Supradiaphragmatic Radiotherapy Research Articles

A Risk Score for Single-Lumen Peripherally Inserted Central Catheter (PICC)-Related Venous Thrombosis in Cancer Patients Undergoing Ambulatory Chemotherapy

Introduction The extended use of peripherally inserted central catheters (PICCs) in cancer patients have simplified the management of the treatment, but also represent an important risk factor of upper limbs thrombosis in a population specially predisposed to thrombotic events. Given the clinical significance of PICC-related venous thrombosis (VT) in cancer patients, a predictive risk model could be helpful. Methods Retrospective unicentric study in which patients with single-lumen PICCs, placed by using ultrasound guidance by a trained nursing team at our centre from January 2015 to May 2019 were included. Inclusion criteria were age ≥18 years-old, histologically confirmed diagnosis of cancer and treatment with ambulatory chemotherapy regimen. The presence of symptomatic PICC-related VT confirmed by ultrasounds, variables regarding PICC (placement, use and removal) and the main clinical and biological characteristics of the patients were recorded. For further analysis, sites of cancer were categorized into "very high risk", those with VT rates of 2-fold or higher than the median risk of the group (lung, testicular, bladder), "high risk", those with rates higher than average (gastric, pancreatic, breast, head and neck), and low risk, those with rates at or below average (colorectal, prostate, lymphoma, gynecologic, and others). The predictive accuracy of the model was assessed: discrimination was evaluated using the c-statistic representing the AUC (area under the receiver-operating characteristic), the Hosmer-Lemeshow test was used to assess model calibration and a bootstrap internal validation procedure with 1000 bootstrap resamples was performed. Results Seventy (6%) of 1170 patients who received PICCs, with a median time of use of 108.5 days [2-525], developed symptomatic, image-confirmed PICC-related VT. Moreover, 10 of the 70 had associated pulmonary embolism. The main characteristics of the patients with and without PICC-VT are summarized in table 1. The median time between PICC placement and thrombosis was 25.5 [1-458] days and VT was more probable on the first 100 days after placement (p=0.002). In univariable analyses, the following variables were significantly associated with the development of symptomatic PICC-VT: primary site of cancer, pre-chemotherapy platelet count ≥350 x109/L and supradiaphragmatic radiotherapy concomitant to PICC use. In addition, PICC tip placement next to the right atrium (in the right atrium or at the lower third of the superior vena cava) is associated with a lower incidence of VT. PICC tip position only could be checked in 447 patients by chest radiography. In the final multivariable logistic regression model (table 2), three variables emerged as risk factors independently associated with PICC-VT: primary site of cancer (very high risk or high risk), pre-chemotherapy platelet count ≥350 x109/L and supradiaphragmatic radiotherapy concomitant to PICC use. PICC tip placement was not considered in the multivariable analysis, since it is a correctable variable. To create the risk score, we assigned points to each of the three variables based on their regression coefficients (table 2). Patients were assigned to one of three risk groups based on cumulative total points: low (score 0), intermediate (score 1), and high (score ≥2). Observed PICC-related VT rates were 3.1% for the low-risk group, 6.4% for the intermediate-risk group and 12.4% for the high-risk group. In a logistic regression model with risk group as a categorical predictor, the risk classification rule was significantly associated with PICC-VT (p <0.001), with odds ratios of 2.136 (95% CI, 1.137-4.011) and 4.456 (95% CI, 2.387-8.320) for intermediate-risk and high-risk groups vs. low-risk group, respectively. C statistic was 0.662 (95%CI 0.598-0.727). Conclusions Primary site of cancer, pre-chemotherapy platelet count and supradiaphragmatic radiotherapy concomitant to the PICC use are independent risk factors for single-lumen PICC-related venous thrombosis in cancer patients undergoing ambulatory chemotherapy. The score proposed herein could be a helpful tool to predict the risk of PICC-related VT. PICC tip placement proximal to the right atrium could reduce the risk of VT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk of thyroid disorders in adult and childhood Hodgkin lymphoma survivors 40 years after treatment

Thyroid abnormalities are well reported following childhood treatment for Hodgkin Lymphoma (HL). Limited information exists for adult patients and after modern treatments. We analyzed risks of thyroid disorders in 237 female participants treated at the Royal Marsden Hospital 1970–2015. Multivariable analyses of risk according to treatment and time-related factors, survival analyses, and Cox regression modeling were undertaken. Overall, 33.8% of patients reported thyroid disorders (hypothyroidism 30.0% and thyroid nodules 6.8%). Cumulative prevalence was 42.9% by 40 years follow-up. Risks were greatest after supradiaphragmatic radiotherapy (RR = 5.0, p < 0.001), and increasing dose (RR = 1.03/Gy, p < 0.001). There was no association with a chemotherapy agent. Risks of thyroid disease were as raised following adult as childhood treatment. There was no trend in risk by decade of supradiaphragmatic radiotherapy treatment. Risks of thyroid disease after supradiaphragmatic radiotherapy are as great after adult as childhood treatment and persist after more recent treatment periods.

Breast Dose in Young Women Treated for Hodgkin Lymphoma Between 2007 and 2018: A Single Institutional Study

<h3>Purpose/Objective(s)</h3> Women receiving supradiaphragmatic radiotherapy (RT) for Hodgkin Lymphoma (HL) aged ≤ 36y have a greater risk of breast cancer (BC) than the general population. Although RT fields have reduced in recent years, breast tissue (BT) is unavoidably irradiated in many women. Despite the long-term risk, dose to BT is not routinely nor consistently reported: published studies report inconsistent breast dose metrics, or only point dose to the site of a subsequent BC. We hypothesize breast dose from HL RT has decreased since the implementation of CT based RT, due to an increased awareness of BC risk. This study also aims to assess the correlations between dose metrics of suspected importance to RT induced BC. <h3>Materials/Methods</h3> All female patients with available RT plans aged ≤ 36y treated with supradiaphragmatic RT from 2007 to 2018 were included. Patients received 3D conformal RT to 30-36 Gy (8/68 received 20 Gy). BT was retrospectively contoured. Dose metrics V4 Gy (volume receiving ≥4 Gy) and V30 Gy (in % and cm³) and mean breast dose (MBD, Gy) were extracted for both breasts to consider total BT at risk. Correlations between dose metrics, and with the target volume (CTV, cm³), were assessed using Pearson's correlation coefficient. Time trends were investigated using chi-square analysis of linear fit. <h3>Results</h3> 68 patients were available for analysis. 1 patient was excluded from % volume and MBD analysis due to truncated BT. MBD was strongly positively correlated with V4 Gy_% (r > 0.9) and moderately positively correlated with V4 Gy_cm³ (r = 0.8), V30 Gy_% (r = 0.5) and V30 Gy_cm³ (r = 0.5). Results suggest no decrease over time for V4 Gy_cm³ or V30 Gy_cm³ (linear regression coefficients of 12 and 0.4; both χ² > 1000). For the 63 patients with CTV available, weak positive linear correlation was seen between CTV and V4 Gy_cm³ (r = 0.2), MBD (r = 0.4), and V30 Gy_cm³ (r = 0.4). Large variations in breast dose were seen between patients (see table). <h3>Conclusion</h3> This is believed to be the first systematic retrospective evaluation of individual breast dose in modern HL RT. Despite increased awareness, our data gives no evidence of reduction in breast dose over time. The large variation in breast dose suggests individualized risk assessment and follow up strategies are needed. This data supports the importance of developing optimized screening strategies through initiatives such as the Breast screening After Radiotherapy Dataset (BARD). Our analysis suggests V4 Gy, V30 Gy and MBD cannot be considered independent. Until there is more evidence of the dose level associated with BC risk, it is recommended that all three are reported with V4 Gy and V30 Gy expressed in cm³ to consider total breast tissue at risk.

Outcomes within Five Years from Diagnosis in Pediatric Hodgkin Lymphoma Patients Following Contemporary Therapy

Background: Survival rates for pediatric Hodgkin lymphoma (HL) exceed 95% with contemporary therapy. To reduce long-term morbidity while maintaining excellent survival, risk-adapted therapy including tailored use of radiation has been developed. Studies of 5-year survivors and cohorts treated in the 1970s-1990s have shown pediatric HL survivors are at increased risk for treatment-related chronic health conditions, including subsequent malignancies, cardiopulmonary disease, thyroid dysfunction, and infertility. However, little is known about chronic conditions associated with contemporary therapy presenting during the first 5 years from diagnosis (early outcomes). The purpose of this study was to analyze survival and early outcomes of pediatric HL patients treated with contemporary therapy.Methods: We conducted a retrospective review of HL patients diagnosed <21 years of age and treated at our institution from 2011-2014. Three patients treated with surgery only were excluded. Three-year overall (OS) and event-free (EFS) survival were calculated with Kaplan Meier statistics using SAS 9.4. Results of screening (per Children's Oncology Group and Institutional Fertility Preservation Screening Guidelines) for targeted toxicities that developed between 2 and 5 years from diagnosis were identified and graded per CTCAE criteria. Censoring occurred at date of death, 5 years after diagnosis, or December 31, 2016. Data from the last collection point were used for prevalence calculations in cases with multiple evaluations. Descriptive statistics were calculated for the cohort.Results: We identified 62 patients (52% male; 39% non-Hispanic white; mean age at diagnosis 13.6 ± 3.6 years) with a median time since diagnosis of 3.3 years (range 0.06-5.0). Initial treatment included: 49 (79%) chemotherapy only and 13 (21%) multimodality treatment. Chemotherapy comprised ABVE-PC (56%), BEACOPP (19%), COPP/ABV (16%), or other (8%). Four patients with relapsed/refractory disease received salvage treatment including chemotherapy (n=1), multimodality therapy (n=1), or multimodality treatment including stem cell transplant (SCT; n=2). One patient remained on treatment at the time of censoring.The 3-year OS across all stages was 98.4% with an EFS of 91.9% (89.7% chemotherapy only, 100% multimodality treatment). The one mortality was due to toxic death during chemotherapy.At our institution, patients are referred to survivor clinic at 2 years from completion of therapy. Of the 44 patients eligible for survivor clinic, 35 (80%) attended during the study period, 5 (11%) were seen after the study period, 3 (7%) were lost to follow-up, and 1 (2%) was followed by the primary oncologist only. Early outcomes for patients who received exposure-based screening are listed in Table 1. No patients developed pulmonary dysfunction greater than CTCAE Grade 1, hyperthyroidism, thyroid nodules, cardiac dysfunction, or a subsequent neoplasm during the study period.Anti-mullerian hormone (AMH) below the normal range was found in all 8 evaluated females who received procarbazine-based regimens (BEACOPP or COPP/ABV; 6 received chemotherapy alone, 2 received chemotherapy with supradiaphragmatic radiation). All 8 females who received ABVE-PC with or without radiation (1 abdominal) had normal AMH levels. No males had abnormal gonadotropins.Conclusions: With the incorporation of novel agents in HL therapy, defining the baseline early outcomes of contemporary regimens is germane to future comparative medicine initiatives. This study is the first to evaluate early outcomes in pediatric HL survivors. While the cohort is young, the results indicate contemporary chemotherapy and a lower rate of radiation therapy utilization leads to excellent 3 year survival rates with minimal early toxicities. Females treated with procarbazine-based regimens are at increased risk for diminished ovarian reserve compared to those receiving ABVE-PC and should be prioritized for fertility preservation approaches prior to initiation of therapy. We plan to further expand our experience to include patients diagnosed since 2005 and evaluate the relationship between cumulative alkylating agent exposure and female gonadal dysfunction.[Chemotherapy abbreviations: (A) Adriamycin, (B) Bleomycin, (C) Cyclophosphamide, (E) Etoposide, (O) Vincristine, (P) Prednisone, (P) Procarbazine, (V) Vinblastine] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Involved Site Radiotherapy Extends Time to Premature Menopause in Infra-Diaphragmatic Female Hodgkin Lymphoma Patients - An Analysis of GHSG HD14- and HD17-Patients.

IntroductionConsolidation radiotherapy in intermediate stage Hodgkin´s lymphoma (HL) has been the standard of care for many years as involved field radiotherapy (IFRT) after chemotherapy. It included initially involved region(s). Based on randomized studies, radiation volumes could be reduced and involved site radiation therapy (ISRT) became the new standard. ISRT includes the initially affected lymph nodes. In young adults suffering from HL, infertility and hypogonadism are major concerns. With regard to these questions, we analyzed the influence of modern radiotherapy concepts such as consolidating ISRT in infradiaphragmatic involvement of HL after polychemotherapy.Patients and MethodsFive hundred twelve patients treated within German Hodgkin Study Group (GHSG) HD14 and HD17 trials were evaluated. We analyzed log-adjusted follicle-stimulating-hormone (FSH)- and luteinizing-hormone (LH)-levels of HD14-patients with infradiaphragmatic radiotherapy (IDRT) in comparison with HD14-patients, who had a supradiaphragmatic radiotherapy (SDRT). In a second step, we compared IFRT with ISRT of female HD17 patients regarding the effects on ovarian function and premature menopause.ResultsWe analyzed FSH- and LH-levels of 258 female and 241 male patients, all treated with IFRT. Of these 499 patients, 478 patients had SDRT and 21 patients had IDRT. In a multiple regression model, we could show that log-adjusted FSH (p=0.0006) and LH values (p=0.0127) were significantly higher after IDRT than after SDRT. The effect of IDRT on gonadal function was comparable to two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc). We compared the effect of IFRT with ISRT in thirteen female HD17 patients with infradiaphragmatic (ID) involvement. The mean ovarian dose after ISRT was significantly lower than after IFRT. The calculated proportion of surviving non-growing follicles (NGFs) increased significantly from 11.87% to 24.48% in ISRT compared to IFRT, resulting in a significantly longer calculated time to menopause. The younger the age at therapy, the greater the absolute time gain until menopause.ConclusionInfradiaphragmatic IFRT impairs gonadal function to a similar extent as two cycles of BEACOPPesc. In comparison, the use of ISRT target volume definition significantly reduced radiation dose to the ovaries and significantly extends the time interval from treatment to premature menopause.

Anthracycline exposure and breast cancer risk in female Hodgkin lymphoma survivors.

12074 Background: Female Hodgkin lymphoma (HL) survivors treated with chest radiotherapy (RT) at a young age have a strongly increased risk of breast cancer (BC). Recently concern has been raised that anthracyclines may also increase BC risk, based on studies in childhood cancer survivors with/without a history of chest RT. So far, the association between anthracyclines and BC risk has not been examined in cancer survivors treated at adolescent/adult ages. Now that RT dose and volumes are decreasing, the potential contribution of anthracyclines to BC risk is an important issue. Methods: We assessed BC risk in a cohort of 2314 female 5-year HL survivors, treated at ages 15-50 years and diagnosed between 1965 and 2008 in 20 Dutch hospitals. Treatment factors were time-dependently included in the analysis, focusing on the effect of anthracycline exposure on BC risk. Results: After a median follow-up of 18.8 years, 258 women developed invasive BC or ductal carcinoma in situ as a subsequent malignancy. The 30-year cumulative incidence was 15.0% (95% Confidence Interval (CI) 12.8-17.4%). Mantle field RT (or other RT involving both axillae) was associated with increased risk of BC (Hazard ratio (HR) 1.9; 95% CI 1.2-2.8) compared to no supradiaphragmatic RT or RT to the neck only (Table 1). Gonadotoxic treatment (&gt;4.2 g/m2 procarbazine or pelvic RT) significantly decreased this risk. In a multivariable analysis, anthracycline exposure was associated with increased BC risk (HR 1.8; 95% CI 1.3-2.5) in patients who received a cumulative dose of &gt;200 mg/m2. Among patients exposed to gonadotoxic treatment, the HR of BC associated with &gt;200mg/m2 anthracyclines was 3.8 (95% CI 2.0-7.2), with a trend for higher risk with higher anthracycline dose (HR 1.58 per 100mg/m2 anthracycline, p&lt;0.001). Conclusions: Our results suggest an association of anthracyclines with BC risk in HL survivors. Also when accounting for the protective effect of gonadotoxic treatment on RT-associated BC risk, anthracyclines significantly contributed to a higher BC risk.[Table: see text]

Analysing breast dose in female lymphoma patients who received radiotherapy: a retrospective audit

Keywords: Lymphoma, Breast cancer, Involved field, Involved node, 3DCRT Introduction: Radiotherapy improves progression-free survival in lymphoma, though it increases the risk of secondary malignancies post-treatment1,2. Second primary breast cancers contribute most to the overall absolute excess risk of secondary malignancy in Hodgkin’s lymphoma patients, with radiotherapy thought to play a major role in carcinogenesis2. However, the relationship between doses received and risk is unclear, and referral to screening programmes is mainly based upon data from out-dated mantle treatments1-5. The aim of this study therefore was to audit breast dose in female patients treatment with conformal radiotherapy approaches for mediastinal-involved lymphoma. Methodology: Patients were selected retrospectively from a locally held database6 of women aged ≤36 who received supradiaphragmatic radiotherapy for lymphoma between 2008-2012. Inclusion criteria: •Mediastinal involvement.•30Gy prescription dose.•AP-PA field arrangement. Exclusion criteria:•Neck only treatments•Plans with breast tissue pre-contoured•Plans with incomplete breast tissue. All breast contours were constructed to RTOG/EORTC guidelines and reviewed by a radiologist7,8. Radiotherapy dose statistics were retrieved from the departmental planning software. Results: 26 patients were analysed. Mean dose to both breasts was 2.3Gy, with some patients with advanced disease receiving at least 4Gy to >80% of a single breast. A mean dose for both breasts of 10.6Gy was observed. Mean Dose to D1% of both breasts combined was 24.5Gy, despite most plans having no breast tissue within the PTV. Discussion and conclusion: Mean dose, V4Gy, V20Gy, and D1% results were predominantly within the maximum and minimum range of mean results in the literature for conformal treatments9-18. Differences in results between patients, stemmed from variability in disease spread and disease location, along with variation in field parameters. Subsequently, advanced stage patients tended to receive significantly higher breast doses, and further audits may wish to examine the implications of this. This audit was limited by a lack of information regarding target volume outlining decision-making and staging. Future audits may also wish to examine the effect of prospective peer review of target volumes on breast dose. Numerical References

Gonadotropin-Releasing Hormone Analogs for Gonadal Protection During Gonadotoxic Chemotherapy: A Systematic Review and Meta-Analysis.

A systematic review and meta-analysis was conducted to investigate whether gonadotropin-releasing hormone analogs (GnRHa) have a protective role in women treated with alkylating agents. Major databases (PubMED, EMBASE, Cochrane Central Register of Controlled Trials), systematic snowballing, and trial registries were screened from the inception dates until September 2017. Comparative studies involving reproductive-aged women undergoing chemotherapy with or without coadministration of GnRHa were included. Spontaneous menstrual resumption was assessed as a main outcome. Statistical analyses were performed with STATA 14.2 statistical software. Effect estimates were presented as risk ratios (RR) with 95% confidence intervals (CIs). The literature search yielded 25 436 citations and 84 papers were assessed in full text. Eighteen studies (11 randomized controlled trials [RCTs] and 7 cohort studies) published between 1987 and 2015 were included in the analysis, revealing a significant protective effect of GnRHa (n = 1043; RR:1.38; 95% CI: 1.18-1.63) although with high heterogeneity (I2 = 83.3%). Subgroup analyses revealed a significant benefit of GnRHa cotreatment both in RCTs and in cohort studies. Statistical significance was found in all subgroups by the underlying disease, that is, hematological malignancies, autoimmune diseases, and breast cancer. Sensitivity analyses in GnRH agonist-treated patients, in patients younger than 40 years old, and in patients without supradiaphragmatic radiotherapy also revealed a significant benefit of GnRHa cotreatment. Our results indicate that concurrent GnRHa administration is an effective method to decrease gonadotoxicity of alkylating agents. The presence of low-quality evidence favoring gonadoprotective effect requires a strong recommendation for offering GnRHa coadministration to young women who are to undergo gonadotoxic chemotherapy. The present systematic review and meta-analysis shows a significant gonadoprotective effect of gonadotropin-releasing hormone analogs in women treated with alkylating agents.

Probability of carcinogenesis due to involved field and involved site radiation therapy techniques for supra- and infradiaphragmatic Hodgkin’s disease

PurposeTo estimate the second cancer risk associated with Hodgkin Lymphoma (HL) radiotherapy at supradiaphragmatic or infradiaphragmatic region, using the involved field (IFRT) and the involved site radiotherapy (ISRT). Materials and methodsIFRT and ISRT treatment plans were created for twenty HL patients. Three dimensional plans (3DRT) were employed for all patients. The organ equivalent dose (OED) and lifetime attributable risk (LAR) for organs at risk were estimated with mechanistic, plateau and bell-shaped model. Estimated risk values were compared with nominal risk of unexposed population. ResultsFor supradiaphragmatic radiotherapy, the mean OED range was 0.63–8.53 Gy and 0.63–7.26 Gy for IFRT and ISRT, respectively. The corresponding range for infradiaphragmatic radiotherapy was 0.18–7.64 Gy and 0.80–4.95 Gy. The LAR for cancer induction in the partially in field organs at risk after IFRT was 0.5%–8.0% and 0.2%–9.3% at supradiaphragmatic and infradiaphragmatic regions, respectively. The corresponding risk after ISRT method was 0.5%–5.2% and 0.9%–6.0%. Estimated cancer risk for breast, lung, thyroid, colon and rectal with ISRT was found significantly reduced compared to IFRT. The risk of secondary malignancies for lung, mouth, pharynx, rectum and colon was assessed more than 1.2 times higher than nominal risk for IFRT. The respective risk using ISRT was above nominal only for pharyngeal cancer. ConclusionISRT compared with IFRT, results in decreased second cancer risk in most organs considered. Second cancer probability with IFRT was higher than the nominal risk for certain organs, while for ISRT remains higher only for pharyngeal cancer.

Comparison of treatment modalities for breast cancer arising in Hodgkin’s lymphoma survivors

Breast cancer (BC) in Hodgkin’s lymphoma (HL) survivors is traditionally treated with mastectomy, especially in those who received prior supradiaphragmatic radiation therapy (RT). Chest irradiation is a contraindication for breast-conserving therapy (BCT); however, retrospective studies have found that BCT is an acceptable treatment option for BCs that arise after prior RT. This study compares BC treatment modalities for female HL survivors. Data was extracted from the Surveillance, Epidemiology, and End Results (SEER) from 1983 to 2009. All female HL survivors who subsequently developed BC and received surgical treatment were included. BC events were grouped by the type of surgical resection and RT utilization. All were staged using the American Joint Committee on Cancer (AJCC) seventh edition criteria. Multivariate analysis was performed to compare treatment groups. There were 413 BC events arising in female HL survivors that received surgical management. Of these BC events, 371 were fully staged. Sixty-one received a bilateral mastectomy, 227 received a mastectomy, and 83 received a lumpectomy. A total of 65 BC events received RT, 19 after mastectomy and 46 after lumpectomy. On multivariate analysis for overall survival (OS) and cause-specific survival (CSS), there were no statistically significant favorable or adverse prognostic factors, including treatment modality. BCT did not have an inferior CSS or OS compared to other treatment modalities for female HL survivors. BCT is an acceptable treatment option for a select group of female HL survivors who develop BC.

A Voxel-Based Approach to Explore Local Dose Differences Associated With Radiation-Induced Lung Damage

To apply a voxel-based (VB) approach aimed at exploring local dose differences associated with late radiation-induced lung damage (RILD). An interinstitutional database of 98 patients who were Hodgkin lymphoma (HL) survivors treated with postchemotherapy supradiaphragmatic radiation therapy was analyzed in the study. Eighteen patients experienced late RILD, classified according to the Radiation Therapy Oncology Group scoring system. Each patient's computed tomographic (CT) scan was normalized to a single reference case anatomy (common coordinate system, CCS) through a log-diffeomorphic approach. The obtained deformation fields were used to map the dose of each patient into the CCS. The coregistration robustness and the dose mapping accuracy were evaluated by geometric and dose scores. Two different statistical mapping schemes for nonparametric multiple permutation inference on dose maps were applied, and the corresponding P<.05 significance lung subregions were generated. A receiver operating characteristic (ROC)-based test was performed on the mean dose extracted from each subregion. The coregistration process resulted in a geometrically robust and accurate dose warping. A significantly higher dose was consistently delivered to RILD patients in voxel clusters near the peripheral medial-basal portion of the lungs. The area under the ROC curves (AUC) from the mean dose of the voxel clusters was higher than the corresponding AUC derived from the total lung mean dose. We implemented a framework including a robust registration process and a VB approach accounting for the multiple comparison problem in dose-response modeling, and applied it to a cohort of HL survivors to explore a local dose-RILD relationship in the lungs. Patients with RILD received a significantly greater dose in parenchymal regions where low doses (∼6Gy) were delivered. Interestingly, the relation between differences in the high-dose range and RILD seems to lack a clear spatial signature.

Risk of Symptomatic Stroke After Radiation Therapy for Childhood Cancer: A Long-Term Follow-Up Cohort Analysis

Long-term childhood cancer survivors are at high risk of late adverse effects, including stroke. We aimed to determine the cumulative incidence of clinically validated symptomatic stroke (transient ischemic attack [TIA], cerebral infarction, and intracerebral hemorrhage [ICH]) and to quantify dose-effect relationships for cranial radiation therapy (CRT) and supradiaphragmatic radiation therapy (SDRT). Our single-center study cohort included 1362 survivors of childhood cancer that were diagnosed between 1966 and 1996. Prescribed CRT and SDRT doses were converted into the equivalent dose in 2-Gy fractions (EQD2). Multivariate Cox regression models were used to analyze the relationship between the EQD2 and stroke. After a median latency time of 24.9years and at a median age of 31.2years, 28 survivors had experienced a first stroke: TIA (n=5), infarction (n=13), and ICH (n=10). At an attained age of 45years, the estimated cumulative incidences, with death as competing risk, among survivors treated with CRT only, SDRT only, both CRT and SDRT, and neither CRT nor SDRT were, respectively, 10.0% (95% confidence interval [CI], 2.5%-17.0%), 5.4% (95% CI, 0%-17.0%), 12.5% (95% CI, 5.5%-18.9%), and 0.1% (95% CI, 0%-0.4%). Radiation at both locations significantly increased the risk of stroke in a dose-dependent manner (hazard ratios: HRCRT 1.02Gy(-1); 95% CI, 1.01-1.03, and HRSDRT 1.04Gy(-1); 95% CI, 1.02-1.05). Childhood cancer survivors treated with CRT, SDRT, or both have a high stroke risk. One in 8 survivors treated at both locations will have experienced a symptomatic stroke at an attained age of 45years. Further research on the pathophysiologic processes involved in stroke in this specific group of patients is needed to enable the development of tailored secondary prevention strategies.

Radiation hazards in pregnancy and methods of prevention

The incidence of malignancy in pregnancy is low and most commonly occurs in breast, gynaecological, skin and haematological sites. The management of pregnant cancer patients is complex requiring a multidisciplinary approach to ensure the welfare of both mother and baby. Foetal radiation exposure, both diagnostic and therapeutic, must be kept to a minimum. Following the description of the deterministic and stochastic effects of foetal radiation exposure doses, radiotherapy should be avoided in the first and early second trimester. This chapter describes the possible diagnostic techniques and treatment for the common malignancies in pregnancy; some case studies indicating supradiaphragmatic radiotherapy may be safe later in pregnancy. Pelvic radiotherapy for gynaecological malignancies is not appropriate.

Parenthood in adult female survivors treated for Hodgkin's lymphoma during childhood and adolescence: a prospective, longitudinal study

Little is known about parenthood in women who were treated for Hodgkin's lymphoma during childhood and adolescence. We aimed to assess the frequency of parenthood in female survivors of Hodgkin's lymphoma younger than 18 years at diagnosis, and to compare it with that in a female population control group. In this prospective, longitudinal study, our cohort consisted of 590 female patients younger than 18 years at diagnosis who participated in one of five Hodgkin's lymphoma treatment studies between June 19, 1978, and July 12, 1995. Women who had been followed up for 5 years or longer, were in continuous complete remission, and had no second malignancy or Hodgkin's lymphoma relapse before parenthood were included in our parenthood analysis. Parenthood was defined as the delivery of a liveborn child. Frequency of parenthood was compared with that in the German female population aged 16-49 years, using data from the 2012 Mikrozensus population survey. We assessed parenthood by estimating cumulative incidences and hazard ratios (HRs) with associated variables. 467 of 590 patients in our cohort had long-term follow-up (median 20·4 years [IQR 16·3-24·8]) and were in continuous complete remission. 228 (49%) of 467 patients had 406 children (median of 1·78 children per mother, range 1-7). Cumulative incidences of parenthood were 67% (95% CI 64-75) at 27·7 years of follow-up (the longest number of years that a patient was followed up before she had her first child) and 69% (61-74) at 39·8 years of age (the oldest age of a patient before she had her first child). The incidence of parenthood did not differ between our cohort and the female German population for any age group up to 49 years, except for the 66 women aged 40-44 years at the time of last information, who had a significantly lower frequency of parenthood compared with the general population (40 [61%] of 66 vs 2,208,000 [78%] of 2,847,000; p=0·001). Procarbazine in cumulative doses up to 11,400 mg/m(2), cyclophosphamide in cumulative doses up to 6000 mg/m(2), alkylating agent dose scores of 1-5, therapy group based on disease stage at diagnosis, abdominal and supradiaphragmatic radiation, and age at treatment had no significant or only minor effects on parenthood. Parenthood was significantly reduced in survivors receiving pelvic radiation compared with those who received abdominal and supradiaphragmatic radiation (HR 0·76, 95% CI 0·61-0·95; p=0·01). The results of this study document an overall favourable prognosis for parenthood in female survivors of Hodgkin's lymphoma. They will assist counselling of female survivors about their positive potential for future parenthood. Deutsche Kinderkrebsstiftung, Jens-Brunken-Stiftung für Leukämie und Lymphomforschung, and Kinderkrebshilfe Münster.

Identifying women at higher risk of breast cancer

We wanted to actively identify all women at higher risk of breast cancer in Northern Ireland. A new surveillance screening programme for this population of women was introduced in April 2013. National (UK) guidance identified the following groups of women as being at higher risk: BRCA 1 or 2 (or equivalent risk); TP53; Ataxia Telangiectasia (heterozygous or homozygous) and women who had supradiaphragmatic radiotherapy under the age of 30. National Institute for Health & Care Excellence and NHS Breast Screening Programme …

Risk of premature menopause after treatment for Hodgkin's lymphoma.

Modern treatment of Hodgkin's lymphoma (HL) has transformed its prognosis but causes late effects, including premature menopause. Cohort studies of premature menopause risks after treatment have been relatively small, and knowledge about these risks is limited. Nonsurgical menopause risk was analyzed in 2127 women treated for HL in England and Wales at ages younger than 36 years from 1960 through 2004 and followed to 2003 through 2012. Risks were estimated using Cox regression, modified Poisson regression, and competing risks. All statistical tests were two-sided. During follow-up, 605 patients underwent nonsurgical menopause before age 40 years. Risk of premature menopause increased more than 20-fold after ovarian radiotherapy, alkylating chemotherapy other than dacarbazine, or BEAM (bis-chloroethylnitrosourea [BCNU], etoposide, cytarabine, melphalan) chemotherapy for stem cell transplantation, but was not statistically significantly raised after adriamycin, bleomycin, vinblastine, dacarbazine (ABVD). Menopause generally occurred sooner after ovarian radiotherapy (62.5% within five years of ≥5 Gy treatment) and BEAM (50.9% within five years) than after alkylating chemotherapy (24.2% within five years of ≥6 cycles), and after treatment at older than at younger ages. Cumulative risk of menopause by age 40 years was 81.3% after greater than or equal to 5Gy ovarian radiotherapy, 75.3% after BEAM, 49.1% after greater than or equal to 6 cycles alkylating chemotherapy, 1.4% after ABVD, and 3.0% after solely supradiaphragmatic radiotherapy. Tables of individualized risk information for patients by future period, treatment type, dose and age are provided. Patients treated with HL need to plan intended pregnancies using personalized information on their risk of menopause by different future time points.

Radiologic Features of Breast Cancer after Mantle Radiation Therapy for Hodgkin Disease: A Study of 230 Cases

To retrospectively review diagnostic mammography in women diagnosed with breast cancer who previously had mantle field radiation therapy for Hodgkin disease in England and Wales over a period of 30 years. From a national cohort study of 5002 women treated with supradiaphragmatic radiation therapy when they were younger than 36 years (mean, 22.1 years) during 1956-2003, 392 patients developed breast cancer. With ethics committee approval and informed consent, mammograms were obtained that showed 230 tumors in 222 (56.6%) patients from 95 hospitals, and the size and appearance of each carcinoma was recorded by two breast radiologists. Comparison was made with a historical report of more than 1000 general-population breast cancers by using Pearson χ(2) test. Thirty-eight tumors were occult on mammograms. Mean tumor maximum diameter was 12.3 mm (n = 81) on oblique view. The quadrant distribution of the tumors was significantly different (P < .001) from the historic controls, and chest radiation therapy patients had a greater proportion of tumors in the upper outer (66.9% [107 of 160] vs 48.7% [385 of 784]) and, to a lesser extent, lower inner (10.6% [17 of 160] vs 7.8% [61 of 784]) quadrants. The dominant radiologic feature was of an irregular mass (56.8% [109 of 192]) followed by microcalcifications (25.0% [48 of 192]). This study suggests that in patients who previously underwent mantle radiation therapy for Hodgkin disease, breast cancers are more commonly seen within the upper outer quadrants than are cancers in the general population. Poorly defined masses were the most common appearance.

Pulmonary damage in Hodgkin's lymphoma patients treated with sequential chemo-radiotherapy: Predictors of radiation-induced lung injury

Background. Our aim was to define predictors of late radiation-induced lung injury (RILI) in Hodgkin's lymphoma (HL) survivors treated with bleomycin-containing chemotherapy and radiotherapy. Material and methods. Eighty consecutive patients treated with chemotherapy and subsequent supradiaphragmatic radiation therapy for HL were retrospectively reviewed for symptoms and/or radiological signs of RILI. Median patient age was 26 years (range 14–55). Left, right, and total lung dosimetric parameters along with clinical, disease, and treatment-related characteristics were analyzed. Multivariate logistic regression analyses were performed. A receiver operator characteristic (ROC) curve analysis was performed to find possible cutoff values dividing patients into high- and low-risk groups. Results. Seven of 80 (9%) patients had lung disease at baseline. Four of 80 (5%) had toxicity after chemotherapy and before the beginning of radiotherapy. These patients were excluded from further evaluation. At a median time of 10 months (range 9–18), 9/69 patients (13%) developed lung radiological changes on computed tomography (CT) after treatment. Four of nine patients were diagnosed RTOG grade ≥ 2. On multivariate analyses, left-lung V30 (p = 0.004, OR = 1.108 95% CI 1.033–1.189) and total-lung V30 (p = 0.009, OR = 1.146 95% CI 1.035–1.270) resulted to be predictors of lung CT changes with a cutoff value of 16% and 15%, respectively. When only symptomatic RILI was considered a left-lung V30 cutoff value of 32% was estimated. Conclusion. Bleomycin and RT may cause lung injury in a small, but significant fraction of HL patients. Left-lung V30 predicts the risk of developing asymptomatic or symptomatic RILI after sequential chemo-radiotherapy.

Breast cancer risk following Hodgkin lymphoma radiotherapy in relation to menstrual and reproductive factors.

Background:Women treated with supradiaphragmatic radiotherapy (sRT) for Hodgkin lymphoma (HL) at young ages have a substantially increased breast cancer risk. Little is known about how menarcheal and reproductive factors modify this risk.Methods:We examined the effects of menarcheal age, pregnancy, and menopausal age on breast cancer risk following sRT in case–control data from questionnaires completed by 2497 women from a cohort of 5002 treated with sRT for HL at ages <36 during 1956–2003.Results:Two-hundred and sixty women had been diagnosed with breast cancer. Breast cancer risk was significantly increased in patients treated within 6 months of menarche (odds ratio (OR) 5.52, 95% confidence interval (CI) (1.97–15.46)), and increased significantly with proximity of sRT to menarche (Ptrend<0.001). It was greatest when sRT was close to a late menarche, but based on small numbers and needing reexamination elsewhere. Risk was not significantly affected by full-term pregnancies before or after treatment. Risk was significantly reduced by early menopause (OR 0.55, 95% CI (0.35–0.85)), and increased with number of premenopausal years after treatment (Ptrend=0.003).Conclusion:In summary, this paper shows for the first time that sRT close to menarche substantially increases breast cancer risk. Careful consideration should be given to follow-up of these women, and to measures that might reduce their future breast cancer risk.

Changes in breast cancer risk associated with different volumes, doses, and techniques in female Hodgkin lymphoma patients treated with supra-diaphragmatic radiation therapy

PurposeThe contribution of thoracic radiation in increasing secondary breast cancer (BC) risk in female Hodgkin lymphoma patients is well known, and recent changes in radiation therapy volumes, doses and techniques are supposed to minimize it. In this study, we compared different radiation therapy solutions in terms of secondary BC induction risk with the aim of selecting which could be considered the most protective. Methods and MaterialsIn 10 female patients under 30 years old we estimated breast cancer risk for different combined treatment solutions (involved field vs involved nodal radiation therapy [IFRT vs INRT], 30 Gy vs 20 Gy, 3-dimensional conformal radiation therapy vs volumetric modulated arc therapy [3DCRT vs VMAT]). The organ equivalent dose (OED) method was used for dose calculation, as OED is directly related to the excess risk. Estimated OED mean values for all options in all patients were then analyzed and compared. ResultsINRT was significantly associated with a lower OED, regardless of total dose and technique (0.43 vs 1.15, P < .0001). The relative OED reduction from IFRT to INRT was approximately 60%. The dose of 20 Gy resulted in a significant reduction of OED, approximately 25% (0.68 vs 0.9, P < .01). VMAT did not show significantly higher OED when compared with 3DCRT (0.84 vs 0.74, P = .15). The combination of INRT and 20 Gy lead to a decrease in OED of approximately 70% if compared with IFRT 30 Gy. ConclusionsThe INRT approach substantially reduces OED, independent of dose and technique; the dose reduction from 30 Gy to 20 Gy also has a significant impact, and as expected INRT-20 Gy resulted to be the solution at lowest risk. No differences were observed when comparing different techniques (3DCRT vs VMAT). The combination of these innovative approaches might lead to a substantial reduction in secondary breast cancer risk in this patient population.