DVH to estimate OAR BT doses (with or without fractionation correction). Coefficients of determination (R2) were calculated for linear relationships between several EBRT DVH parameters and a BT DVH parameter of interest. The largest R2 value decided the relationship that best predicted the BT DVH parameter. The composite dose value was then calculated by adding the EBRT DVH and the estimated BT DVH parameter values and was compared to the reference composite value (in 1200 OAR/patient/parameter cases)., Results: The linear relationships had an average R2 of 0.68 (range 0.42-0.88). Only one ninth of the 1200 estimated composite DVH values differed more than 2 Gy from their reference values., Conclusion: Given a successful implementation, the proposed method only requires original or simulated BT plan data for a subset of patients to estimate composite doses for large study populations in a time-efficient manner. This can assist in evaluating radiation-induced late toxicity in multimodality treatments with limited OAR dose data.

Purpose: To evaluate the dose-response relationship between radiation-induced atelectasis after stereotactic body radiation therapy (SBRT) and bronchial dose., Methods and Materials: Seventy-four patients treated with SBRT for tumors close to main, lobar, or segmental bronchi were selected. The association between incidence of atelectasis and bronchial dose parameters (maximum point-dose and minimum dose to the high-dose bronchial volume [ranging from 0.1 cm(3) up to 2.0 cm(3)]) was statistically evaluated with survival analysis models., Results: Prescribed doses varied between 4 and 20 Gy per fraction in 2-5 fractions. Eighteen patients (24.3%) developed atelectasis considered to be radiation-induced. Statistical analysis showed a significant correlation between the incidence of radiation-induced atelectasis and minimum dose to the high-dose bronchial volumes, of which 0.1 cm(3) (D(0.1cm3)) was used for further analysis. The median value of D(0.1cm3) (α/β = 3 Gy) was EQD(2,LQ) = 147 Gy3 (range, 20-293 Gy3). For patients who developed atelectasis the median value was EQD(2,LQ) = 210 Gy3, and for patients who did not develop atelectasis, EQD(2,LQ) = 105 Gy3. Median time from treatment to development of atelectasis was 8.0 months (range, 1.1-30.1 months)., Conclusion: In this retrospective study a significant dose-response relationship between the incidence of atelectasis and the dose to the high-dose volume of the bronchi is shown., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to investigate what bowel organ and delivered dose levels are most relevant for the development of 'emptying of all stools into clothing without forewarning' so that the related dose-responses could be derived as an aid in avoiding this distressing symptom in the future., Material and Methods: Of the 77 gynecological cancer survivors treated with radiotherapy (RT) for gynecological cancer, 13 developed the symptom. The survivors were treated between 1991 and 2003. The anal-sphincter region, the rectum, the sigmoid and the small intestines were all delineated and the dose-volume histograms were exported for each patient. The dose-volume parameters were estimated fitting the data to the Relative Seriality (RS), the Lyman and the generalized Equivalent Uniform Dose (gEUD) model., Results: The dose-response parameters for all three models and four organs at risk (OARs) were estimated. The data from the sigmoid fits the studied models best: D50 was 58.8 and 59.5 Gy (RS, Lyman), γ50 was 1.60 and 1.57 (RS, Lyman), s was 0.32, n was 0.13 and a was 7.7 (RS, Lyman, gEUD). The estimated volume parameters indicate that the investigated OARs behave serially for this endpoint. Our results for the three models studied indicate that they have the same predictive power (similar LL values) for the symptom as a function of the dose for all investigated OARs., Conclusions: In our study, the anal-sphincter region and sigmoid fit our data best, but all OARs were found to have steep dose-responses for 'emptying of all stools into clothing without forewarning' and thus, the outcome can be predicted with an NTCP model. In addition, the dose to the four studied OARs may be considered when minimizing the risk of the symptom.

Purpose: To investigate how treatment-related and non-treatment-related factors impact urethral pain among long-term prostate cancer survivors., Methods and Materials: Men treated for prostate cancer with radiation therapy at the Sahlgrenska University Hospital in Göteborg, Sweden from 1993 to 2006 were approached with a study-specific postal questionnaire addressing symptoms after treatment, including urethral burning pain during urination (n=985). The men had received primary or salvage external-beam radiation therapy (EBRT) or EBRT in combination with brachytherapy (BT). Prescribed doses were commonly 70 Gy in 2.0-Gy fractions for primary and salvage EBRT and 50 Gy plus 2×10.0 Gy for EBRT+BT. Prostatic urethral doses were assessed from treatment records. We also recruited 350 non-pelvic-irradiated, population-based controls matched for age and residency to provide symptom background rates., Results: Of the treated men, 16% (137 of 863) reported urethral pain, compared with 11% (27 of 242) of the controls. The median time to follow-up was 5.2 years (range, 1.1-14.3 years). Prostatic urethral doses were similar to prescription doses for EBRT and 100% to 115% for BT. Fractionation-corrected dose and time to follow-up affected the occurrence of the symptom. For a follow-up≥3 years, 19% of men (52 of 268) within the 70-Gy EBRT+BT group reported pain, compared with 10% of men (23 of 222) treated with 70 Gy primary EBRT (prevalence ratio 1.9; 95% confidence interval 1.2-3.0). Of the men treated with salvage EBRT, 10% (20 of 197) reported urethral pain., Conclusions: Survivors treated with EBRT+BT had a higher risk for urethral pain compared with those treated with EBRT. The symptom prevalence decreased with longer time to follow-up. We found a relationship between fractionation-corrected urethral dose and pain. Among long-term prostate cancer survivors, the occurrence of pain was not increased above the background rate for prostatic urethral doses up to 70 Gy3., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Adult patients with hypothalamic-pituitary disorders have compromised quality of life (QoL). Whether this is due to their endocrine consequences (hypopituitarism), their underlying hypothalamic-pituitary disorder or both is still under debate. The aim of this trial was to measure quality of life (QoL) in long-term cancer survivors who have received a radiation dose to the basal part of the brain and the pituitary., Methods: Consecutive patients (n=101) treated for oropharyngeal or epipharyngeal cancer with radiotherapy followed free of cancer for a period of 4 to10 years were identified. Fifteen patients (median age 56 years) with no concomitant illness and no hypopituitarism after careful endocrine evaluation were included in a case-control study with matched healthy controls. Doses to the hypothalamic-pituitary region were calculated. QoL was assessed using the Symptom check list (SCL)-90, Nottingham Health Profile (NHP), and Psychological Well Being (PGWB) questionnaires. Level of physical activity was assessed using the Baecke questionnaire., Results: The median accumulated dose was 1.9 Gy (1.5-2.2 Gy) to the hypothalamus and 2.4 Gy (1.8-3.3 Gy) to the pituitary gland in patients with oropharyngeal cancer and 6.0-9.3 Gy and 33.5-46.1 Gy, respectively in patients with epipharyngeal cancer (n=2). The patients showed significantly more anxiety and depressiveness, and lower vitality, than their matched controls., Conclusion: In a group of long time survivors of head and neck cancer who hade received a low radiation dose to the hypothalamic-pituitary region and who had no endocrine consequences of disease or its treatment QoL was compromised as compared with well matched healthy controls.

Purpose: To investigate the relative importance of patient-reported hip and sacral pain after pelvic radiotherapy (RT) for gynecological cancer and its relationship to the absorbed doses in these organs., Methods and Materials: We used data from a population-based study that included 650 long-term gynecological cancer survivors treated with pelvic RT in the Gothenburg and Stockholm areas in Sweden with a median follow-up of 6 years (range, 2-15) and 344 population controls. Symptoms were assessed through a study-specific postal questionnaire. We also analyzed the hip and sacral dose-volume histogram data for 358 of the survivors., Results: Of the survivors, one in three reported having or having had hip pain after completing RT. Daily pain when walking was four times as common among the survivors compared to controls. Symptoms increased in frequency with a mean absorbed dose >37.5 Gy. Also, two in five survivors reported pain in the sacrum. Sacral pain also affected their walking ability and tended to increase with a mean absorbed dose >42.5 Gy., Conclusions: Long-term survivors of gynecological cancer treated with pelvic RT experience hip and sacral pain when walking. The mean absorbed dose was significantly related to hip pain and was borderline significantly related to sacral pain. Keeping the total mean absorbed hip dose below 37.5 Gy during treatment might lower the occurrence of long-lasting pain. In relation to the controls, the survivors had a lower occurrence of pain and pain-related symptoms from the hips and sacrum compared with what has previously been reported for the pubic bone., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The present investigation is a continuation of a previous study on the effect of the diameter of the air cavity in cylindrical ionization chambers on perturbation correction factors. Measurements were made using high-energy radiotherapy photon beams (4, 6 and 15 MV) in a water phantom. Two different pairs of cylindrical ionization chambers were used. The chambers in each pair had identical materials and construction but different air cavity diameters. The same methods were employed as in our previous investigation. The diameter of the air cavity in cylindrical ionization chambers influences the mass ionization (the measured ionization expressed per unit mass of air in the chamber air cavity) at the depth where the maximum ionization is observed and a normalization at this depth is therefore not correct. The corrections obtained at depths of 50 and 100 mm in the phantom showed that the air cavity diameter in cylindrical ionization chambers has a greater effect on the perturbation effects than the photon beam quality. The corrections found at depths of 50 and 100 mm are smaller than those currently used in dosimetry protocols.

Purpose: Postoperative radiotherapy decreases breast cancer mortality. However, studies have revealed a long-lasting breast pain among some women after radiotherapy. The purpose of this study was to identify risk factors that contribute to breast pain after breast cancer radiotherapy., Methods and Materials: We identified 1,027 recurrence-free women in two cohorts of Swedish women treated for breast cancer. The women had breast-conserving surgery and postoperative radiotherapy, the breast was treated to 48 Gy in 2.4-Gy fractions or to 50 Gy in 2.0-Gy fractions. Young women received a boost of up to 16 Gy. Women with more than three lymph node metastases had locoregional radiotherapy. Systemic treatments were given according to health-care guidelines. Three to 17 years after radiotherapy, we collected data using a study-specific questionnaire. We investigated the relation between breast pain and potential risk modifiers: age at treatment, time since treatment, chemotherapy, photon energy, fractionation size, boost, loco-regional radiotherapy, axillary surgery, overweight, and smoking., Results: Eight hundred seventy-seven women (85%) returned the questionnaires. Among women up to 39 years of age at treatment, 23.1% had breast pain, compared with 8.7% among women older than 60 years (RR 2.66; 95% CI 1.33-5.36). Higher age at treatment (RR 0.96; 95% CI 0.94-0.98, annual decrease) and longer time since treatment (RR 0.93; 95% CI 0.88-0.98, annual decrease) were related to a lower occurrence of breast pain. Chemotherapy increased the occurrence of breast pain (RR 1.72; 95% CI 1.19-2.47). In the multivariable model only age and time since treatment were statistically significantly related to the occurrence of breast pain. We found no statistically significant relation between breast pain and the other potential risk modifiers., Conclusions: Younger women having undergone breast-conserving surgery with postoperative radiotherapy report a higher occurrence of long-lasting breast pain compared to older women. Time since treatment may decrease the occurrence of pain., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background and Purpose: Irradiation of the supraclavicular lymph nodes has historically increased the risk of brachial plexopathy. We report long-term symptoms after modern radiotherapy (based on 3D dose planning) in breast cancer patients with or without irradiation of the supraclavicular lymph nodes., Material and Methods: We collected information from 814 women consecutively treated with adjuvant radiotherapy for breast cancer. The women had breast surgery with axillary dissection (AD) or sentinel node biopsy (SNB). The breast area was treated to 50 Gy in 2.0 Gy fractions. Women with >three lymph node metastases had regional radiotherapy (RRT) to the supraclavicular lymph nodes. Three to eight years after radiotherapy, they received a questionnaire asking about paraesthesia, oedema, pain, and strength in the upper limb., Results: Paraesthesia was reported by 38/192 (20%) after AD with RRT compared to 68/505 (13%) after AD without RRT (relative risk [RR] 1.47; 95% confidence interval [CI] 1.02-2.11) and by 9/112 (8%) after SNB without RRT (RR 2.46; 95% CI 1.24-4.90). Corresponding risks adjusted for oedema (RR 1.28; 95% CI 0.93-1.76) and (RR 1.75; 95% CI 0.90-3.39). In women ≤ 49years with AD and RRT, 27% reported paraesthesia. No significant pain or decreased strength was reported after RRT., Conclusion: Radiotherapy to the supraclavicular lymph nodes after axillary dissection increases the occurrence of paraesthesia, mainly among younger women. When adjusted for oedema the contribution from radiotherapy is no longer formally statistically significant indicating that there is also an indirect effect mediated by the oedema., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Tobacco smoking can cause vascular injury, tissue hypoxia and fibrosis as can ionizing radiation. However, we do not know if tobacco smoking increases the risk of long-term side effects after radiotherapy for prostate cancer., Methods: We identified 985 men treated with radiotherapy for prostate cancer between 1993 and 2006. In 2008, long-lasting symptoms appearing after radiotherapy for prostate cancer were assessed through a study-specific questionnaire as were smoking habits and demographic factors of all these men. In the questionnaire the prostate-cancer survivors were asked to report symptom occurrence the previous six months., Results: We obtained information on tobacco smoking from 836 of the 985 prostate-cancer survivors with a median time to follow-up of six years (range 2-14 years). The prevalence ratio of defecation urgency among current smokers compared to never smokers was 1.6 (95% CI 1.2-2.2). Corresponding prevalence ratio for diarrhea was 2.8 (95% CI 1.2-6.5), the sensation of bowel not completely emptied after defecation 2.1 (95% CI 1.3-3.3) and for sudden emptying of all stools into clothing without forewarning 4.7 (95% CI 2.3-9.7)., Conclusion: Tobacco smoking among prostate-cancer survivors treated with radiotherapy increases the risk of certain long-lasting symptoms from the bowel and anal-sphincter region., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

In the late 1970s, Johansson et al (1978 Int. Symp. National and International Standardization of Radiation Dosimetry (Atlanta 1977) vol 2 (Vienna: IAEA) pp 243-70) reported experimentally determined displacement correction factors (p(dis)) for cylindrical ionization chamber dosimetry in ⁶⁰Co and high-energy photon beams. These p(dis) factors have been implemented and are currently in use in a number of dosimetry protocols. However, the accuracy of these factors has recently been questioned by Wang and Rogers (2009a Phys. Med. Biol. 54 1609-20), who performed Monte Carlo simulations of the experiments performed by Johansson et al. They reported that the inaccuracy of the p(dis) factors originated from the normalization procedure used by Johansson et al. In their experiments, Johansson et al normalized the measured depth-ionization curves at the depth of maximum ionization for each of the different ionization chambers. In this study, we experimentally investigated the effect of air cavity size of cylindrical ionization chambers in a PMMA phantom and ⁶⁰Co γ-beam. Two different pairs of air-filled cylindrical ionization chambers were used. The chambers in each pair had identical construction and materials but different air cavity volume (diameter). A 20 MeV electron beam was utilized to determine the ratio of the mass of air in the cavity of the two chambers in each pair. This ratio of the mass of air in each pair was then used to compare the ratios of the ionizations obtained at different depths in the PMMA phantom and ⁶⁰Co γ-beam using the two pairs of chambers. The diameter of the air cavity of cylindrical ionization chambers influences both the depth at which the maximum ionization is observed and the ionization per unit mass of air at this depth. The correction determined at depths of 50 mm and 100 mm is smaller than the correction currently used in many dosimetry protocols. The results presented here agree with the findings of Wang and Rogers' Monte Carlo simulations and show that the normalization procedure employed by Johansson et al is not correct.

Purpose: To analyze the relationship between mean absorbed dose to the pubic bone after pelvic radiotherapy for gynecological cancer and occurrence of pubic bone pain among long-term survivors., Methods and Materials: In an unselected, population-based study, we identified 823 long-term gynecological cancer survivors treated with pelvic radiotherapy during 1991-2003. For comparison, we used a non-radiation-treated control population of 478 matched women from the Swedish Population Register. Pain, intensity of pain, and functional impairment due to pain in the pubic bone were assessed with a study-specific postal questionnaire., Results: We analyzed data from 650 survivors (participation rate 79%) with median follow-up of 6.3 years (range, 2.3-15.0 years) along with 344 control women (participation rate, 72 %). Ten percent of the survivors were treated with radiotherapy; ninety percent with surgery plus radiotherapy. Brachytherapy was added in 81%. Complete treatment records were recovered for 538/650 survivors, with dose distribution data including dose-volume histograms over the pubic bone. Pubic bone pain was reported by 73 survivors (11%); 59/517 (11%) had been exposed to mean absorbed external beam doses <52.5 Gy to the pubic bone and 5/12 (42%) to mean absorbed external beam doses ≥ 52.5 Gy. Thirty-three survivors reported pain affecting sleep, a 13-fold increased prevalence compared with control women. Forty-nine survivors reported functional impairment measured as pain walking indoors, a 10-fold increased prevalence., Conclusions: Mean absorbed external beam dose above 52.5 Gy to the pubic bone increases the occurrence of pain in the pubic bone and may affect daily life of long-term survivors treated with radiotherapy for gynecological cancer., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background and Purpose: Studies on accelerated fractionation (AF) in head and neck cancer have shown increased local control and survival compared with conventional fractionation (CF), while others have been non-conclusive. In 1998 a national Swedish group decided to perform a randomised controlled clinical study of AF., Materials and Methods: Patients with verified squamous cell carcinoma of the oral cavity, oropharynx, larynx (except glottic T1-T2, N0) and hypopharynx were included. Patients with prior chemotherapy or surgery were excluded. Patients were randomised to either CF (2Gy/day, 5days/week for 7 weeks, total dose 68Gy) or to AF (1.1Gy+2.0Gy/day, 5days/week for 4.5weeks, total dose 68Gy). An extensive quality assurance protocol was followed throughout the study. The primary end point was loco-regional tumour control (LRC) at two years after treatment., Results: The study was closed in 2006 when 750 patients had been randomised. Eighty-three percent of the patients had stages III-IV disease. Forty eight percent had oropharyngeal, 21% laryngeal, 17% hypopharyngeal and 14% oral cancers. There were no significant differences regarding overall survival (OS) or LRC between the two regimens. The OS at two years was 68% for AF and 67% for CF. The corresponding figures for LRC were 71% and 67%, respectively. There was a trend towards improved LRC for oral cancers treated (p=0.07) and for large tumours (T3-T4) (p=0.07) treated with AF. The AF group had significantly worse acute reactions, while there was no significant increase in late effects., Conclusion: Overall the AF regimen did not prove to be more efficacious than CF. However, the trend towards improved results in AF for oral cancers needs to be further investigated., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: For many tumour sites, external beam radiation therapy (EBRT) is delivered with a sequential two-phase treatment regime. Yet, there is a lack of consensus of how to add two different non-uniform dose distributions in order to evaluate the late radiation effect for normal tissue. The purpose of this novel investigation is to quantify the dose differences between non-corrected and fractionation-corrected combined non-uniform dose distributions., Material and Methods: We used a model of an organ at risk (OAR) located in six different positions relative the treated volume giving 16 clinically representative two-phase treatment situations (46 Gy + 22 Gy). The linear-quadratic model was applied to correct for fractionation effects in each voxel before the doses were added. Dose differences were quantified using mean and maximum doses with corresponding fractionation-corrected doses as reference., Results: Non-corrected doses were higher than fractionation-corrected doses in all treatment situations (mean dose: p<0.001; maximum dose: p=0.003). With the OAR outside the treated volume, non-corrected doses were 3-6 Gy higher representing 10-50% of the reference dose (10-25 Gy); with the OAR included in the treated volume, 1-6 Gy higher representing 1-15% (30-60 Gy). Mean dose differences were generally larger than maximum dose differences., Conclusion: Substantial dose differences were present in all of the simulated treatment situations but more apparent when the OAR was located outside the treated volume in both phases. Our findings require verification in clinical cases but nevertheless indicate a need for fractionation-corrected doses in two-phase treatments both in the daily clinical routine as well as in the modelling of late radiation effects. Our data suggest that adjusting for fractionation effects would lead to lower tolerance doses than currently suggested, in particular for OARs with parallel tissue architecture.

Background: Postoperative radiotherapy decreases the risk for local recurrence and improves overall survival in women with breast cancer. We have limited information on radiotherapy-induced symptoms 10-17 years after therapy., Material and Methods: Between 1991 and 1997, women with lymph node-negative breast cancer were randomised in a Swedish multi-institutional trial to breast conserving surgery with or without postoperative radiotherapy. In 2007, 10-17 years after randomisation, the group included 422 recurrence-free women. We collected data with a study-specific questionnaire on eight pre-selected symptom groups., Results: For six symptom groups (oedema in breast or arm, erysipelas, heart symptoms, lung symptoms, rib fractures, and decreased shoulder mobility) we found similar occurrence in both groups. Excess occurrence after radiotherapy was observed for pain in the breast or in the skin, reported to occur "occasionally" by 38.1% of survivors having undergone radiotherapy and surgery versus 24.0% of those with surgery alone (absolute difference 14.1%; p=0.004) and at least once a week by 10.3% of the radiotherapy group versus 1.7% (absolute difference 8.6%; p=0.001). Daily life and analgesic use did not differ between the groups., Conclusions: Ten to 17 years after postoperative radiotherapy 1 in 12 women had weekly pain that could be attributed to radiotherapy. The symptoms did not significantly affect daily life and thus the reduced risk for local recurrence seems to outweigh the risk for long-term symptoms for most women., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: In preparation for studies of dose volume of ionizing radiation and long-term side effects, we assessed both variation in position and volume of organs at risk in the small pelvis., Material and Methods: On 10 men and seven women we delineated the sigmoid, rectum, anal sphincter, bladder, penile bulb, and cavernous bodies in two CT scans taken between five to 69 days apart., Results: The measured overlap of the two delineated volumes divided by the maximum possible overlap, was below 50% for the sigmoid in six of 17 patients, for the distal 4 cm of the sigmoid in five of 17 patients, for the rectum in none of 17 patients, for the anal sphincter in three of 17 patients and for the urinary bladder in none of 17 patients. The smaller volume divided by the larger volume was below 50% in three of 17 patients for the sigmoid, in six of 17 patients for the 4 distal cm of the sigmoid, in two of 17 patients for the rectum, in two of 17 patients for the anal sphincter and in seven of 17 patients for the urinary bladder. For the urinary bladder the largest deviation was found cranially, 4.0 cm (SD 2.0 cm), the caudal part being relatively fixed. For the rectum the largest deviation was found in the anterior wall, 1.8 cm (SD 0.7 cm), with maximum documented variation in cranial direction of 3.2 cm (SD 1.8 cm)., Conclusions: The sigmoid varies considerably in documented position with the largest deviation anteriorly, the urinary bladder change in volume with the extension mainly located cranially and for the rectum the anterior wall is the most mobile with the distension becoming more pronounced cranially. In modeling dose-volume effects one may consider our results.

Background and Purpose: The existence of a hypersensitive radiation response to doses below 0.5Gy is well established for many normal and tumour cell lines. There is also evidence for hypersensitive tissue responses in acute skin damage and kidney function in mice. Recently, we have identified that a hypersensitive gammaH2AX response exists in human epidermis. The aim of this study was to investigate the dose-response of basal clonogenic keratinocytes in normal skin to fractionated radiotherapy with low dose fractions., Materials: Skin punch biopsies were taken before and during radiotherapy from prostate cancer patients undergoing radiotherapy with a curative intent. Areas of epidermis receiving daily fractions of approximately 0.1, 0.2, 0.45 and 1.1Gy were biopsied on the same occasion to determine dose-response for each individual patient. In total, 89 cases were assessed either at 1, 2.5, 3, 4, 5 or 6.5 weeks in the treatment course. Biopsy sampling of another 25 patients was performed from areas receiving 0.45 and 1.1Gy per fraction at regular intervals throughout the 7-week treatment period. The number of basal keratinocytes per mm of the interfollicular epidermis was determined. The DNA damage response of the basal keratinocytes was investigated by immunohistochemical staining for molecular markers of growth arrest, mitosis and cell death, using p21, phospho-H3 and gammaH2AX, respectively. The number of stained keratinocytes in the basal layer was counted manually. The p21 staining was also quantified by digital image analysis., Results: The individual dose-response relationships revealed a low-dose hypersensitivity for reduction of basal keratinocytes throughout 7 weeks of radiotherapy (p<0.01). Growth arrest and cell proliferation assessed at 1 week and 6.5 weeks showed, in both cases, hypersensitive increase of p21 (p<0.01) and hypersensitive depression of mitosis (p<0.01). Manual counting and digital image analysis of p21 showed good agreement. Cell death was infrequent but increased significantly between 1 and 6.5 weeks and displayed a hypersensitive dose-response at the end of the treatment period., Conclusions: A low-dose hypersensitivity in basal skin keratinocyte reduction is present throughout 7 weeks of radiotherapy. A persistent hypersensitive growth arrest response and cell killing mediate this effect., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The impact of stereotactic body radiotherapy (SBRT) on 3-year progression-free survival of medically inoperable patients with stage I non-small-cell lung cancer (NSCLC) was analyzed in a prospective phase II study., Patients and Methods: Fifty-seven patients with T1NOMO (70%) and T2N0M0 (30%) were included between August 2003 and September 2005 at seven different centers in Sweden, Norway, and Denmark and observed up to 36 months. SBRT was delivered with 15 Gy times three at the 67% isodose of the planning target volume., Results: Progression-free survival at 3 years was 52%. Overall- and cancer-specific survival at 1, 2, and 3 years was 86%, 65%, 60%, and 93%, 88%, 88%, respectively. There was no statistically significant difference in survival between patients with T1 or T2 tumors. At a median follow-up of 35 months (range, 4 to 47 months), 27 patients (47%) were deceased, seven as a result of lung cancer and 20 as a result of concurrent disease. Kaplan-Meier estimated local control at 3 years was 92%. Local relapse was observed in four patients (7%). Regional relapse was observed in three patients (5%). Nine patients (16%) developed distant metastases. The estimated risk of all failure (local, regional, or distant metastases) was increased in patients with T2 (41%) compared with those with T1 (18%) tumors (P = .027)., Conclusion: With a 3-year local tumor control rate higher than 90% with limited toxicity, SBRT emerges as state-of-the-art treatment for medically inoperable stage I NSCLC and may even challenge surgery in operable instances.

Background and Purpose: The aim of this study is to analyse the dose-response and the volume-response of radiation-induced rib fractures after hypofractionated stereotactic body radiation therapy (SBRT)., Materials and Methods: During the period 1998-2005, 68 patients with medically inoperable stage I non-small cell lung cancer (NSCLC) were treated with hypofractionated SBRT to 45 Gy in 3 fractions. Among the 33 patients with complete treatment records and radiographic follow-up exceeding 15 months (median: 29 months), 13 fractures were found in seven patients. Identifying all ribs receiving at least 21 Gy, 81 ribs (13 with and 68 without fracture) in 26 patients were separately contoured and their dose-volume histograms (DVHs) were obtained. The DVHs were assessed with the mean dose and cut-off models. Maximum likelihood estimation was used to fit dose-response and volume-response curves to each model., Results: It was possible to quantify the risk of radiation-induced rib fracture using response curves and information contained in the DVHs. Absolute volumes provided better fits than relative volumes and dose-response curves were more suitable than volume-response curves. For the dose given by the 2 cm(3) cut-off volume, D(2 cm(3)), the logistic dose-response curve for three fractions was parameterised by D(50)=49.8 Gy and gamma(50)=2.05. Consequently, for a median follow-up of 29 months, if D(2 cm(3))<3 x 7.0 Gy the risk is close to 0, and the 5% and 50% risks are given by D(2 cm(3))=3 x 9.1 Gy and 3 x 16.6 Gy, respectively., Conclusions: In this group of patients, the risk for radiation-induced rib fracture following hypofractionated SBRT was related to the dose to 2 cm(3) of the rib.

Background and Aims: In a retrospective study using stereotactic body radiotherapy (SBRT) in medically inoperable patients with stage I NSCLC we previously reported a local control rate of 88% utilizing a median dose of 15Gyx3. This report records the toxicity encountered in a prospective phase II trial, and its relation to coexisting chronic obstructive pulmonary disease (COPD) and cardio vascular disease (CVD)., Material and Methods: Sixty patients were entered in the study between August 2003 and September 2005. Fifty-seven patients (T1 65%, T2 35%) with a median age of 75 years (59-87 years) were evaluable. The baseline mean FEV1% was 64% and median Karnofsky index was 80. A total dose of 45Gy was delivered in three fractions at the 67% isodose of the PTV. Clinical, pulmonary and radiological evaluations were made at 6 weeks, 3, 6, 9, 12, 18, and 36 months post-SBRT. Toxicity was graded according to CTC v2.0 and performance status was graded according to the Karnofsky scale., Results: At a median follow-up of 23 months, 2 patients had relapsed locally. No grade 4 or 5 toxicity was reported. Grade 3 toxicity was seen in 12 patients (21%). There was no significant decline of FEV1% during follow-up. Low grade pneumonitis developed to the same extent in the CVD 3/17 (18%) and COPD 7/40 (18%) groups. The incidence of fibrosis was 9/17 (53%) and pleural effusions was 8/17 (47%) in the CVD group compared with 13/40 (33%) and 5/40 (13%) in the COPD group., Conclusion: SBRT for stage I NSCLC patients who are medically inoperable because of COPD and CVD results in a favourable local control rate with a low incidence of grade 3 and no grade 4 or 5 toxicity.

Background and Purpose: A low-dose hypersensitivity to radiation can be observed in vitro for many human cell types in terms of increased cell kill per dose unit for doses below 0.5Gy. Quantification of the double-strand break marker gammaH2AX in samples taken in clinical radiotherapy practice has the potential to provide important information about how induction and repair of severe DNA damage and apoptosis are linked to low-dose hypersensitivity., Material and Methods: The effects of exposure to low doses (0.05-1.1Gy) were investigated in skin biopsies taken from prostate cancer patients undergoing the first week of radiotherapy. gammaH2AX foci and apoptotic cells were visualised by immunohistochemistry and quantified by image analysis., Results: The gammaH2AX foci pattern in biopsies taken 30min after a single fraction revealed a low-dose hypersensitivity below 0.3Gy (p=0.0009). The result was consistent for repeated fractions (p=0.00001). No decrease in foci numbers could be detected when comparing biopsies taken 30min and 2h after single fractions of 0.4 and 1.2Gy. The result was consistent for repeated fractions. Only 43 of 168,000 cells in total were identified as apoptotic, yet a dose dependency could be detected after 1week of radiotherapy (p=0.003)., Conclusions: We describe a method based on gammaH2AX to study DNA damage response and apoptosis in a clinical setting. A gammaH2AX hypersensitive response to low doses can be observed in epidermal skin, already 30min following delivered fraction. A very low frequency of apoptosis in normal epithelium suggests that this effect is not an important part of the in vivo response to low doses.

Aim: This paper describes the quality assurance (QA) work performed in the Swedish multicenter ARTSCAN (Accelerated RadioTherapy of Squamous cell CArcinomas in the head and Neck) trial to guarantee high quality in a multicenter study which involved modern radiotherapy such as 3DCRT or IMRT., Materials and Methods: The study was closed in June 2006 with 750 randomised patients. Radiation therapy-related data for every patient were sent by each participating centre to the QA office where all trial data were reviewed, analysed and stored. In case of any deviation from the protocol, an interactive process was started between the QA office and the local responsible clinician and/or physicist to increase the compliance to the protocol for future randomised patients. Meetings and workshops were held on a regular basis for discussions on various trial-related issues and for the QA office to report on updated results., Results and Discussion: This review covers the 734 patients out of a total of 750 who had entered the study. Deviations early in the study were corrected so that the overall compliance to the protocol was very high. There were only negligible variations in doses and dose distributions to target volumes for each specific site and stage. The quality of the treatments was high. Furthermore, an extensive database of treatment parameters was accumulated for future dose-volume vs. endpoint evaluations., Conclusions: This comprehensive QA programme increased the probability to draw firm conclusions from our study and may serve as a concept for QA work in future radiotherapy trials where comparatively small effects are searched for in a heterogeneous tumour population.

Background: The aim of this treatment planning study was to investigate the potential advantages of intensity-modulated (IM) proton therapy (IMPT) compared with IM photon therapy (IMRT) in nasopharyngeal carcinoma (NPC)., Methods: Eight NPC patients were chosen. The dose prescriptions in cobalt Gray equivalent (GyE) for gross tumor volumes of the primary tumor (GTV-T), planning target volumes of GTV-T and metastatic (PTV-TN) and elective (PTV-N) lymph node stations were 72.6 GyE, 66 GyE, and 52.8 GyE, respectively. For each patient, nine coplanar fields IMRT with step-and-shoot technique and 3D spot-scanned three coplanar fields IMPT plans were prepared. Both modalities were planned in 33 fractions to be delivered with a simultaneous integrated boost technique. All plans were prepared and optimized by using the research version of the inverse treatment planning system KonRad (DKFZ, Heidelberg)., Results: Both treatment techniques were equal in terms of averaged mean dose to target volumes. IMPT plans significantly improved the tumor coverage and conformation (P < 0.05) and they reduced the averaged mean dose to several organs at risk (OARs) by a factor of 2-3. The low-to-medium dose volumes (0.33-13.2 GyE) were more than doubled by IMRT plans., Conclusion: In radiotherapy of NPC patients, three-field IMPT has greater potential than nine-field IMRT with respect to tumor coverage and reduction of the integral dose to OARs and non-specific normal tissues. The practicality of IMPT in NPC deserves further exploration when this technique becomes available on wider clinical scale.

Nasopharyngeal carcinoma (NPC) is a rare disease in Sweden. For evaluation of the treatment outcomes in our NPC patients, 52 new cases that were referred to our department between 1991 and 2002 were retrospectively analysed. Tumor stage, according to the 1997 AJCC staging system, was I in five, II in ten, III in 12 and IV in 25 patients. Majority of the patients (87%) had World Health Organization type II-III tumors. Neoadjuvant chemotherapy was delivered in 33 patients. Thirty-two patients received hyperfractionated accelerated radiation therapy with a median dose of 64.6Gy (1.7Gy/fr bid). Conventional external irradiation with a median dose of 66Gy (2Gy/fr) was delivered to 18 patients. An intracavitary brachy-boost of 4.5-12Gy was delivered to 40 patients. Two patients were excluded from the analysis due to treatment refusal. For the patients with tumor stages I-IVB, the 5-year disease-free and overall survival rates were 61% and 55%, respectively. The 5-year local, regional, and distant relapse-free survival rates were 70%, 92% and 77%, respectively. The most frequent late side effects were xerostomia (98%), otitis (70%) and hearing deterioration (64%). Our data suggest that optimization of the treatment outcomes in NPC patients requires implementation of new therapeutic strategies.

The use of untraditional treatment modalities for external beam radiotherapy such as intensity modulated radiation therapy (IMRT) and proton beam therapy is increasing. This review focuses on the changes in the dose distribution and the impact on radiation related risks for long-term cancer survivors. We compare conventional radiotherapy, IMRT, and proton beam therapy based on published treatment planning studies as well as published measurements and Monte Carlo simulations of out-of-field dose distributions. Physical dose parameters describing the dose distribution in the target volume, the conformity index, the dose distribution in organs at risk, and the dose distribution in non-target tissue, respectively, are extracted from the treatment planning studies. Measured out-of-field dose distributions are presented as the dose equivalent as a function of distance from the treatment field. Data in the literature clearly shows that, compared with conventional radiotherapy, IMRT improves the dose distribution in the target volume, which may increase the probability of tumor control. IMRT also seems to increase the out-of-field dose distribution, as well as the irradiated non-target volume, although the data is not consistent, leading to a potentially increased risk of radiation induced secondary malignancies, while decreasing the dose to normal tissues close to the target volume, reducing the normal tissue complication probability. Protons show no or only minor advantage on the dose distribution in the target volume and the conformity index compared to IMRT. However, the data consistently shows that proton beam therapy substantially decreases the OAR average dose compared to the other two techniques. It is also clear that protons provide an improved dose distribution in non-target tissues compared to conventional radiotherapy and IMRT. IMRT and proton beam therapy may significantly improve tumor control for cancer patients and quality of life for long-term cancer survivors.

In forthcoming multicentre studies on stereotactic body radiotherapy (SBRT) compliance with volume and dose prescriptions will be mandatory to avoid unnecessary heterogeneity bias. To evaluate compliance in a multicentre setting we used two cases from an ongoing phase II study of SBRT of T1-T2N0M0 inoperable NSCLC in a dummy run oriented on volumes and doses. Six Scandinavian centres participated. Each centre received CT-scans covering the whole lung volumes of two patients with instructions to follow the study protocol when outlining tumour and target volumes, prescribing doses and creating dose plans. Volumes and doses of the 12 dose plans were evaluated according to the study protocol. For the two patients the GTV volume range was 24 to 39 cm3 and 26 to 41 cm3, respectively. The PTV volume range was 90 to 116 cm3, and 112 to 155 cm3, respectively. For all plans the margin between CTV and PTV in all directions followed in detail the protocol. The prescribed dose was for all centres 45 Gy/3 fractions (isocentre dose about 66 Gy). The mean GTV doses ranged from 63 to 67 Gy and from 63 to 68 Gy, respectively. The minimum doses for GTV were between 50-64 Gy and between 55-65 Gy, respectively. The dose distribution was conformed to PTV for 10 of 12 plans and 2 of 12 plans from one centre had sub-optimal dose distribution. Most of the volume and dose parameters for the participating centres showed fully acceptable compliance with the study protocol.

Unlabelled: Medically inoperable patients with stage I NSCLC are mainly offered conventionally fractionated radiotherapy with a limited chance of local control and some toxicity. A technique for stereotactic precision therapy for extracranial tumors using a linear accelerator and a body frame for patient immobilization was applied in an attempt to improve the local control and decrease toxicity for consecutive patients with inoperable stage I NSCLC at Sahlgrenska University hospital since 1998. A hypofractionated schedule with three fractions of 15Gy to a total of 45 Gy during 1 week was used which represents a biological equivalent dose (BED) of 112.5 Gy. Planning target volume (PTV) was a 5mm margin around the tumor in the transversal plane and 10mm in the cranial-caudal direction and the dose was prescribed in the periphery of the PTV. Forty-five patients were treated between September 98 and March 03, 25 men and 20 women, median age 74 years (58-84) and median Karnofsky 80 (100-60). TNM: 18 T1N0, 27 T2N0., Histology: 18 squamous cell carcinoma, 15 adenocarcinoma, 3 NSCLC and histology was missing in nine patients. The majority, 51%, did not experience any toxicity at all, four had esophagitis grade I, nine had skin reactions, four had transient chest pain and four had infections. Late toxicity was two rib fractures and three patients with atelectasias. After a median follow-up of 43 months had nine patients developed local recurrence or never achieved local control, two had regional recurrence and nine distant metastases. The 1-, 2-, 3- and 5-year overall survival was 80, 71, 55 and 30%, respectively, with a median survival of 39 months. No prognostic factor for survival could be identified among histology, tumor stage and size, gender and age. We think this hypofractionated stereotactic radiotherapy shows encouraging survival and a relatively low toxicity in this elderly population with substantial comorbidity. A multicenter randomized trial comparing this treatment with conventional fractionated radiotherapy is under way.

We reviewed results of SBRT treatment of 138 patients with medically inoperable stage I NSCLC treated during 1996-2003 at five different centres in Sweden and Denmark. Mean age was 74 years (range 56-90) with 69 men and 72 women. SBRT was delivered using a 3D conformal multifield technique and a stereotactic body frame. Doses delivered were 30-48 Gy (65% isodose at the periphery of planning target volume, PTV) in 2-4 fractions. Equivalent dose in 2 Gy fractions (EQD2) was in the range of 50-100 Gy. Mean gross tumour volume (GTV) was 39 cm3 (2-436), and planning target volume was 101 cm3 (11-719). Overall response rate (CR, PR) was 61% (84/138). SD was noted in 36% (50/138). During a median follow-up period of 33 months (1-107), 16 (12%) local failures occurred, ten of which also included distant metastases. Local failure was associated with tumour size, target definition and central or pleura proximity. Distant metastases occurred in 25% (35/138) of the patients. Ninety-one (65%) patients died during follow-up of which 55 patients (60%) died of other causes than lung cancer. Three- and 5-year overall survival was 52 and 26% respectively. Lung cancer specific 3- and 5-year overall survival was 66 and 40% respectively. Fifty nine percent (83/138) of the patients had no side effects. Fourteen patients experienced grade 3-4 toxicity according to radiation therapy oncology group (RTOG). EQD2 (> v.s.<55.6 Gy) showed a statistically significant benefit survival for the higher doses. SBRT for stage I NSCLC results in favourable local control not inferior to fractionated RT and with acceptable toxicity.

Background and Purpose: High dose rate brachytherapy (HDR-BT) in prostate cancer (PC) is receiving increasing interest. The steep dose gradient gives a possibility to escalate the dose to the prostate. If the alpha/beta ratio is low for PC, hypofractionation will be of advantage. A retrospective analysis of outcome in patients (pts) consecutively treated with combined HDR-BT and conformal external beam radiotherapy (ERT) was performed., Material and Methods: Data from 214 pts treated consecutively from 1988 to 2000 were analysed. The median age was 64 years (50-77). Median follow up was 4 years (12-165 months). Pre-irradiatory endocrine therapy was given to 150 pts (70%). The pts were divided into low-, intermediate- and high (80/87/47 pts) risk groups according to the occurrence of none, one, or more risk factors defined by T-classification, PSA and histopathology. ERT was given with 2 Gy fractions to 50 Gy. HDR-BT consisted of two 10 Gy fractions., Results: Overall 5-year biochemical no evidence of disease (bNED) was 82%, and for the low-, intermediate-, and high-risk group bNED was 92, 88 and 61%, respectively. PSA-relapse was found in 17, local recurrence in 3 and distant metastases in 13 pts. Five pts died of PC. No recurrences were observed after 5 years. Severe late complications were few. Urethral stricture (13 pts) was the most frequent. No severe rectal complications were seen., Conclusion: Dose escalation with HDR-BT is safe and effective in radiotherapy of localised PC.

The purpose of this study was to evaluate a single institution's outcome for patients with advanced laryngeal cancer treated with accelerated radiotherapy (RT). Fifty-eight patients with advanced laryngeal cancer (T3/T4N0/N + M0) were treated with curative intent with accelerated RT during the period 1990-1998. Patients received radiotherapy alone or with induction chemotherapy. The 5-year local control (LC) and loco-regional control (LRC) probabilities were both 49% for T3 and 75% for T4 tumors. The 5-year disease-free survival probability was 46% and 68% and overall survival probability was 30% and 39% for T3 and T4 tumors respectively. No significant statistical difference in outcome was found, either between T3 and T4 tumors, or between patients who received induction chemotherapy and those who did not. The treatment results for advanced laryngeal cancer at this institution were comparable to those reported in the literature. The results for T3 and T4 were similar. T4 classification alone should not be an exclusion criterion for larynx preservation. Overall survival was poor, partly because of a high incidence of deaths from intercurrent diseases.

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).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). 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. 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.

Background and Purpose: Following induction of double strand breaks the histone H2AX is rapidly phosphorylated at regions flanking the breaks resulting in nuclear gamma H2AX foci. The purpose of this study was to use this endogenous signalling system to quantify the in vivo response to radiation in normal tissue., Patients and Methods: Skin biopsies were taken from prostate cancer patients undergoing radiotherapy with a curative intent. Biopsies were taken at locations corresponding to 5 different doses in the range below 1.1 Gy per fraction. Biopsies were taken from patients 30 min following the first fraction and then once again following the fraction given after the first weekend break in the treatment course. The DNA double strand breaks were visualised as gamma H2AX foci using immunohistochemistry. Images were acquired using a CCD-camera and a fluorescence microscope and the gamma H2AX foci were quantified using digital image analysis including the basic procedures of top-hat transformation, threshold setting and labelling., Results: Repeated assessments of the biopsies showed a high reproducibility in quantifying the number of foci per DNA area of the nucleated cells in epidermis. The reproducibility was equally good for the two biopsy occasions. A linear dose response was observed for the epidermis in the dose region 0-1 Gy., Conclusions: We have established a method to measure the relative amount of DNA double strand breaks by detecting gamma H2AX foci in patients exposed to radiotherapy. The method provides a tool to study induction and repair of DNA double strand breaks and has the potential to predict individual radiosensitivity.

Background and Purpose: There is a general concern about intensity modulated radiation therapy (IMRT) treatments being more sensitive to patient positioning than conventional treatments. The aim of this study was to evaluate the International Commission on radiation units and measurements (ICRU) method for taking systematic set-up errors into account for IMRT treatments and to compare the effects on the dose distribution with the effects of conventional treatments., Material and Methods: A planning margin to account for set-up errors was added to the clinical target volumes and to the spinal cords, for three head and neck patients, according to the ICRU. No margin was added to organs at risk with mainly parallel structure if they were situated adjacent to the target volume, for example, the parotid glands. The effects of set-up errors in six IMRT plans and three conventional plans were simulated in the planning system and analysed with physical dose parameters., Results and Conclusions: In general, the ICRU method of taking set-up errors into account works satisfactorily for IMRT treatments as well as for conventional treatments with no difference between the treatment techniques. The sensitivity to set-up errors regarding the target volume is dependent on the quality of the treatment plan, i.e. the part of the target covered with a dose >95 and <105% and the effect in the critical organs is dependent on the sharpness of the dose gradients outside the critical organ. However, the method makes it difficult to include organs at risk with mainly parallel structure if they are situated adjacent to the target volume.

Background and Purpose: This is an investigation of a dose-based conjugated gradient optimization method (implemented in the CadPlan/Helios system) applied for head and neck tumours. Optimized field fluence distributions are created and transformed into dynamic multileaf collimator (MLC) movements. The aim was to gain knowledge about the influence of different parameters on the dose distribution and how to use the optimization algorithm in an optimum way., Material and Methods: Parameters such as the number of beams, collimator angle and constraints and weight factors have been investigated. Dose escalation to the target volume, the target volume in the build-up region and the way of prescribing the target dose were also investigated. The dose distributions were mainly analysed with physical parameters., Results and Conclusions: The optimization algorithm is well suited to create clinical Intensity modulated radiation therapy (IMRT) treatment plans for head and neck tumours even when the target volume is situated in the build-up region. The number of beams is a critical parameter and has a great influence on the dose distribution. The choice of collimator angles is not a critical parameter. The constraints and weight factors have a great influence on the dose distribution and varying these could easily control priorities regarding dose to the target volume or to the surrounding critical organs. Because of dose variations inside the target volume, prescribing to, normalizing to and reporting the mean dose in the target volume for IMRT treatment plans is preferable to the absorbed dose at a point, for example the isocentre point.

In an investigation by the Swedish Cancer Society, the present status critical issues and future aspects and potentials in each of nine major areas of radiation therapy research were described by an expert group. The report presented here deals with radiation therapy dose delivery. dose distributions, beam shaping and intensity modulation.

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. The present report deals with the potential of proton and light ion beams in radiotherapy.

In an investigation by the Swedish Cancer Society, the present status, critical issues and future aspects and prospects were described by an expert group for each of nine major areas of radiation research. A summary of the investigation is presented in this report. A more extensive summary (in Swedish) can be found at www.Cancerfonden.se. It is concluded that radiation therapy plays an increasingly important role in curative and palliative tumour treatment and presents a considerable challenge to research. Several suggestions are made that could improve the possibilities for high-quality radiation therapy research in Sweden.

Purpose: To evaluate the effect of shortening overall treatment time by hyperfractionated-accelerated radiotherapy for T2N(0)M(0) glottic carcinomas. Results for local control and survival were calculated and compared to those for T1N(0)M(0) tumors treated with a once-a-day fractionated schedule., Methods and Materials: Between 1990 and 1998, 92 patients with T1N(0)M(0) and 45 patients with T2N(0)M(0) glottic cancers were treated with radical radiotherapy. The T1N(0)M(0) tumors were treated with a once-a-day fractionated schedule lasting 6.5 weeks to a total dose of 62.4 Gy. The T2N(0)M(0) tumors received a split-course hyperfractionated-accelerated treatment over a total of 4.5 weeks to a total dose of 64.6 Gy., Results: The 5-year local control was 85% for T1N(0)M(0) and 88% for T2N(0)M(0), whereas the 5-year locoregional control was 85% for both groups. The 5-year overall survival was 70% and 53% for T1N(0)M(0) and T2N(0)M(0), respectively. No significant statistical difference was found between the two groups for the parameters analyzed. The number of serious late complications was few and comparable for the two groups., Conclusions: Hyperfractionated-accelerated radiotherapy proved beneficial for T2N(0)M(0) glottic cancer, giving local control rates comparable to those for T1N(0)M(0) tumors.

In an investigation by the Swedish Cancer Society, the present status, critical issues and future aspects and prospects were described by an expert group for each of nine major areas of radiation research. A summary of the investigation is presented in this report. A more extensive summary (in Swedish) can be found at www.Cancerfonden.se. It is concluded that radiation therapy plays an increasingly important role in curative and palliative tumour treatment and presents a considerable challenge to research. Several suggestions are made that could improve the possibilities for high-quality radiation therapy research in Sweden.