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• The amygdala is critical to emotional processing, fear recognition, and memory. • We measured amygdala volumes in brain tumor patients treated with radiation (RT). • RT dose-dependent amygdala atrophy was observed at 1 year after treatment. • Amygdala atrophy after brain RT may contribute to neuropsychological deficits. The amygdalae are deep brain nuclei critical to emotional processing and the creation and storage of memory. It is not known whether the amygdalae are affected by brain radiotherapy (RT). We sought to quantify dose-dependent amygdala change one year after brain RT. 52 patients with primary brain tumors were retrospectively identified. Study patients underwent high-resolution, volumetric magnetic resonance imaging before RT and 1 year afterward. Images were processed using FDA-cleared software for automated segmentation of amygdala volume. Tumor, surgical changes, and segmentation errors were manually censored. Mean amygdala RT dose was tested for correlation with amygdala volume change 1 year after RT via the Pearson correlation coefficient. A linear mixed-effects model was constructed to evaluate potential predictors of amygdala volume change, including age, tumor hemisphere, sex, seizure history, and bevacizumab treatment during the study period. As 51 of 52 patients received chemotherapy, possible chemotherapy effects could not be studied. A two-tailed p -value <0.05 was considered statistically significant. Mean amygdala RT dose (r = −0.28, p = 0.01) was significantly correlated with volume loss. On multivariable analysis, the only significant predictor of amygdala atrophy was radiation dose. The final linear mixed-effects model estimated amygdala volume loss of 0.17% for every 1 Gy increase in mean amygdala RT dose (p = 0.008). The amygdala demonstrates dose-dependent atrophy one year after radiotherapy for brain tumors. Amygdala atrophy may mediate neuropsychological effects seen after brain RT. [ABSTRACT FROM AUTHOR]

Background and purpose The high plasticity of the intestinal epithelium is maintained by a resilient reserve stem cell population, whose extent and biology are a matter of ongoing debate. The in vivo clonogenic assay (IVCA), presents a well established and efficient analysis of radiation insult to the intestinal crypts. However, we found that inadequate mathematical analysis over the last four decades led to systematic errors and contradictory results in estimates of radio-sensitivity and size of the reserve stem cell pool. Material and methods We devised a refinement of the IVCA via development of a biomathematical model that delivers a full statistical dynamic description of epithelial radiation injury and subsequent regeneration. We validated the model against cellular and crypt distribution statistics obtained from IVCA experiments and through systematic re-analysis of experimental data from 27 publications. Results A full dynamic description of the evolution of stem cell niche population statistics is obtained. A systematic re-analysis reveals a consistent clonogenic content of the crypt of 31 ± 6 cells. The stem cell reserve manifests to be, contrary to prior predictions, radio-resistant: α = (0.22 ± 0.04) Gy−1. Conclusion We established a precision tool for the quantitative analysis of radiation insult to the intestinal crypts, which we employ to show that the reserve stem cell population is small, radio-resistant, and remarkably immutable against a large variety of interventions. The increased resolution of the model allows not only a reduction of the number of animals by about 75%, but also to quantify experimentally the influence of additional agents on damage and on regeneration of the stem cell niche. [ABSTRACT FROM AUTHOR]

Radiation is an important therapy for cancer with many benefits; however, its side effects, such as impaired wound healing, are a major problem. While many attempts have been made to overcome this particular disadvantage, there are few effective treatments for impaired wound healing in an X-ray-irradiated field. One reason for this deficiency is the lack of experimental models, especially animal models. We have previously reported a mouse model of impaired wound healing in which the irradiation area was restricted to the hindlimbs. In this mouse model, due to the size of the animal, a diameter of five millimeters was considered the largest wound size suitable for the model. In addition, the transplanted cells had to be harvested from other inbred animals. To investigate larger wounds and the impact of autologous specimen delivery, a rabbit model was developed. Rabbits were kept in a special apparatus to shield the body and hindlimbs while the irradiation field was exposed to radiation. Six weeks after irradiation, a 2 x 2 cm, full-thickness skin defect was made inside the irradiation field. Then, the wound area was observed over time. The wound area after irradiation was larger than that without irradiation at all time points. Both angiogenesis and collagen formation were reduced. For further study, as an example of using this model, the effect of autologous platelet-rich plasma (PRP) was observed. Autologous PRP from peripheral blood (pb-PRP) and bone marrow aspirate (bm-PRP) was processed and injected into the wounds in the irradiated field. Two weeks later, the wounds treated with bm-PRP were significantly smaller than those treated with phosphate buffer vehicle controls. In contrast, the wounds treated with pb-PRP were not significantly different from the controls. This rabbit model is useful for investigating the mechanism of impaired wound healing in an X-ray-irradiated field. [ABSTRACT FROM AUTHOR]

Radiation-induced mucositis is a dose-limiting factor in the effective treatment of head and neck (H & N) cancers. The objective of this study was to understand the efficacy of honey in mitigating radiation-induced mucositis and whether it would interfere with tumor control. This was a single-blinded, randomized, controlled study and was carried out in patients with H & N cancer requiring curative radiotherapy (>62 Gy (Gray)). The patients meeting the inclusion criteria were randomly assigned to receive either honey (n = 25) or povidone-iodine (active comparator) (n = 25) during radiotherapy. Oral mucositis was assessed using the RTOG (Radiation Therapy Oncology Group) grading system before the start, during, and at the end of the treatment by an investigator unaware of the treatment. The results indicate that when compared with the active comparator, honey reduced the radiation-induced oral mucositis, decreased the incidence of intolerable mucositis, treatment breaks, loss of treatment days (p < 0.0001 and < 0.0003) and did not affect the radiation-induced tumor response. The clinical observations indicate that honey mitigates the radiation-induced mucositis and does not interfere with tumor cell killing. [ABSTRACT FROM AUTHOR]

To reduce the high risk of radiation toxicity and enhance the quality of life of patients with non-small cell lung cancer (NSCLC), we quantified the metabolic tumor volumes (MTVs) from baseline to the late-course of radiotherapy (RT) by fluorodeoxyglucose positron emission tomography computerized tomography (FDG PET-CT) and discussed the potential benefit of late-course adaptive plans rather than original plans by dose volume histogram (DVH) comparisons. Seventeen patients with stage II-III NSCLC who were treated with definitive conventionally fractionated RT were eligible for this prospective study. FDG PET-CT scans were acquired within 1 week before RT (pre-RT) and at approximately two-thirds of the total dose during-RT (approximately 40 Gy). MTVs were taken as gross tumor volumes (GTVs) that included the primary tumor and any involved hilar or mediastinal lymph nodes. An original plan based on the baseline MTVs and adaptive plans based on observations during-RT MTVs were generated for each patient. The DVHs for lung, heart, esophagus and spinal cord were compared between the original plans and composite plans at 66 Gy. At the time of approximately 40 Gy during-RT, MTVs were significantly reduced in patients with NSCLC (pre-RT 136.2±82.3 ml vs. during-RT 64.7±68.0 ml, p = 0.001). The composite plan of the original plan at 40 Gy plus the adaptive plan at 26 Gy resulted in better DVHs for all the organs at risk that were evaluated compared to the original plan at 66 Gy (p<0.05), including V5, V10, V15, V20, V25, V30 and the mean dose of total lung, V10, V20, V30, V40, V50, V60 and the mean dose of heart, V35, V40, V50, V55, V60, the maximum dose and mean dose of the esophagus, and the maximum dose of the spinal-cord. PET-MTVs were reduced significantly at the time of approximately 40 Gy during-RT. Late course adaptive radiotherapy may be an effective way to reduce the dose volume to the organs at risk, thus reducing radiation toxicity in patients with NSCLC. [ABSTRACT FROM AUTHOR]

Purpose To evaluate long-term radiation toxicity and biochemical control of two moderately hypofractionated radiotherapy regimens for prostate cancer. Material and methods Eligible men with localized prostate cancer received image-guided intensity modulated radiotherapy (IG-IMRT) to a dose of 60 or 66 Gy in 3 Gy fractions in a phase II trial. Endpoints included late gastrointestinal (GI) and genitourinary (GU) toxicity and biochemical failure (FFBF). Results Ninety-six men received 60 Gy and 27 received 66 Gy. Accrual to the 66 Gy cohort terminated early due to excessive Grade 3–4 late toxicity. Median follow-up was 128 months (60 Gy) and 108 months (66 Gy). In the 60 Gy cohort, cumulative late Grade ⩾2 GI and GU toxicity at 8 years was 4% and 12% respectively. In the 66 Gy cohort, late Grade ⩾2 GI and GU toxicity was 21% and 4% respectively at 8 years. The 5- and 8-year FFBF for 60 Gy was 81% and 66%, and for 66 Gy was 88% and 80%. Conclusions Moderate hypofractionation with IG-IMRT to 60 Gy was associated with favorable late toxicity although late urinary toxicity and biochemical failures were observed beyond 5 years. Dose escalation to 66 Gy was associated with significantly worse late toxicity. [ABSTRACT FROM AUTHOR]

Background Advanced radiotherapy techniques reduce normal tissue dose by conforming closely to target volumes. In cervical cancer radiotherapy, organ filling affects clinical target volume (CTV; cervix, uterus) position. This study estimates the dosimetric effect of this primary CTV position variation during chemoradiation. Methods/materials Twice weekly cone-beam computed tomography (CBCT) images of ten patients undergoing cervical chemoradiation were retrospectively analysed. Primary CTV, bladder and rectum were delineated. RapidArc plans were created using 10–15 mm CTV–PTV margins and dose delivered to CTV based on each CBCT position was calculated using a novel vector approach. Dose delivered along the central uterine, mid-uterus and cervix vectors were analysed as well as dose delivered to points at uterine tip, anterior mid-uterus and anterior cervix. Additional RapidArc plans were created for large planning bladder volume cases using the CTV acquired with bladder volume at 150–300 cc. Results 105 scans for 10 patients were analysed. Vector analysis revealed CTV underdosing in certain cases. Below 95% average vector coverage was found for all three vectors in 2 cases and one vector in 1 case. Volumetric analysis revealed D99 < 95% in 48% of fractions. Patients with large planning bladder volumes (>300 cc) demonstrated the largest variation. Replanning improved this coverage. The anterior mid-uterus point was least well-covered; median 98.7% dose, reducing to 91.4% in cases with large planning bladder volumes. Again, replanning significantly improved this. D99 > 95% was maintained in 93% of fractions when bladder volume was 50 cc below to 150 cc above planning volume compared to 24% of fractions if bladder volume was outside this range. Similarly, D95 > 95% was 100% versus 84%. Conclusion Organ position variation detrimentally affected dose delivered to CTV including cervix. Large planning bladder volumes (>300 cc) led to more variation. We recommend bladder volumes of 150–300 cc at planning and a range of 50 cc below to 150 cc above planning for treatment. [ABSTRACT FROM AUTHOR]

Background and purpose To evaluate outcomes and toxicity in patients treated with hyperfractionated pelvic reirradiation for recurrent rectal cancer. Materials and methods 102 patients with recurrent rectal adenocarcinoma were treated with pelvic reirradiation with a hyperfractionated accelerated approach, consisting of 1.5 Gy twice daily fractions to a total dose of 30–45 Gy (median 39 Gy), with the most common total dose 39 Gy ( n = 90, 88%). The median dose of prior pelvic radiation therapy (RT) was 50.4 Gy (range: 25–63 Gy). Results The median follow-up was 40 months for living patients (range, 3–150 months). The 3-year freedom from local progression (FFLP) rate was 40% and the 3-year overall survival (OS) rate was 39%. Treatment with surgery was significantly associated with improved FFLP and OS, with 3-year FFLP rate of 49% vs. 30% ( P = 0.013), and 3-year OS rate of 62% vs. 20% ( P < 0.0001), compared to those without surgery. The actuarial 3-year rate of grade 3–4 late toxicity was 34%; patients who underwent surgery had a significantly higher rate of grade 3–4 late toxicity compared to those without surgery (54% vs. 16%, P = 0.001). Conclusions This large, retrospective, single-institution study shows that hyperfractionated accelerated reirradiation was well tolerated. The rate of FFLP was promising, given that the study comprised heavily pre-treated patients with recurrences. Rates of FFLP and OS were particularly impressive in patients who underwent both reirradiation and surgery. [ABSTRACT FROM AUTHOR]

Background and purpose The safety of a simultaneous integrated boost (SIB) in combination with prone hypofractionated whole-breast irradiation (WBI) was investigated. Materials and methods 167 patients were randomized between WBI with a sequential boost (SeB) or SIB. All patients were treated in prone position to 40.05 Gy in 15 fractions to the whole breast. In the control arm, a SeB of 10 Gy in 4 fractions (negative surgical margins) or 14.88 Gy in 6 fractions (transsection) was prescribed. In the experimental arm a SIB of 46.8 or 49.95 Gy (negative and positive surgical margins, respectively) was prescribed. Results Patient age was the only significantly different parameter between treatment arms with patients in the SIB arm being slightly older. In both arms, 6/83 patients developed moist desquamation. Grade 2/3 dermatitis was significantly more frequent in the SeB arm (38/83 vs 24/83 patients, p = 0.037). In the SIB and SeB arm, respectively, 36 patients (43%) and 51 patients (61%) developed pruritus ( p = 0.015). The incidence of oedema was lower in the SIB arm (59 vs 68 patients), but not statistically significant ( p = 0.071). Conclusions The primary endpoint, moist desquamation, was not significantly different between treatment arms. [ABSTRACT FROM AUTHOR]

Purpose:A minority of patients exhibits severe late normal tissue toxicity after radiotherapy (RT), possibly related to their inherent individual radiation sensitivity. This study aimed to evaluate four different candidate in vitro cellular radiosensitivity assays for prediction of late normal tissue reactions, in a retrospective matched case-control set-up of breast cancer patients. Methods:The study population consists of breast cancer patients expressing severe radiation toxicity (12 cases) and no or minimal reactions (12 controls), with a follow-up for at least 3 years. Late adverse reactions were evaluated by comparing standardized photographs pre- and post-RT resulting in an overall cosmetic score and by clinical examination using the LENT-SOMA scale. Four cellular assays on peripheral blood lymphocytes reported to be associated with normal tissue reactions were performed after in vitro irradiation of patient blood samples to compare case and control radiation responses: radiation-induced CD8+ late apoptosis, residual DNA double-strand breaks, G0 and G2 micronucleus assay. Results:A significant difference was observed for all cellular endpoints when matched cases and controls were compared both pairwise and grouped. However, it is important to point out that most case-control pairs showed a substantial overlap in standard deviations, which questions the predictive value of the individual assays. The apoptosis assay performed best, with less apoptosis seen in CD8+ lymphocytes of the cases (average: 14.45%) than in their matched controls (average: 30.64%) for 11 out of 12 patient pairs (p < .01). The number of residual DNA DSB was higher in cases (average: 9.92 foci/cell) compared to their matched control patients (average: 9.17 foci/cell) (p < .01). The average dose response curve of the G0 MN assay for cases lies above the average dose response curve of the controls. Finally, a pairwise comparison of the G2 MN results showed a higher MN yield for cases (average: 351 MN/1000BN) compared to controls (average: 219 MN/1000BN) in 9 out of 10 pairs (p < .01). Conclusion:This matched case-control study in breast cancer patients, using different endpoints for in vitro cellular radiosensitivity related to DNA repair and apoptosis, suggests that patients’ intrinsic radiosensitivity is involved in the development of late normal tissue reactions after RT. Larger prospective studies are warranted to validate the retrospective findings and to use in vitro cellular assays in the future to predict late normal tissue radiosensitivity and discriminate individuals with marked RT responses. [ABSTRACT FROM AUTHOR]

In human skin, keratinopoiesis is based on a functional hierarchy among keratinocytes, with rare slow-cycling stem cells responsible for the long-term maintenance of the tissue through their self-renewal potential, and more differentiated daughter progenitor cells actively cycling to permit epidermal renewal and turn-over every month. Skin is a radio-responsive tissue, developing all types of radiation damage and pathologies, including early tissue reactions such as dysplasia and denudation in epidermis, and later fibrosis in the dermis and acanthosis in epidermis, with the TGF-beta 1 pathway as a known master switch. Also there is a risk of basal cell carcinoma, which arises from epidermal keratinocytes, notably after oncogenic events in PTCH1 or TP53 genes. This review will cover the mechanisms of adverse human skin reactions and carcinogenesis after various types of exposures to ionizing radiation, with comparison with animal data when necessary, and will discuss the possible role of stem cells and their progeny in the development of these disorders. The main endpoints presented are basal cell intrinsic radiosensitivity, genomic stability, individual factors of risk, dose specific responses, major molecular pathways involved and the cellular origin of skin reactions and cancer. Although major advances have been obtained in recent years, the precise implications of epidermal stem cells and their progeny in these processes are not yet fully characterized. [ABSTRACT FROM AUTHOR]

Background: To consolidate literature reports of serious late gastrointestinal toxicities after hypofractionated radiation treatment of pancreatic cancer and attempt to derive normal tissue complication probability (NTCP) parameters using the Lyman-Kutcher-Burman model. Methods: Published reports of late grade 3 or greater gastrointestinal toxicity after hypofractionated treatment of pancreatic cancer were reviewed. The biologically equivalent dose in 1.8 Gy fractions was calculated using the EQD model. NTCP parameters were calculated using the LKB model assuming 1-5 % of the normal tissue volume was exposed to the prescription dose with α/β ratios of 3 or 4. Results: A total of 16 human studies were examined encompassing a total of 1160 patients. Toxicities consisted of ulcers, hemorrhages, obstructions, strictures, and perforations. Non-hemorrhagic and non-perforated ulcers occurred at a rate of 9.1 % and were the most commonly reported toxicity. Derived NTCP parameter ranges were as follows: n = 0.38-0.63, m = 0.48-0.49, and TD50 = 35-95 Gy. Regression analysis showed that among various study characteristics, dose was the only significant predictor of toxicity. Conclusions: Published gastrointestinal toxicity reports after hypofractionated radiotherapy for pancreatic cancer were compiled. Median dose was predictive of late grade ≤ 3 gastrointestinal toxicity. Preliminary NTCP parameters were derived for multiple volume constraints. [ABSTRACT FROM AUTHOR]

Purpose: This study examined the status of radiation-induced liver injury in adjuvant or palliative gastric cancer radiation therapy (RT), identified risk factors of radiation-induced liver injury in gastric cancer RT, analysed the dose-volume effects of liver injury, and developed a liver dose limitation reference for gastric cancer RT. Methods and Materials: Data for 56 post-operative gastric cancer patients and 6 locoregional recurrent gastric cancer patients treated with three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) from Sep 2007 to Sep 2009 were analysed. Forty patients (65%) were administered concurrent chemotherapy. Pre- and post-radiation chemotherapy were given to 61 patients and 43 patients, respectively. The radiation dose was 45–50.4 Gy in 25–28 fractions. Clinical parameters, including gender, age, hepatic B virus status, concurrent chemotherapy, and the total number of chemotherapy cycles, were included in the analysis. Univariate analyses with a non-parametric rank test (Mann–Whitney test) and logistic regression test and a multivariate analysis using a logistic regression test were completed. We also analysed the correlation between RT and the changes in serum chemistry parameters [including total bilirubin, (TB), direct bilirubin (D-TB), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and serum albumin (ALB)] after RT. Results: The Child-Pugh grade progressed from grade A to grade B after radiotherapy in 10 patients. A total of 16 cases of classic radiation-induced liver disease (RILD) were observed, and 2 patients had both Child-Pugh grade progression and classic RILD. No cases of non-classic radiation liver injury occurred in the study population. Among the tested clinical parameters, the total number of chemotherapy cycles correlated with liver function injury. V35 and ALP levels were significant predictive factors for radiation liver injury. Conclusions: In 3D-CRT for gastric cancer patients, radiation-induced liver injury may occur and affect the overall treatment plan. The total number of chemotherapy cycles correlated with liver function injury, and V35 and ALP are significant predictive factors for radiation-induced liver injury. Our dose limitation reference for liver protection is feasible. [ABSTRACT FROM AUTHOR]

Radiation proctopathy is a complication of pelvic radiotherapy, which occurs in patients treated for carcinoma of the prostate, rectum, urinary bladder, cervix, uterus, and testes. If it presents within 6 weeks to 9 months after therapy, it is called acute radiation proctitis/ proctopathy (ARP), and if it occurs 9 months to a year after treatment, it is classified as chronic radiation proctitis/proctopathy (CRP). CRP occurs in 5%-20% of patients receiving pelvic radiation, depending on the radiation dose and the presence or absence of chemotherapy. In many cases, CRP resolves spontaneously, but in some, it can lead to persistent rectal bleeding. Other symptoms of CRP include diarrhea, mucoid discharge, urgency, tenesmus, rectal pain, and fecal incontinence. Despite the availability of several therapies, many patients fail to respond, and continue to suffer in their quality of life. Radiofrequency ablation (RFA) is a newer endoscopic technique that uses radiofrequency energy to ablate tissue. This is an emerging way to treat radiation proctopathy and other mucosal telangiectasia. We present three cases of radiation proctopathy treated with RFA at our institute and review the literature on treatment modalities for CRP. We were also able to find 16 other cases of CRP that used RFA, and review their literature as well as literature on other treatment modalities. [ABSTRACT FROM AUTHOR]

Purpose To identify factors associated with grade ≥3 treatment related late esophageal toxicity after lung or liver stereotactic body radiation therapy (SBRT). Methods and Materials This was a retrospective review of 52 patients with a planning target volume within 2 cm of the esophagus from a prospective registry of 607 lung and liver SBRT patients treated between 2005 and 2011. Patients were treated using a risk-adapted dose regimen to a median dose of 50 Gy in 5 fractions (range, 37.5-60 Gy in 3-10 fractions). Normal structures were contoured using Radiation Therapy Oncology Group (RTOG) defined criteria. Results The median esophageal point dose and 1-cc dose were 32.3 Gy (range, 8.9-55.4 Gy) and 24.0 Gy (range, 7.8-50.9 Gy), respectively. Two patients had an esophageal fistula at a median of 8.4 months after SBRT, with maximum esophageal point doses of 51.5 and 52 Gy, and 1-cc doses of 48.1 and 50 Gy, respectively. These point and 1-cc doses were exceeded by 9 and 2 patients, respectively, without a fistula. The risk of a fistula for point doses exceeding 40, 45, and 50 Gy was 9.5% (n=2/21), 10.5% (n=2/19), and 12.5% (n=2/16), respectively. The risk of fistula for 1-cc doses exceeding 40, 45, and 50 Gy was 25% (n=2/9), 50% (n=2/4), and 50% (n=2/4), respectively. Eighteen patients received systemic therapy after SBRT (11 systemic chemotherapy, and 6 biologic agents, and 1 both). Both patients with fistulas had received adjuvant anti-angiogenic (vascular endothelial growth factor) agents within 2 months of completing SBRT. No patient had a fistula in the absence of adjuvant VEGF-modulating agents. Conclusions Esophageal fistula is a rare complication of SBRT. In this series, fistula was seen with esophageal point doses exceeding 51 Gy and 1-cc doses greater than 48 Gy. Notably, however, fistula was seen only in those patients who also received adjuvant VEGF-modulating agents after SBRT. The potential interaction of dose and adjuvant therapy should be considered when delivering SBRT near the esophagus. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to assess for changes in quality of life (QOL) among cancer patients who undergo radiotherapy (RT) and to identify factors that influence QOL in this group. Materials and methods: Three hundred sixty-seven cancer patients who received curative RT were investigated using the EORTC QLQ-C30 questionnaire at the start of RT, end of RT, and 1 and 6 months post-RT. Results: The patients were 49 % women, 51 % men, and median age at diagnosis was 57 years (range, 16-86 years). Compared to pre-RT, at the end of RT, the global health status score ( p < 0.001), nausea/vomiting ( p < 0.001), and apetite loss scores ( p < 0.001) were significantly poorer. Compared to the end of RT, at 1 and 6 months post-RT, global health status, all functional, and all symptom scores were significantly improved ( p < 0.001). Patient sex influenced scores for pain ( p = 0.036), appetite loss ( p = 0.027), and financial difficulty ( p = 0.003). Performance status influenced scores for global health status ( p = 0.006), physical functioning ( p < 0.001), cognitive functioning ( p = 0.001), and role functioning ( p = 0.021). Comorbidity influenced fatigue score ( p < 0.001). Cancer stage influenced scores for physical functioning ( p = 0.001), role functioning ( p = 0.010), and fatigue ( p < 0.001). Treatment modality (chemoRT vs. RT alone) influenced scores for physical functioning ( p = 0.016), fatigue ( p < 0.001), nausea/vomiting ( p = 0.009), and appetite loss ( p < 0.001); and RT field influenced scores for nausea/vomiting ( p = 0.001), appetite loss ( p = 0.003), and diarrhea ( p = 0.037). Radiotherapy dose functioning ( p < 0.001), cognitive functioning ( p < 0.001), social functioning ( p < 0.001), fatigue ( p < 0.001), and pain (<60 vs ≥60 Gy) had an effect on scores for physical functioning ( p < 0.001), role functioning ( p < 0.001), emotional ( p < 0.001), insomnia ( p < 0.001), constipation ( p < 0.001). Conclusion: While RT negatively affects cancer patients' QOL, restoration tends to be rapid and patients report significant improvement by 1 month post-RT. Various patient- and disease-specific factors and RT modality affect QOL in this patient group. We advocate measuring cancer patients' QOL regularly as part of routine patient management. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Mitochondrial DNA common variants have been reported to be associated with the development of radiation-induced toxicity. Using a large cohort of patients, we aimed to validate these findings by investigating the potential role of common European mitochondrial DNA SNPs (mtSNPs) to the development of radio-toxicity. Material and methods: Overall acute and late toxicity data were assessed in a cohort of 606 prostate cancer patients by means of Standardized Total Average Toxicity (STAT) score. We carried out association tests between radiation toxicity and a selection of 15 mtSNPs (and the haplogroups defined by them). Results: Statistically significant association between mtSNPs and haplogroups with toxicity could not be validated in our Spanish cohort. Conclusions: The present study suggests that the mtDNA common variants analyzed are not associated with clinically relevant increases in risk of overall radiation-induced toxicity in prostate cancer patients. [Copyright &y& Elsevier]

Abstract: Background and purpose: Mast cells are involved in the pathogenesis of radiation fibrosis and may be a therapeutic target. The mechanism of increased mast cell number in relation to acute and late tissue responses in human skin was investigated. Materials and methods: Punch biopsies of skin 1 and 15–18months after breast radiotherapy and a contralateral control biopsy were collected. Mast cells were quantified by immunohistochemistry using the markers c-Kit and tryptase. Stem cell factor (SCF) and collagen-1 expression was analysed by qRT-PCR. Clinical photographic scores were performed at post-surgical baseline and 18months and 5years post-radiotherapy. Primary human dermal microvascular endothelial cell (HDMEC) cultures were exposed to 2Gy ionising radiation and p53 and SCF expression was analysed by Western blotting and ELISA. Results: Dermal mast cell numbers were increased at 1 (p =0.047) and 18months (p =0.040) using c-Kit, and at 18months (p =0.024) using tryptase immunostaining. Collagen-1 mRNA in skin was increased at 1month (p =0.047) and 18months (p =0.032) and SCF mRNA increased at 1month (p =0.003). None of 16 cases scored had a change in photographic appearance at 5years, compared to baseline. SCF expression was not increased in HDMECs irradiated in vitro. Conclusions: Increased mast cell number was associated with up-regulated collagen-1 expression in human skin at early and late time points. This increase could be secondary to elevated SCF expression at 1month after radiotherapy. Although mast cells accumulate around blood vessels, no endothelial cell secretion of SCF was seen after in vitro irradiation. Modification of mast cell number and collagen-1 expression may be observed in skin at 1 and 18months after radiotherapy in breast cancer patients with no change in photographic breast appearance at 5years. [Copyright &y& Elsevier]

Abstract: Background and purpose: Intensity-modulated radiation therapy for thoracic malignancies increases the exposure of healthy lung tissue to low-dose radiation. The biological impact of repetitive low-dose radiation on the radiosensitive lung is unclear. Materials and methods: In the present study, using mouse strains with different genetic DNA repair capacities, we monitored the extent of DNA damage in lung parenchyma after 2, 4, 6, 8, and 10weeks of daily low-dose 100-mGy radiation. Results: Using 53BP1 as a marker for double-strand breaks, we observed DNA damage accumulation during fractionated low-dose radiation with increasing cumulative doses. The amount of radiation-induced 53BP1 varied significantly between bronchiolar and alveolar epithelial cells, suggesting that different cell populations in the lung parenchyma had varying vulnerabilities to ionizing radiation. The genetic background of DNA repair determined the extent of cumulative low-dose radiation damage. Moreover, increased DNA damage during fractionated low-dose radiation affected replication, and apoptosis in the lung parenchyma, which may influence overall lung function. Conclusion: Collectively, our results suggest that low, yet damaging, doses of radiation increase the risk of toxicity to normal lung tissue and the probability of developing secondary malignancies. [Copyright &y& Elsevier]

Purpose: The risk of developing secondary cancer after radiotherapy, especially after treatment of childhood cancers, remains a matter of concern. The high biological effects of carbon-ion radiation have enabled powerful radiotherapy, yet the approach is commonly restricted to the treatment of adults. Susceptibility of the fetus to particle radiation–induced cancer is also unclear. The present study is aimed to investigate the effect of carbon-ion irradiation in childhood on breast carcinogenesis. Methods and Materials: We irradiated female Sprague-Dawley rats of various ages (embryonic days 3, 13, and 17 and 1, 3, 7, and 15 weeks after birth) with 137Cs γ rays or a 290-MeV/u monoenergetic carbonion beam (linear energy transfer, 13 keV/μm). All animals were screened weekly for mammary carcinoma by palpation until they were 90 weeks old. Results: Irradiation of fetal and mature (15-week-old) rats with either radiation source at a dose of 0.2 or 1 Gy did not substantially increase the hazard ratio compared with the nonirradiated group. Dose responses (0.2-2.0 Gy) to γ rays were similar among the groups of rats irradiated 1, 3, and 7 weeks after birth. The effect of carbon ions increased along with the age at the time of irradiation, indicating relative biological effectiveness values of 0.2 (−0.3, 0.7), 1.3 (1.0, 1.6), and 2.8 (1.8, 3.9) (mean and 95% confidence interval) for animals that were 1, 3, and 7 weeks of age, respectively. Conclusions: Our findings imply that carbonion therapy may be associated with a risk of secondary breast cancer in humans, the extent of which may depend on the age of the patient at the time of irradiation. [Copyright &y& Elsevier]

Purpose: To evaluate biliary toxicity after stereotactic body radiation therapy (SBRT) for liver tumors. Methods and Materials: Among 297 consecutive patients with liver tumors treated with SBRT of 35 to 50 Gy in 5 fractions, patients who were irradiated with >20 Gy to the central biliary system (CBS), including the gallbladder, and had follow-up times >6 months were retrospectively analyzed. Toxicity profiles, such as clinical symptoms and laboratory and radiologic data especially for obstructive jaundice and biliary infection, were investigated in relation to the dose volume and length relationship for each biliary organ. Results: Fifty patients with 55 tumors were irradiated with >20 Gy to the CBS. The median follow-up period was 18.2 months (range, 6.0-80.5 months). In the dose length analysis, 39, 34, 14, and 2 patients were irradiated with >20 Gy, >30 Gy, >40 Gy, and >50 Gy, respectively, to >1 cm of the biliary tract. Seven patients were irradiated with >20 Gy to >20% of the gallbladder. Only 2 patients experienced asymptomatic bile duct stenosis. One patient, metachronously treated twice with SBRT for tumors adjacent to each other, had a transient increase in hepatic and biliary enzymes 12 months after the second treatment. The high-dose area >80 Gy corresponded to the biliary stenosis region. The other patient experienced biliary stenosis 5 months after SBRT and had no laboratory changes. The biliary tract irradiated with >20 Gy was 7 mm and did not correspond to the bile duct stenosis region. No obstructive jaundice or biliary infection was found in any patient. Conclusions: SBRT for liver tumors adjacent to the CBS was feasible with minimal biliary toxicity. Only 1 patient had exceptional radiation-induced bile duct stenosis. For liver tumors adjacent to the CBS without other effective treatment options, SBRT at a dose of 40 Gy in 5 fractions is a safe treatment with regard to biliary toxicity. [Copyright &y& Elsevier]

Purpose: To test the hypothesis that intensity modulated radiation therapy (IMRT) aiming to spare the salivary glands and swallowing structures would reduce or eliminate the effects of xerostomia and dysphagia on quality of life (QOL). Methods and Materials: In this prospective, longitudinal study, 72 patients with stage III-IV oropharyngeal cancer were treated uniformly with definitive chemo-IMRT sparing the salivary glands and swallowing structures. Overall QOL was assessed by summary scores of the Head Neck QOL (HNQOL) and University of Washington QOL (UWQOL) questionnaires, as well as the HNQOL “Overall Bother” question. Quality of life, observer-rated toxicities (Common Toxicity Criteria Adverse Effects scale, version 2), and objective evaluations (videofluoroscopy assessing dysphagia and saliva flow rates assessing xerostomia) were recorded from before therapy through 2 years after therapy. Correlations between toxicities/objective evaluations and overall QOL were assessed using longitudinal repeated measures of analysis and Pearson correlations. Results: All observer-rated toxicities and QOL scores worsened 1-3 months after therapy and improved through 12 months, with minor further improvements through 24 months. At 12 months, dysphagia grades 0-1, 2, and 3, were observed in 95%, 4%, and 1% of patients, respectively. Using all posttherapy observations, observer-rated dysphagia was highly correlated with all overall QOL measures (P<.0001), whereas xerostomia and mucosal and voice toxicities were significantly correlated with some, but not all, overall QOL measures, with lower correlation coefficients than dysphagia. Late overall QOL (≥6 or ≥12 months after therapy) was primarily associated with observer-rated dysphagia, and to a lesser extent with xerostomia. Videofluoroscopy scores, but not salivary flows, were significantly correlated with some of the overall QOL measures. Conclusion: After chemo-IMRT, although late dysphagia was on average mild, it was still the major correlate of QOL. Further efforts to reduce swallowing dysfunction are likely to yield additional gains in QOL. [Copyright &y& Elsevier]

Purpose: The purpose of this study was to clarify the incidence, the clinical risk factors, and the dose–volume relationship of radiation-induced rib fracture (RIRF) after hypofractionated stereotactic body radiation therapy (SBRT). Methods and Materials: One hundred sixteen patients treated with SBRT for primary or metastatic lung cancer at our institution, with at least 6 months of follow-up and no previous overlapping radiation exposure, were included in this study. To determine the clinical risk factors associated with RIRF, correlations between the incidence of RIRF and the variables, including age, sex, diagnosis, gross tumor volume diameter, rib–tumor distance, and use of steroid administration, were analyzed. Dose–volume histogram analysis was also conducted. Regarding the maximum dose, V10, V20, V30, and V40 of the rib, and the incidences of RIRF were compared between the two groups divided by the cutoff value determined by the receiver operating characteristic curves. Results: One hundred sixteen patients and 374 ribs met the inclusion criteria. Among the 116 patients, 28 patients (46 ribs) experienced RIRF. The estimated incidence of rib fracture was 37.7% at 3 years. Limited distance from the rib to the tumor (<2.0 cm) was the only significant risk factor for RIRF (p = 0.0001). Among the dosimetric parameters used for receiver operating characteristic analysis, the maximum dose showed the highest area under the curve. The 3-year estimated risk of RIRF and the determined cutoff value were 45.8% vs. 1.4% (maximum dose, ≥42.4 Gy or less), 51.6% vs. 2.0% (V40, ≥0.29 cm3 or less), 45.8% vs. 2.2% (V30, ≥1.35 cm3 or less), 42.0% vs. 8.5% (V20, ≥3.62 cm3 or less), or 25.9% vs. 10.5% (V10, ≥5.03 cm3 or less). Conclusions: The incidence of RIRF after hypofractionated SBRT is relatively high. The maximum dose and high-dose volume are strongly correlated with RIRF. [Copyright &y& Elsevier]

Purpose: To identify dosimetric parameters that correlate with acute hematologic toxicity (HT) in patients with squamous cell carcinoma of the anal canal treated with definitive chemoradiotherapy (CRT). Methods and Materials: We analyzed 33 patients receiving CRT. Pelvic bone (PBM) was contoured for each patient and divided into subsites: ilium, lower pelvis (LP), and lumbosacral spine (LSS). The volume of each region receiving at least 5, 10, 15, 20, 30, and 40 Gy was calculated. Endpoints included grade ≥3 HT (HT3+) and hematologic event (HE), defined as any grade ≥2 HT with a modification in chemotherapy dose. Normal tissue complication probability (NTCP) was evaluated with the Lyman-Kutcher-Burman (LKB) model. Logistic regression was used to test associations between HT and dosimetric/clinical parameters. Results: Nine patients experienced HT3+ and 15 patients experienced HE. Constrained optimization of the LKB model for HT3+ yielded the parameters m = 0.175, n = 1, and TD50 = 32 Gy. With this model, mean PBM doses of 25 Gy, 27.5 Gy, and 31 Gy result in a 10%, 20%, and 40% risk of HT3+, respectively. Compared with patients with mean PBM dose of <30 Gy, patients with mean PBM dose ≥30 Gy had a 14-fold increase in the odds of developing HT3+ (p = 0.005). Several low-dose radiation parameters (i.e., PBM-V10) were associated with the development of HT3+ and HE. No association was found with the ilium, LP, or clinical factors. Conclusions: LKB modeling confirms the expectation that PBM acts like a parallel organ, implying that the mean dose to the organ is a useful predictor for toxicity. Low-dose radiation to the PBM was also associated with clinically significant HT. Keeping the mean PBM dose <22.5 Gy and <25 Gy is associated with a 5% and 10% risk of HT, respectively. [Copyright &y& Elsevier]

Purpose: To report on toxicity after postoperative intensity-modulated arc therapy (IMAT) for cervical (CC) and endometrial cancer (EC). Methods and Materials: Twenty-four CC and 41 EC patients were treated with postoperative IMAT. If indicated, para-aortic lymph node irradiation (preventive or when affected, PALN) and/or concomitant cisplatin (40 mg/m², weekly) was administered. The prescribed dose for IMAT was 45 Gy (CC, 25 fractions) and 46 Gy (EC, 23 fractions), followed by a brachytherapeutic boost if possible. Radiation-related toxicity was assessed prospectively. The effect of concomitant cisplatin and PALN irradiation was evaluated. Results: Regarding acute toxicity (n = 65), Grade 3 and 2 acute gastrointestinal toxicity was observed in zero and 63% of patients (79% CC, 54% EC), respectively. Grade 3 and 2 acute genitourinary toxicity was observed in 1% and 18% of patients, respectively. Grade 2 (21%) and 3 (12%) hematologic toxicity (n = 41) occurred only in CC patients. Seventeen percent of CC patients and 2% of EC patients experienced Grade 2 fatigue and skin toxicity, respectively. Adding cisplatin led to an increase in Grade >2 nausea (57% vs. 9%; p = 0.01), Grade 2 nocturia (24% vs. 4%; p = 0.03), Grade ≥2 hematologic toxicity (38% vs. nil, p = 0.003), Grade ≥2 leukopenia (33% vs. nil, p = 0.009), and a strong trend toward more fatigue (14% vs. 2%; p = 0.05). Para-aortic lymph node irradiation led to an increase of Grade 2 nocturia (31% vs. 4%, p = 0.008) and a strong trend toward more Grade >2 nausea (44% vs. 18%; p = 0.052). Regarding late toxicity (n = 45), no Grade 3 or 4 late toxicity occurred. Grade 2 gastrointestinal toxicity, genitourinary toxicity, and fatigue occurred in 4%, 9%, and 1% of patients. Neither concomitant cisplatin nor PALN irradiation increased late toxicity rates. Conclusions: Postoperative IMAT for EC or CC is associated with low acute and late toxicity. Concomitant chemotherapy and PALN irradiation influences acute but not late toxicity. [Copyright &y& Elsevier]

Purpose: To investigate whether the volumes of rectum exposed to intermediate doses, from 30 to 50 Gy, contribute to the risk of Grade ≥2 late rectal toxicity among patients with prostate cancer receiving radiotherapy. Methods and Materials: Data from 1009 patients treated on Radiation Therapy Oncology Group protocol 94-06 were analyzed using three approaches. First, the contribution of intermediate doses to a previously published fit of the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model was determined. Next, the extent to which intermediate doses provide additional risk information, after taking the LKB model into account, was investigated. Third, the proportion of rectum receiving doses higher than a threshold, VDose, was computed for doses ranging from 5 to 85 Gy, and a multivariate Cox proportional hazards model was used to determine which of these parameters were significantly associated with time to Grade ≥2 late rectal toxicity. Results: Doses <60 Gy had no detectable impact on the fit of the LKB model, as expected on the basis of the small estimate of the volume parameter (n = 0.077). Furthermore, there was no detectable difference in late rectal toxicity among cohorts with similar risk estimates from the LKB model but with different volumes of rectum exposed to intermediate doses. The multivariate Cox proportional hazards model selected V75 as the only value of VDose significantly associated with late rectal toxicity. Conclusions: There is no evidence from these data that intermediate doses influence the risk of Grade ≥2 late rectal toxicity. Instead, the critical doses for this endpoint seem to be ≥75 Gy. It is hypothesized that cases of Grade ≥2 late rectal toxicity occurring among patients with V75 less than approximately 12% may be due to a “background” level of risk, likely due mainly to biological factors. [Copyright &y& Elsevier]

Purpose: Postorchiectomy adjuvant radiotherapy (RT) for Stage I seminoma can be associated with long-term toxicity, and management strategies with a lower treatment burden achieve the same excellent cure rate. Because studies suggest that radiation oncologists in the United States continue to recommend RT for these patients, we sought to identify factors associated with management recommendations. Methods and Materials: We conducted a one-time internet-based survey among 491 randomly selected American radiation oncologists self-described as specializing in genitourinary oncology. Results: Response rate was 53% (n = 261). Forty-nine percent of respondents worked in university-affiliated practices. Sixty-two percent of respondents always/usually recommended adjuvant RT for patients with Stage I seminoma, whereas 21% always/usually recommended surveillance and 3% always/usually recommended chemotherapy. One third (33%) expressed concerns that patients who experienced relapse during surveillance could not be salvaged. Although 88% of physicians were aware of an increased risk of second malignant neoplasms (SMN) after adjuvant RT, 85% underestimated its magnitude. Compared with physicians not typically recommending RT, physicians who always/usually recommended RT were more likely to believe that patients might not be salvaged at relapse during surveillance (p = 0.008) and were less aware of the association between RT and SMN (p = 0.04). Conclusions: Respondents who always/usually recommend postorchiectomy RT for patients with Stage I seminoma are more likely to underestimate late RT morbidity and to believe that surveillance is associated with increased mortality. Given the equivalent efficacy and reduced morbidity of surveillance compared with RT, our findings underscore the need for ongoing physician education to increase appropriate clinical implementation of surveillance strategies. [Copyright &y& Elsevier]

Abstract: Normal tissue toxicity caused by radiotherapy conditions the success of the treatment and the quality of life of patients. Radiotherapy is combined with surgery in both the preoperative or postoperative setting for the treatment of most localized solid tumour types. Furthermore, radical radiotherapy is an alternative to surgery in several tumour locations. The possibility of predicting such radiation-induced toxicity would make possible a better treatment schedule for the individual patient. Radiation-induced toxicity is, at least in part, genetically determined. From decades, several predictive tests have been proposed to know the individual sensitivity of patients to the radiotherapy schedules. Among them, initial DNA damage, radiation-induced apoptosis, gene expression profiles, and gene polymorphisms have been proposed. We report here an overview of the main studies regarding to this field. Radiation-induced apoptosis in peripheral blood lymphocytes seem to be the most promising assay tested in prospective clinical trials, although they have to be validated in large clinical studies. Other promising assays, as those related with single nucleotide polymorphisms, need to be validated as well. [Copyright &y& Elsevier]

Abstract: Radiotherapy is a major treatment of pelvic tumours. It exposes to the risk of acute and long-term side effects, such as radiation proctitis. Radiation proctitis is a complex disease requiring support ranging from initial contact with the patient until several years after completion of radiotherapy. This care includes preventive measures (clinical and dosimetric factors), detection and medical and surgical treatments. This article aims to make a review of radiation proctitis induced during the treatment of pelvic cancers. [Copyright &y& Elsevier]

Purpose: Scoring of radiation pneumonitis (RP), a dose-limiting toxicity after thoracic radiochemotherapy, is subjective and thus inconsistent among studies. Here we investigated whether the extent of change in diffusing capacity of the lung for carbon monoxide (DLCO) after radiation therapy (RT) for non-small-cell lung cancer (NSCLC) could be used as an objective means of quantifying RP. Patients and Methods: We analyzed potential correlations between DLCO and RP in 140 patients who received definitive RT (≥60 Gy) with or without chemotherapy for primary NSCLC. All underwent DLCO analysis before and after RT. Post-RT DLCO values within 1 week of the RP diagnosis (Grade 0, 1, 2, or 3) were selected and compared with that individual’s preradiation values. Percent reductions in DLCO and RP grade were compared by point biserial correlation in the entire patient group and in subgroups stratified according to various clinical factors. Results: Patients experiencing Grade 0, 1, 2, or 3 RP had median percentage changes in DLCO after RT of 10.7%, 13%, 22.1%, or 35.2%. Percent reduction in DLCO correlated with RP Grade ≤1 vs. ≥2 (p = 0.0004). This association held for the following subgroups: age ≥65 years, advanced stage, smokers, use of chemotherapy, volume of normal lung receiving at least 20 Gy ≥30%, and baseline DLCO or forced expiratory volume in 1 second ≥60%. Conclusions: By correlating percent change in DLCO from pretreatment values at the time of diagnosis of RP with RP grade, we were able to identify categories of RP based on the change in DLCO. These criteria provide a basis for an objective scoring system for RP based on change in DLCO. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: This secondary analysis was performed to identify predictive factors for severe late radiotherapy (RT)-related toxicity after treatment with hyperfractionated RT +/− concomitant cisplatin in locally advanced head and neck cancer. Materials and methods: Patients were retrospectively analyzed from the previously reported randomized phase III trial: SAKK 10/94. Severe late RT-related toxicity was defined as late RTOG grade 3 toxicity starting 3months after end of RT and/or potential treatment-related death within 3years of randomization. Results: Two hundred and thirteen randomized patients were analyzed; 84 (39%) experienced severe late RT-related toxicity. With median follow-up of 9.7years (range, 0.4–15.4years), median time to severe late RT-related toxicity was 9.6years. In the univariate Cox proportional hazards model the following variables were associated with severe late RT-related toxicity: advanced N-classification (p <0.001); technically unresectable disease (p =0.04); weight loss ratio (p =0.003); supportive measures (p =0.009) and severe acute dysphagia (p =0.001). In the subsequent multivariate analysis all variables except use of supportive measures remained statistically significant. Conclusions: Chemotherapy did not appear to affect severe late RT-related toxicity, but advanced N-classification, technically unresectable disease, weight loss ratio, and severe acute dysphagia were independent predictive factors for severe late RT-related toxicity. [Copyright &y& Elsevier]

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Patients diagnosed with GBM have a poor prognosis, and it has been reported that tumor malignancy and GBM recurrence are promoted by STAT3 signaling. As resveratrol (RV), a polyphenol in grapes, is reported to be a potent and non-toxic cancer-preventive compound, the aim of this study was to investigate the therapeutic effect and molecular mechanisms of RV on GBM-derived radioresistant tumor initiating cells (TIC). Firstly, our results showed that primary GBM-CD133+ TIC presented high tumorigenic and radiochemoresistant properties as well as increased protein levels of phosphorylated STAT3. We consistently observed that treatment with shRNA-STAT3 (sh-STAT3) or AG490, a STAT3 inhibitor, significantly inhibited the cancer stem-like cell properties and radioresistance of GBM-CD133+ in vitro and in vivo. Furthermore, treatment of GBM-CD133+ with 100 µM RV induced apoptosis and enhanced radiosensitivity by suppressing STAT3 signaling. Microarray results suggested that RV or AG490 inhibited the stemness gene signatures of GBM-CD133+ and facilitated the differentiation of GBM-CD133+ into GBM-CD133− or astrocytoma cells. Finally, xenotransplant experiments indicated that RV or sh-STAT3 therapy could significantly improve the survival rate and synergistically enhance the radiosensitivity of radiation-treated GBM-TIC. In summary, RV can reduce in vivo tumorigenicity and enhance the sensitivity of GBM-TIC to radiotherapies through the STAT3 pathway. J. Cell. Physiol. 227: 976-993, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose: Preoperative chemoradiotherapy (CRT) is superior to radiotherapy (RT) in locally advanced rectal cancer, but the survival gain is limited. Late toxicity is, therefore, important. The aim was to compare late bowel, urinary, and sexual functions after CRT or RT. Methods and Materials: Patients (N = 207) with nonresectable rectal cancer were randomized to preoperative CRT or RT (2 Gy × 25 ± 5-fluorouracil/leucovorin). Extended surgery was often required. Self-reported late toxicity was scored according to the LENT SOMA criteria in a structured telephone interview and with questionnaires European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), International Index of Erectile Function (IIEF), and sexual function -vaginal changes questionnaire (SVQ). Results: Of the 105 patients alive in Norway and Sweden after 4 to 12 years of follow-up, 78 (74%) responded. More patients in the CRT group had received a stoma (73% vs. 52%, p = 0.09). Most patients without a stoma (7 of 12 in CRT group and 9 of 16 in RT group) had incontinence for liquid stools or gas. No stoma and good anal function were seen in 5 patients (11%) in the CRT group and in 11 (30%) in the RT group (p = 0.046). Of 44 patients in the CRT group, 12 (28%) had had bowel obstruction compared with 5 of 33 (15%) in the RT group (p = 0.27). One-quarter of the patients reported urinary incontinence. The majority of men had severe erectile dysfunction. Few women reported sexual activity during the previous month. However, the majority did not have concerns about their sex life. Conclusions: Fecal incontinence and erectile dysfunction are frequent after combined treatment for locally advanced rectal cancer. There was a clear tendency for the problems to be more common after CRT than after RT. [ABSTRACT FROM AUTHOR]

Abstract: Background: Radiation therapy is commonly used to treat localized prostate cancer; however, representative data regarding treatment-related toxicities compared with conservative management are sparse. Objective: To evaluate gastrointestinal (GI) toxicities in men treated with either primary radiation or conservative management for T1–T2 prostate cancer. Design, setting, and participants: We performed a population-based cohort study, using Medicare claims data linked to the Surveillance Epidemiology and End Results data. Competing risk models were used to evaluate the risks. Measurements: GI toxicities requiring interventional procedures occurring at least 6 mo after cancer diagnosis. Results and limitations: Among 41 737 patients in this study, 28 088 patients received radiation therapy. The most common GI toxicity was GI bleeding or ulceration. GI toxicity rates were 9.3 per 1000 person-years after three-dimensional conformal radiotherapy, 8.9 per 1000 person-years after intensity-modulated radiotherapy, 5.3 per 1000 person-years after brachytherapy alone, 20.1 per 1000 person-years after proton therapy, and 2.1 per 1000 person-years for conservative management patients. Radiation therapy is the most significant factor associated with an increased risk of GI toxicities (hazard ratio [HR]: 4.74; 95% confidence interval [CI], 3.97–5.66). Even after 5 yr, the radiation group continued to experience significantly higher rates of new GI toxicities than the conservative management group (HR: 3.01; 95% CI, 2.06–4.39). Because our cohort of patients were between 66 and 85 yr of age, these results may not be applicable to younger patients. Conclusions: Patients treated with radiation therapy are more likely to have procedural interventions for GI toxicities than patients with conservative management, and the elevated risk persists beyond 5 yr. [Copyright &y& Elsevier]

Abstract: The radiotherapy of thoracic cancers exposes the heart to late radiation-induced complications. The physiopathological and clinical consequences of heart irradiation have been mostly studied in patients with Hodgkin lymphoma and breast cancer. The main cause of cardiac morbidity is radiation-induced coronaropathy with a relative risk estimated between 2 and 3 in earlier studies. Preexisting factors of cardiovascular risk, including chemotherapy, potentalize the cardiotoxicity of radiotherapy. Conformational radiotherapy, adapting the ballistics and the energy to the delineated volumes while carefully evaluating the dose–volume distribution in the organs at risk, allowed a drastic reduction in cardiac mortality. This toxicity no longer seems to be significant if the cardiac volume has received less than 30Gy. Nevertheless, the prolonged life expectancy of cancer patients and the expanding use of new cardiotoxic anticancer drugs underline the persistent need to further reduce the dose delivered to the heart. Indeed, 1Gy added to the mean heart dose would increase the cardiotoxic risk by 4% (IC 95%: 2–6%, P= 0.0002). A strengthened collaboration between the radiation oncologist and the cardiologist aims at detecting and treating long-term complications after thoracic radiotherapy. [Copyright &y& Elsevier]

Purpose: To address the characteristics and the causative factors of radiation-induced cranial nerve palsy (CNP) in nasopharyngeal carcinoma (NPC) patients with an extensive period of followed-up. Patients and Methods: A total of 317 consecutive and nonselected patients treated with definitive external-beam radiotherapy between November 1962 and February 1995 participated in this study. The median doses to the nasopharynx and upper neck were 71 Gy (range, 55–86 Gy) and 61 Gy (range, 34–72 Gy), respectively. Conventional fractionation was used in 287 patients (90.5%). Forty-five patients (14.2%) received chemotherapy. Results: The median follow-up was 11.4 years (range, 5.1–38.0 years). Ninety-eight patients (30.9%) developed CNP, with a median latent period of 7.6 years (range, 0.3–34 years). Patients had a higher rate of CNP (81 cases, 25.5%) in lower-group cranial nerves compared with upper group (44 cases, 13.9%) (χ2 = 34.444, p < 0.001). Fifty-nine cases experienced CNP in more than one cranial nerve. Twenty-two of 27 cases (68.8%) of intragroup CNP and 11 of 32 cases (40.7%) of intergroup CNP occurred synchronously (χ2 = 4.661, p = 0.031). The cumulative incidences of CNP were 10.4%, 22.4%, 35.5%, and 44.5% at 5, 10, 15, and 20 years, respectively. Multivariate analyses revealed that CNP at diagnosis, chemotherapy, total radiation dose to the nasopharynx, and upper neck fibrosis were independent risk factors for developing radiation-induced CNP. Conclusion: Radiation-induced fibrosis may play an important role in radiation-induced CNP. The incidence of CNP after definitive radiotherapy for NPC remains high after long-term follow-up and is dose and fractionation dependent. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Polymorphisms in genes responsible for DNA damage signaling and repair might modulate DNA repair capacity and, therefore, affect cell and tissue response to radiation and influence individual radiosensitivity. The purpose of the present prospective investigation was to evaluate the association of single nucleotide polymorphisms in XRCC1 with radiation-induced late side effects in prostate cancer patients treated with radiotherapy. Material and methods: To analyze the role of XRCC1 polymorphisms for late toxicity 603 participants from the Austrian PROCAGENE study treated with three-dimensional conformal radiotherapy were included in the present investigation. Three non-synonymous candidate polymorphisms in the X-ray repair cross-complementing group 1 (XRCC1) gene (Arg194Trp; Arg280His; Arg399Gln) were selected and determined by 5´-nuclease (TaqMan) assays. Results: Within a median follow-up time of 35months, 91 patients (15.7%) developed high-grade late toxicities (defined as late bladder and/or rectal toxicity RTOG⩾2). In a Kaplan–Meier analysis, carriers of the XRCC1 Arg280His polymorphism were at decreased risk of high-grade late toxicity (p =0.022), in multivariate analysis including clinical and dosimetric parameters as potential confounders the XRCC1 Arg280His polymorphism remained a significant predictor for high-grade late toxicity (HR=0.221, 95% CI 0.051–0.956; p =0.043). No significant associations were found for the remaining polymorphisms. Conclusions: We conclude that the XRCC1 Arg280His polymorphism may be protective against the development of high-grade late toxicity after radiotherapy in prostate cancer patients. [Copyright &y& Elsevier]

Abstract: The majority of patients tolerate radiotherapy well, but some of them suffer from severe side effects. To find genes possibly predictive for radiosensitivity, mRNA profiles were generated before and 6h after in vitro irradiation with 5Gy. We analyzed lymphocytes from four head and neck and eight breast cancer patients with strong acute radiation toxicity and from 12 matching normal reacting patients in a blind study. Expression was also measured in lymphocyte subpopulations and Epstein–Barr transformed lymphocytes. Radiation response in whole lymphocyte populations was most similar to that of B cells. In peripheral blood lymphocytes of all patients; 153 genes were identified which were statistically significantly altered by a fold change of more than 50% by irradiation. The signatures of radio-responsive genes differed tremendously between primary and transformed cells. Pathway analysis revealed genes involved in p53 signalling, cell cycle control and apoptosis in response to radiation in primary lymphocytes. In these cells, a set of 67 radiation-induced genes was identified capable of differentiating between severe radiosensitive and normal reacting patients. More than one third of such classifying genes belong to the group of apoptosis or cell cycle regulating genes. The classifying potential of the expression signature has now to be validated in further patient cohorts. [Copyright &y& Elsevier]

Purpose: To evaluate the efficacy, post-treatment function, toxicity, and complications of carbon ion radiotherapy (RT) for sacral chordoma compared with surgery. Methods and Materials: The records of 17 primary sacral chordoma patients treated since 1990 with surgery (n =10) or carbon ion RT (n =7) were retrospectively analyzed for disease-specific survival, local recurrence-free survival, complications, and functional outcome. The applied carbon ion dose ranged from 54.0 Gray equivalent (GyE) to 73.6 GyE (median 70.4). Results: The mean age at treatment was 55 years for the surgery group and 65 years for the carbon ion RT group. The median duration of follow-up was 76 months for the surgery group and 49 months for the carbon ion RT group. The local recurrence-free survival rate at 5 years was 62.5% for the surgery and 100% for the carbon ion RT group, and the disease-specific survival rate at 5 years was 85.7% and 53.3%, respectively. Urinary-anorectal function worsened in 6 patients (60%) in the surgery group, but it was unchanged in all the patients who had undergone carbon ion RT. Postoperative wound complications requiring reoperation occurred in 3 patients (30%) after surgery and in 1 patient (14%) after carbon ion RT. The functional outcome evaluated using the Musculoskeletal Tumor Society scoring system revealed 55% in the surgery group and 75% in the carbon ion RT group. Of the six factors in this scoring system, the carbon ion RT group had significantly greater scores in emotional acceptance than did the surgery group. Conclusion: Carbon ion RT results in a high local control rate and preservation of urinary-anorectal function compared with surgery. [ABSTRACT FROM AUTHOR]

Purpose: To estimate the parameters of the Lyman normal-tissue complication probability model using censored time-to-event data for Grade ≥2 late rectal toxicity among patients treated on Radiation Therapy Oncology Group 94-06, a dose-escalation trial designed to determine the maximum tolerated dose for three-dimensional conformal radiotherapy of prostate cancer. Methods and Materials: The Lyman normal-tissue complication probability model was fitted to data from 1,010 of the 1,084 patients accrued on Radiation Therapy Oncology Group 94-06 using an approach that accounts for censored observations. Separate fits were obtained using dose–volume histograms for whole rectum and dose–wall histograms for rectal wall. Results: With a median follow-up of 7.2 years, the crude incidence of Grade ≥2 late rectal toxicity was 15% (n = 148). The parameters of the Lyman model fitted to dose–volume histograms data, with 95% profile-likelihood confidence intervals, were TD50 = 79.1 Gy (75.3 Gy, 84.3 Gy), m = 0.146 (0.107, 0.225), and n = 0.077 (0.041, 0.156). The fit based on dose–wall histogram data was not significantly different. Patients with cardiovascular disease had a significantly higher incidence of late rectal toxicity (p = 0.015), corresponding to a dose-modifying factor of 5.3%. No significant association with late rectal toxicity was found for diabetes, hypertension, rectal volume, rectal length, neoadjuvant hormone therapy, or prescribed dose per fraction (1.8 Gy vs. 2 Gy). Conclusions: These results, based on a large cohort of patients from a multi-institutional trial, are expected to be widely representative of the ability of the Lyman model to describe the long-term risk of Grade ≥2 late rectal toxicity after three-dimensional conformal radiotherapy of prostate cancer. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Determination of the dose–response relations for oesophageal stricture after radiotherapy of the head and neck. Material and methods: In this study 33 patients who developed oesophageal stricture and 39 patients as controls are included. The patients received radiation therapy for head and neck cancer at Karolinska University Hospital, Stockholm, Sweden. For each patient the 3D dose distribution delivered to the upper 5cm of the oesophagus was analysed. The analysis was conducted for two periods, 1992–2000 and 2001–2005, due to the different irradiation techniques used. The fitting has been done using the relative seriality model. Results: For the treatment period 1992–2005, the mean doses were 49.8 and 33.4Gy, respectively, for the cases and the controls. For the period 1992–2000, the mean doses for the cases and the controls were 49.9 and 45.9Gy and for the period 2001–2005 were 49.8 and 21.4Gy. For the period 2001–2005 the best estimates of the dose–response parameters are D 50 =61.5Gy (52.9–84.9Gy), γ= 1.4 (0.8–2.6) and s =0.1 (0.01–0.3). Conclusions: Radiation-induced strictures were found to have a dose response relation and volume dependence (low relative seriality) for the treatment period 2001–2005. However, no dose response relation was found for the complete material. [ABSTRACT FROM AUTHOR]

Abstract: Radistion thoracic tumors may be associated with cardiac toxicity because of the central position of the heart in the thorax. The present review aims to describe the cardiotoxicity during radiotherapy of different tumor sites most associated with this complication and the risk factors of cardiotoxicity during radiation therapy. Medline literature searches were performed using the following cardiac – heart – radiotherapy – toxicity – cardiotoxicity – breast cancer – lymphoma. Cardiac toxicity after breast cancer and mediastinal lymphoma is the most reported radiation-induced complication. The most frequent clinical complications are pericarditis, congestive heart failure, and heart infarction. These events are mostly asymptomatic. Thus clinicians have to give particular attention to these complications. Anthracyclin treatment is a major risk factor for additional cardiotoxicity during radiotherapy with a synergistic effect. Correction of cardiovascular risk is an important point of the prevention of heart complications. Total dose delivered to the planned target volume (PTV), the dose per fraction and the irradiated volume were correlated to the risk of cardiotoxicity. Volume of heart receiving 35Gy must be inferior to 30% and dose per fraction should not exceed 2Gy when dose of prescription exceeds 30Gy. Maximum heart distance (maximal thickness of heart irradiated) must be less than 1cm during irradiation of breast cancer. Modern irradiation techniques seem to be associated with a limited risk of heart complication. The use of anthracycline, other cardiotoxic chemotherapies and targeted therapies should incite for great caution by performing a careful treatment planning and optimisation. [ABSTRACT FROM AUTHOR]

Abstract: Radiation pneumonitis is the most common dose limiting complication of thoracic radiation. Clinically significant radiation pneumonitis usually develops in 10–20% of patients. Characteristic clinical features associated with radiation pneumonitis include dyspnea, non-productive cough, radiographic opacification confined to the outlines of the field of radiation treatment and changes in pulmonary function measures. The risk of radiation pneumonitis is related to the cumulative dose of radiation to normal tissue and to patients and tumor features. Some studies demonstrated that preexisting pulmonary lung dysfunction, tumour location in lower lobes, use of concurrent chemotherapy could increase the risk of radiation pneumonitis. Controversies persist about which dosimetric parameter optimally predicts the risk of radiation pneumonitis. Mean lung dose, V20 and V30 are the most studied parameters. However, no ideal dosimetric parameter has been identified. The objective of this review is to summarize predictive factors of radiation pneumonitis, and to evaluate the predictive ability of various dose–volume histogram parameters for routine practice. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether the inhibition of Kupffer cells before radiotherapy (RT) would protect hepatocytes from radiation-induced apoptosis. Materials and Methods: A single 30-Gy fraction was administered to the upper abdomen of Sprague-Dawley rats. The Kupffer cell inhibitor gadolinium chloride (GdCl3; 10 mg/kg body weight) was intravenously injected 24 h before RT. The rats were divided into four groups: group 1, sham RT plus saline (control group); group 2, sham RT plus GdCl3; group 3, RT plus saline; and group 4, RT plus GdCl3. Liver tissue was collected for measurement of apoptotic cytokine expression and evaluation of radiation-induced liver toxicity by analysis of liver enzyme activities, hepatocyte micronucleus formation, apoptosis, and histologic staining. Results: The expression of interleukin-1β, interleukin-6, and tumor necrosis factor-α was significantly attenuated in group 4 compared with group 3 at 2, 6, 24, and 48 h after injection (p <0.05). At early points after RT, the rats in group 4 exhibited significantly lower levels of liver enzyme activity, apoptotic response, and hepatocyte micronucleus formation compared with those in group 3. Conclusion: Selective inactivation of Kupffer cells with GdCl3 reduced radiation-induced cytokine production and protected the liver against acute radiation-induced damage. [Copyright &y& Elsevier]

Abstract: Purpose: To deploy an inductive process for radiotherapy risk management in a regional cancer centre and to infer the actions required to solve the situations of criticality. Methods: Close collaboration between the department of radiation oncology-biophysics and the department of quality and risk management in the same institution allowed to create a multiprofessional and multidisciplinary task force and to make the experience feedback easier. A preliminary risk analysis method was used to identify the generic dangers, the mapping of risks and the specification of the scales of criticality. This method helped to evaluate and to rate each apprehended event. Four scales have been defined: seriousness scale in five levels, likelihood scale in five classes, endeavour scale in four levels and criticality scale in three categories: acceptable (criticality 1) tolerable under control (criticality 2) and unacceptable (criticality 3). Results: Fifty-seven level 1 dangerous situations linked to 78 scenarios of criticality acceptable, tolerable and unacceptable in 24, 44 and 10 cases respectively have been identified in the department of radiotherapy leading to carry out 28 risk reduction actions. Conclusions: The performed risk analysis offered an original frame for a collective thinking among the care providers and contributed to modify their mode of conceiving both security and radioprotection. The study allowed us to give a relevant answer to the High Authority of Health and the Authority of Nuclear Security demands either in terms of efficient management of the risks in radiotherapy or regarding the daily concerns of the caregivers. [Copyright &y& Elsevier]

Purpose: To prospectively determine the effect of deodorant use on acute skin toxicity and quality of life during breast radiotherapy (RT). Methods and Materials: Before breast RT, 84 patients were randomly assigned to the deodorant group (n = 40) or the no-deodorant group (n = 44). The patients were stratified by axillary RT and previous chemotherapy. Toxicity evaluations were always performed by the principal investigator, who was unaware of the group assignment, at the end of RT and 2 weeks after completion using the Radiation Therapy Oncology Group acute skin toxicity criteria. Symptoms of acute skin toxicity (i.e., discomfort, pain, pruritus, sweating) and quality of life were self-evaluated. For each criterion, the point estimate of rate difference with the 95% one-sided upper confidence limit was computed. To claim noninferiority owing to deodorant use, the 95% one-sided upper confidence limit had to be lower than the noninferiority margin, fixed to 12.8%. Results: In the deodorant vs. no-deodorant groups, Grade 2 axillary radiodermatitis occurred in 23% vs. 30%, respectively, satisfying the statistical criteria for noninferiority (p = .019). Grade 2 breast radiodermatitis occurred in 30% vs. 34% of the deodorant vs. no-deodorant groups, respectively, also satisfying the statistical criteria for noninferiority (p = .049). Similar results were observed for the self-reported evaluations. The deodorant group reported less sweating (18% vs. 39%, p = .032). No Grade 3 or 4 radiodermatitis was observed. Conclusion: According to our noninferiority margin definition, the occurrence of skin toxicity and its related symptoms were statistically equivalent in both groups. No evidence was found to prohibit deodorant use (notwithstanding the use of an antiperspirant with aluminum) during RT for breast cancer. [Copyright &y& Elsevier]

Purpose: To evaluate the feasibility, tolerance, and preliminary outcome of an open MRI-guided prostate partial-volume high-dose-rate brachytherapy (HDR-BT) schedule in a group of selected patients with nonmetastatic, locally aggressive prostatic tumors. Methods and Materials: After conventional fractionated three-dimensional conformal external radiotherapy to 64–64.4 Gy, 77 patients with nonmetastatic, locally aggressive (e.g., perineural invasion and/or Gleason score 8–10) prostate cancer were treated from June 2000 to August 2004, with HDR-BT using temporary open MRI-guided 192Ir implants, to escalate the dose in the boost region. Nineteen, 21, and 37 patients were sequentially treated with 2 fractions of 6 Gy, 7 Gy, and 8 Gy each, respectively. Neoadjuvant androgen deprivation was given to 62 patients for 6–24 months. Acute and late toxicity were scored according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scoring system. Results: All 77 patients completed treatment as planned. Only 2 patients presented with Grade ≥3 acute urinary toxicity. The 3-year probability of Grade ≥2 late urinary and low gastrointestinal toxicity–free survival was 91.4% ± 3.4% and 94.4% ± 2.7%, respectively. Rates of 3-year biochemical disease-free survival (bDFS) and disease-specific survival were 87.1% ± 4.1% and 100%, respectively. Conclusions: Boosting a partial volume of the prostate with hypofractionated HDR-BT for aggressive prostate cancer was feasible and showed limited long-term toxicity, which compared favorably with other dose-escalation methods in the literature. Preliminary bDFS was encouraging if one considers the negatively selected population of high-risk patients in this study. [Copyright &y& Elsevier]

Radiation therapy for head and neck cancer causes significant secondary side-effects in normal salivary glands, resulting in diminished quality of life for these individuals. Salivary glands are exquisitely sensitive to radiation and display acute and chronic responses to radiotherapy. This review will discuss clinical implications of radiosensitivity in normal salivary glands, compare animal models used to investigate radiation-induced salivary gland damage, address therapeutic advances, and project future directions in the field. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate late cardiopulmonary toxicities after concurrent chemoradiotherapy (CCRT) for esophageal carcinomas. Methods and Materials: From February 2002 through April 2005, 74 patients with clinical Stage I–IVB carcinoma of the esophagus were treated with CCRT. Sixty-nine patients with thoracic squamous cell carcinoma were the core of this analysis. Patients received 60 Gy of radiation therapy in 30 fractions over 8 weeks, including a 2-week break, and received 2 cycles of fluorouracil/cisplatin chemotherapy concomitantly. Initial radiation fields included primary tumors, metastatic lymph nodes, and supraclavicular, mediastinal, and celiac nodes areas. Late toxicities were assessed with the late radiation morbidity scoring scheme of the Radiation Therapy Oncology Group/European Organiation for Research and Treatment of Cancer. Results: The median age was 67 years (range, 45–83 years). The median follow-up time was 26.1 months for all patients and 51.4 months for patients still alive at the time of analysis. Five cardiopulmonary toxic events of Grade 3 or greater were observed in 4 patients, Grade 5 heart failure and Grade 3 pericarditis in 1 patient, and Grade 3 myocardial infarction, Grade 3 radiation pneumonitis, and Grade 3 pleural effusion. The 2-year cumulative incidence of late cardiopulmonary toxicities of Grade 3 or greater for patients 75 years or older was 29% compared with 3% for younger patients (p = 0.005). Conclusion: The CCRT used in this study with an extensive radiation field is acceptable for younger patients but is not tolerated by patients older than 75 years. [Copyright &y& Elsevier]

Purpose: To compare patterns of failure, late toxicities, and survival in locally advanced cervical cancer patients treated by either low-dose-rate (LDR) or conformal high-dose-rate (HDRc) brachytherapy as a part of curative radiotherapy. Materials and Methods: A retrospective comparative study of 217 advanced cervix cancer patients was conducted; 90 of these patients received LDR and 127 received HDRc brachytherapy. All patients were staged using International Federation of Gynecology and Obstetrics (FIGO) rules, had pretreatment magnetic resonance imaging (MRI), and were treated with concurrent cisplatin chemoradiotherapy. Both groups matched for FIGO stage, MRI tumor volume, and uterine invasion status. Results: Local and pelvic failures were similar 12–13% and 14% both in both groups. Abdominal and systemic failures in LDR group were 21% and 24%, whereas corresponding failures in HDRc group were 20% and 24%. Sixty-eight percent (87/127) of patients treated by HDRc remained asymptomatic, whereas 42% (38/90) of patients were asymptomatic from the bowel and bladder symptoms after treatment with LDR. The 5-year OS rate was 60% (SE = 4%). The 5-year failure-free survival rate was 55% (SE = 3%). There was no significant difference between the groups. Conclusions: Image-guided HDRc planning led to a large decrease in late radiation effects in patients treated by HDRc. Patterns of failure and survival were similar in patients treated either by LDR or HDRc. [Copyright &y& Elsevier]