Survivors Of Hodgkin's Disease Research Articles

Second Primary Malignancies and Cardiovascular Mortality in Hodgkin disease Survivors — a Surveillance, Epidemiology, and End Results Registry Database Study

BackgroundOver the last few decades there has been significant improvements in survival in patients with Hodgkin disease (HD). But long-term HD survivors, especially those treated with radiation therapy (RT) have an increased risk of second primary malignancy and cardiovascular disease (CVD) related mortality. In this context, we conducted this population based study to analyze trends in CVD related mortality and incidence of lung and thyroid cancer in HD survivors treated with RT.Materials and methodsWe used the Surveillance, Epidemiology, and End Results 9 database to calculate the Standardized Incidence Ratio (SIR) and Excess Absolute Risk (EAR) of lung and thyroid cancer as second primary malignancies in survivors of HD diagnosed between 1973 and 2011, and who were treated with RT. Poisson regression models were used to calculate adjusted incidence of lung and thyroid cancer. We further divided the patients diagnosed with HD during this period into two groups based on if or not they received RT and calculated the mortality due to CVD for each group, by year of diagnosis. Poisson regression models were used to calculate adjusted CVD mortality by year of HD diagnosis for each group. In all three cases, trends in incidence or mortality were evaluated by calculating the Estimated Annual Percentage Change (EAPC) from the regression coefficient for year of diagnosis.ResultsWe identified 11,916 HD cases that received RT from the SEER database, who were followed up for a median duration of 160 months (range - 12 to 480 months). Table 1 provides characteristics of the study population. 319 patients developed lung cancer (SIR of 3.72, 95% CI 3.32 - 4.15; EAR of 13.19 per 10,000 person years at risk) and 86 patients developed thyroid cancer (SIR of 3.67, 95% CI 2.94 - 4.53; EAR of 3.54 per 10,000 person years at risk). Median ages at diagnosis of secondary lung and thyroid cancers were 59 years and 42 years respectively, with median latency periods of 16 years and 17 years respectively. 965 patients among 11,916 patients who received RT died from CVD while the number of CVD deaths was 1,182 among the 12,507 patients who were not administered RT.Using Poisson regression models, we calculated the adjusted incidence of secondary lung cancer and thyroid cancer and the adjusted mortality from CVD, by year of diagnosis. Year of diagnosis, age at diagnosis of HD and latency (time since diagnosis of HD) were the independent variables used in the regression model. Between 1973 and 2011, the adjusted incidence of lung cancer declined at an EAPC of -2.68 (95% CI -13.06 to -3.92) and that of thyroid cancer declined at an EAPC of -3.35 (95% CI -5.73 to -1.00) (Figure 1). Over the same period, CVD mortality per 10,000 person years at risk for patients who received RT declined at an EAPC of -4.34 (95% CI -4.97 to -3.73) and that of patients who did not receive RT declined at an EAPC of -1.92 (95% CI -2.47 to -1.39) (Figure 2).ConclusionWe observed a decline in incidence of lung and thyroid malignancies and CVD mortality in HD survivors over the study period. The decline in CVD mortality over time in patients who received RT was steeper compared to that of patients who did not receive RT. Though our study was limited by the lack of details regarding RT, chemotherapy and comorbidities, these findings are most likely a reflection of recent trends in use of reduced doses and field of RT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

231P - The changing landscape of breast cancer incidence after treatment for Hodgkin’s disease

BackgroundBreast cancer (BC) incidence increases after treatment for Hodgkin’s disease (HD). Over time, radiation techniques (RT) have reduced in dose and irradiated volume, and fewer alkylating (and gonadotoxic) chemotherapy (CT) agents used. We investigated BC incidence in the context of treatment changes over almost 4 decades and known risk factors. MethodsPubMed abstracts were identified using search terms ‘Hodgkin disease’, ‘Breast neoplasm’ and ‘risk’. Articles in English between 01/01/1990-31/12/2018 reporting on risk of BC in HD survivors were included. Outcomes included relative risk (RR), standardized incidence ratio (SIR), absolute excess risk (AER), cumulative incidence (CI), hazard ratio (HR) and odds ratio (OR) of BC in HD survivors. Results30/245 articles were included. 6 report BC incidence alone (n=7573). Other factors were RT dose and volume, CT, age at HD and its proximity to menarche and menopause. 10 studies looked at 2 factors (n=34637), 7 at 3 factors (n=15253), 4 at 4 factors (n=5763), and 2 at 5 factors (n=6110). 1 study was on radiation volume only (n=734). SIR of BC ranged from 2.4-75.3; AER from 9.2-83.6/10,000 years; RR was 1.9-10.6. Variation is due to differences in cohort characteristics, and incomplete follow-up. BC incidence peaks 11-35 years post HD. Risk remains high at age 50-59 (SIR 3.8), when women are no longer annually screened. BC risk increases if RT is given within 6 months menarche (OR 5.52 (1.97–15.46). Earlier menopause reduces BC risk. BC risk increases linearly with increasing radiation dose. The OR can increase 11-fold with breast doses >40Gy compared to 0Gy. Mantle vs. mediastinal RT doubles HR. CT reduces the BC risk compared with RT alone. Newer RTs reduce BC risk; as a result, some studies demonstrate lower BC incidence in more recent treatment periods (SIR 3.2 in 1970s vs. 1.3 1990-2007). Other studies show no temporal change in incidence. ConclusionsReduction in BC risk from lower doses and volumes of RT may be offset by reduced CT gonadotoxicity from newer regimens and, therefore, the impact of treatment changes over 4 decades on BC incidence requires further investigation. Current guidelines on screening HD survivors need to be adapted to reflect the changes in treatment regimens. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Second Primary Malignancies and Cardiovascular Mortality in Hodgkin Disease (HD) Survivors – A SEER Database Study

Over the last few decades there has been significant improvements in survival in patients (pts) with HD. But long-term HD survivors, especially those treated with radiation therapy (RT) have an increased risk of second primary malignancy (SPM) and cardiovascular disease (CVD) related mortality. We conducted this population based study to analyze trends in CVD related mortality and incidence of lung and thyroid cancer (CA) in HD survivors treated with RT. We used the SEER 9 database to calculate the Standardized Incidence Ratio (SIR) and Excess Absolute Risk (EAR) of lung and thyroid CA as SPM in survivors of HD diagnosed between 1973 and 2011, who were treated with RT. Poisson regression models were used to calculate adjusted incidence of lung and thyroid CA. We also divided the pts diagnosed with HD during this period into two groups based on if or not they received RT and calculated the mortality due to CVD for each group, by year of diagnosis (YOD). Poisson regression models were used to calculate adjusted CVD mortality by YOD for each group. In all three cases, trends in incidence or mortality were evaluated by calculating the Estimated Annual Percentage Change (EAPC) from the regression coefficient for YOD. We identified 11,916 HD cases that received RT, who were followed up for a median duration of 160 months (range – 12 to 480 months). 319 pts developed lung CA (SIR of 3.72, 95% CI 3.32 – 4.15; EAR of 13.19 per 10,000 person years at risk (PYAR)) and 86 pts developed thyroid CA (SIR of 3.67, 95% CI 2.94 – 4.53; EAR of 3.54 per 10,000 PYAR). Median ages at diagnosis of secondary lung and thyroid CA were 59 yrs and 42 yrs, with median latency periods of 16 yrs and 17 yrs respectively. 965 pts among 11,916 pts who received RT died from CVD while the number of CVD deaths was 1,182 among the 12,507 pts who were not given RT. Using Poisson regression models, we calculated the adjusted incidence of secondary lung CA and thyroid CA and the adjusted mortality from CVD, by YOD. YOD, age at diagnosis of HD and latency (time since diagnosis of HD) were the independent variables used in the regression model. Between 1973 and 2011, the adjusted incidence of lung CA declined at an EAPC of -2.68 (95% CI -13.06 to -3.92) and that of thyroid CA declined at an EAPC of -3.35 (95% CI -5.73 to -1.00). Over the same period, CVD mortality per 10,000 PYAR for pts who received RT declined at an EAPC of -4.34 (95% CI -4.97 to -3.73) and that of pts who did not receive RT declined at an EAPC of -1.92 (95% CI -2.47 to -1.39). We observed a decline in incidence of lung and thyroid CA and CVD mortality in HD survivors over the study period. The decline in CVD mortality over time in pts who received RT was steeper compared to that of pts who did not receive RT. Though our study was limited by the lack of details regarding RT, chemotherapy and comorbidities, these findings are most likely a reflection of recent trends in use of reduced doses and field of RT.

Feasibility and Acceptability of a Web Site to Promote Survivorship Care in Survivors of Hodgkin Disease.

Evaluate rates of enrollment, completion, and patient-reported acceptability of an educational survivorship-care Web site for survivors of Hodgkin disease (HD). The study was a mixed-method evaluation design. Eligible participants were adults who had completed treatment of a primary diagnosis of HD ≥ 2 years before enrollment. Patients were recruited through postal mail and telephone and were asked to review a Web site, complete an adapted version of the Acceptability E-scale (total score of 24 or greater indicates acceptability), and respond to a structured telephone or e-mail interview to discuss experiences with the Web site. Of 259 potentially eligible participants identified by medical record review, 124 survivors had confirmed contact with study staff and were invited to participate; 63 people (50.8%; 90% CI, 43% to 59%) enrolled; 37 participants (58.7%) were men. The median age at time of enrollment was 51.0 years (range, 29.3 to 80.0 years), and the median time since completion of treatment of HD was 14.9 years (range, 3 to 38.75 years). Overall, 82.5% of those enrolled viewed all Web site content. Forty-eight participants completed the acceptability survey, which resulted in a mean acceptability score of 26.5 (standard deviation, 3.5). The majority of enrollees (67%) completed a follow-up interview. Overall, HD survivor participants viewed the content and reviewed it favorably. A Web-based intervention is a promising way to provide survivors of HD with information about how to manage the long-term and late effects from cancer and treatment, and provide trusted survivorship resources.

Late Effects of Total-Body Gamma Irradiation on Cardiac Structure and Function in Male Rhesus Macaques.

Heart disease is an increasingly recognized, serious late effect of radiation exposure, most notably among breast cancer and Hodgkin's disease survivors, as well as the Hiroshima and Nagasaki atomic bomb survivors. The purpose of this study was to evaluate the late effects of total-body irradiation (TBI) on cardiac morphology, function and selected circulating biomarkers in a well-established nonhuman primate model. For this study we used male rhesus macaques that were exposed to a single total-body dose of ionizing gamma radiation (6.5-8.4 Gy) 5.6-9.7 years earlier at ages ranging from ∼3-10 years old and a cohort of nonirradiated controls. Transthoracic echocardiography was performed annually for 3 years on 20 irradiated and 11 control animals. Myocardium was examined grossly and histologically, and myocardial fibrosis/collagen was assessed microscopically and by morphometric analysis of Masson's trichrome-stained sections. Serum/plasma from 27 irradiated and 13 control animals was evaluated for circulating biomarkers of cardiac damage [N-terminal pro B-type natriuretic protein (nt-proBNP) and troponin-I], inflammation (CRP, IL-6, MCP-1, sICAM) and microbial translocation [LPS-binding protein (LBP) and sCD14]. A higher prevalence of histological myocardial fibrosis was observed in the hearts obtained from the irradiated animals (9/14) relative to controls (0/3) (P = 0.04, χ(2)). Echocardiographically determined left ventricular end diastolic and systolic diameters were significantly smaller in irradiated animals (repeated measures ANOVA, P < 0.001 and P < 0.008, respectively). Histomorphometric analysis of trichrome-stained sections of heart tissue demonstrated ∼14.9 ± 1.4% (mean ± SEM) of myocardial area staining for collagen in irradiated animals compared to 9.1 ± 0.9 % in control animals. Circulating levels of MCP-1 and LBP were significantly higher in irradiated animals (P < 0.05). A high incidence of diabetes in the irradiated animals was associated with higher plasma triglyceride and lower HDLc but did not appear to be associated with cardiovascular phenotypes. These results demonstrate that single total-body doses of 6.5-8.4 Gy produced long-term effects including a high incidence of myocardial fibrosis, reduced left ventricular diameter and elevated systemic inflammation. Additional prospective studies are required to define the time course and mechanisms underlying radiation-induced heart disease in this model.

Bone mineral density in pediatric survivors of Hodgkin and non-Hodgkin lymphomas

PurposeTo assess skeletal mass in survivors of childhood Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) 1–5 years after treatment, and to identify potential risk factors influencing bone mineral density (BMD). Patients/methodsThis cross-sectional study was conducted in a cohort of 43 survivors (HD=31; NHL=12); mean age: 16.21±4.4. Total body bone mineral content (TBMC) and density (TBBMD), and lumbar spine density (LSBMD) were determined using dual-energy X-ray absorptiometry. ResultsThree of all 43 patients developed low BMD. No significant differences in height, weight, and/or BMD Z-scores were found between HD and NHL survivors, children who received and did not receive radiotherapy, and the groups with different chemotherapeutic blocks. No differences were noted between the Z-scores of BMC (mean±SD: 0.31±1.29 vs. −0.089±0.61, p=0.165), TBBMD (mean±SD: −0.32±1.21 vs. −0.27±0.91, p=0.76), or the LSBMD (mean±SD: −0.183±1.54 vs. −0.17±0.87, p=0.637) in subgroups, in accordance with time after therapy (subgroup I<2 years and subgroup II>2 years after treatment). In HD survivors, age at diagnosis only affected the TBBMD Z-score (a decrease of 0.127 in total BMD Z-score per each year, R2=0.999, p<0.001). ConclusionsChildhood lymphoma survivors demonstrate no significant deficits in bone mass and tend to maintain their BMD within the normal range when presenting during one to five years’ follow-up. However, this specific group requires longitudinal investigation to assess the pattern of peak bone mass achievement and the risk of future bone loss.

Quality of life in long-term survivors following treatment for Hodgkin's disease during childhood and adolescence in the German multicentre studies between 1978 and 2002

The purpose of this study was to cross-sectionally assess quality of life (QoL) in survivors of childhood Hodgkin's disease (HD) in a cohort treated for HD in the successive German-Austrian therapy studies HD-78, HD-82, HD-85, HD-87, HD-90, HD-95, respectively, in accordance with the HD-Interval-Treatment recommendation between 1978 and 2002. Data from QoL questionnaires were provided by 1,202 (66 %) of 1,819 invited survivors. These included the EORTC QLQ-C30 and socio-demographic variables. Data of a homogenous sub-sample (n = 725) defined by age (21-41 years) and event- free-survival (no progress, relapse or secondary malignancies) were compared to an age-adjusted German reference sample (n = 659). While the global and physical QoL scores were comparable to those of the general population, survivors' mean scores were more than 10 points lower on the EORTC QLQ-C30 scales "Emotional" and "Social Functioning". On the symptom scales, higher mean scores, exceeding 10 points, were obtained for the scales "Fatigue" and "Sleep". In general, there was a gender effect showing lower functioning and higher symptom levels in women, most prominently in the group of young women (21-25 years). The results within the group of HD survivors could not be associated with the time since treatment, the age of HD survivors at diagnosis or the extent of therapy burden. Clinicians engaged in follow-up care should be sensitive to aspects of fatigue and related (emotional) symptoms in HD childhood cancer survivors and encourage their patients to seek further support if needed.

Late valvular and other cardiac diseases after different doses of mediastinal radiotherapy for hodgkin disease in children and adolescents: Report from the longitudinal GPOH follow-up project of the German-Austrian DAL-HD studies

To analyze the impact of mediastinal irradiation on the incidence of cardiac late effects in long-term survivors of pediatric Hodgkin disease (HD). The study cohort comprised 1,132 survivors of HD who received treatment before 18 years of age in consecutive trials between 1978 and 1995. They had maintained remission without secondary malignancy for 3.1-29.4 years. The cumulative doxorubicin dose was uniformly 160 mg/m(2), the mediastinal radiation dose (MedRD) was 36, 30, 25, 20, or 0 Gy. Follow-up questionnaires complemented by additional contacts served to collect information on late effects from patients and physicians. A central expert panel reviewed all reported cardiac abnormalities. By October 2008, cardiac diseases (CD) had been diagnosed in 50 of 1,132 patients aged 15.0-41.7 (median 32.2) years. The interval since HD therapy was 3.0-28.2 (median 19.5) years. Valvular defects were diagnosed most frequently, followed by coronary artery diseases, cardiomyopathies, conduction disorders, and pericardial abnormalities. The cumulative incidence of CD after 25 years was highest in the MedRD-36 group (21%) decreasing to 10%, 6%, 5%, and 3% in the lower MedRD groups (P < 0.001). Multivariate Cox analysis of several putative risk factors showed MedRD to be the only significant variable predicting for CD-free survival (P = 0.0025). Our results indicate that lower MedRDs are less cardiotoxic. Consequently, reduction of cardiac late effects may be expected with the lower radiation doses used in current HD protocols. Longer follow-up is needed to confirm the present results.

Cardiac Magnetic Resonance Imaging Findings in 20-year Survivors of Mediastinal Radiotherapy for Hodgkin's Disease

The recognition of the true prevalence of cardiac toxicity after mediastinal radiotherapy requires very long follow-up and a precise diagnostic procedure. Cardiac magnetic resonance imaging (MRI) permits excellent quantification of cardiac function and identification of localized myocardial defects and has now been applied to a group of 20-year Hodgkin's disease survivors. Of 143 patients treated with anterior mediastinal radiotherapy (cobalt-60, median prescribed dose 40 Gy) for Hodgkin's disease between 1978 and 1985, all 53 survivors were invited for cardiac MRI. Of those, 36 patients (68%) presented for MRI, and in 31 patients (58%) MRI could be performed 20-28 years (median, 24) after radiotherapy. The following sequences were acquired on a 1.5-T MRI: transversal T1-weighted TSE and T2-weighted half-fourier acquisition single-shot turbo-spin-echo sequences, a steady-state free precession (SSFP) cine sequence in the short heart axis and in the four-chamber view, SSFP perfusion sequences under rest and adenosine stress, and a SSFP inversion recovery sequence for late enhancement. The MRI findings were correlated with previously reconstructed doses to cardiac structures. Clinical characteristics and reconstructed doses were not significantly different between survivors undergoing and not undergoing MRI. Pathologic findings were reduced left ventricular function (ejection fraction <55%) in 7 (23%) patients, hemodynamically relevant valvular dysfunction in 13 (42%), late myocardial enhancement in 9 (29%), and any perfusion deficit in 21 (68%). An association of regional pathologic changes and reconstructed dose to cardiac structures could not be established. In 20-year survivors of Hodgkin's disease, cardiac MRI detects pathologic findings in approximately 70% of patients. Cardiac MRI has a potential role in cardiac imaging of Hodgkin's disease patients after mediastinal radiotherapy.

The late effects of mantle field radiotherapy: The information and support needs of women survivors of Hodgkin's disease

Purpose To improve understanding of the information and support needs of women at risk from breast cancer after earlier treatment with mantle field radio therapy for Hodgkin's disease. Method A multiple case study approach presenting the detailed accounts of three participants has been used to represent the issues raised by a wider sub-set of 15 Hodgkin's disease survivors. These women were participants in a larger qualitative study of 50 long term survivors of adolescent cancer. They were interviewed in depth either face to face or via the telephone. Data were analysed using methods of data reduction, display and conclusion drawing, three case studies were then purposively selected to illustrate key themes in the wider data set. Key Results Discovering the risk of late effect breast cancer, particularly via the media, caused shock. Reliable information was difficult to locate and the support needs of the women were not met by medical services. The impact of the new risk was exacerbated by the earlier cancer experience. Conclusion Information on the risk of late effects to cancer survivors regarded as trustworthy is not easy to access. When the risk of a treatment related malignancy is identified there must be a reliable way of informing both those at risk and primary health care physicians who then need to take into account the cancer history of the patient and its ongoing effect on their emotional vulnerability.

Hospitalization Rates Among Long-Term Survivors of Childhood Leukemia and Lymphoma: A Report From the Childhood Cancer Survivor Study (CCSS).

Abstract 4633 BackgroundChronic health conditions are commonly reported by survivors of childhood leukemia and lymphoma. To further understand the socio-economic impact of these reported conditions, we sought to determine overall and cause-specific rates of hospitalization among survivors of childhood leukemia/lymphoma and to compare these rates with those of the U.S. population. MethodsFrom the CCSS, 5,637 5 year survivors of childhood leukemia/lymphoma, who participated in the 2000 follow-up questionnaire, were identified. Data related to hospitalizations occurring during the years 1992-2005 were collected and hospitalization rates among survivors were determined. For comparison, hospitalization rates in the general U.S. population were obtained from the National Hospital Discharge Survey (NHDS). Indirect standardization was used to calculate age- and sex- standardized incidence ratios (SIR) and absolute excess risks (AER). The reasons for hospitalization were described and cause specific hospitalization rates were also compared with those of the general U.S. population. ResultsAt follow up, the mean age was 29.2 years (SD: 7.6; range: 14.0-51.0) and the mean time since diagnosis was 20.8 years (SD: 4.6; range 13.3-31.7). Overall, the hospitalization rates of survivors of childhood leukemia, non-Hodgkin lymphoma (NHL) and Hodgkin disease (HD) were 1.3 (95% CI: 1.2-1.3), 1.2 (95% CI: 1.1, 1.3) and 1.9 times (95% CI: 1.8, 2.0) that of the general U.S. population, respectively. Survivors, regardless of diagnosis, were more likely than the general population to be hospitalized for infection, endocrine, cardiovascular, gastrointestinal and genitourinary reasons, as well as external causes (Figure 1). The greatest AER was associated with hospitalization for neoplasm. Survivors of leukemia and NHL were approximately 5 times [SIRleukemia: 5.4 (95% CI: 4.8; 6.2) and SIRNHL: 4.8; (95% CI: 3.6, 6.1)] and HD survivors 10.2 times (95% CI: 8.9, 11.7) more likely than the general population to be hospitalized for this reason. Survivors of HD had 6.5 times (95%CI: 5.6, 7.5) the rate of hospitalization for cardiovascular causes and 4.4 times (95% CI: 3.6, 5.2) the rate of hospitalization for pulmonary causes when compared with the general U.S. population. These findings are consistent with reports indicating an increased risk for second cancers, particularly breast cancer after chest irradiation, and conditions such as pneumonitis, lung fibrosis, cardiomyopathy and coronary artery disease among Hodgkin patients. Survivors of leukemia had 5.2 times (95% CI: 4.4, 6.2) the rate of hospitalization for neurological reasons compared with the general population, likely reflecting late effects of treatment with cranial and spinal radiation. Interestingly, survivors have a significantly lower rate of hospitalization for psychological reasons when compared with the U.S. population (Figure 1). ConclusionsLong-term survivors of childhood leukemia/lymphoma experience a significantly increased rate of hospitalization. Additional research is needed to further quantify the overall healthcare utilization and economic impact of treatment-related complications as this population ages. These findings also emphasize the importance of ongoing medical surveillance that includes screening and prevention strategies, which may impact the occurrence of serious medical conditions resulting in hospitalization. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Health-Related Quality of Life in Adults With Hodgkin's Disease

Hodgkin's disease (HD) affects younger and older adults and can disrupt developmental tasks and cause multiple medical sequelae. Since long-term survival is excellent, understanding issues related to all domains of health-related quality of life (HRQOL)-physical, psychological, social/functional, and spiritual-after completion of treatment is a critical step in designing and testing interventions to improve survivors' adjustment and return to their previous level of functioning. This article is an integrative review of empirical studies of HRQOL in HD survivors. Following Ganong's guidelines, 35 studies were identified and reviewed. Commonly reported physical consequences of HD include fatigue, anticipatory nausea and vomiting, and cognitive problems that lasted several years after treatment completion, as well as long-term life-threatening adverse effects including secondary cancers and cardiovascular and respiratory complications. Psychological consequences include emotional distress, especially depression and anxiety, and social/functional difficulty, including inability to return to work and adjustment to the workplace environment secondary to diminished capacity to complete work tasks. Within the spiritual domain, survivors reported that they had a greater appreciation for life after treatment. Development of appropriate theory-guided interventions to improve the HRQOL for HD survivors can be achieved through more rigorous study designs and standardization of HRQOL measurements.

Identifying and assessing women at high risk for breast cancer

There has been progress in the identification of factors that confer important risk for the development of breast cancer. The factors include: heritable mutations in susceptibility genes; exposure to therapeutic radiation during breast development (as for Hodgkin's disease survivors who received therapeutic radiation to the chest); and histologic lesions, including LCIS and atypical hyperplasias. Testing for mutations in the BRCA1 and BRCA2 breast ovarian cancer susceptibility genes has become part of the established care of breast cancer patients. Genetic information from BRCA1/2 testing is used to help healthy at-risk women to avoid breast and/or ovarian cancer, and ultimately to avoid death from those cancers. Data accumulated over the past decade have provided evidence that breast cancer surveillance can be improved with the addition of breast MRI, that prophylactic oophorectomy substantially reduces the risk of ovarian cancer and, when performed before menopause, can reduce the risk of breast cancer as well, and that prophylactic mastectomy reduces the risk of breast cancer by more than 90%. It has been observed that approximately 80% of BRCA1-associated breast cancers are negative for ER, PR and HER2 (so-called triple negative) and cluster with basal-like breast cancers by DNA microarray, while 80% of BRCA2-associated breast cancers are ER+ and PR+, but HER2 negative, and luminal. These data are surprising given the close relationships between these genes in their DNA repair activities, and raise some concern that hormonal interventions will not successfully reduce the risk of BRCA1-associated breast cancers. Other strategies may be necessary to reduce breast cancer risk for this group. Genetic information has been shown to have important implications for women with breast cancer as well. Women with strong family histories of breast and/or ovarian cancer, and women diagnosed before age 40 may consider testing at the time of breast cancer diagnosis if they would use the information to make treatment decisions. Some women choose bilateral mastectomies over breast-conserving treatment if they learn that their risk of second primary breast cancer exceeds 50%, and if their prognosis from the original breast cancer is good. Some women opt for oophorectomy as part of the management of their ER+ breast cancer if they are premenopausal mutation carriers (and could participate in TEXT). Recently, novel agents, the PARP inhibitors, have been shown to be effective in the phase II trials in women with BRCA1 or BRCA2 mutations and metastatic ovarian or breast cancer. These drugs target DNA repair pathways that are particularly vulnerable in women with BRCA1/2 mutations. The agents may also be effective in women with sporadic breast cancer, and are currently in trials in Europe and the United States alone and in combination with cytotoxic agents.

Second malignant neoplasms among survivors of pediatric Hodgkin disease treated with low-dose radiation (15–25.5 Gy) and chemotherapy

10003 Background: Second malignant neoplasms (SMN) are a known complication of Hodgkin disease (HD) treatment. While it is theorized that lower radiation doses may be associated with lower SMN risk, long-term follow-up of children treated with low-dose radiation is lacking. We report the occurrence of SMN among pediatric HD survivors treated at Stanford with chemotherapy and low-dose radiation from 1970 to 1990. Methods: Patients received 6 cycles of MOPP (mechlorethamine, vincristine, prednisone, procarbazine) with 15–25.5 Gy radiation ± 10 Gy boost or 3 MOPP and 3 ABVD cycles (doxorubicin, bleomycin, vinblastine, dacarbazine) with 15 Gy radiation ± 10 Gy boost. Follow-up was obtained through 9/1/2007. Standardized incidence ratios (SIRs) and absolute excess risk (AER) for SMN were calculated using the SEER9 database (1973–2004). Cumulative SMN incidence was determined by the Kaplan-Meier method. Univariate associations were evaluated with the chi-square test or t-test. Multivariate analysis was performed with Cox proportional hazards regression using chronological age as the time scale. Results: One hundred ten of 112 patients achieved remission; median follow-up is 20.6 years. Four patients developed secondary leukemia. Fifteen patients developed 17 secondary solid tumors (5 thyroid carcinomas, 6 breast carcinomas, 4 sarcomas, 1 bladder paraganglioma, 1 melanoma) at a median of 15.4 years. All solid tumors except the melanoma occurred within or at the margin of radiation fields, ranging in dose from 15–26.5 Gy. There were no cases of lung, gastric, or colorectal carcinoma. Cumulative incidence of any SMN is 17% (95%CI 10.5–26.7) at 20 years following HD diagnosis. The SIR for any SMN is 22.9 (95%CI 14.2–35) with an AER of 93.7 cases per 10,000 person-years. In univariate analysis, older age at HD diagnosis (&gt;11 years) and female gender were associated with SMN (p&lt;0.05). In multivariate analysis, there were no statistically significant associations. Conclusions: The incidence of SMN in pediatric HD survivors is elevated following treatment with chemotherapy and low-dose radiation. Sarcomas, breast, and thyroid carcinomas occurred with similar frequency and latency as found in studies of HD survivors who received high-dose radiation. No significant financial relationships to disclose.

Partial Breast Brachytherapy as the Primary Treatment for Breast Cancer Diagnosed After Mantle Radiation Therapy for Hodgkin's Disease

Mastectomy is the most widely accepted treatment for managing breast cancer in patients who have previously received mantle radiation therapy (RT). With accumulating evidence supporting partial breast irradiation, we treated newly diagnosed breast cancer among lymphoma survivors who had history of RT with lumpectomy and breast brachytherapy. Five patients, with history of Hodgkin disease (HD) underwent lumpectomy and sentinel lymphadenectomy +/- axillary dissection followed by low dose rate Ir-192 interstitial brachytherapy. A multicatheter technique was used and all patients received 45 Gy to the target volume over 4 to 5 day time interval. Adjuvant systemic therapy when indicated was administered after completion of brachytherapy. The median time from the treatment of the HD to the diagnosis of breast cancer was 242 months (range: 68-322 months). The median T-size of the invasive breast cancer is 0.7 cm. The range of follow up after brachytherapy is 5 to 67 months. All 5 patients have an intact breast and are without evidence of relapse. No patients developed an infection. No skin toxicity > or =grade 2 was observed. All patients have an excellent cosmetic result. No excessive fibrosis or necrosis has been observed. The preliminary experience using partial breast brachytherapy (PBB) in patients with previous history of mantle RT suggests low complication rates, and acceptable cosmetic results. The excellent local control and freedom from mastectomy for local recurrence warrants further investigation to establish brachytherapy as an acceptable alternative to mastectomy for early stage breast cancer among HD survivors with history of prior RT.

Subsequent Malignancies in Children Treated for Hodgkin's Disease: Associations With Gender and Radiation Dose

Subsequent malignant neoplasms (SMNs) are a dominant cause of morbidity and mortality in children treated for Hodgkin's disease (HD). We evaluated select demographic and therapeutic factors associated with SMNs, specifically gender and radiation dose. A total of 930 children treated for HD at five institutions between 1960 and 1990 were studied. Mean age at diagnosis was 13.6 years, and mean follow-up was 16.8 years (maximum, 39.4 years). Treatment included radiation alone (43%), chemotherapy alone (9%), or both (48%). We found that SMNs occurred in 102 (11%) patients, with a 25-year actuarial rate of 19%. With 15,154 patient years of follow-up, only 7.18 cancers were expected (standardized incidence ratio [SIR] = 14.2; absolute excess risk [AER] = 63 cases/10,000 years). The SIR for female subjects, 19.93, was significantly greater than for males, 8.41 (p < 0.0001). After excluding breast cancer, the SIR for female patients was 15.4, still significantly greater than for male patients (p = 0.0012). Increasing radiation dose was associated with an increasing SIR (p = 0.0085). On univariate analysis, an increased risk was associated with female gender, increasing radiation dose, and age at treatment (12-16 years). Using logistic regression, mantle radiation dose increased risk, and this was 2.5-fold for female patients treated with more than 35 Gy primarily because of breast cancer. Survivors of childhood HD are at risk for SMNs, and this risk is greater for female individuals even after accounting for breast cancer. Although SMNs occur in the absence of radiation therapy, the risk increases with RT dose.

Evidenced-Based Report on the Occurrence of Fatigue in Long-Term Cancer Survivors

Although some cancer survivors report persistent fatigue years after treatment, little is known about the prevalence of the symptom in this population as compared with the general population. This article examines current evidence for the occurrence of fatigue in long-term cancer survivors by reviewing published population-based studies that incorporated controls from the general population. Using the search criteria "fatigue AND cancer survivors" in PubMed, the authors identified 16 articles (based on 15 cross-sectional datasets) comparing fatigue severities in survivors of adult cancers with those in the general population. When data allowed, Hedges' g effect size calculations were generated. A total of 8096 cancer survivors were examined across datasets. Cancer survivor sample sizes ranged from 15 to 1933 per dataset. Most datasets focused on either breast cancer (7) or Hodgkin's disease survivors (6). Four studies did not clearly exclude patients undergoing active treatment. Nine articles (based on 8 datasets) showed statistically significant (P < .05) differences among groups; 4 articles showed negative results; and 3 showed both positive and negative results depending on fatigue dimension measured. Among the studies that reported scores for the fatigue subscale of the European Organization for Research and Treatment of Cancer Core Questionnaire for Quality of Life (most studies), mean fatigue levels in cancer survivors ranged from 28.7 to 36.5 out of an overall score of 100, and mean fatigue levels in matched general population controls ranged from 20 to 30 out of 100. No associations between instruments and results were apparent. Although the small numbers of studies prevented comparisons among cancer subtypes, equal positive and negative studies were seen in breast cancer survivors and, notably, no negative studies were seen involving Hodgkin's disease survivors. Most effect sizes calculated were small. Fatigue was a burden to both cancer survivors and members of the general population. While evidence for greater fatigue severity in cancer survivors was mixed, most studies reported greater fatigue in cancer survivors as compared with controls. The magnitude of this effect was generally small. Inferences from the data were limited by variability in both the definition of survivor and the fatigue assessments used, as well as by the cross-sectional design of the studies. Prospective longitudinal studies are needed to determine causal relationships between excessive fatigue and surviving cancer.

Tailoring Treatment to Prognosis for Childhood Localized Non-Hodgkin's Lymphoma

Tailoring Treatment to Prognosis for Childhood Localized Non-Hodgkin's Lymphoma

Multi‐dimensional quality of life among long‐term (5+ years) adult cancer survivors

Survival from cancer has improved over the past decade resulting in more long-term survivors. The literature on multi-dimensional quality of life (QOL) among long-term (5+ years) adult survivors is reviewed for each of seven cancer sites (i.e. breast, ovarian, cervical, prostate, colorectal, head and neck, and Hodgkin's disease survivors). Overall, long-term survivors experience good to excellent QOL. Physical domain QOL was the most frequently measured while spiritual domain QOL was the least frequently measured. QOL varies according to treatment received and by age for all groups with older persons (excepting head and neck and Hodgkin's disease survivors) reporting better QOL. QOL improves with time for breast cancer survivors and tends to decrease over time for prostate cancer survivors. Issues regarding sexual functioning affected the social domain-especially for breast and prostate cancer survivors. Social support improves psychological domain QOL for breast, cervical, and colorectal survivors. Review of findings may assist researchers and clinicians wishing to enhance the QOL of the long-term survivor population by identifying the most pressing and widely experienced concerns and by providing directions for future research.

Perceptions of breast cancer risk and cancer screening: A qualitative study of Young, female Hodgkin’s Disease survivors

Young female Hodgkins Disease (HD) survivors are at high risk for breast cancer following chest irradiation. We explored health perceptions, screening behaviors, and barriers of this population. Three focus groups and nine individual interviews (n = 22) were conducted. Women expressed significant misperceptions about breast cancer risk and screening. Screening barriers included avoidance, insurance issues, and lack of physician support. Female HD survivors would likely benefit from tailored education that links current beliefs with their previous cancer experience. Education about cancer risk may be more effective if delivered in a health-promoting rather than disease-detection framework.