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Abstract: 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. [Copyright &y& Elsevier]

Summary: 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 45Gy during 1 week was used which represents a biological equivalent dose (BED) of 112.5Gy. 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. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Abstract: 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 2–14years). 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 &y& Elsevier]

Abstract: 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 45Gy in 3 fractions. Among the 33 patients with complete treatment records and radiographic follow-up exceeding 15months (median: 29months), 13 fractures were found in seven patients. Identifying all ribs receiving at least 21Gy, 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 2cm3 cut-off volume, D 2cm3, the logistic dose–response curve for three fractions was parameterised by D 50 =49.8Gy and γ 50 =2.05. Consequently, for a median follow-up of 29months, if D 2cm3 <3×7.0Gy the risk is close to 0, and the 5% and 50% risks are given by D 2cm3 =3×9.1Gy and 3×16.6Gy, respectively. Conclusions: In this group of patients, the risk for radiation-induced rib fracture following hypofractionated SBRT was related to the dose to 2cm3 of the rib. [Copyright &y& Elsevier]

Following induction of double strand breaks the histone H2AX is rapidly phosphorylated at regions flanking the breaks resulting in nuclear γH2AX foci. The purpose of this study was to use this endogenous signalling system to quantify the in vivo response to radiation in normal tissue.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 1.1Gy per fraction. Biopsies were taken from patients 30min 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 γH2AX foci using immunohistochemistry. Images were acquired using a CCD-camera and a fluorescence microscope and the γH2AX foci were quantified using digital image analysis including the basic procedures of top-hat transformation, threshold setting and labelling.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 0–1Gy.We have established a method to measure the relative amount of DNA double strand breaks by detecting γH2AX 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. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

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) (1.1 Gy + 2 Gy per day, 5 days/week for 4.5 weeks, total dose 68 Gy) and conventional fractionation (CF) (2 Gy per day, 5 days/week for 7 weeks, total dose 68 Gy). 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 5 years 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 5 years 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. [ABSTRACT FROM AUTHOR]

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 V 40 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. [ABSTRACT FROM AUTHOR]

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 cm3 up to 2.0 cm3]) 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 cm3 (D0.1cm3) was used for further analysis. The median value of D0.1cm3 (α/β = 3 Gy) was EQD2,LQ = 147 Gy3 (range, 20-293 Gy3). For patients who developed atelectasis the median value was EQD2,LQ = 210 Gy3, and for patients who did not develop atelectasis, EQD2,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. [ABSTRACT FROM AUTHOR]

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 &y& Elsevier]

Abstract: 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 50Gy in 2.0Gy 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 &y& Elsevier]

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 &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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 &y& Elsevier]

Abstract: 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 10–17years 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, 10–17years 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 17years 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 &y& Elsevier]

Abstract: 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 γH2AX 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 6.5weeks 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 γH2AX, 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 7weeks of radiotherapy (p <0.01). Growth arrest and cell proliferation assessed at 1week and 6.5weeks 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 6.5weeks 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 7weeks of radiotherapy. A persistent hypersensitive growth arrest response and cell killing mediate this effect. [Copyright &y& Elsevier]

Abstract: 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 γH2AX 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. γH2AX foci and apoptotic cells were visualised by immunohistochemistry and quantified by image analysis. Results: The γH2AX 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 γH2AX to study DNA damage response and apoptosis in a clinical setting. A γH2AX 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. [Copyright &y& Elsevier]

Abstract: 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 15Gy×3. 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. [Copyright &y& Elsevier]

Abstract: 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 α/β 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 2Gy fractions to 50Gy. HDR-BT consisted of two 10Gy 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. [Copyright &y& Elsevier]

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 &y& Elsevier]