DEGRO practical guidelines for radiotherapy of breast cancer V: Therapy for locally advanced and inflammatory breast cancer, as well as local therapy in cases with synchronous distant metastases.

AIM: The purpose of this work is to give practical guidelines for radiotherapy of locally advanced, inflammatory and metastatic breast cancer at first presentation. METHODS: A comprehensive survey of the literature using the search phrases "locally advanced breast cancer", "inflammatory breast cancer", "breast cancer and synchronous metastases", "de novo stage IV and breast cancer", and "metastatic breast cancer" and "at first presentation" restricted to "clinical trials", "randomized trials", "meta-analysis", "systematic review", and "guideline" was performed and supplemented by using references of the respective publications. Based on the German interdisciplinary S3 guidelines, updated in 2012, this publication addresses indications, sequence to other therapies, target volumes, dose, and fractionation of radiotherapy. RESULTS: International and national guidelines are in agreement that locally advanced, at least if regarded primarily unresectable and inflammatory breast cancer should receive neoadjuvant systemic therapy first, followed by surgery and radiotherapy. If surgery is not amenable after systemic therapy, radiotherapy is the treatment of choice followed by surgery, if possible. Surgery and radiotherapy should be administered independent of response to neoadjuvant systemic treatment. In patients with a de novo diagnosis of breast cancer with synchronous distant metastases, surgery and radiotherapy result in considerably better locoregional tumor control. An improvement in survival has not been consistently proven, but may exist in subgroups of patients. CONCLUSION: Radiotherapy is an important part in the treatment of locally advanced and inflammatory breast cancer that should be given to all patients regardless to the intensity and effect of neoadjuvant systemic treatment and the extent of surgery. Locoregional radiotherapy in patients with primarily distant metastatic disease should be prescribed on an individual basis.

MRI-based treatment of rectal cancer: is prognostication of the recurrence risk solid enough to render radiation redundant?

BACKGROUND: Most current guidelines recommend neoadjuvant short course radiotherapy (sRT) or radio-chemotherapy (nRCT) for rectal cancer stage II and III. After the introduction of total mesorectal excision (TME) and magnetic resonance imaging (MRI), this proceeding has been questioned and omission of neoadjuvant treatment according to preoperative MRI-criteria has been propagated. Aim of the present paper is to review the state of evidence regarding MRI-based treatment decision depending on the predicted width of the circumferential resection margin (CRM). METHODS: A comprehensive survey of the literature was performed using the search terms "rectal cancer", "radiotherapy", "radio-chemotherapy", "MRI-based therapy", "circumferential resection margin". Data from lately published observational studies were compared to results from randomized trials and outcome analyses of the Norwegian national cancer registry. RESULTS: Only one observational study using MRI-based treatment according to the anticipated CRM provided 5 year local recurrence data, however only for 65 patients. The second study did not yet evaluate recurrence rates. Two randomized trials comparing sRT to primary TME showed significantly worse outcome for non-irradiated patients. Data from the Norwegian rectal cancer registry demonstrate that TME alone is associated with higher LRR than achievable with preoperative RT. CONCLUSIONS: Current evidence does not support the omission of neoadjuvant treatment for stage II-III rectal cancer on the basis of an MRI-predicted negative CRM. Randomized studies are warranted to clarify whether and for which subgroups TME alone is safe in terms of local recurrences.

DEGRO practical guidelines for radiotherapy of breast cancer IV: radiotherapy following mastectomy for invasive breast cancer.

BACKGROUND AND PURPOSE: Since the last recommendations from the Breast Cancer Expert Panel of the German Society for Radiation Oncology (DEGRO) in 2008, evidence for the effectiveness of postmastectomy radiotherapy (PMRT) has grown. This growth is based on updates of the national S3 and international guidelines, as well as on new data and meta-analyses. New aspects were considered when updating the DEGRO recommendations. METHODS: The authors performed a comprehensive survey of the literature. Data from recently published (meta-)analyses, randomized clinical trials and international cancer societies' guidelines yielding new aspects compared to 2008 were reviewed and discussed. New aspects were included in the current guidelines. Specific issues relating to particular PMRT constellations, such as the presence of risk factors (lymphovascular invasion, blood vessel invasion, positive lymph node ratio >20 %, resection margins <3 mm, G3 grading, young age/premenopausal status, extracapsular invasion, negative hormone receptor status, invasive lobular cancer, size >2 cm or a combination of ≥ 2 risk factors) and 1-3 positive lymph nodes are emphasized. RESULTS: The evidence for improved overall survival and local control following PMRT for T4 tumors, positive resection margins, >3 positive lymph nodes and in T3 N0 patients with risk factors such as lymphovascular invasion, G3 grading, close margins, and young age has increased. Recently identified risk factors such as invasive lobular subtype and negative hormone receptor status were included. For patients with 1-3 positive lymph nodes, the recommendation for PMRT has reached the 1a level of evidence. CONCLUSION: PMRT is mandatory in patients with T4 tumors and/or positive lymph nodes and/or positive resection margins. PMRT should be strongly considered in patients with T3 N0 tumors and risk factors, particularly when two or more risk factors are present.

Radiotherapy for prevention and therapy of gynecomastia due to antiandrogen treatment in prostate cancer patients: a patterns-of-care study.

BACKGROUND: Gynecomastia is a frequent side effect of antiandrogen therapy for prostate cancer and may compromise quality of life. Although it has been successfully treated with radiotherapy (RT) for decades, the priority of RT as a preferred treatment option has recently been disputed as tamoxifen was also demonstrated to be effective. The aim of the present paper is to provide an overview of indications, frequency, and technique of RT in daily practice in Germany, Switzerland, and Austria. PATIENTS AND METHODS: On behalf of the DEGRO-AG GCG-BD (German Cooperative Group on Radiotherapy of Benign Diseases) a standardized questionnaire was sent to 294 RT institutions. The questionnaires inquired about patient numbers, indications, RT technique, dose, and - if available - treatment results. Moreover, the participants were asked whether they were interested in participating in a prospective study. RESULTS: From a total of 294 institutions, 146 replies were received, of which 141 offered RT for gynecomastia. Seven of those reported prophylactic RT only, whereas 129 perform both preventive and symptomatic RT. In 110 of 137 departments, a maximum of 20 patients were treated per year. Electron beams (76%) were used most often, while 24% of patients received photon beams or orthovolt x-rays. Total doses were up to 20 Gy for prophylactic and up to 40 Gy for therapeutic RT. Results were reported by 19 departments: prevention of gynecomastia was observed in 60-100% of patients. Only 13 institutions observed side effects. CONCLUSION: Prophylactic and symptomatic RT is widely used in the German-speaking countries, but patient numbers are small. The clinical results indicate that RT is a highly effective and well-tolerated treatment.

Intraoperative radiotherapy as accelerated partial breast irradiation for early breast cancer : beware of one-stop shops?

Intraoperative radiotherapy (IORT) was originally introduced in breast cancer treatment as an "anticipated boost" during the procedure of breast conserving surgery (BCS). In addition to whole breast irradiation (WBI), it has yielded excellent long-term results [31, 38]. Under the assumption that the majority of in-breast tumor recurrences (IBTR) occur in the originally affected site, accelerated partial breast irradiation (APBI) as the sole treatment modality was initiated in several studies and with different techniques, one of which was IORT first with electrons, later also with conventional x-rays [29]. The question whether and for whom the gold standard of WBI may be replaced by APBI - especially IORT - alone has recently been one of the most controversial issues of adjuvant therapy for breast cancer. Two recently published studies by Veronesi et al. [36] and Vaidya et al. [35] presenting shortterm results of single shot IORT with electrons (ELIOT) and with an orthovoltage system (TARGIT), respectively, have further invigorated this discussion as illustrated by several letters to the editor commenting on the TARGIT study. While Vaidya et al. [35] indicate their results of IORT alone as "an alternative to WBI for selected patients" and one editorial even proclaims it as standard [6], all the authors of the respective letters [10, 16, 27, 33] strongly disagree with this conclusion. The present editorial comments on the two publications and, furthermore, provides respective statements of the breast cancer expert panel of the German Society of Radiation Oncology (DEGRO).

DEGRO Practical Guidelines for palliative radiotherapy of breast cancer patients: brain metastases and leptomeningeal carcinomatosis.

PURPOSE: To provide recommendations for palliative treatment of brain metastases (BM) and leptomeningeal carcinomatosis (LC) in breast cancer patients with specific emphasis on radiooncologic aspects. METHODS: The breast cancer expert panel of the German Society of Radiation Oncology (DEGRO) performed a comprehensive survey of the literature comprising national and international guidelines, lately published randomized trials, and relevant retrospective analyses. The search included publications between 1995-2008 (PubMed and Guidelines International Network [G-I-N]). Recommendations were devised according to the panel's interpretation of the evidence referring to the criteria of EBM. RESULTS: Aim of any treatment of BM and LC is to alleviate symptoms and improve neurologic deficits. Close interdisciplinary cooperation facilitates rapid diagnosis and onset of therapy, tailored to the individual and clinical situation. Treatment decisions for BM should be based on the allocation to three prognostic groups defined by recursive partitioning analysis (RPA). Karnofsky Performance Score (KPS) is the strongest prognostic parameter. Together with the extent of the disease, KPS determines whether excision or radiosurgery/stereotactic radiotherapy is feasible and if exclusive or additional whole-brain radiotherapy (WBRT) is indicated. With adequate therapy, survival may be up to 3 years. For LC, treatment is mostly indicated for patients with positive cytology or in case of strongly indicative signs and symptoms. Radiotherapy (WBRT and involved-field irradiation of bulky spinal lesions) and chemotherapy (systemically or intrathecally applied methotrexate, thiotepa and cytarabine) are both effective and may prolong survival from several weeks to 4-6 months. CONCLUSION: Radiotherapy is an effective tool for palliative treatment of BM and LC.

DEGRO practice guidelines for palliative radiotherapy of metastatic breast cancer: bone metastases and metastatic spinal cord compression (MSCC).

PURPOSE: To provide practice guidelines and clinical recommendations on preferred standard palliative radiation therapy of bone metastases as well as metastatic spinal cord compression (MSCC) for metastatic breast cancer patients. METHODS: The breast cancer expert panel of the German Society of Radiation Oncology (DEGRO) performed a comprehensive survey of the literature comprising recently published data from clinical controlled trials. The literature search encompassed the period 1995-2008 using databases of PubMed and Guidelines International Network (G-I-N). Search terms were "breast cancer", "bone metastasis", "osseous metastasis", "metastatic spinal cord compression" as well as "radiotherapy" and "radiation therapy". Clinical recommendations were formulated based on the panel's interpretation of the level of evidence referring to the criteria of evidence-based medicine. RESULTS: Different therapeutic goals (pain relief, local tumor control, prevention or improvement of motor deficits, stabilization of the spine or other bones) require complex approaches considering individual factors (i.e., life expectancy, tumor progression at other sites). Best results are achieved by close interdisciplinary cooperation minimizing the interval between diagnosis and onset of treatment. Most important criteria for prognosis and choice of treatment (mostly combined multimodal therapy) are neurologic status at diagnosis of MSCC, time course of duration and progression of the neurologic symptoms. Radiation therapy is effective and regarded as treatment of choice for MSCC with or without motor deficits and/or bone metastases, which do not need immediate surgical intervention. It may be used either postoperatively or as primary treatment in case of inoperability. An optimal dose fractionation schedule or optimal standard dose for treatment of bone metastases has not been established. With regard to different therapeutic goals, different dose concepts and fractionation schedules, single- versus multifraction palliative radiation therapy (1 x 8, 5 x 4, 10 x 3, 15 x 2.5, 20 x 2 Gy), should be adapted individually. CONCLUSION: Bone metastases as well as MSCC should be managed in an interdisciplinary approach mostly as combined-modality treatment according to the specific clinical situation. The present practice guidelines offer criteria and recommendations for different radiooncologic treatment schedules based on the best available levels of evidence. Preferred technique, targeting and different dose schedules are described in detail.

Genetic predictors of long-term toxicities after radiation therapy for breast cancer.

Telangiectasia and subcutaneous fibrosis are the most common late dermatologic side effects observed in response to radiation treatment. Radiotherapy acts on cancer cells largely due to the generation of reactive oxygen species (ROS). ROS also induce normal tissue toxicities. Therefore, we investigated if genetic variation in oxidative stress-related enzymes confers increased susceptibility to late skin complications. Women who received radiotherapy following lumpectomy for breast cancer were followed prospectively for late tissue side effects after initial treatment. Final analysis included 390 patients. Polymorphisms in genes involved in oxidative stress-related mechanisms (GSTA1, GSTM1, GSTT1, GSTP1, MPO, MnSOD, eNOS, CAT) were determined from blood samples by MALDI-TOF. The associations between telangiectasia and genotypes were evaluated by multivariate unconditional logistic regression models. Patients with variant GSTA1 genotypes were at significantly increased risk of telangiectasia (OR 1.86, 95% CI 1.11-3.11). Reduced odds ratios of telangiectasia were noted for women with lower-activity eNOS genotype (OR 0.58, 95% CI 0.36-0.93). Genotype effects were modified by follow-up time, with the highest risk observed after 4 years of radiotherapy for gene polymorphisms in ROS-neutralizing enzymes. Decreased risk with eNOS polymorphisms was significant only among women with less than 4 years of follow-up. All other risk estimates were nonsignificant. Late effects of radiation therapy on skin appear to be modified by variants in genes related to protection from oxidative stress. The application of genomics to outcomes following radiation therapy holds the promise of radiation dose adjustment to improve both cosmetic outcomes and quality of life for breast cancer patients.

Polymorphisms in genes related to oxidative stress (CAT, MnSOD, MPO, and eNOS) and acute toxicities from radiation therapy following lumpectomy for breast cancer.

PURPOSE: Because radiotherapy exerts cytotoxic effects via generation of massive oxidative stress, we hypothesized that catalase, manganese superoxide dismutase, myeloperoxidase (MPO), and endothelial nitric oxide synthase (eNOS) genotypes might result in greater risk of radiotoxicity. EXPERIMENTAL DESIGN: Cases (n = 446) were Caucasian women with breast cancer who received radiotherapy following lumpectomy. Genotypes were determined by matrix-assisted laser desorption/ionization time-of-flight. The development of acute reactions (moist desquamation) associated with genotypes was modeled using the Cox proportional hazards model, accounting for cumulative biologically effective radiation dose. RESULTS: Genotypes associated with higher levels of reactive oxygen species (ROS) were not associated with risk of radiotoxicity. However, relationships between overweight/obesity [body mass index (BMI), >25] and radiotoxicity risk seemed to be modified by eNOS and MPO genotypes associated with higher generation of nitric oxide and ROS, respectively. Women with high BMI (>25) and eNOS GG genotypes were at more than a 6-fold increase in risk (hazard ratio, 6.39; 95% confidence interval, 2.53-16.15) compared with those with BMI <25, and for MPO, those with high BMI (>25) and GG genotypes also had greater risk of radiotoxicity (hazard ratio, 3.61; 95% confidence interval, 1.78-7.35) compared with those with BMI <25. Overweight/obesity was not a strong risk factor among women with other eNOS and MPO genotypes. Exploratory analysis using classification and regression trees indicated that total number of risk alleles contributed, in part, to acute toxicity outcomes among a subgroup of women. CONCLUSIONS: Associations between BMI and radiotoxicity risk may be most apparent among women with genotypes related to higher levels of oxidative stress. Regression trees may be useful in future studies to examine the contributions of multiple factors to individual susceptibility to adverse effects of cancer treatment.

HIV-Associated Anal Dysplasia and Anal Carcinoma.

Anal carcinoma shows an increasing incidence in people living with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) in whom it is also much more common compared to the HIV-negative population. Human papillomavirus infection is the etiological basis of malignant development in the anal epithelium. Therefore, adequate diagnosis and treatment of the precursor lesions (anal intraepithelial neoplasia) is of clinical importance. In cases with preserved immune function, anal cancer can be treated according to guidelines issued for HIV-negative patients. This review summarizes the current knowledge regarding anal malignancies in HIV-positive patients.

Current controversies in radiotherapy for breast cancer.

Multimodal treatment approaches have substantially improved the outcome of breast cancer patients in the last decades. Radiotherapy is an integral component of multimodal treatment concepts used in curative and palliative intention in numerous clinical situations from precursor lesions such as ductal carcinoma in situ (DCIS) to advanced breast cancer. This review addresses current controversial topics in radiotherapy with special consideration of DCIS, accelerated partial breast irradiation (APBI) and regional nodal irradiation (RNI) and provides an update on the clinical practice guidelines of the Breast Cancer Expert Panel of the German Society of Radiation Oncology (DEGRO).

Genetic predictors of acute toxicities related to radiation therapy following lumpectomy for breast cancer: a case-series study.

INTRODUCTION: The cytotoxic effects of radiation therapy are mediated primarily through increased formation of hydroxyl radicals and reactive oxygen species, which can damage cells, proteins and DNA; the glutathione S-transferases (GSTs) function to protect against oxidative stress. We hypothesized that polymorphisms encoding reduced or absent activity in the GSTs might result in greater risk for radiation-associated toxicity. METHODS: Women receiving therapy in radiation units in Germany following lumpectomy for breast cancer (1998-2001) provided a blood sample and completed an epidemiological questionnaire (n = 446). Genotypes were determined using Sequonom MALDI-TOF (GSTA1, GSTP1) and Masscode (GSTM1, GSTT1). Biologically effective radiotherapy dose (BED) was calculated, accounting for differences in fractionation and overall treatment time. Side effects considered were grade 2c and above, as classified using the modified Common Toxicity Criteria. Predictors of toxicity were modelled using Cox regression models in relation to BED, with adjustment for treating clinic, photon field, beam energy and boost method, and potential confounding variables. RESULTS: Low activity GSTP1 genotypes were associated with a greater than twofold increase in risk for acute skin toxicities (adjusted hazard ratio 2.28, 95% confidence interval 1.04-4.99). No associations were noted for the other GST genotypes. CONCLUSION: These data indicate that GSTP1 plays an important role in protecting normal cells from damage associated with radiation therapy. Studies examining the effects of GSTP1 polymorphisms on toxicity, recurrence and survival will further inform individualized therapeutics based on genotypes.

Association between polymorphisms in the DNA repair genes, XRCC1, APE1, and XPD and acute side effects of radiotherapy in breast cancer patients.

PURPOSE: Several DNA repair gene polymorphisms have been described, which affect DNA repair capacity and modulate cancer susceptibility. We evaluated the association of six polymorphisms in the DNA repair genes: XRCC1 (Arg194Trp, Arg280His, and Arg399Gln), APE1 (Asp148Glu), and XPD (Lys751Gln and Asp312Asn), with the risk of acute skin reactions following radiotherapy. DESIGN: We conducted a prospective study of 446 female patients with breast cancer who received radiotherapy after breast-conserving surgery. Individual genetic polymorphisms were determined using melting point analysis of sequence-specific hybridization probes. The development of acute skin reactions (moist desquamation) associated with DNA repair gene polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. RESULTS: Overall, the development of acute toxicity, which presented in 77 patients, was not associated with the genetic variants studied, although the hazard ratios (HR) were generally below 1. Risks were however differential by body mass index. Among normal-weight patients only, both carriers of the APE1 148Glu and the XRCC1 399Gln alleles had decreased risk of acute skin reactions after radiotherapy (HR, 0.49 and 0.51, respectively). The results for XRCC1 were confirmed by haplotype analysis. When considering joint effects, we observed that compared with homozygote carriers of the wild-type allele in both genes, the risk was most strongly reduced in carriers of both APE1 148Glu and XRCC1 399Gln alleles with normal weight [HR, 0.19; 95% confidence interval (95% CI), 0.06-0.56] but not in those with overweight (HR, 1.39; 95% CI, 0.56-3.45; Pinteraction = 0.009). CONCLUSION: The XRCC1 399Gln or APE1 148Glu alleles may be protective against the development of acute side effects after radiotherapy in patients with normal weight.

Radiotherapy for stages IIA/B testicular seminoma: final report of a prospective multicenter clinical trial.

PURPOSE: A prospective multicenter trial was initiated to evaluate the role of modern radiotherapy with reduced treatment portals for stage IIA and IIB testicular seminoma. PATIENTS AND METHODS: Patients with stages IIA/B disease (Royal Marsden classification) were assessable for the trial. Staging comprised computed tomography of the chest, abdomen, and pelvis as well as analysis of tumor markers alpha-fetoprotein and beta human chorionic gonadotropin. Linac-based radiotherapy was delivered to para-aortic and high ipsilateral iliac lymph nodes. The total doses were 30 Gy for stage IIA and 36 Gy for stage IIB disease. RESULTS: Between April 1991 and March 1994, 94 patients were enrolled for the trial by 30 participating centers throughout Germany. Seven patients were lost to follow-up. Median time to follow-up of 87 assessable patients was 70 months. There were 66 stage IIA and 21 stage IIB patients. One mediastinal and one field-edge relapse were observed in the stage IIA group. In the stage IIB group, there was one mediastinal and one mediastinal/pulmonary relapse. All patients were treated with a salvage regimen of platinum-based chemotherapy. Actuarial relapse-free survival at 6 years was 95.3% (95% confidence interval [CI], 88.9% to 100%) and 88.9% (95% CI, 74.4% to 100%) for stage IIA and IIB groups, respectively. Maximum acute side effects were 8% grade 3 nausea for stage IIA and 10% grade 3 nausea and diarrhea for stage IIB groups. No late toxicity was observed. CONCLUSION: Radiotherapy for stages IIA/B seminoma with reduced portals yields excellent tumor control at a low rate of acute toxicity and no late toxicity, which supports the role of radiotherapy as the first treatment choice for these patients.

Radiotherapy of the Lymphatic Pathways in Early Breast Cancer.

International guidelines reveal substantial differences regarding indications for regional nodal irradiation (RNI). Recently, several randomized studies provided new insights and these are discussed here. Patients with 1-3 positive nodes seem to profit from RNI compared to whole-breast (WBI) or chest-wall irradiation (CWI) alone, both with regard to locoregional control and disease-free survival. Irradiation of the regional lymphatics including axillary, supraclavicular and internal mammary nodes provided a small but significant survival benefit in recent randomized trials and 1 meta-analysis. Lymph node irradiation yields comparable tumor control in comparison to axillary lymph node dissection while reducing the rate of lymph edema. Data concerning the impact of 1-2 macroscopically affected sentinel nodes or microscopic metastases on prognosis are equivocal. Recent data suggest that the current restrictive use of RNI should be scrutinized, as the hazard-benefit relation appears to shift towards an improvement of outcome.

XRCC1 Polymorphism Associated With Late Toxicity After Radiation Therapy in Breast Cancer Patients.

PURPOSE: To identify single-nucleotide polymorphisms (SNPs) in oxidative stress-related genes associated with risk of late toxicities in breast cancer patients receiving radiation therapy. METHODS AND MATERIALS: Using a 2-stage design, 305 SNPs in 59 candidate genes were investigated in the discovery phase in 753 breast cancer patients from 2 prospective cohorts from Germany. The 10 most promising SNPs in 4 genes were evaluated in the replication phase in up to 1883 breast cancer patients from 6 cohorts identified through the Radiogenomics Consortium. Outcomes of interest were late skin toxicity and fibrosis of the breast, as well as an overall toxicity score (Standardized Total Average Toxicity). Multivariable logistic and linear regression models were used to assess associations between SNPs and late toxicity. A meta-analysis approach was used to summarize evidence. RESULTS: The association of a genetic variant in the base excision repair gene XRCC1, rs2682585, with normal tissue late radiation toxicity was replicated in all tested studies. In the combined analysis of discovery and replication cohorts, carrying the rare allele was associated with a significantly lower risk of skin toxicities (multivariate odds ratio 0.77, 95% confidence interval 0.61-0.96, P=.02) and a decrease in Standardized Total Average Toxicity scores (-0.08, 95% confidence interval -0.15 to -0.02, P=.016). CONCLUSIONS: Using a stage design with replication, we identified a variant allele in the base excision repair gene XRCC1 that could be used in combination with additional variants for developing a test to predict late toxicities after radiation therapy in breast cancer patients.

Radiation-induced DNA damage and repair in lymphocytes from breast cancer patients and their correlation with acute skin reactions to radiotherapy.

PURPOSE: Repair of radiation-induced DNA damage plays a critical role for both the susceptibility of patients to side effects after radiotherapy and their subsequent cancer risk. The study objective was to evaluate whether DNA repair data determined in vitro are correlated with the occurrence of acute side effects during radiotherapy. METHODS AND MATERIALS: Breast cancer patients receiving radiation therapy after a breast-conserving surgery were recruited in a prospective epidemiologic study. As an indicator for clinical radiosensitivity, adverse reactions of the skin were recorded. Cryo-preserved lymphocytes from 113 study participants were gamma-irradiated with 5 Gy in vitro and analyzed using the alkaline comet assay. Reproducibility of the assay was determined by repeated analysis (n = 26) of cells from a healthy donor. A coefficient of variation of 0.3 was calculated. RESULTS: The various parameters determined to characterize the individual DNA repair capacity showed large differences between patients. Eleven patients were identified with considerably enhanced DNA damage induction, and 7 patients exhibited severely reduced DNA repair capacity after 15 and 30 min. Six patients were considered as clinically radiosensitive, indicated by moist desquamation of the skin after a total radiation dose of about 50 Gy. CONCLUSIONS: Using the alkaline comet assay as described here, breast cancer patients were identified showing abnormal cellular radiation effects, but this repair deficiency corresponded only at a very limited extent to the acute radiation sensitivity of the skin. Because impaired DNA repair could be involved in the development of late irradiation effects, individuals exhibiting severely reduced DNA repair capacity should be followed for the development of late clinical symptoms.

Personal characteristics, therapy modalities and individual DNA repair capacity as predictive factors of acute skin toxicity in an unselected cohort of breast cancer patients receiving radiotherapy.

BACKGROUND AND PURPOSE: Intrinsic and extrinsic factors can affect the occurrence of side effects of radiotherapy. The influence of therapy modalities, personal characteristics and individual DNA repair capacity on the risk of acute skin toxicity was thus evaluated. MATERIALS AND METHODS: In a prospective study of 478 female breast cancer patients receiving adjuvant radiotherapy of the breast after breast-conserving surgery, acute skin toxicity was documented systematically using a modified version of the common toxicity criteria. Prognostic personal and treatment characteristics were identified for the entire cohort. Individual DNA repair capacity was determined in a subgroup of 113 patients with alkaline comet assay using phytohemagglutinin stimulated lymphocytes. Using proportional hazards analysis to account for cumulative biologically effective radiation dose, the hazard for the development of acute skin reactions (moist desquamation) associated with DNA repair capacity was modeled. RESULTS: Of the 478 participants, 84 presented with acute reactions by the end of treatment. Higher body mass index was significantly associated with an increased risk for acute reactions (hazard ratio=1.09 per 1 kg/m(2)), adjusted for treating hospital and photon beam quality. The comet assay parameters examined, including background DNA damage in non-irradiated cells, DNA damage induced by 5 Gy, and DNA repair capacity, were not significantly associated with risk of acute skin toxicity. CONCLUSIONS: Higher BMI is predictive of acute skin toxicity, however, individual repair parameters as determined by the alkaline comet assay are not informative enough. More comprehensive analyses including late effects of radiotherapy and repair kinetics optimized for different radiation-induced DNA lesions are warranted.