Nicola S. Russell

Breast Cancer Risk in Female Survivors of Hodgkin's Lymphoma: Lower Risk After Smaller Radiation Volumes

PURPOSE We assessed the long-term risk of breast cancer (BC) after treatment for Hodgkins lymphoma (HL). We focused on the volume of breast tissue exposed to radiation and the influence of gonadotoxic chemotherapy (CT). PATIENTS AND METHODS We performed a cohort study among 1,122 female 5-year survivors treated for HL before the age of 51 years between 1965 and 1995. We compared the incidence of BC with that in the general population. To assess the risk according to radiation volume and hormone factors, we performed multivariate Cox regression analyses. RESULTS After a median follow-up of 17.8 years, 120 women developed BC (standardized incidence ratio [SIR], 5.6; 95% CI, 4.6 to 6.8), absolute excess risk 57 per 10,000 patients per year. The overall cumulative incidence 30 years after treatment was 19% (95% CI, 16% to 23%); for those treated before age 21 years, it was 26% (95% CI, 19% to 33%). The relative risk remained high after prolonged follow-up (> 30 years after treatment: SIR, 9.5; 95% CI, 4.9 to 16.6). Mantle field irradiation (involving the axillary, mediastinal, and neck nodes) was associated with a 2.7-fold increased risk (95% CI, 1.1 to 6.9) compared with similarly dosed (36 to 44 Gy) mediastinal irradiation alone. Women with >or= 20 years of intact ovarian function after radiotherapy at young ages (< 31 years) experienced significantly higher risks for BC than those with fewer than 10 years of intact ovarian function. CONCLUSION Reduction of radiation volume appears to decrease the risk for BC after HL. In addition, shorter duration of intact ovarian function after irradiation is associated with a significant reduction of the risk for BC.

Variability in target volume delineation on CT scans of the breast

PURPOSE To determine the intra- and interobserver variation in delineation of the target volume of breast tumors on computed tomography (CT) scans in order to perform conformal radiotherapy. MATERIALS AND METHODS The clinical target volume (CTV) of the breast was delineated in CT slices by four radiation oncologists on our clinically used delineation system. The palpable glandular breast tissue was marked with a lead wire on 6 patients before CT scanning, whereas 4 patients were scanned without a lead wire. The CTV was drawn by each observer on three separate occasions. Planning target volumes (PTVs) were constructed by expanding the CTV by 7 mm in each direction, except toward the skin. The deviation in the PTV extent from the average extent was quantified in each orthogonal direction for each patient to find a possible directional dependence in the observer variations. In addition, the standard deviation of the intra- and interobserver variation in the PTV volume was quantified. For each patient, the common volumes delineated by all observers and the smallest volume encompassing all PTVs were also calculated. RESULTS The patient-averaged deviations in PTV extent were larger in the posterior (42 mm), cranial (28 mm), and medial (24 mm) directions than in the anterior (6 mm), caudal (15 mm), and lateral (8 mm) directions. The mean intraobserver variation in volume percentage (5.5%, 1 SD) was much smaller than the interobserver variation (17.5%, 1 SD). The average ratio between the common and encompassing volume for the four observers separately was 0.82, 0.74, 0.82, and 0.80. A much lower combined average ratio of 0.43 was found because of the large interobserver variations. For the observer who placed the lead wire, the intraobserver variation in volume was decreased by a factor of 4 on scans made with a lead wire in comparison to scans made without a lead wire. For the other observers, no improvement was seen. Based on these results, an improved delineation protocol was designed. CONCLUSIONS Intra- and especially interobserver variation in the delineation of breast target volume on CT scans can be rather large. A detailed delineation protocol making use of CT scans with lead wires placed on the skin around the palpable breast by the delineating observer reduces the intraobserver variation. To reduce the interobserver variation, better imaging techniques and pathology studies relating glandular breast tissue to imaging may be needed to provide more information on the extent of the clinical target volume.

A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 ( REL ), 8q24.21 and 10p14 ( GATA3 )

To identify susceptibility loci for classical Hodgkins lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL, odds ratio (OR) = 1.22, combined P = 1.91 × 10−8), 8q24.21 (rs2019960, PVT1, OR = 1.33, combined P = 1.26 × 10−13) and 10p14 (rs501764, GATA3, OR = 1.25, combined P = 7.05 × 10−8). Furthermore, we confirmed the role of the major histocompatibility complex in disease etiology by revealing a strong human leukocyte antigen (HLA) association (rs6903608, OR = 1.70, combined P = 2.84 × 10−50). These data provide new insight into the pathogenesis of cHL.

Vascular Damage as an Underlying Mechanism of Cardiac and Cerebral Toxicity in Irradiated Cancer Patients

Abstract Radiation is an independent risk factor for cardiovascular and cerebrovascular disease in cancer patients. Modern radiotherapy techniques reduce the volume of the heart and major coronary vessels exposed to high doses, but some exposure is often unavoidable. Radiation damage to the myocardium is caused primarily by inflammatory changes in the microvasculature, leading to microthrombi and occlusion of vessels, reduced vascular density, perfusion defects and focal ischemia. This is followed by progressive myocardial cell death and fibrosis. Clinical studies also demonstrate regional perfusion defects in non-symptomatic breast cancer patients after radiotherapy. The incidence and extent of perfusion defects are related to the volume of left ventricle included in the radiation field. Irradiation of endothelial cells lining large vessels also increases expression of inflammatory molecules, leading to adhesion and transmigration of circulating monocytes. In the presence of elevated cholesterol, invading monocytes transform into activated macrophages and form fatty streaks in the intima, thereby initiating the process of atherosclerosis. Experimental studies have shown that radiation predisposes to the formation of inflammatory plaque, which is more likely to rupture and cause a fatal heart attack or stroke. This paper presents a brief overview of the current knowledge on mechanisms for development of radiation-induced cardiovascular and cerebrovascular damage. It does not represent a comprehensive review of the literature, but reference is made to several excellent recent reviews on the topic.

CLINICAL RESULTS OF IMAGE-GUIDED DEEP INSPIRATION BREATH HOLD BREAST IRRADIATION

PURPOSE To evaluate the feasibility, cardiac dose reduction, and the influence of the setup error on the delivered dose for fluoroscopy-guided deep inspiration breath hold (DIBH) irradiation using a cone-beam CT for irradiation of left-sided breast cancer patients. METHODS AND MATERIALS Nineteen patients treated according to the DIBH protocol were evaluated regarding dose to the ipsilateral breast (or thoracic wall), heart, (left ventricle [LV] and left anterior descending artery [LAD]), and lung. The DIBH treatment plan was compared to the free-breathing (FB) treatment planning and to the dose data in which setup error was taken into account (i.e., actual delivered dose). RESULTS The largest setup variability was observed in the direction perpendicular to the RT field (μ = -0.8 mm, Σ = 2.9 mm, σ = 2.0 mm). The mean (D(mean)) and maximum (D(max)) doses of the DIBH treatment plan was significantly lower compared with the FB treatment plan for the heart (34% and 25%, p < 0.001), LV (71% and 28%, p < 0.001), and LAD (52% and 39.8%, p < 0.001). For some patients, large differences were observed between the heart D(max) according to the DIBH treatment plan and the actual delivered dose (up to 71%), although D(max) was always smaller than the planned FB dose (mean group reduction = 29%, p < 0.001). CONCLUSION The image-guided DIBH treatment protocol is a feasible irradiation method with small setup variability that significantly reduces the dose to the heart, LV, and LAD.

Single-Dose and Fractionated Irradiation Promote Initiation and Progression of Atherosclerosis and Induce an Inflammatory Plaque Phenotype in ApoE−/− Mice

PURPOSE Increased risk of atherosclerosis and stroke has been demonstrated in patients receiving radiotherapy for Hodgkins lymphoma and head-and-neck cancer. We previously showed that 14 Gy to the carotid arteries of hypercholesterolemic ApoE(-/-) mice resulted in accelerated development of macrophage-rich, inflammatory atherosclerotic lesions. Here we investigate whether clinically relevant fractionated irradiation schedules and lower single doses also predispose to an inflammatory plaque phenotype. METHODS AND MATERIALS ApoE(-/-) mice were given 8 or 14 Gy, or 20 x 2.0 Gy in 4 weeks to the neck, and the carotid arteries were subsequently examined for presence of atherosclerotic lesions, plaque size, and phenotype. RESULTS At 4 weeks, early atherosclerotic lesions were found in 44% of the mice after single doses of 14 Gy but not in age-matched controls. At 22 to 30 weeks after irradiation there was a twofold increase in the mean number of carotid lesions (8-14 Gy and 20 x 2.0 Gy) and total plaque burden (single doses only), compared with age-matched controls. The majority of lesions seen at 30 to 34 weeks after fractionated irradiation or 14-Gy single doses were granulocyte rich (100% and 63%, respectively), with thrombotic features (90% and 88%), whereas these phenotypes were much less common in age-matched controls or after a single dose of 8 Gy. CONCLUSIONS We showed that fractionated irradiation accelerated the development of atherosclerosis in ApoE(-/-) mice and predisposed to the formation of an inflammatory, thrombotic plaque phenotype.

Lack of Correlation of Human Fibroblast Radiosensitivity in Vitro with Early Skin Reactions in Patients Undergoing Radiotherapy

Fibroblasts from breast cancer patients were obtained as outgrowths in vitro from punch biopsies and their radiosensitivity tested in early passages. Skin erythema reactions in the same patients were also measured, as degree of redness using reflectance spectrophotometry. Measurements were taken before and during a 4-week radiotherapy treatment with electrons to the thoracic wall. Of 59 biopsies studied, radiosensitivity and erythema were concurrently studied in 32. In 24, evaluable data from both clinic and laboratory were obtained. A population growth assay in 96-well plates, using absorption of sulphur rhodamine B as the stain for cell numbers, showed good agreement with the colony-formation assay. Plating efficiencies and growth rates in the colony assay were higher using human serum in place of foetal calf serum. Cell survival curves with human serum were mostly exponential with little shoulder. The parameters of survival at 2 Gy (SF2) and the dose required to give 10% survival (D10) were used in the correlations with clinical data; these were 0.25 +/- 0.09 and 3.03 +/- 0.50 Gy, respectively. There was a strong correlation between these two survival curve parameters (r = 0.98). Skin redness was found to linearly increase with time during radiotherapy. The slope of the increase differed markedly from patient to patient, with a range of a factor approx. 10. No correlation was found between SF2 and erythema response in the 24 evaluable patients (r = 0.13, p > 0.5). A similar lack of correlation was found using D10 as the radiosensitivity parameter (r = 0.12, p > 0.5). These data indicate that fibroblast radiosensitivity measured in vitro cannot be used to predict erythema reactions to radiotherapy in breast cancer patients.

Novel insights into pathological changes in muscular arteries of radiotherapy patients.

BACKGROUND AND PURPOSE Vascular disease is increased after radiotherapy and is an important determinant of late treatment-induced morbidity and excess mortality. This study evaluates the nature of underlying pathologic changes occurring in medium-sized muscular arteries following irradiation. MATERIALS AND METHODS Biopsies of irradiated medium-sized arteries and unirradiated control arteries were taken from 147 patients undergoing reconstructive surgery with a vascularised free flap following treatment for head and neck (H&N) or breast cancer (BC). Relative intimal thickening was derived from the ratio of the thickness of the intima to the thickness of the media (IMR) on histological sections. Proteoglycan, collagen and inflammatory cell content were also scored. RESULTS Intimal thickness was significantly increased in irradiated vessels: in the H&N group the IMR was 1.5-fold greater without correction for the control artery (p=0.018); in the BC group the IMR increased 1.4-fold after correction for the control artery (p=0.056) at a mean of 4 years following irradiation. There was an increase in the proteoglycan content of the intima of the irradiated IMA vessels, from 65% to 73% (p=0.024). Inflammatory cell content was increased in the intima of the irradiated H&N vessels (p=0.014). CONCLUSIONS Radiation-induced vascular pathology differs quantitatively and qualitatively from age-related atherosclerosis.

The frequency, magnitude and timing of post-diagnosis body weight gain in Dutch breast cancer survivors.

To evaluate the association between systemic treatments and post-diagnosis weight gain in breast cancer patients during longer follow-up periods, we conducted a retrospective cohort study (n=271). Information on adjuvant systemic treatments and repeated body weight measurements was obtained from medical records, and analysed using multi-level regressions. During the first year, a mean weight change of +2.0kg (SD 4.9) was observed. Overall, 29% of all breast cancer patients had gained 5kg or more in body weight during total follow-up (median: 3 years). In multi-level analyses, women who received combined systemic treatment gained significantly more weight as compared with women who received no systemic treatment (4.5kg versus 2.0kg at 5 years post-diagnosis, p<0.05). Significant weight gain occurs in breast cancer patients in the Netherlands during the first year post-diagnosis. After the first year, further weight gain mainly occurs in women who receive chemotherapy in combination with endocrine therapy.

Detection of extra-axillary lymph node involvement with FDG PET/CT in patients with stage II-III breast cancer.

PURPOSE The aim of this prospective study was to assess the incidence of extra-axillary lymph node involvement on baseline FDG PET/CT in patients with stage II-III breast cancer scheduled for neo-adjuvant chemotherapy. METHODS Patients with invasive breast cancer of >3 cm and/or proven axillary lymph node metastasis were included for before neo-adjuvant chemotherapy. Baseline ultrasound of the infra- and supraclavicular regions was performed with fine-needle biopsy as needed. Subsequently FDG PET/CT was performed. All visually FDG-positive nodes were regarded as metastatic based on the previously reported high specificity of the technique. RESULTS Sixty patients were included. In 17 patients (28%) extra-axillary lymph nodes were detected by FDG PET/CT, localised in an intra-mammary node (1 lymph node in 1 patient), mediastinal (2 lymph nodes in 2 patients), internal mammary chain (9 lymph nodes in 8 patients), intra- and interpectoral (6 lymph nodes in 4 patients), infraclavicular (5 lymph nodes in 4 patients) and in the contralateral axilla (3 lymph nodes in 2 patients). Ultrasound-guided cytology had detected extra-axillary lymph node involvement in seven of these patients, but was unable to detect extra-axillary nodes in the other 10 patients with positive extra-axillary lymph nodes on FDG PET/CT. Radiotherapy treatment was altered in 7 patients with extra-axillary involvement (12% of the total group). CONCLUSIONS FDG PET/CT detected extra-axillary lymph node involvement in almost one-third of the patients with stage II-III breast cancer, including regions not evaluable with ultrasound. FDG PET/CT may be useful as an additional imaging tool to assess extra-axillary lymph node metastasis, with an impact on the adjuvant radiotherapy management.