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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: 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 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 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.)

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.)

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.

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.