Dietrich von Fournier

Radiation dose and second cancer risk in patients treated for cancer of the cervix

The risk of cancer associated with a broad range of organ doses was estimated in an international study of women with cervical cancer. Among 150,000 patients reported to one of 19 population-based cancer registries or treated in any of 20 oncology clinics, 4188 women with second cancers and 6880 matched controls were selected for detailed study. Radiation doses for selected organs were reconstructed for each patient on the basis of her original radiotherapy records. Very high doses, on the order of several hundred gray, were found to increase the risk of cancers of the bladder [relative risk (RR) = 4.0], rectum (RR = 1.8), vagina (RR = 2.7), and possibly bone (RR = 1.3), uterine corpus (RR = 1.3), cecum (RR = 1.5), and non-Hodgkins lymphoma (RR = 2.5). For all female genital cancers taken together, a sharp dose-response gradient was observed, reaching fivefold for doses more than 150 Gy. Several gray increased the risk of stomach cancer (RR = 2.1) and leukemia (RR = 2.0). Although cancer of the pancreas was elevated, there was no evidence of a dose-dependent risk. Cancer of the kidney was significantly increased among 15-year survivors. A nonsignificant twofold risk of radiogenic thyroid cancer was observed following an average dose of only 0.11 Gy. Breast cancer was not increased overall, despite an average dose of 0.31 Gy and 953 cases available for evaluation (RR = 0.9); there was, however, a weak suggestion of a dose response among women whose ovaries had been surgically removed. Doses greater than 6 Gy to the ovaries reduced breast cancer risk by 44%. A significant deficit of ovarian cancer was observed within 5 years of radiotherapy; in contrast, a dose response was suggested among 10-year survivors. Radiation was not found to increase the overall risk of cancers of the small intestine, colon, ovary, vulva, connective tissue, breast, Hodgkins disease, multiple myeloma, or chronic lymphocytic leukemia. For most cancers associated with radiation, risks were highest among long-term survivors and appeared concentrated among women irradiated at relatively younger ages.

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.

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.

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.

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.

Genetic Polymorphisms in the DNA Double-Strand Break Repair Genes XRCC3, XRCC2, and NBS1 Are Not Associated with Acute Side Effects of Radiotherapy in Breast Cancer Patients

Clinical sensitivity to ionizing radiation varies considerably among patients, and radiation-induced adverse effects developing in normal tissue can be therapy limiting in >10% of patients ([1][1]). Ionizing radiation induces both DNA single-strand breaks and double-strand breaks (DSB), with the

PDR brachytherapy with flexible implants for interstitial boost after breast-conserving surgery and external beam radiation therapy

BACKGROUND AND PURPOSE For radiobiological reasons the new concept of pulsed dose rate (PDR) brachytherapy seems to be suitable to replace traditional CLDR brachytherapy with line sources. PDR brachytherapy using a stepping source seems to be particularly suitable for the interstitial boost of breast carcinoma after breast-conserving surgery and external beam irradiation since in these cases the exact adjustment of the active lengths is essential in order to prevent unwanted skin dose and consequential unfavorable cosmetic results. The purpose of this study was to assess the feasibility and morbidity of a PDR boost with flexible breast implants. MATERIALS AND METHODS Sixty-five high risk patients were treated with an interstitial PDR boost. The criteria for an interstitial boost were positive margin or close margin, extensive intraductal component (EIC), intralymphatic extension, lobular carcinoma, T2 tumors and high nuclear grade (GIII). Dose calculation and specification were performed following the rules of the Paris system. The dose per pulse was 1 Gy. The pulse pauses were kept constant at 1 h. A geometrically optimized dose distribution was used for all patients. The treatment schedule was 50 Gy external beam to the whole breast and 20 Gy boost. PDR irradiations were carried out with a nominal 37 GBq 192-Ir source. RESULTS The median follow-up was 30 months (minimum 12 months, maximum 54 months). Sixty percent of the patients judged their cosmetic result as excellent, 27% judged it as good, 11% judged it as fair and 2% judged it as poor. Eighty-six percent of the patients had no radiogenous skin changes in the boost area. In 11% of patients minimal punctiform telangiectasia appeared at single puncture sites. In 3% (2/65) of patients planar telangiectasia appeared on the medial side of the implant. The rate of isolated local recurrence was 1.5%. In most cases geometrical volume optimization (GVO) yields improved dose distributions with respect to homogeneity and compensation of underdosage at the margins of the implant. Only in 9% of patients was the dose distribution impaired by GVO. However, GVO causes a number of substantial changes of the dose distribution which have consequences for its application. CONCLUSIONS The interstitial CLDR boost of the breast can be replaced by the PDR technique without severe acute and late complications and without deterioration of the cosmetic results.